Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults

  • Review
  • Intervention

Authors


Abstract

Background

Pneumonia is the most common hospital-acquired infection affecting patients in the intensive care unit (ICU). However, the optimal duration of antibiotic therapy for hospital-acquired pneumonia (HAP) is uncertain.

Objectives

To assess the effectiveness of short versus prolonged-course antibiotic administration for HAP in critically ill adults, including patients with ventilator-associated pneumonia (VAP).

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to February week 4, 2011), EMBASE (1974 to March 2011), LILACS (1985 to March 2011) and Web of Science (1985 to March 2011).

Selection criteria

We considered all randomised controlled trials (RCTs) comparing fixed durations of antibiotic therapy, or comparing a protocol intended to limit duration of therapy with standard care, for HAP (including patients with VAP) in critically ill adults.

Data collection and analysis

Two review authors conducted data extraction and assessment of risk of bias. We contacted trial authors for additional information.

Main results

Eight studies (1703 patients) were included. Methodology varied considerably and we found little evidence regarding patients with a high probability of HAP who were not mechanically ventilated. For patients with VAP, a short seven to eight-day course of antibiotics compared with a prolonged 10 to 15-day course (three studies, N = 508) increased 28-day antibiotic-free days (mean difference (MD) 4.02; 95% confidence interval (CI) 2.26 to 5.78) and reduced recurrence of VAP due to multi-resistant organisms (odds ratio (OR) 0.44; 95% CI 0.21 to 0.95), without adversely affecting other outcomes. However, for cases of VAP due to non-fermenting Gram-negative bacilli (NF-GNB), recurrence was greater after short-course therapy (OR 2.18; 95% CI 1.14 to 4.16; two studies, N = 176), though other outcome measures did not significantly differ. Discontinuation strategies utilising clinical features (one study; N = 302) or procalcitonin (three studies; N = 323) led to a reduction in duration of therapy and, in the procalcitonin studies, increased 28-day antibiotic-free days (MD 2.80; 95% CI 1.39 to 4.21) without negatively affecting other outcomes.

Authors' conclusions

We conclude that for patients with VAP not due to NF-GNB, a short fixed-course (seven or eight days) antibiotic therapy may be more appropriate than a prolonged course (10 to 15 days). Use of an individualised strategy (incorporating clinical features or serum procalcitonin) appears to safely reduce duration of antibiotic therapy for VAP.

Résumé scientifique

Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults

Contexte

La pneumonie est l'infection nosocomiale la plus commune chez les patients en unité de soins intensifs (USI). Toutefois, la durée optimale du traitement antibiotique pour la pneumonie nosocomiale (PN) reste incertaine.

Objectifs

Évaluer l'efficacité d’une antibiothérapie courte dans la PN par rapport à une antibiothérapie prolongée chez l’adulte en phase critique, y compris chez les patients avec pneumonie sous ventilation assistée (PVA).

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre Cochrane des essais contrôlés (CENTRAL) (The Cochrane Library 2011, numéro 1), qui contient le registre spécialisé du groupe Cochrane sur les infections respiratoires aiguës, ainsi que dans MEDLINE (1950 jusqu'à 4ème semaine de février 2011), EMBASE (1974 à mars 2011), LILACS (1985 à mars 2011) et Web of Science (1985 à mars 2011).

Critères de sélection

Nous avons pris en compte tous les essais cliniques randomisés (ECR) comparant des durées fixes d'antibiothérapie, ou bien comparant un protocole destiné à limiter la durée du traitement avec un traitement standard, pour la PN (y compris PVA) de l'adulte en phase critique.

Recueil et analyse des données

Deux auteurs de la revue ont réalisé l'extraction des données et l'évaluation des risques de biais. Nous avons contacté des auteurs d'essais pour obtenir des informations supplémentaires.

Résultats principaux

Huit études (1703 patients) ont été incluses. La méthodologie était très variable et nous n'avons trouvé que peu de données concernant des patients à probabilité élevée de PN mais non ventilés mécaniquement. Pour les patients avec PVA, une antibiothérapie courte de sept à huit jours, en comparaison à une antibiothérapie prolongée de 10 à 15 jours, (trois études, N = 508) avait augmenté le nombre de jours où le patient était sans antibiotique à 28 jours (risque relatif approché (OR) 4,02 ; intervalle de confiance (IC) à 95% 2,26 à 5,78) et avait réduit la récurrence de la PVA due à des micro-organismes multi-résistants (OR 0,44 ; IC 95% 0,21 à 0,95), sans affecter négativement les autres résultats. Toutefois, pour les cas de PVA causés par des bacilles non-fermentant Gram négatif (BNFGN), la récidive était plus importante après traitement court (OR 2,18 ; IC 95% 1,14 à 4,16 ; deux études, N = 176), bien que d'autres mesures ne diffèrent pas significativement. Les stratégies de traitement discontinu utilisant des éléments cliniques (une étude, N = 302) ou la procalcitonine (trois études, N = 323) ont conduit à une réduction de la durée du traitement et, pour les études portant sur la procalcitonine, ont augmenté le nombre de jours où le patient était sans antibiotique à 28 jours (différence moyenne (DM ) 2,80 ; IC 95% 1,39 à 4,21) sans affecter négativement d'autres résultats.

Conclusions des auteurs

Nous concluons que pour les patients avec PVA non causée par des BNFGN, une antibiothérapie courte et fixe (sept ou huit jours) pourrait être plus appropriée qu'un traitement prolongé (10 à 15 jours). L'utilisation d'une stratégie individualisée (incorporant des éléments cliniques ou de la procalcitonine sérum) semble réduire sans risque la durée du traitement antibiotique pour les PVA.

摘要

重症病人於院內感染肺炎適用的短期療程對比延長療程的抗生素治療

背景

肺炎是常見的院內感染,影響在加護病房(ICU)中的病患。然而,院內感染肺炎(HAP)適用的最佳抗生素治療期程仍不確定。

目的

評估短期對比延長療程的抗生素給葯在重症病患HAP上的有效性,包含患有呼吸相關肺炎(VAP)的病患。

搜尋策略

我們搜尋了考科藍對照試驗的中央註冊(CENTRAL)(The Cochrane Library2011年第1期),其中包含了考科藍急性呼吸道感染群組的專業註冊(the Cochrane Acute Respiratory Infections Group's Specialised Register)、MEDLINE(1950年到2011年2月第4週)、EMBASE(1974年到2011年3月)、LILACS(1985年到2011年3月)以及Web of Science(1985年到2011年3月)。

選擇標準

我們考量了所有比較抗生素治療混合期間的隨機對照試驗(RCTs),或是比較預計利用標準照護限制治療期間的作業流程,適用在HAP(包含VAP患者)的重症成人病患。

資料收集與分析

兩位文獻回顧作者執行資料擷取,並評估偏誤風險。我們聯絡試驗作者以取得額外資訊。

主要結果

包含了8個試驗(1,703名病患)。研究方法學差異極大,在高HAP機率病患、且沒有採用機械式呼吸器的病人,我們發現很少的證據。就VAP的病患而言,短期7到8天的抗生素治療與延長10到15天的療程相比(3個研究,N=508),增加了28天無使用抗生素的天數(平均數差異(MD)4.02;95% 信賴區間(CI)2.26-5.78),並因為多抗有機體(multi-resistant organisms)降低VAP的復發(勝算比(odd ratio, OR)0.44;95% CI 0.21到0.95),並且,無不良的影響其它成果。然而,在VAP的個案中,因為非發酵革蘭氐陰性菌(NF-GNB)的緣故,復發率在短期療程治療後較大(OR 2.18;95% CI 1.14到4.16;2個研究,N=176),雖然其它成果測量沒有明顯的差異。 利用臨床特性的停葯策略(1個研究;N=302)或是前降鈣素(3個研究;N=323)導致減少治療期程,在前降鈣素研究中,增加了28天的無抗生素天數(MD 2.80;95% CI 1.39到4.21),而無負面的影響其它成果。

作者結論

我們的結論是: 不是因為NF-GNB而患有VAP的病患,短期固定療程(7或8天)抗生素治療可能較延長的療程(10到15天)更為適當。個別化策略(結合臨床特性或血清前降鈣素)的利用似乎可安全的降低VAP患者在抗生素的治療期間。

Plain language summary

A review of strategies intended to limit duration of antibiotic therapy for hospital-acquired pneumonia in intensive care unit patients

Hospital-acquired pneumonia (HAP) is the major cause of hospital-acquired infection in the intensive care unit (ICU). There are a number of factors which predispose the critically ill to developing pneumonia, among which the most important may be tracheal intubation to enable mechanical ventilation; indeed, the majority of ICU patients with HAP have what is termed ventilator-associated pneumonia (VAP).

There is concern that unnecessary prolongation of antibiotic therapy may lead to the patient acquiring antibiotic-resistant organisms, which may be more difficult to treat when they cause infection, and will increase pharmacy costs. On the other hand, too short a course of therapy risks the treatment failing.

We aimed to evaluate the evidence from randomised controlled trials (RCTs) comparing a short with a long course of antibiotics, or comparing a protocol that aimed to shorten the course of antibiotics with standard care, for ICU patients with HAP (including those with VAP).

The eight RCTs (involving 1703 patients) we identified applied diverse methodological approaches to patient populations which differed substantially, limiting opportunities for combining data in a meta-analysis. Furthermore, we found very few data regarding duration of antibiotic therapy for ICU patients who have HAP, but are not mechanically ventilated. However, for patients with VAP, a course of seven or eight days of antibiotics was associated with an overall decrease in antibiotic administration and reduced the recurrence of pneumonia due to resistant organisms when compared with a 10 to 15-day course. Nevertheless, in cases when the VAP was due to a particular type of organism ('non-fermenting Gram-negative bacilli') which can be difficult to eradicate with antibiotics, the risk of pneumonia recurring appeared higher after a short course of antibiotics.

Lastly, some studies indicated that having an individualised stop-point for antibiotics (for example, clinical features, such as temperature, or results of a blood test) was associated with a shorter course of treatment and reduction in overall antibiotic exposure without negatively affecting other outcomes.

Résumé simplifié

Revue des stratégies destinées à limiter la durée du traitement antibiotique pour pneumonie nosocomiale chez les patients en unité de soins intensifs

La pneumonie nosocomiale (PN) est la principale cause d'infection nosocomiale en unité de soins intensifs (USI). Il y a un certain nombre de facteurs qui prédisposent les malades en phase critique à faire une pneumonie, dont le plus important est probablement l'intubation trachéale avant la ventilation mécanique ; en effet, la majorité des patients en USI atteints de PN ont ce qu'on appelle une pneumonie sous ventilation assistée (PVA).

Il est à craindre que la prolongation inutile du traitement antibiotique puisse causer l'apparition chez le patient de micro-organismes résistants aux antibiotiques, qui pourront être plus difficiles à traiter s'ils causent une infection, et accroîtront le coût en médicaments. En revanche, un traitement trop court risque de conduire à un échec.

Nous avons cherché à évaluer les résultats d'essais cliniques randomisés (ECR) comparant les antibiothérapies courtes et prolongées, ou comparant un protocole visant à raccourcir l'antibiothérapie avec le traitement standard, chez les patients en USI atteints de PN (y compris ceux avec PVA).

Les huit ECR (impliquant 1703 patients) identifiés avaient appliqué aux populations de patients une méthodologie qui différait sensiblement, limitant ainsi les possibilités de combinaison des données dans une méta-analyse. En outre, nous n'avons trouvé que très peu de données concernant la durée de l'antibiothérapie pour les patients en USI atteints de PN mais non ventilés mécaniquement. Toutefois, pour les patients avec PVA, un traitement antibiotique de sept ou huit jours était associé à une diminution globale de l'administration d'antibiotiques et réduisait la récurrence de la pneumonie due à des micro-organismes résistants, en comparaison à un traitement de 10 à 15 jours. Néanmoins, dans les cas où la PVA était due à un type particulier de micro-organisme (« bacilles non-fermentant Gram négatif ») qui peuvent être difficiles à éradiquer avec des antibiotiques, le risque de récurrence de la pneumonie semblait plus élevé après une antibiothérapie courte.

Enfin, certaines études indiquaient qu’une décision individualisée de l'arrêt des antibiotiques (utilisant par exemple des éléments cliniques tels que la température ou les résultats d'un test sanguin) était associée à une plus courte durée de traitement et à une réduction globale de l'exposition aux antibiotiques, sans affecter négativement les autres résultats..

Notes de traduction

Traduit par: French Cochrane Centre 1st November, 2011
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

淺顯易懂的口語結論

一項策略的文獻回顧試圖限制加護病房中院內感染肺炎病患的抗生素治療期程。

院內感染肺炎(HAP)是加護病房(ICU)院內感染的主要成因。有許多預先造成重症病患發展出肺炎的因素,其中最重要的可能是插管進行機械式給氧;確實,患HAP的ICU病患大多數具有被稱為呼吸器相關肺炎(VAP)的問題。

對於不必要的抗生素治療延長可能導致病患得到抗葯性有機體尚仍有憂慮,當他們造成感染時可能更難治療,並將增加葯物成本。另一方面,太短的治療療程風險是治療失敗。

我們目標放在評估來自隨機對照試驗(RCTs)的證據,比較短期與長期抗生素治療,或是比較目標放在縮短抗生素治療與標準照護上的作業流程,適用於有HAP(包含有VAP的)加護病房病患。

8個我們所找出的RCTs(涵蓋1,703名病患)應用多種方法學方法在病患族群上,且有方法學明顯的不同,此限制了在統合分析中結合數據進行分析的可能性。我們也發現非常少的證據與加護病房患有HAP、但非利用機械給氧的加護病房病患在抗生素療程期間有關的資料。然而,就患有VAP的病患而言,7或8天的抗生素療程與整體抗生素服用的減少有關,並降低肺炎的復發,因為與10到15天療程比較時,其具有扺抗的有機體。然而,在VAP是因為特定有機體類型造成的情形中('非發酵革蘭氐陰性菌'),其可能難以利用抗生素根除,肺炎復發的風險似乎在短期抗生素治療後較高。

最後,某些研究顯示,具有個別抗生素停用點(例如:臨床特性,像是體溫或根據血液測試結果)與短期治療療程及整體抗生素曝露的減少有關,並且無負面的影響其他成果。

譯註

翻譯: East Asian Cochrane Alliance
翻譯補助: 台灣衛生福利部/台北醫學大學實證醫學研究中心

Summary of findings(Explanation)

Summary of findings for the main comparison. Should short (fixed duration)-course antibiotic therapy versus prolonged-course antibiotic therapy be used for critically ill patients with hospital-acquired pneumonia?
Should short (fixed duration)-course antibiotic therapy versus prolonged-course antibiotic therapy be used for critically ill patients with hospital-acquired pneumonia?
Patient or population: critically ill patients with hospital-acquired pneumonia
Settings: ICU
Intervention: short (fixed duration)-course antibiotic therapy
Comparison: prolonged course antibiotic therapy
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Prolonged-course antibiotic therapyShort (fixed duration)-course antibiotic therapy
28-day mortalityStudy populationOR 1.08
(0.66 to 1.76)
431
(2 studies)
  
186 per 1000198 per 1000
(131 to 287)
Medium-risk population
270 per 1000285 per 1000
(196 to 394)
28-day mortality - NF-GNBStudy populationOR 0.71
(0.32 to 1.56)
127
(1 study)
See comment 
302 per 1000235 per 1000
(122 to 403)
Medium-risk population
302 per 1000235 per 1000
(122 to 403)
28-day mortality - MRSAStudy populationOR 1.28
(0.32 to 5.09)
42
(1 study)
See comment 
238 per 1000286 per 1000
(91 to 614)
Medium-risk population
238 per 1000286 per 1000
(91 to 614)
Recurrence of pneumoniaStudy populationOR 1.37
(0.87 to 2.17)
508
(3 studies)
  
245 per 1000308 per 1000
(220 to 413)
Medium-risk population
227 per 1000287 per 1000
(203 to 389)
Recurrence of pneumonia - NF-GNBStudy populationOR 2.18
(1.14 to 4.16)
176
(2 studies)
  
247 per 1000417 per 1000
(272 to 577)
Medium-risk population
241 per 1000409 per 1000
(266 to 569)
Recurrence of pneumonia - MRSAStudy populationOR 1.56
(0.12 to 19.61)
49
(2 studies)
  
370 per 1000478 per 1000
(66 to 920)
Medium-risk population
298 per 1000398 per 1000
(48 to 893)
28-day antibiotic-free days The mean 28-day antibiotic-free days in the intervention groups was
4.02 higher
(2.26 to 5.78 higher)
 431
(2 studies)
  
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MRSA: methicillin-resistant Staphylococcus aureus; NF-GNB: non-fermenting Gram-negative bacilli; OR: odds ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Discontinuation of antibiotics according to Clinical Pulmonary Infection Score for critically ill adults with hospital-acquired pneumonia

Summary of findings 2. Discontinuation of antibiotics according to Clinical Pulmonary Infection Score for critically ill adults with hospital-acquired pneumonia
Discontinuation of antibiotics according to Clinical Pulmonary Infection Score for critically ill adults with hospital-acquired pneumonia
Patient or population: critically ill adults with hospital-acquired pneumonia
Settings: ICU
Intervention: discontinuation of antibiotics according to Clinical Pulmonary Infection Score
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlDiscontinuation of antibiotics according to Clinical Pulmonary Infection Score
30-day mortalityStudy populationOR 0.33
(0.1 to 1.03)
81
(1 study)
See comment 
310 per 1000129 per 1000
(43 to 316)
Medium-risk population
310 per 1000129 per 1000
(43 to 316)
Episodes of superinfection or antimicrobial resistanceStudy populationOR 0.29
(0.09 to 0.92)
81
(1 study)
See comment 
333 per 1000126 per 1000
(43 to 315)
Medium-risk population
333 per 1000126 per 1000
(43 to 315)
Duration of antibiotic therapySee commentSee commentNot estimable81
(1 study)
See comment 
Duration of ITU staySee commentSee commentNot estimable81
(1 study)
See comment 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; ITU: intensive therapy unit; OR: odds ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Discontinuation of antibiotics according to clinical guideline for hospital-acquired pneumonia in critically ill adults

Summary of findings 3. Discontinuation of antibiotics according to clinical guideline for hospital-acquired pneumonia in critically ill adults
Discontinuation of antibiotics according to clinical guideline for hospital-acquired pneumonia in critically ill adults
Patient or population: patients with hospital-acquired pneumonia in critically ill adults
Settings: ICU
Intervention: discontinuation of antibiotics according to clinical guideline
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlDiscontinuation of antibiotics according to clinical guideline
Recurrence of pneumoniaStudy populationOR 0.88
(0.48 to 1.59)
290
(1)
See comment 
193 per 1000174 per 1000
(103 to 275)
Medium-risk population
193 per 1000174 per 1000
(103 to 275)
Duration of antibiotic therapy The mean duration of antibiotic therapy in the intervention groups was
2 lower
(3.21 to 0.79 lower)
 290
(1)
See comment 
In-hospital mortalityStudy populationOR 0.8
(0.49 to 1.29)
290
(1)
See comment 
371 per 1000321 per 1000
(224 to 432)
Medium-risk population
371 per 1000321 per 1000
(224 to 432)
Duration of ICU stay The mean duration of ICU stay in the intervention groups was
0.2 lower
(1.75 lower to 1.35 higher)
 290
(1)
See comment 
Duration of hospital stay The mean duration of hospital stay in the intervention groups was
0.3 higher
(3.63 lower to 4.23 higher)
 290
(1)
See comment 
Duration of mechanical ventilation The mean duration of mechanical ventilation in the intervention groups was
0.3 lower
(1.79 lower to 1.19 higher)
 290
(1)
See comment 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; ICU: intensive care unit; OR: odds ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 4 Discontinuation of antibiotic therapy according to serum procalcitonin level for hospital-acquired pneumonia in critically ill adults

Summary of findings 4. Discontinuation of antibiotic therapy according to serum procalcitonin level for hospital-acquired pneumonia in critically ill adults
Discontinuation of antibiotic therapy according to serum procalcitonin level for hospital-acquired pneumonia in critically ill adults
Patient or population: hospital-acquired pneumonia in critically ill adults
Settings: ICU
Intervention: discontinuation of antibiotic therapy according to serum procalcitonin level
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlDiscontinuation of antibiotic therapy according to serum procalcitonin level
28-day mortalityStudy populationOR 0.66
(0.39 to 1.14)
308
(3 studies)
  
265 per 1000192 per 1000
(123 to 291)
Medium-risk population
258 per 1000187 per 1000
(119 to 284)
Recurrence of pneumoniaStudy populationOR 2.06
(0.74 to 5.7)
66
(1 study)
See comment 
286 per 1000452 per 1000
(229 to 695)
Medium-risk population
286 per 1000452 per 1000
(229 to 695)
28-day antibiotic-free days The mean 28-day antibiotic-free days in the intervention groups was
2.8 higher
(1.39 to 4.21 higher)
 167
(2 studies)
  
Duration of antibiotic therapy
days
 The mean duration of antibiotic therapy in the intervention groups was
3.2 lower
(4.45 to 1.95 lower)
 308
(3 studies)
  
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; ICU: intensive care unit; OR: odds ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Hospital-acquired pneumonia (HAP), pneumonia occurring 48 hours or more after hospital admission and not incubating at time of admission (ATS/IDSA 2005), remains an important cause of healthcare-associated morbidity and mortality. HAP occurs among the general hospitalised population with a rate of 5 to 10 per 1000 hospital admissions (ATS/IDSA 2005). However, for patients in the intensive care unit (ICU, also referred to as intensive therapy unit, ITU) the incidence increases significantly; pneumonia is the most common cause of hospital-acquired infection in ICUs in both Europe and the United States (Richards 2000; Vincent 2009).

Ventilator-associated pneumonia (VAP), which may be defined as pneumonia occurring more than 48 to 72 hours after tracheal intubation (ATS/IDSA 2005), affects as many as 10% to 20% of patients receiving mechanical ventilation for more than 48 hours (Safdar 2005). Patients with VAP represent a significant sub-set of ICU patients with HAP. Up to 90% of ICU episodes of HAP occur while patients are mechanically ventilated (ATS/IDSA 2005). Endotracheal intubation is thought to increase the risk of developing pneumonia by facilitating colonisation of the respiratory tract with potential bacterial pathogens (Chastre 2002). Additional factors predisposing the critically ill towards the development of VAP include severity of illness, organ failure, increasing age and prior surgery (Chastre 2002).

HAP in the critically ill carries appreciable morbidity and mortality. Associated mortality rates of up to 50% have been observed with VAP (ATS/IDSA 2005) and lengths of ICU and hospital stay are significantly prolonged, with estimated additional costs ranging from USD 10,000 to USD 40,000 per patient (Rello 2002; Safdar 2005).

Description of the intervention

A number of strategies to guide duration of antibiotic therapy in the treatment of HAP for the critically ill have been described. Antibiotics may be administered according to a fixed duration (Chastre 2003a; Ibrahim 2001). Alternatively, therapy may be 'individualised' and discontinued according to resolution of clinical features (Micek 2004), quantitative reduction in culture of respiratory specimens (Mueller 2007) or a relevant biomarker (Bouadma 2010; Stolz 2009a). Furthermore, antibiotics have been restricted to a short course of treatment if it is deemed that HAP is of only low probability (Kollef 2005; Rello 2004; Singh 2000). Current national guidelines recommend a course of antibiotic therapy for HAP of up to eight days when there has been good response to therapy (ATS/IDSA 2005; BSAC 2008), but a prolonged course of two to three weeks if response has been poor or when infection has been due to non-fermenting Gram-negative bacilli (NF-GNB), such as Pseudomonas aeruginosa (P. aeruginosa) (ATS/IDSA 2005). Compared with the application of a fixed empiric rule for all, a reliable measure of response to treatment has theoretical appeal as a means of discriminating between those for whom a shorter course of therapy may or may not be appropriate (Bouadma 2010; Nobre 2008).

How the intervention might work

Clinical resolution seems to occur, at least in a sizeable subgroup of patients, within the first six days of antibiotic therapy for HAP (Dennesen 2001; Luna 2003); in such patients, prolongation of therapy may confer little additional benefit, but may contribute to the emergence of resistant organisms (Chastre 2003a; Dennesen 2001), may increase the risk of developing Clostridium difficile (C. difficile)-associated disease (Bignardi 1998; Pepin 2005) and antibiotic-related toxicity, and will increase pharmacy costs.

Why it is important to do this review

Pneumonia is the most common nosocomial infection in the ICU (Vincent 1995) and a very high proportion (71%) of intensive care patients receive antibiotic therapy (Vincent 2009). The duration of antibiotic therapy is clearly an important consideration in the optimal antimicrobial management of critically ill patients with HAP; too short a course of therapy risks treatment failure, whereas too long a course of therapy carries unnecessary costs and poses potential risks for the individual patient and to other patients through the emergence of resistant organisms.

The optimal duration of antibiotic therapy for HAP is uncertain, whether administered according to a fixed course, or discontinued after resolution of clinical features or biomarker. Furthermore, HAP is not a homogenous disease and higher risk of treatment failure associated with short-course therapy might be expected, for example, when HAP is due to NF-GNB. NF-GNB such as P. aeruginosa are particularly difficult to eradicate from the respiratory tract despite initial in vitro sensitivity to antibiotic therapy (Dennesen 2001; Visscher 2008) and infection with NF-GNB represents an independent risk factor for VAP recurrence and mortality (Combes 2007; Kollef 1995).

Objectives

To assess the effects of short-course versus prolonged-course antibiotics for hospital-acquired pneumonia (HAP) (including ventilator-associated pneumonia (VAP)) in critically ill adults.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) comparing fixed ('short' versus 'prolonged') courses of antibiotic therapy or comparing protocol-directed antibiotic administration with standard care for relevant outcomes in critically ill patients with established HAP (including VAP).

Types of participants

ICU patients (16 years and older) with HAP (including patients with VAP) diagnosed by clinical and/or radiological features and/or quantitative culture of respiratory specimens. We intended to exclude data from patients with haematological malignancy, chemically-induced immune-suppression or HIV/AIDS where possible.

Types of interventions

RCTs comparing two fixed durations of antibiotic therapy (a 'short-course' versus a 'prolonged-course') or comparing a protocol intended to reduce duration of antibiotic therapy with standard care; such protocols might include a directive to discontinue antibiotics according to clinical resolution of pneumonia or according to a bio-marker, for example procalcitonin.

Types of outcome measures

Primary outcomes
  1. 28-day mortality.

  2. Recurrence of pneumonia (diagnosed on the basis of clinical and/or microbiological criteria).

  3. 28-day antibiotic-free days.

  4. Duration of antibiotic therapy (in studies without fixed duration of therapy).

Secondary outcomes
  1. ICU mortality.

  2. In-hospital mortality.

  3. Non-resolution of pneumonia (according to clinical and/or microbiological criteria).

  4. Subsequent infection due to 'resistant organisms' (for example, methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA)).

  5. Duration of ICU stay.

  6. Duration of hospital stay.

  7. Duration of mechanical ventilation (where appropriate).

  8. Mechanical ventilation-free days (where appropriate).

  9. Mortality attributable to HAP.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to February week 4, 2011), EMBASE (1974 to March 2011), LILACS (1985 to March 2011) and Web of Science (1985 to March 2011).

We used the following search strategy to search MEDLINE and CENTRAL. We combined the MEDLINE search strategy with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2011). We modified these terms to search EMBASE (see Appendix 1), LILACS (see Appendix 2) and Web of Science (see Appendix 3).

We imposed no publication or language restrictions.

MEDLINE (Ovid)

1 Pneumonia/
2 pneumon*.tw.
3 1 or 2
4 Respiration, Artificial/
5 exp Ventilators, Mechanical/
6 Cross Infection/
7 (respirator* or ventilat*).tw.
8 or/4-7
9 3 and 8
10 Pneumonia, Ventilator-Associated/
11 (pneumon* adj5 (hospital or ventilator or nosocomial)).tw.
12 (hap or vap).tw.
13 or/9-12
14 exp Anti-Bacterial Agents/
15 antibiot*.tw,nm.
16 14 or 15
17 13 and 16

Searching other resources

We also searched registers of controlled clinical trials, the metaRegister of controlled trials and clinicaltrials.gov. We searched the Database of Abstracts of Reviews of Effects (DARE) for additional reviews (Centre for Reviews and Dissemination (CRD), University of York, UK). We searched reference lists of identified studies and reviews. We searched databases of grey literature, including OpenSIGLE and mindcull.com. We also searched abstracts of recent conferences: International Symposium for Intensive Care and Emergency Medicine, European Society for Intensive Care Medicine, Society of Critical Care Medicine, American Thoracic Society, British Thoracic Society, European Respiratory Society, Chest, Infectious Disease Society of America, Interscience Conference on Antimicrobial Agents, and Chemotherapy.

Data collection and analysis

Selection of studies

Two review authors (RP, CG) independently analysed and reviewed the titles and abstracts of retrieved records for possible inclusion in this review. We used the following inclusion criteria: RCT, participants including ICU patients with HAP, comparison of fixed durations of therapy or intervention intended to limit duration of therapy and relevant outcome data. We attempted to contact all trial authors to clarify methods where necessary. We resolved any disagreements about study inclusion through consensus and, where needed, involved a third review author (GD).

Data extraction and management

We used a standardised data extraction form. Two review authors (RP, CG) extracted data and entered it into a Review Manager (RevMan) (RevMan 2011) program for statistical analysis. We contacted trial authors for any missing data.

Assessment of risk of bias in included studies

Two review authors (RP, GD) independently assessed the validity of studies using the Cochrane 'Risk of bias' tool (Stern 2011). We resolved disagreements through consensus.

Measures of treatment effect

We utilised dichotomous data for measures of treatment effect of:

  • mortality;

  • non-resolution;

  • recurrence;

  • infection with 'resistant organism'; and

  • mortality attributable to HAP.

We used continuous data for:

  • durations of stay;

  • duration of mechanical ventilation; and

  • ventilation- and antibiotic-free days.

Unit of analysis issues

We did not identify significant unit of analysis issues (for example, randomisation of a group of individuals rather than an individual in a cluster-randomised trial, or allocation of an individual to multiple interventions in a cross-over trial).

Dealing with missing data

We intended to analyse data according to an intention-to-treat (ITT) principle, i.e. all patients included in the study at the point of randomisation were analysed according to their assigned treatment group, regardless of whether or not treatment was completed. However, we were not able to do this for all studies.

Assessment of heterogeneity

We anticipated the following sources of heterogeneity: participation factors (preceding durations of hospitalisation and mechanical ventilation, bacterial pathogen, prior antibiotic administration and illness severity) and intervention factors (class of antibiotic and method of administration). We anticipated that methodological diversity would be a significant source of heterogeneity and that studies may have to be grouped according to the intervention strategy (for example, procalcitonin-guided antibiotic algorithm) as the inclusion criteria were so broad. We assessed heterogeneity on the basis of the I2 statistic (Higgins 2002), interpreting a value < 40% as not suggestive of important heterogeneity.

Assessment of reporting biases

We attempted to minimise reporting bias by searching for unpublished trials and references to trial registries. Due to the low number of studies identified, we did not perform funnel plot tests for funnel plot asymmetry.

Data synthesis

We used mean difference (MD) as a summary statistic for continuous measures and odds ratio (OR) for dichotomous measures. We chose a random-effects model for meta-analysis having been unable to adequately explore potential sources of heterogeneity between studies.

Subgroup analysis and investigation of heterogeneity

A priori subgroups were:

  • duration of hospitalisation prior to development of pneumonia;

  • ventilator- and non-ventilator-associated HAP;

  • duration of mechanical ventilation prior to development of pneumonia;

  • administration of antibiotic therapy during hospital admission prior to development of pneumonia;

  • severity of illness;

  • chronic respiratory illness;

  • bacterial pathogen: NF-GNB and MRSA; and

  • class of antibiotic(s).

Outcome data were insufficiently reported for individual subgroups to enable investigation of sources of heterogeneity with the exception of bacterial pathogen.

Sensitivity analysis

We felt it was not appropriate to perform sensitivity analysis due to the small number of included studies. This is considered to be a potential source of bias. See Potential biases in the review process.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Results of the search

Searches produced the following results: MEDLINE (Ovid) from 1950 to February week 4, 2011)) 1045 results; CENTRAL (2011, Issue 1) 767 search results; Embase.com (from 1974 to March 2011) 1268 search results; Web of Science (1985 to March 2011) 485 search results; and LILACS (1985 to March 2011) 283 search results. With duplicates removed this left 2587 records. Of 2587 abstracts, we undertook a full-text review of 13 potentially eligible studies (Bouadma 2010; CCCTG 2006; Chastre 2003a; Chastre 2003b; Fagon 2000; Fekih Hassen 2009; Kim 2009; Micek 2004; Pontet 2007; Sanchez-Nieto 1998; Singh 1998; Singh 2000; Stolz 2009a). We identified nine other potential studies (Hochreiter 2009; Ibrahim 2001; Kollef 2005; Nobre 2008; Peery 2001; Rello 2004; Schroeder 2007; Sole 2000; Svoboda 2007) from examination of review articles and relevant papers. We found a further four studies (Cai 2001; Maldonado-Ortiz 2004; Medina 2007; Wolff 2003) on investigation of the 'grey literature', including relevant database searches and review of conference abstracts. In addition, a review of trials registers indicated several potentially relevant ongoing studies (NCT00934011; NCT00987818; PASS; Pro-SEPS; SAPS; SISPCT) and one terminated study (ProBac).

Included studies

We included eight studies in the review (Bouadma 2010; Chastre 2003a; Fekih Hassen 2009; Medina 2007; Micek 2004; Pontet 2007; Singh 2000; Stolz 2009a). Those considered to be studies directly comparing durations of antibiotic therapy were Chastre 2003a, Fekih Hassen 2009 and Medina 2007. Studies investigating a strategy of discontinuation of antibiotics on the basis of clinical features were Micek 2004 and Singh 2000. Studies investigating strategies to discontinue antibiotic therapy according to the biomarker procalcitonin were Bouadma 2010, Pontet 2007 and Stolz 2009a. We have presented summary data accordingly in the Characteristics of included studies table.

1. Studies directly comparing durations of antibiotic therapy

Three RCTs were identified (Chastre 2003a; Fekih Hassen 2009; Medina 2007), each examining duration of antibiotic therapy specifically for VAP. Two of these studies were unblinded (Chastre 2003a; Medina 2007); details about blinding were not available for Fekih Hassen 2009. In terms of patient numbers, the multi-centre French Pneuma study was by far the largest study, having recruited 401 patients (Chastre 2003a). The Uruguayan study, Medina 2007, which recruited 77 patients has not to date been published in full text. A smaller single-centre Tunisian study, which recruited 30 patients, has been published in a French language journal (Fekih Hassen 2009).

The Pneuma study was specifically designed to compare durations of antibiotic therapy in a population likely to have a high proportion of more resistant bacteria, including NF-GNB such as P. aeruginosa, by excluding patients with early VAP (within the first five days of mechanical ventilation) and no antimicrobial therapy within the preceding 15 days (Chastre 2003a). Interestingly, VAP due to NF-GNB actually accounted for a higher proportion of cases of VAP in the other two studies: 33% in Chastre 2003a, compared with 72% in Fekih Hassen 2009 and 64% in Medina 2007. The proportion of episodes of VAP due to MRSA was similar for Chastre 2003a (11%) and for Medina 2007 (9%).

VAP diagnostic criteria differed between studies; the Pneuma study required microbiological diagnosis of VAP (and recurrence) according to quantitative analysis of broncho-alveolar lavage (BAL) or protected specimen brush (PSB). In contrast, for Medina 2007 and Fekih Hassen 2009, microbiological confirmation of VAP was permitted on the basis of culture of: endotracheal aspirate (ETA) (Fekih Hassen 2009; Medina 2007); PSB (Fekih Hassen 2009); and BAL, blood or pleural fluid (Medina 2007).

Antibiotics had been administered prior to the onset of VAP in 84% of patients in Chastre 2003a and 68% of patients in Medina 2007. Duration of mechanical ventilation prior to onset of VAP did not appear to differ greatly between studies: 14 days (Chastre 2003a); nine days (Medina 2007) and 10 days (Fekih Hassen 2009). Presence of underlying respiratory disease was not reported in sufficient detail to enable comparisons between studies. Severity of illness scores were not directly comparable across all groups; however, mean SAPS II (Simplified Acute Physiology Score II) scores were 45 for Chastre 2003a and 43 for Fekih Hassen 2009, with SOFA (Sequential Organ Failure Assessment) scores a mean 7.3 for Chastre 2003a compared and median 6 for Medina 2007.

Durations of antibiotic therapy differed between studies. Chastre 2003b allocated patients to receive either eight days or 15 days of antibiotic therapy, Medina 2007 to eight days or 12 days of therapy and Fekih Hassen 2009 to seven days or 10 days of therapy.

The most common classes of antibiotics used early in Chastre 2003a were an aminoglycoside or quinolone plus beta-lactam (91%); in Medina 2007, beta-lactams were used in 90% of cases and aminoglycosides in 27% overall; similar data are not available for Fekih Hassen 2009. Initial antibiotic therapy was appropriate (according to respiratory specimen culture and sensitivity results) in 94% to 100% cases for Chastre 2003a (patients treated with inappropriate initial antibiotics were excluded from this study), Medina 2007 and Fekih Hassen 2009, where, in all three cases, initial choice of therapy was left to the discretion of the treating physician/microbiology advice.

2. Studies evaluating strategies intended to reduce antibiotic duration according to clinical features

Two RCTs intended to evaluate strategies to reduce antibiotic duration according to clinical features (Micek 2004; Singh 2000). Neither of these studies were blinded.

In terms of participants, the larger study was Micek 2004, a single-centre study from the USA, which enrolled 302 patients specifically with VAP. In contrast, Singh 2000 recruited non-mechanically ventilated ICU patients with HAP as well as patients with VAP; only 47 out of 81 patients (58%) were mechanically ventilated at enrolment.

An important consideration is that Singh 2000 sought to recruit patients with low probability of pneumonia, as determined by a Clinical Pulmonary Infection Score (CPIS) < 7 at Day 1 and Day 3. Diagnosis of HAP was made on the basis of new pulmonary infiltrates and "suspected of having pneumonia". Notably, microbiological confirmation of a potential bacterial pathogen was not an essential criterion. In contrast, VAP was diagnosed in Micek 2004 according to specific modified American College of Chest Physician criteria, including clinical, microbiological and radiological features; predictably, mean CPIS was higher for Micek 2004 (7.1) than for Singh 2000 (4.9).

Patients recruited in Singh 2000 were slightly older than for Micek 2004, at 67 years and 60 years, but the incidence of chronic obstructive airways disease was similar at 27% and 29%, respectively. Illness severity scores were not directly comparable; P. aeruginosa or Acinetobacter baumannii (A. baumannii) accounted for a comparatively low 11% of cases of VAP, and MRSA for 20% of cases in Micek 2004; in Singh 2000, microbiological characteristics are presented for subgroups of patients only. The proportion of patients receiving appropriate initial antibiotic therapy was presented in Micek 2004 (93%), but not in Singh 2000.

Interventions differed significantly between studies. In Singh 2000, 39 patients allocated on Day 1 to the experimental group received a total of three days' ciprofloxacin monotherapy when the CPIS (a composite score based upon high or low temperature, leukocyte count, quality of tracheal secretion, oxygenation and presence of radiographic infiltrates, and at Day 3 microbiological culture and radiographic progression) remained < 7 at Day 3; in contrast, the 42 patients allocated standard therapy received antibiotics of class and duration according to the discretion of the treating physician (standard duration at the beginning of the trial 10 to 21 days). For the 154 patients randomised to the discontinuation group in Micek 2004, an investigator advised the treating physician on week days to stop antibiotic therapy when radiological infiltrates seemed not to be due to infectious cause, or when temperature, white cell count, sputum, PaO2/ FiO2 ratio (ratio of arterial blood partial pressure of oxygen: fraction of inspired oxygen in inhaled gas) and radiological features of respiratory infection had resolved. Duration of antibiotic therapy for the 148 patients in the control group was determined entirely by the treating physician.

3. Studies evaluating strategies to reduce antibiotic exposure according to serum procalcitonin level

Three RCTs investigated strategies to reduce antibiotic exposure on the basis of a biomarker (in each case procalcitonin) in studies of patients with VAP (Bouadma 2010; Pontet 2007; Stolz 2009a); one study also included patients with HAP not requiring mechanical ventilation (Bouadma 2010) though outcome data presented for these patients were very limited. None of these were blinded studies. Pontet 2007 recruited 81 patients to a Uruguayan multi-centre study investigating procalcitonin as a guide to discontinuation of antibiotic therapy in patients with VAP; currently this study is published in abstract form only. Stolz 2009a recruited 101 patients to the international (USA and Switzerland) multi-centre ProVAP study investigating a procalcitonin-guided strategy for discontinuation of antibiotics for VAP. In contrast, the multi-centre French PRORATA trial was designed to study a broader population of 630 ICU patients with suspected bacterial infection (Bouadma 2010). The experimental strategy advocated withholding antibiotics when the baseline serum procalcitonin level was low and/or discontinuing antibiotic therapy according to subsequent serum levels. The study included 214 patients with VAP or HAP (not requiring mechanical ventilation), of whom 141 specifically had VAP. A very low proportion of enrolled patients overall were surgical (11%).

VAP was diagnosed in Pontet 2007 on the basis of specific radiological, clinical and microbiological criteria; furthermore, in their per-protocol analysis, patients in the intervention procalcitonin group were excluded on the basis of serum procalcitonin levels < 0.5 ng/ml in the first 48 hours; in the standard-therapy group, patients were excluded on the basis of negative BAL culture. In Stolz 2009a, VAP was diagnosed on the basis of radiological and clinical criteria; microbiological confirmation was not an essential criterion and indeed for 27% of patients a causative micro-organism was not identified. In Bouadma 2010, diagnostic criteria for HAP and VAP were not provided.

Microbiological data were not presented in Bouadma 2010. However, in Pontet 2007, 23% of cases of VAP were due to NF-GNB and 6% due to MRSA; in Stolz 2009a, NF-GNB accounted for 36% of cases of VAP, and MRSA for 10% of cases. SOFA scores were lower in Pontet 2007 (4.8) compared with Stolz 2009a (7.8). Illness severity scores and other baseline characteristic data were not available for patients with HAP or VAP included in Bouadma 2010.

Interventions differed substantially between these studies. Of 81 patients randomised on day of diagnosis (Day 1) in Pontet 2007, 41 were allocated to procalcitonin-guided therapy and 40 to standard therapy. Nine patients were excluded from the analysis in the experimental group because the low procalcitonin level on Day 1 or Day 2 was felt to be inconsistent with VAP. In addition, six patients were excluded from the standard-therapy group, because of negative BAL or short treatment, leaving 35 patients. In the experimental group, serum procalcitonin level was measured again at Day 7; for those patients with procalcitonin level < 0.5 ng/ml, antibiotic therapy was discouraged. In the standard-therapy group, duration of antibiotic therapy was left to the treating physician. In Stolz 2009a, patients with suspected VAP were randomised on day of diagnosis (Day 0), and had serum procalcitonin levels measured daily until Day 10. In the intervention group, from Day 2 onwards, procalcitonin levels were relayed to the treating physician, who was advised on a daily basis to discontinue antibiotics if and when procalcitonin levels fell below 0.25 µg/L (0.25 ng/ml) or fell to less than 20% of the level on Day 0. However, in the control group, information regarding the procalcitonin level was not relayed to the treating physician. In Bouadma 2010, serum procalcitonin levels were measured in all patients in the intervention group; guidance was to withhold antibiotics when the procalcitonin level was < 0.5 µg/L on the day of study entry, or subsequently to discontinue if and when procalcitonin levels fell to < 0.5 µg/L or to less than 20% peak level of procalcitonin. In the control group, a proportion of patients also underwent procalcitonin measurement but results were not provided to the treating physician and antibiotics were administered according to a pre-agreed guideline.

Excluded studies

Studies were excluded on the basis of having been published as a full paper elsewhere (Chastre 2003b; Singh 1998; Wolff 2003), of not being RCTs (Ibrahim 2001; Kollef 2005; Rello 2004), of investigating a diagnostic strategy rather than an intervention intended to guide duration of antibiotic therapy for pneumonia (Cai 2001; CCCTG 2006; Fagon 2000; Peery 2001; Sanchez-Nieto 1998; Sole 2000) and for lack of data relating specifically to patients with HAP (including VAP) (Hochreiter 2009; Nobre 2008; Schroeder 2007; Svoboda 2007). Two other studies published in abstract form only were also excluded, Maldonado-Ortiz 2004 because of inadequate outcome data and significant risk of bias and Kim 2009 because the de-escalation protocol was inadequately described and relevant outcome data were not presented. Please refer to Characteristics of excluded studies table.

Risk of bias in included studies

Risk of bias is presented in detail in the Characteristics of included studies table, presented graphically in Figure 1 and summarised in Figure 2.

Figure 1.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Sequence generation was adequate in five studies and unclear in three studies. Allocation concealment was adequate in five studies and unclear in three studies.

Blinding

In none of the studies was adequate blinding described: blinding was unclear in one study and unblinded in seven studies.

Incomplete outcome data

Incomplete outcome data reporting was adequate in six studies, unclear in one and inadequate in one study.

Selective reporting

Selective reporting appears to have been a feature of two studies and was unclear in six.

Other potential sources of bias

There were other significant potential sources of bias in the three studies investigating a procalcitonin-guided strategy. With particular regard to two of the three studies, protocol violation rates were either high (Bouadma 2010) or incompletely reported (Stolz 2009a). In addition, one study had analysed data on a per-protocol as opposed to ITT basis, which was considered to carry a high risk of bias (Pontet 2007).

Effects of interventions

See: Summary of findings for the main comparison Should short (fixed duration)-course antibiotic therapy versus prolonged-course antibiotic therapy be used for critically ill patients with hospital-acquired pneumonia?; Summary of findings 2 Discontinuation of antibiotics according to Clinical Pulmonary Infection Score for critically ill adults with hospital-acquired pneumonia; Summary of findings 3 Discontinuation of antibiotics according to clinical guideline for hospital-acquired pneumonia in critically ill adults; Summary of findings 4 Discontinuation of antibiotic therapy according to serum procalcitonin level for hospital-acquired pneumonia in critically ill adults

Outcomes are presented in detail (including forest plots) in the Data and analyses section below.

1. Studies directly comparing durations of antibiotic therapy

Outcomes are summarised in Summary of findings for the main comparison below.

a. Antibiotic exposure

Chastre 2003a and Fekih Hassen 2009 provided data on 28-day antibiotic-free days; antibiotic-free days were significantly greater in the short-course group (mean difference (MD) 4.02 days; 95% confidence interval (CI) 2.26 to 5.78; Analysis 1.3).

b. Mortality

Outcome measures used by these studies were not uniform. Twenty-eight-day mortality (incorporating data from Chastre 2003a and from Fekih Hassen 2009) did not differ significantly between short-course and prolonged-course therapy (odds ratio (OR) 1.08; 95% CI 0.66 to 1.76; Analysis 1.1). Only Chastre 2003a provided data on 28-day mortality according to bacterial pathogen; there were no significant differences between treatment groups for subgroups with VAP due to NF-GNB or MRSA. Regarding in-hospital mortality, there are only data from Chastre 2003a; there are no significant differences between treatment groups, overall and for subgroups with VAP due to NF-GNB or MRSA (Analysis 1.6). ICU mortality data are available for Medina 2007 and for Fekih Hassen 2009 but without data relating to VAP due to specific bacterial pathogen; there were no significant differences between short and prolonged-courses and antibiotics (Analysis 1.4). Only Medina 2007 presented data on VAP-related mortality, which did not differ between groups (Analysis 1.12).

c. Non-resolution and recurrence

Chastre 2003a described a condition of "Pulmonary infection recurrence before the end of treatment," on the basis of quantitative culture of BAL or PBS, which may clinically overlap with "Non-resolution." However, data specifically relating to "Non-resolution" (referred to as "Therapeutic failure") were presented only by Medina 2007; there was a trend to greater non-resolution overall in the short-course group (OR 1.80; 95% CI 0.65 to 5.02; Analysis 1.5) and for NF-GNB (OR 1.89; 95% CI 0.49 to 7.40; Analysis 1.5).

Recurrence data are presented by both Chastre 2003a and Medina 2007. There was a trend to greater recurrence of VAP overall in the short-course group (OR 1.37; 95% CI 0.87 to 2.17; Analysis 1.2), and a significantly greater recurrence for VAP due to NF-GNB in the short-course group (OR 2.18; 95% CI 1.14 to 4.16; P = 0.02; Analysis 1.2; antibiotic duration eight days versus 12 or 15 days in this comparison). However, recurrent pulmonary infection due to multi-resistant organism was lower in the short-course group (OR 0.44; 95% CI 0.21 to 0.95; data from Chastre 2003a only; Analysis 1.2).

d. Other continuous data

Durations of ICU stay, hospital stay and mechanical ventilation did not differ significantly between short-course and prolonged-course therapy. Twenty-eight-day mechanical ventilation-free days was not significantly different between short and prolonged-course groups; the I2 statistic was 72% for this outcome measure, however, indicating a high degree of heterogeneity (Analysis 1.11).

2. Studies evaluating strategies intended to reduce antibiotic duration according to clinical features

Outcomes are summarised in Summary of findings 2 and Summary of findings 3 below.

a. Antibiotic exposure

For patients randomised to the short-course therapy group in Singh 2000, overall, 28% of patients received antibiotics for > three days, compared with 97% in the standard-therapy group (P = 0.0001); for patients with CPIS < 7, 0 patients in the short-course group received antibiotics > three days, compared with 96% in standard therapy (P = 0.0001). Allocation to the discontinuation group was associated with significantly reduced duration of antibiotic therapy for VAP in Micek 2004 (6.0 days versus 8.0 days; P = 0.001; Analysis 3.2).

b. Mortality

There were no significant differences for 30-day mortality in Singh 2000 (short-course versus standard therapy, 13% versus 31%, P = 0.06; Analysis 2.1), nor for in-hospital mortality in Micek 2004 (discontinuation group versus conventional group 32% versus 37%; P = 0.36; Analysis 3.3).

c. Non-resolution and recurrence

In Singh 2000, a composite measure of antibiotic resistance and/or superinfection was reported; in the short-course group, this rate was found to be significantly lower at 13% versus 33% (P = 0.03; Analysis 2.2). There was no significant difference in rates of VAP recurrence in Micek 2004 (discontinuation group versus standard-therapy group 17.3% versus 19.3%; P = 0.67; Analysis 3.1).

d. Other continuous data

Singh 2000 reports a significantly reduced mean length of ICU stay in the short-course group (9.4 versus 14.7 days; standard deviation (SD) data not presented; P = 0.04). There were no significant differences in duration of ICU or hospital stay and duration of mechanical ventilation between groups in Micek 2004 (Analysis 3.4; Analysis 3.5; Analysis 3.6).

3. Studies evaluating strategies to reduce antibiotic exposure according to serum procalcitonin level

Outcomes are summarised in Summary of findings 4 below.

a. Antibiotic exposure

Duration of antibiotic therapy was significantly shorter in patients treated according to a procalcitonin-guided strategy than for patients allocated to standard therapy (mean 9.1 versus 12.1 days; MD (random-effects analysis) -3.20 days; 95% CI -4.45 to -1.95; Bouadma 2010; Pontet 2007; Stolz 2009a; Analysis 4.4). Similarly, 28-day antibiotic-free days were significantly greater in patients treated using a procalcitonin-guided strategy (MD 2.80 days; 95% CI 1.39 to 4.21 days; Pontet 2007; Stolz 2009a; Analysis 4.3). Interestingly, for 11/75 (15%) patients with VAP in Bouadma 2010, use of a PCT-guided strategy led to a more prolonged course of antibiotics than recommendations for the control group would have advised.

b. Mortality

Twenty-eight-day mortality (OR 0.66; 95% CI 0.39 to 1.14; Bouadma 2010; Pontet 2007; Stolz 2009a; Analysis 4.1), in-hospital mortality (OR 0.63; 95% CI 0.25 to 1.58; Stolz 2009a; Analysis 4.5) and ICU mortality (OR 0.76; 95% CI 0.26 to 2.22; Pontet 2007; Analysis 4.6) were not significantly different between procalcitonin-guided therapy and standard-therapy groups.

c. Non-resolution and recurrence

Non-resolution and recurrence data are presented in Pontet 2007 only; the greater recurrence of pneumonia was observed in the procalcitonin-guided therapy group and was not statistically significant (OR 2.06; 95% CI 0.74 to 5.7; Analysis 4.2).

d. Other continuous data

The shorter duration of ICU stay observed in the procalcitonin-guided therapy group was not statistically significant (MD -2.68 days; 95% CI -6.01 to 0.66; Pontet 2007; Stolz 2009a; Analysis 4.9). Durations of mechanical ventilation and hospital stay did not differ significantly between intervention groups.

With a very small number of identified trials and inconsistent reported outcomes, no attempt has been made to perform indirect comparisons of outcomes from studies using fixed duration of antibiotic therapy with studies utilising a procalcitonin-guided strategy. However, it may be noted that mean durations of therapy for the procalcitonin groups (9.2 days versus 12.1 days) were not very dissimilar to the intended fixed durations of therapy (seven to eight days versus 10 to 15 days) presented above.

Discussion

Summary of main results

Strategies to guide duration of antibiotic therapy for hospital-acquired pneumonia (HAP) in the critically ill have varied considerably between trials. Broadly, they may be grouped into strategies involving a fixed course of antibiotics, or strategies which advocate discontinuation of therapy on the basis of clinical features (or improvement in clinical features) or a biomarker.

From the three randomised controlled trials (RCTs) which compared fixed durations of antibiotic therapy for ventilator-associated pneumonia (VAP) (seven to eight days versus 10 to 15 days), a fixed shorter course of therapy was associated with significantly reduced antibiotic exposure in terms of 28-day antibiotic-free days (mean difference (MD) 4.02 days; 95% confidence interval (CI) 2.26 to 5.78), without significantly affecting mortality, duration of mechanical ventilation or duration of hospital stay. One study reported that a shorter course of antibiotic therapy was associated with a significant reduction in VAP recurrence due to multi-resistant organisms (Chastre 2003a; odds ratio (OR) 0.44; 95% CI 0.21 to 0.95). However, there was a trend towards greater recurrence of VAP for patients treated with a shorter course of therapy (OR 1.37; 95% CI 0.87 to 21.7) and for patients with VAP due to non-fermenting Gram-negative bacilli (NF-GNB) (but not for patients with methicillin-resistant Staphylococcus aureus (MRSA)), this risk was significant (Chastre 2003a; Medina 2007; OR 2.18; 95% CI 1.14 to 4.16). Despite this, fixed short-course therapy for VAP due to NF-GNB in these two studies was not associated with other negative outcomes, i.e. 28-day mortality, in-hospital mortality, 28-day mechanical ventilation-free days or duration of intensive care unit (ICU) stay. Outcome data are summarised in Summary of findings for the main comparison.

The two identified trials which intended to discontinue antibiotics on the basis of clinical features adopted such different approaches that we made no attempt to perform meta-analysis. For patients with suspected HAP (whether mechanically ventilated or not) but low probability of pneumonia (according to Day 1 and Day 3 clinical pulmonary infection score (CPIS) < 7; Singh 2000), discontinuing antibiotic therapy at Day 3 was associated with significantly shorter duration of antibiotic therapy (mean three days versus 9.8 days; P = 0.0001 reported), significantly reduced composite rate of superinfection and antimicrobial resistance (OR 0.29, 95% CI 0.09 to 0.92) and significantly reduced duration of ICU stay (see Summary of findings 2). Outcome data were not presented for those subgroups of patients who were mechanically ventilated and those who were not. In Micek 2004, patients with VAP allocated to the discontinuation strategy received a significantly shorter course of antibiotic therapy (6.0 days versus 8.0 days; MD 2.0 days; 95% CI -3.91 to -0.81), without a significant rise in rates of in-hospital mortality and recurrence, or in duration of mechanical ventilation, ICU stay or hospital stay; it should be noted that a relatively low proportion of patients in this study had VAP due to NF-GNB (11%). Outcome data were summarised in Summary of findings 3.

Outcome data were available from three trials investigating the use of the biomarker, procalcitonin, to guide antibiotic therapy in patients with VAP. This is summarised in Summary of findings 4. A strategy which incorporated a recommendation regarding duration of therapy on the basis of procalcitonin level was associated with significantly reduced duration of antibiotic therapy (mean difference -3.20 days; 95% CI -4.45 to -1.95) and 28-day antibiotic-free days (MD 2.80 days; 95% CI 1.39 to 4.21). There were no significant differences in other outcomes, though a trend towards greater recurrence was observed in Pontet 2007 (OR 2.06; 95% CI 0.74 to 5.70).

Overall completeness and applicability of evidence

RCTs included in this systematic review enrolled medical and surgical (including cardio-thoracic and neuro-surgical) critically ill adults with HAP from ICUs in Europe, Africa, and North and South America. However, the studies were few in number and the methodology and reported outcomes varied considerably between studies, limiting opportunities for data synthesis. Furthermore, we identified only one study presenting outcome data for patients with HAP who were not receiving mechanical ventilation; separate outcome data are not presented for those subgroups of patients who were and were not receiving mechanical ventilation, and indeed all of the enrolled patients were deemed to have "low probability" of pneumonia according to CPIS (Singh 2000). All other included studies focused entirely on patients with VAP. This lack of evidence is important since there appear to be significant differences in patient characteristics and in bacterial aetiology between ICU cases of nosocomial pneumonia acquired in the presence or absence of assisted mechanical ventilation (Kohlenberg 2010); extrapolating from studies of patients with VAP to non-ventilated patients with HAP may be inappropriate.

For critically ill patients (not necessarily requiring mechanical ventilation) with new radiographic infiltrates and a suspicion but low probability of pneumonia (for example according to CPIS on day of diagnosis and 72 hours later), a short course (three days) of appropriate antibiotic therapy appears to be more suitable than a prolonged (10 to 21-day) course (Singh 2000), though the generalisability of empiric ciprofloxacin monotherapy may be debated. Current American (ATS/IDSA 2005), British (BSAC 2008) and Canadian (Rotstein 2008) guidelines do not make any specific recommendations for this particular scenario. However, such a CPIS-guided strategy is readily applicable in the intensive care environment, without requirement for an additional novel investigation.

On the basis of the 401 patients enrolled in the PNEUMA study, risk factors for adverse outcomes (i.e. recurrence or death) following VAP have been identified via multivariable regression analysis, including: age, female sex, illness severity at VAP onset, severity of lung injury, requirement for prolonged mechanical ventilation, persistent fever, and NF-GNB or MRSA pathogen (Combes 2007). Unfortunately, comparisons for subgroups of patients at risk of adverse outcome were largely unreported in the identified studies, with the exception being data related to bacterial pathogen.

Both a fixed seven to eight-day course (rather than 10 to 15-day course) of antibiotic therapy and the strategies incorporating clinical or biomarker response to treatment reduce overall antibiotic exposure and appear to reduce risk of further infection associated with resistant organisms. However, on the basis of pooled data from two studies enrolling a total of 176 patients with VAP due to NF-GNB, a fixed short course of antibiotic therapy (seven or eight days) was associated with significantly increased risk of recurrence compared with a more prolonged course (12 or 15 days). There are inadequate data to compare recurrence rates between procalcitonin-guided therapy groups and control groups for patients with VAP due to NF-GNB; indeed only one of these studies reported recurrence data at all (Pontet 2007).

Both American (ATS/IDSA 2005) and British (BSAC 2008) guidelines recommend that efforts should be made to shorten antibiotic therapy for HAP (including patients with VAP) to a duration of seven to eight days, where there has been clinical response and, in the case of ATS/IDSA guidelines, where the causative organism is not P. aeruginosa. Our review of studies of fixed durations of therapy is consistent with these recommendations, though with greater recurrence demonstrated in a sample size of patients with VAP due to NF-GNB nearly 40% larger than previously reported (Chastre 2003a), routine use of short-course therapy for VAP due to NF-GNB might now appear less appropriate still.

Strategies to reduce antibiotic duration other than using a fixed course have included clinical response and use of the biomarker procalcitonin. There is theoretical appeal to using an individualised variable as opposed to a fixed-course of therapy; clearly response to treatment of HAP or specifically VAP can vary considerably, as studies included in this review (Bouadma 2010; Micek 2004; Singh 2000; Stolz 2009a) and others previously have shown (Dennesen 2001; Luna 2003). Use of a clinical guideline in a population with a relatively low proportion of NF-GNB VAP was associated with reduction in mean duration of antibiotic therapy, without evidence of adverse effects on mortality or recurrence in Micek 2004. Furthermore, compliance with this guideline was high (discontinuation occurred within 48 hours of recommendation in 88.7% patients), though its implementation seemed to be dependent upon the weekday presence of one of the investigators.

There has been much recent interest in the potential use of procalcitonin to guide antibiotic therapy in the critically ill (Hochreiter 2009; Kopterides 2010; Nobre 2008; Schroeder 2007), though limited availability may currently limit the wider applicability of procalcitonin measurement and the national guidelines referred to above do not include such a strategy at present. Our review has indicated that a procalcitonin-guided strategy is associated with a consistent reduction in duration of antibiotic therapy; we have not found evidence to suggest that mortality is adversely affected and there are limited data with respect to recurrence. Other potential limitations to applicability of these studies should also be mentioned. The PRORATA study examined a procalcitonin-guided strategy for patients including those with VAP, among whom the overwhelming majority were medical (89%) rather than surgical patients (Bouadma 2010). Durations of antibiotic therapy in the ProVAP study were also much higher than those advocated in the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines (mean 12.5 days in procalcitonin group versus 15.7 days in standard therapy group), and possibly may not reflect practice in the wider critical care community (Stolz 2009a). Furthermore, the low rate of algorithm adherence in the PRORATA study could be an indication of the relative difficulty of implementing a variable duration protocol in contrast with a fixed-duration policy (Bouadma 2010).

Given the small number of identified studies and lack of constant reported outcomes, we made no attempt to perform indirect comparisons of outcome data from studies using fixed short-duration antibiotic therapy with studies utilising a procalcitonin-guided strategy. Interestingly, as Bouadma 2010 demonstrate, application of an individualised procalcitonin (PCT)-guided strategy may in a subgroup of patients with VAP actually lead to a more prolonged course of antibiotics than recommendations for the control group would otherwise have advised.

Quality of the evidence

Methodological differences between studies (for example, fixed durations of therapy versus duration determined by clinical features or biomarker, different outcome measures) ensured that the number of studies contributing to a particular summary statistic was very small. Sequence generation and allocation concealment were adequate in five of the eight studies but in none of the studies did blinding appear to have taken place. In three of the eight studies was there an additional potential source of bias, including protocol violation rates (Bouadma 2010), selective reporting (incomplete data regarding protocol violation (Stolz 2009a)) and contamination of control group with early termination of the study (Singh 2000).

Potential biases in the review process

We attempted to minimise bias in a number of ways. Our search strategy utilised the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version. In addition, we performed review searches of review articles and the 'grey literature' to minimise reporting bias. We established inclusion criteria prior to conduct of searches and, where necessary, we contacted trial authors to clarify study eligibility. We collected data using a standardised data collection form; when not available, we contacted trial authors to provide additional relevant data. We systematically assessed internal validity using the Cochrane Collaboration's 'Risk of bias' tool. Where it was felt that study methodology precluded combining outcome data, we divided up studies into subgroups according to methodological approach. There was clearly potential for study heterogeneity, for example, in terms of methodology, diagnostic criteria, illness severity and antibiotic class. We identified relevant subgroups a priori. However, outcome data were typically not presented in sufficient detail to enable adequate subgroup analysis and we used a random-effects model for meta-analysis. One study (Pontet 2007) presented data according to a per-protocol analysis, which was considered to carry a high risk of bias. Given the different methodological approaches adopted in the included studies, we were able to meta-analyse data from a maximum of three (and frequently only two) studies per outcome. We considered that sensitivity analysis would not be appropriate in these circumstances. However, this means that we have not attempted to re-analyse data while excluding studies which, for example, have yet to be published in full, which have not analysed according to intention-to-treat principle, or which have included patients we had wished to exclude.

Agreements and disagreements with other studies or reviews

Two previous systematic reviews specifically focusing on duration of antibiotic therapy for VAP have been published (Dugan 2003; Grammatikos 2008). Both these reviews included observational studies and studies focused on diagnostic strategies (for example, invasive versus noninvasive diagnosis of VAP, Fagon 2000); notably the Dugan review also appears to have been written before publication of the PNEUMA study, the largest RCT to date to investigate duration of therapy for VAP (Chastre 2003a). Conclusions of Grammatikos 2008, namely that short-course antibiotic therapy for VAP not caused by NF-GNB does not appear to adversely affect mortality, recurrence or lengths of stay (Grammatikos 2008), is consistent with findings from our own review. Dugan 2003 concluded that a shorter course therapy may be associated with reduced antimicrobial resistance, which again is consistent with our review. However, studies published subsequent to their review have been less supportive of the benefits of short-course therapy in reducing ICU and hospital lengths of stay.

Our finding that short-course antibiotic therapy for VAP in the absence of NF-GNB may be adequate, without increased risk of recurrence or mortality, is consistent with data from observational studies (though these observational studies have not been reviewed systematically). Dennesen 2001 demonstrated in 27 cases of VAP treated with appropriate initial antimicrobial therapy that clinical resolution occurred within the first six days of treatment and that S. pneumoniae, H. influenzae and S. aureus were eradicated within this period. In contrast, P. aeruginosa was isolated from endotracheal aspirates in all patients 15 days after the initiation of therapy, despite a mean 12.7 days of antibiotic treatment. El Solh 2007 also observed a disparity between clinical response after seven days' appropriate antibiotic therapy for VAP and persistent respiratory colonisation, with P. aeruginosa continuing to be cultured from broncho-alveolar lavage (BAL) despite improvements in CPIS. This persistence may be clinically significant; Zhuo 2008 demonstrated that the bacterial load in mechanically-ventilated patients colonised with P. aeruginosa but without meeting clinical criteria for VAP may predict outcome; high P. aeruginosa load (> 103 cfu/mL BAL or > 106 cfu/mL endo-tracheal aspirate (ETA)) was associated with a significantly greater 28-day mortality (adjusted hazard ratio 37.53; 95% CI 3.79 to 371.96; P = 0.002). Thus, the increased rate of recurrence of VAP due to NF-GNB among patients administered a fixed short-course antibiotic therapy demonstrated in our review may reflect inadequate bacterial eradication for a proportion of patients and may be of clinical significance.

Authors' conclusions

Implications for practice

Potential strategies intended to guide duration of antibiotic therapy for pneumonia include a fixed course of therapy, or a course of treatment which is individualised according to clinical or microbiological features and/or a relevant biomarker. However, our review has indicated that there is a lack of data regarding the appropriate duration of antibiotic therapy for intensive care unit (ICU) patients with hospital-acquired pneumonia (HAP) who are not mechanically ventilated.

Where HAP is suspected (in mechanically or non-mechanically ventilated patients), but there is a low probability of pneumonia according to clinical pulmonary infection score (CPIS), a fixed three-day course of therapy appears to significantly reduce antibiotic administration, risk of emergence of resistant organism or superinfection, and duration of ICU stay.

For patients specifically with ventilator-associated pneumonia (VAP), adopting a fixed seven or eight-day course of antibiotic therapy in the absence of non-fermenting Gram-negative bacilli (NF-GNB) infection is associated with a significant increase in 28-day antibiotic-free days and reduced VAP recurrence due to multi-resistant organisms, without adverse effects on overall recurrence or mortality, compared with a 10 to 15-day course.

However, for patients with VAP due to NF-GNB organisms, a prolonged 12 to 15-day course is associated with a lower rate of VAP recurrence than a short eight-day course, on the basis of pooled data from two studies. This greater risk of recurrence does not appear to translate into an increased mortality, or prolonged requirement for mechanical ventilation or duration of ICU stay, but it appears likely that a fixed short-course antibiotic therapy is not appropriate for all patients with VAP due to NF-GNB. Studies evaluating an individualised strategy (guiding duration of therapy according to clinical, microbiological and/or biomarker features) specifically for VAP due to NF-GNB are lacking.

Considering individualised approaches to therapy, application of an antibiotic discontinuation policy which is based upon clinical response to treatment appears to reduce antibiotic administration without adversely affecting recurrence, hospital mortality or ICU lengths of stay at a centre with a low proportion of cases of NF-GNB VAP.

Use of a strategy incorporating a procalcitonin (PCT)-guided antibiotic discontinuation algorithm is associated with a significantly reduced duration of antibiotic therapy and increased 28-day antibiotic-free days, without adversely affecting 28-day mortality; the limited data available do not suggest an increase in recurrence using this strategy. In particular, data regarding subgroups of patients at increased risk of adverse outcomes, for example, those with NF-GNB VAP, are lacking. Lastly, as the Bouadma 2010 trial demonstrates, application of a PCT-guided algorithm may in some centres be associated with a longer treatment duration than is recommended in guidelines for short-course fixed-duration therapy.

Implications for research

There is inadequate data regarding appropriate duration of antibiotic therapy for HAP in non-mechanically ventilated patients; characteristics differ sufficiently between this group and those with VAP for this to warrant further research. However, even for patients with VAP, there are very few RCTs evaluating strategies intended to limit unnecessary antibiotic treatment.

The relative merits of fixed versus variable-course antibiotic therapy have been under-explored. Perhaps in the absence of infection due to NF-GNB, future studies could include a comparison of a fixed short-course (for example, seven days) of antibiotic therapy with variable-course therapy (for example, guided by CPIS or procalcitonin) for patients with VAP.

The optimal duration of therapy for patients with NF-GNB VAP is particularly unclear. Short-course therapy does not appear to be appropriate for all patients with VAP due to NF-GNB, and clinical response to treatment may be at variance with bacterial persistence. Establishing a reliable guide to continued antibiotic administration beyond seven to eight days for NF-GNB VAP may be of benefit. The relationships between serum procalcitonin levels, bacterial persistence and clinical outcome could be explored in more detail for VAP due to NF-GNB. Indeed, future studies could potentially compare a strategy limiting duration of therapy for NF-GNB according to a marker such as procalcitonin or quantitative respiratory tract culture with a prolonged 14-day course of treatment.

Acknowledgements

We would like to thank Julio Medina, Julio Pontet and Daiana Stolz for making available additional study data, and to thank the following authors for their assistance: Marcel Hochreiter, Stefan Schröder, Vandack Nobre and Jerome Pugin. We are very grateful to the Cochrane Acute Respiratory Infections Group editorial staff for their help with the conduct of the review, in particular to Elizabeth Dooley, and to Sarah Thorning for her assistance with design and conduct of our searches. We also wish to thank the follow for commenting on the draft review: SM Shariful Islam, Despoina Koulenti, Jonathan Li, Guy W. Soo Hoo, Nelcy Rodriguez and Allen Cheng.

Data and analyses

Download statistical data

Comparison 1. Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 28-day mortality2431Odds Ratio (M-H, Random, 95% CI)1.08 [0.66, 1.76]
1.1 NF-GNB1127Odds Ratio (M-H, Random, 95% CI)0.71 [0.32, 1.56]
1.2 MRSA142Odds Ratio (M-H, Random, 95% CI)1.28 [0.32, 5.09]
1.3 Non NF-GNB/MRSA1232Odds Ratio (M-H, Random, 95% CI)1.65 [0.73, 3.73]
1.4 Unspecified organism130Odds Ratio (M-H, Random, 95% CI)0.93 [0.21, 4.11]
2 Recurrence of pneumonia3508Odds Ratio (M-H, Random, 95% CI)1.37 [0.87, 2.17]
2.1 NF-GNB2176Odds Ratio (M-H, Random, 95% CI)2.18 [1.14, 4.16]
2.2 MRSA249Odds Ratio (M-H, Random, 95% CI)1.56 [0.12, 19.61]
2.3 Non NF-GNB/MRSA2253Odds Ratio (M-H, Random, 95% CI)0.98 [0.55, 1.78]
2.4 Unspecified organism130Odds Ratio (M-H, Random, 95% CI)1.17 [0.14, 9.59]
3 28-day antibiotic-free days2431Mean Difference (IV, Random, 95% CI)4.02 [2.26, 5.78]
3.1 NF-GNB1127Mean Difference (IV, Random, 95% CI)4.5 [2.25, 6.75]
3.2 MRSA142Mean Difference (IV, Random, 95% CI)8.0 [4.14, 11.86]
3.3 Non NF-GNB/ MRSA1232Mean Difference (IV, Random, 95% CI)3.70 [2.09, 5.31]
3.4 Unspecified organism130Mean Difference (IV, Random, 95% CI)2.3 [1.03, 3.57]
4 ITU mortality2107Odds Ratio (M-H, Random, 95% CI)0.85 [0.37, 1.91]
5 Non-resolution of pneumonia177Odds Ratio (M-H, Fixed, 95% CI)1.80 [0.65, 5.02]
5.1 NF-GNB149Odds Ratio (M-H, Fixed, 95% CI)1.89 [0.49, 7.40]
5.2 MRSA17Odds Ratio (M-H, Fixed, 95% CI)11.0 [0.28, 433.80]
5.3 Non NF-GNB/MRSA121Odds Ratio (M-H, Fixed, 95% CI)1.0 [0.16, 6.25]
6 In-hospital mortality1401Odds Ratio (M-H, Fixed, 95% CI)1.09 [0.71, 1.67]
6.1 NF-GNB1127Odds Ratio (M-H, Fixed, 95% CI)0.75 [0.36, 1.53]
6.2 MRSA142Odds Ratio (M-H, Fixed, 95% CI)1.47 [0.43, 4.95]
6.3 Non NF-GNB/MRSA1232Odds Ratio (M-H, Fixed, 95% CI)1.32 [0.72, 2.42]
7 Recurrence due to multi-resistant organism1110Odds Ratio (M-H, Fixed, 95% CI)0.44 [0.21, 0.95]
8 Duration of ITU stay2431Mean Difference (IV, Random, 95% CI)-0.01 [-2.30, 2.27]
8.1 NF-GNB1127Mean Difference (IV, Random, 95% CI)0.90 [-5.40, 7.20]
8.2 MRSA142Mean Difference (IV, Random, 95% CI)2.90 [-8.39, 14.19]
8.3 Non NF-GNB/MRSA1232Mean Difference (IV, Random, 95% CI)2.70 [-1.88, 7.28]
8.4 Unspecified organism130Mean Difference (IV, Random, 95% CI)-1.60 [-4.61, 1.41]
9 Duration of hospital stay130Mean Difference (IV, Fixed, 95% CI)-1.0 [-4.11, 2.11]
10 Duration of mechanical ventilation2107Mean Difference (IV, Random, 95% CI)-0.01 [-0.57, 0.55]
11 28-day mechanical ventilation-free days2431Mean Difference (IV, Random, 95% CI)0.47 [-0.97, 1.92]
11.1 NF-GNB1127Mean Difference (IV, Random, 95% CI)1.50 [-1.77, 4.77]
11.2 MRSA142Mean Difference (IV, Random, 95% CI)-1.30 [-6.37, 3.77]
11.3 Non NF-GNB/MRSA1232Mean Difference (IV, Random, 95% CI)-1.20 [-3.54, 1.14]
11.4 Unspecified organism130Mean Difference (IV, Random, 95% CI)1.30 [-0.03, 2.63]
12 Mortality associated with VAP177Mean Difference (IV, Fixed, 95% CI)1.0 [-8.85, 10.85]
Analysis 1.1.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 1 28-day mortality.

Analysis 1.2.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 2 Recurrence of pneumonia.

Analysis 1.3.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 3 28-day antibiotic-free days.

Analysis 1.4.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 4 ITU mortality.

Analysis 1.5.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 5 Non-resolution of pneumonia.

Analysis 1.6.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 6 In-hospital mortality.

Analysis 1.7.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 7 Recurrence due to multi-resistant organism.

Analysis 1.8.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 8 Duration of ITU stay.

Analysis 1.9.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 9 Duration of hospital stay.

Analysis 1.10.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 10 Duration of mechanical ventilation.

Analysis 1.11.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 11 28-day mechanical ventilation-free days.

Analysis 1.12.

Comparison 1 Short (fixed)-course antibiotic therapy versus prolonged-course antibiotic therapy for HAP, Outcome 12 Mortality associated with VAP.

Comparison 2. Discontinuation of antibiotics according to Clinical Pulmonary Infection Score
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 30-day mortality181Odds Ratio (M-H, Fixed, 95% CI)0.33 [0.10, 1.03]
2 Episodes of superinfection or antimicrobial resistance181Odds Ratio (M-H, Fixed, 95% CI)0.29 [0.09, 0.92]
3 Duration of antibiotic therapy181Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Duration of ITU stay181Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Discontinuation of antibiotics according to Clinical Pulmonary Infection Score, Outcome 1 30-day mortality.

Analysis 2.2.

Comparison 2 Discontinuation of antibiotics according to Clinical Pulmonary Infection Score, Outcome 2 Episodes of superinfection or antimicrobial resistance.

Analysis 2.3.

Comparison 2 Discontinuation of antibiotics according to Clinical Pulmonary Infection Score, Outcome 3 Duration of antibiotic therapy.

Analysis 2.4.

Comparison 2 Discontinuation of antibiotics according to Clinical Pulmonary Infection Score, Outcome 4 Duration of ITU stay.

Comparison 3. Discontinuation of antibiotics according clinical guideline
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Recurrence of pneumonia1290Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.48, 1.59]
2 Duration of antibiotic therapy1290Mean Difference (IV, Fixed, 95% CI)-2.0 [-3.21, -0.79]
3 In-hospital mortality1290Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.49, 1.29]
4 Duration of ITU stay1290Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.75, 1.35]
5 Duration of hospital stay1290Mean Difference (IV, Fixed, 95% CI)0.30 [-3.63, 4.23]
6 Duration of mechanical ventilation1290Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.79, 1.19]
Analysis 3.1.

Comparison 3 Discontinuation of antibiotics according clinical guideline, Outcome 1 Recurrence of pneumonia.

Analysis 3.2.

Comparison 3 Discontinuation of antibiotics according clinical guideline, Outcome 2 Duration of antibiotic therapy.

Analysis 3.3.

Comparison 3 Discontinuation of antibiotics according clinical guideline, Outcome 3 In-hospital mortality.

Analysis 3.4.

Comparison 3 Discontinuation of antibiotics according clinical guideline, Outcome 4 Duration of ITU stay.

Analysis 3.5.

Comparison 3 Discontinuation of antibiotics according clinical guideline, Outcome 5 Duration of hospital stay.

Analysis 3.6.

Comparison 3 Discontinuation of antibiotics according clinical guideline, Outcome 6 Duration of mechanical ventilation.

Comparison 4. Discontinuation of antibiotic therapy according to serum procalcitonin level
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 28-day mortality3308Odds Ratio (M-H, Random, 95% CI)0.66 [0.39, 1.14]
2 Recurrence of pneumonia166Odds Ratio (M-H, Fixed, 95% CI)2.06 [0.74, 5.70]
3 28-day antibiotic-free days3308Mean Difference (IV, Random, 95% CI)2.80 [1.39, 4.21]
4 Duration of antibiotic therapy3308Mean Difference (IV, Random, 95% CI)-3.20 [-4.45, -1.95]
5 In-hospital mortality1101Odds Ratio (M-H, Fixed, 95% CI)0.63 [0.25, 1.58]
6 ITU mortality166Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.26, 2.22]
7 Non-resolution of pneumonia166Odds Ratio (M-H, Fixed, 95% CI)1.17 [0.38, 3.62]
8 Recurrence due to resistant organism166Odds Ratio (M-H, Fixed, 95% CI)1.75 [0.49, 6.21]
9 ITU duration of stay2167Mean Difference (IV, Random, 95% CI)-2.68 [-6.01, 0.66]
10 Duration of hospital stay1101Mean Difference (IV, Fixed, 95% CI)-2.40 [-6.40, 1.60]
11 Duration of mechanical ventilation2167Mean Difference (IV, Random, 95% CI)-0.35 [-3.24, 2.54]
Analysis 4.1.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 1 28-day mortality.

Analysis 4.2.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 2 Recurrence of pneumonia.

Analysis 4.3.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 3 28-day antibiotic-free days.

Analysis 4.4.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 4 Duration of antibiotic therapy.

Analysis 4.5.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 5 In-hospital mortality.

Analysis 4.6.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 6 ITU mortality.

Analysis 4.7.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 7 Non-resolution of pneumonia.

Analysis 4.8.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 8 Recurrence due to resistant organism.

Analysis 4.9.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 9 ITU duration of stay.

Analysis 4.10.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 10 Duration of hospital stay.

Analysis 4.11.

Comparison 4 Discontinuation of antibiotic therapy according to serum procalcitonin level, Outcome 11 Duration of mechanical ventilation.

Appendices

Appendix 1. Embase.com search strategy

21. #17 AND #20
20. #18 OR #19
19. random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR factorial*:ab,ti OR volunteer*:ab,ti OR allocat*:ab,ti OR assign*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
18. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
17. #13 AND #16
16. #14 OR #15
15. antibiot*:ab,ti
14. 'antibiotic agent'/exp
13. #9 OR #10 OR #11 OR #12
12. hap:ab,ti OR vap:ab,ti
11. (pneumon* NEAR/5 (hospital OR ventilator OR nosocomial)):ab,ti
10. 'ventilator associated pneumonia'/de
9. #3 AND #8
8. #4 OR #5 OR #6 OR #7
7. respirator*:ab,ti OR ventilat*:ab,ti
6. 'hospital infection'/de
5. 'ventilator'/de
4. 'artificial ventilation'/exp
3. #1 OR #2
2. pneumon*:ab,ti
1. 'pneumonia'/de

Appendix 2. LILACS search strategy

(Mh Pneumonia, Ventilator-Associated OR Tw Neumonia Asociada al Ventilador OR Tw Pneumonia Associada à Ventilação Mecânica) OR ((Mh pneumonia OR Tw pneumon$ OR Tw neumon$) AND (Mh Respiration, Artificial OR Mh Ventilators, Mechanical OR Mh Cross Infection OR Tw ventila$ OR Tw respira$ OR Tw Respiración Artificial OR Tw Respiração Artificial OR Tw Ventiladores Mecánicos OR Tw Ventiladores Mecânicos OR Tw nosocomia$)) [Words] and Mh Anti-Bacterial Agents OR Tw Agentes Antibacterianos OR Tw antibacter$ OR Tw antibiot$ [Words] and ((Pt randomized controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh double-blind method OR Mh single-blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR w aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal))) [Words]

Appendix 3. Web of Science search strategy

Topic=("hospital-acquired pneumonia" or "ventilator-associated pneumonia" or "health-care associated pneumonia" or "nosocomial pneumonia") AND Topic=(antibiotic* or antibacterial*)
Refined by: Topic=(random* or placebo* or rct or "clinical trial" or "clinical trials")
Timespan=1985-2010. Databases=SCI-EXPANDED, CPCI-S

What's new

Last assessed as up-to-date: 9 March 2011.

DateEventDescription
11 January 2012AmendedAbstract error corrected

History

Protocol first published: Issue 1, 2009
Review first published: Issue 10, 2011

Contributions of authors

Ged Dempsey (GD) conceived the idea for the systematic review.
Richard Pugh (RP), Chris Grant (CG), Richard Cooke (RC) and GD contributed to the drafting of the protocol and final review.
RP and CG were responsible for study selection, quality assessment and data extraction.
GD assisted in resolution of any disagreement over study selection and quality assessment.
RC and GD provided content expertise.

Declarations of interest

None.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Cochrane Acute Respiratory Infections Group, Australia.

    Development and conduct of literature search, and editorial support.

Differences between protocol and review

Between publication of the review protocol in January 2009 and writing the review, it had become evident that promising approaches to reducing unnecessary antibiotic administration in HAP other than comparing two fixed durations of therapy were being investigated, including procalcitonin-guided therapy. For this reason we broadened the inclusion criteria from "RCTs comparing fixed durations of antibiotic therapy..." to also include: "or comparing a protocol intended to reduce duration of antibiotic therapy with standard care." Since this would involve studies with variable durations of therapy, it was felt important to include "Duration of antibiotic therapy" as a further outcome measure.

Our original intention was to exclude trials enrolling patients with haematological malignancy, chemically-induced immune-suppression or HIV/AIDS; this was subsequently revised to: "We intended to exclude data from patients with haematological malignancy, chemically-induced immune-suppression or HIV/AIDS where possible."

Lastly, anticipating potential variation in outcome reporting, other modifications to outcome measures included: separation of non-resolution and recurrence outcomes and the addition of ICU mortality and duration of mechanical ventilation.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bouadma 2010

MethodsThe PRORATA study. A multi-centre study based in France. Unblinded, randomised controlled trial comparing strategy utilising serum procalcitonin measurement to guide initiation and cessation of antibiotics for ICU patients with suspected bacterial infection, with antibiotic administration according to an agreed guideline
Participants

630 adult ICU patients (8 medical, surgical or medical-surgical ICUs; 6 hospitals). Mean age was 62; 66% male; SAPS II 47; SOFA score 7.8) with suspected bacterial infection (either at admission or during ICU stay). 89% patients were medical.16% enrolled patients were defined as being "Immunocompromised" (including patients with AIDS, solid organ transplant, haematological malignancy, prior chemotherapy or radiotherapy, and long-term corticosteroid or other immunosuppressant therapy); identifying and excluding data from these patients for the purpose of the systematic review was not possible. There appear not to have been significant differences in baseline characteristics between treatment groups. Of 621 patients entered into the analysis, 214 (34%) had VAP or "HAP": 141 (23%) patients were diagnosed with VAP, and 73 (12%) patients had HAP not requiring mechanical ventilation. For all patients with microbiologically-confirmed infection, initial antibiotic therapy was appropriate in 92% cases. Diagnostic criteria for VAP and HAP were not provided in the full-text article

Exclusions: pregnancy, expected ICU stay < 3 days, bone marrow transplant or chemotherapy-induced neutropenia, infections requiring long-term course antibiotic therapy (e.g. infective endocarditis), poor chance of survival (SAPS II > 65), DNR order

Interventions

Patients randomised to intervention group (311 randomised; 4 withdrew consent; 307 included in analysis; 75 patients with VAP; 29 with HAP not requiring mechanical ventilation) had serum procalcitonin level measured at inclusion, at each infectious episode until day 28, and for every morning that antibiotics were administered. The guidance for withholding or stopping antibiotic therapy was: i. antibiotics to be withheld when procalcitonin was < 0.5 µg/L on day of study entry; ii. antibiotics to be discontinued when procalcitonin level had fallen to < 0.5 µg/L or to less than 20% of the peak procalcitonin concentration

For patients randomised to control group (319 randomised; 4 withdrew; 1 randomised twice; 314 included in analysis; 66 patients with VAP; 44 patients with HAP not requiring mechanical ventilation), physicians were encouraged to administer antibiotics according to agreed recommendations (including duration of therapy)

Outcomes

Most outcome data were presented for all patients, without specific reference to patients with VAP or HAP (non-ventilated)

For all patients, the following outcomes were presented:

  • Mortality (28-day and 60-day)

  • Number of days without antibiotics (28-day)

  • Relapse or superinfection (28-day)

  • Mechanical ventilation-free days (28-day)

  • SOFA scores (Days 1, 7, 14, 21 and 28)

  • Duration of stay in ICU

  • Duration of stay in hospital

  • Days of exposure to each antibiotic per 1000 patient days

  • Number of days of continuous antibiotic treatment (28-day)

  • Duration of antibiotic treatment according to infection site

  • Percentage of emerging multi-drug resistant bacteria isolated from routine microbiological assessment (28-day)

For patients specifically with VAP, the following outcomes were presented:

  • Duration of first episode of antibiotic treatment

  • Number of days without antibiotics (28-day)

  • Mortality (28-day)

NotesProcalcitonin measurements were used to guide whether to initiate antibiotic therapy as well as when to discontinue therapy. A very low proportion of recruited patients were surgical, which may limit generalisability of results. There was a high incidence of protocol non-adherence; the algorithm for antimicrobial therapy administration was not followed (overall) in 162 patients (53%) in the intervention group, nor for 141 patients in the control group (45%). For all patients, a non-significant increase in 60-day mortality was observed in the procalcitonin group (92/307 (30%) versus 82/ 314 (26.1%)] in the control group). Furthermore, the study may have been under-powered to determine non-inferiority of PCT-guided therapy in terms of death, since it was based upon a 35% absolute mortality in the control group and a 10% between-group mortality difference. For all patients, in the procalcitonin group there were non-significantly greater relapse rates (20/ 307 (6.5%) versus 16/ 314 (5.1%) in control group; P = 0.45) and superinfection rates (106/ 307 (34.5%) versus 97/ 314 (30.9%) in the control group; P = 0.29)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Independent, centralised, computer-generated randomisation sequence... was used to randomly assign patients."
Allocation concealment (selection bias)Low risk"Investigators were masked to assignment before... randomisation."
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded study
Incomplete outcome data (attrition bias)
All outcomes
Low risk2 patients lost to follow-up, 1 from intervention and 1 from control group. This is unlikely to have a clinically relevant impact
Selective reporting (reporting bias)Unclear riskUnclear
Other biasHigh riskThe algorithm for antimicrobial therapy administration was not followed (overall) in 162 patients (53%) for the intervention group, nor for 141 patients in the control group (45%)

Chastre 2003a

MethodsThe PNEUMA study, a multi-centre study based in France. Unblinded, randomised controlled trial comparing fixed durations (8-day versus 15-day) of antibiotic therapy for VAP. Randomisation occurred 3 days after bronchoscopy confirming diagnosis of VAP
Participants401 adult patients. 51 French ICUs. 72% male; mean age 61; episodes due to NF-GNB 32.5%, MRSA 11.2%; mean SAPS II score 45; mean SOFA score 7.4 at admission. VAP was diagnosed according to the following criteria: new and persistent radiographic infiltrate, plus 1 of: purulent tracheal secretions, temperature of 38.4 °C or higher, or leukocyte count > 10,000/µL; and positive quantitative culture of 104 cfu/mL from BAL or 103 cfu/mL from PSB. Duration of mechanical ventilation prior to VAP: 13.6 days. No significant differences between groups at baseline, with the exception of significantly higher proportion of men (76.6%) in 8-day regimen versus men in 15-day regimen (67.6%; P = 0.046). All patients received appropriate initial antibiotics. Exclusions included early onset pneumonia (within 5 days of commencing mechanical ventilation) in patients who had received no antimicrobial therapy in the 15 days prior to diagnosis of pneumonia, and immunocompromised state, characterised by: neutropenia, AIDS, long-term corticosteroids or other immunosuppressant therapy
Interventions197 patients received fixed 8-day course of antibiotics (chosen by treating physician); 204 patients received a 15-day course
Outcomes

The following outcome measures were reported:

  • Death from any cause (28-day and 60-day)

  • Microbiologically-confirmed pulmonary infection recurrence (28-day)

  • Antibiotic-free days (28-day)

  • Mechanical ventilation-free days (28-day)

  • Number of organ failure-free days (28-day)

  • Evolution of parameters comprising the SOFA score and ODIN score (Day 1 to 28)

  • Clinical features relevant to pulmonary infection (fever, leukocyte count, PaO2/ FiO2 ratio, radiologic score; Day 1 to 28)

  • Duration of stay ITU

  • Rate of unfavourable outcome (death, recurrence, prescription of new antibiotic therapy)

  • In-hospital mortality

  • Percentage of emerging multiresistant bacteria during ITU in bronchoscopic samples collected to investigate possible recurrence

NotesRepeat bronchoscopy was performed on the basis of fever, purulent secretions, new or progressive pulmonary infiltrates, or deterioration in respiratory or haemodynamic parameters. It was not performed routinely, e.g. on completion of 8-day course of therapy, and consequently data regarding persistent colonisation with NF-GNB is not available
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomisation was performed...and stratified... according to a computer-generated random-number table."
Allocation concealment (selection bias)Low risk"Randomisation performed centrally, using an interactive voice system... randomisation was not communicated to the investigators until day 8... On that day, investigators had to telephone the randomisation centre to receive the treatment assignment by fax."
Blinding (performance bias and detection bias)
All outcomes
High risk"...Patients, medical and nursing staffs, and pharmacists remained blinded until [day 8]." However, importantly, no attempt was made to blind from day 8, i.e. the point from which thereafter allocation might make a significant difference
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollowing randomisation, 0 patients were lost to follow-up. 1 patient excluded from analysis following withdrawal of consent
Selective reporting (reporting bias)Unclear riskStudy protocol not available for examination. However, outcome measures are those expected and appropriately presented within the report
Other biasLow risk

There was a significantly higher proportion of men in the 8-day group (76.6%) compared with the 15-day group (67.6%; P = 0.046). However, there were not significant differences in illness severity scores, prior duration of mechanical ventilation, prior antibiotic administration, micro-organisms responsible for VAP, and antibiotic regimes to treat VAP

Data regarding proportions of patients who contrary to protocol did not receive a full 8-day or 15-day course of antibiotics are not provided. However, absolute antibiotic-treatment days and 28-day antibiotic-free day data indicates significantly less antibiotic exposure as a consequence of allocation to short or prolonged-course therapy

Fekih Hassen 2009

MethodsSingle-centre study based in Tunisia. RCT comparing fixed durations (7-day versus 10-day) of antibiotic therapy for VAP
Participants

Medical ICU. 30 adult patients (63% male; mean age 63 years; NF-GNB 72%; SAPS II 42.4). VAP (onset more than 48 hours after mechanical ventilation in ICU) diagnosed was suspected on the basis of: new and persistent radiographic infiltrate, purulent secretions, fever or deteriorating gas exchange or white cell count and confirmed on quantitative analysis of culture of endotracheal aspirate (> 104 cfu/ml) or protected distal respiratory specimens (>103 cfu/ml). Mean onset of VAP after institution of mechanical ventilation: 10 days. Initial antibiotics were appropriate in 94% of cases. No significant differences in baseline characteristics between the 2 groups

Exclusions include: second episode of pneumonia during single hospitalisation, terminal illness, failure to isolate bacterial growth

30 patients randomised from 39 patients with clinical features of VAP: 9 not enrolled because of terminal illness or failure to isolate bacteria

Interventions

14 patients randomised to receive 7-day course of antibiotics; 16 patients to receive 16-day course. Choice of antibiotic: on microbiology advice, taking into account whether early (up to including 5 days after commencing mechanical ventilation) or late-onset VAP, and whether risk factors for multi-resistant bacteria present, and modified according to culture/sensitivity results

94% patients received appropriate initial antibiotic therapy

Outcomes

The following outcome measures were presented:

  • Mortality (14-day and 28-day)

  • Antibiotic-free days (28-day)

  • Microbiological resolution (timescale not specified)

  • CPIS resolution (days 1, 10, 14)

  • Mechanical ventilation-free days (28-day)

  • Recurrence: relapse or super-infection (timescale not specified)

  • Duration of ITU stay

NotesData regarding protocol violations and patients lost to follow-up not available. Unable to make contact trial with authors to request supplementary information
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUse of random number table
Allocation concealment (selection bias)Unclear riskInadequately reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskInadequately reported
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInadequately reported
Selective reporting (reporting bias)Unclear riskInadequately reported
Other biasLow riskNo evidence of other source of bias

Medina 2007

Methods2 centre study, based in Uruguay, conducted May 2003 to December 2006 (during the period December 2005 to April 2006 recruitment was interrupted while eligible patients were enrolled in the Pontet 2007 study). Randomised controlled study comparing fixed short (8-day) and long (12-day) courses of antibiotic therapy for VAP.
Participants77 patients (medical, surgical and neurosurgical; mean age 59 years, 53% male, 63.6% NF-GNB, 9.1% MRSA; median APACHE II score 21, MODS score 5, SOFA score 6) with VAP. VAP was diagnosed on the basis of: new and persistent radiographic infiltrates, 2 of temperature ≥38.5 ºC or <36 ºC, leukocytes ≥12,000/ mm3 or ≤ 4 x103/ mm3, and BAL culture ≥ 104 cfu/ml, or positive ETA plus CPIS > 6, or micro-organism in ≥ 2 blood cultures with identical sensitivity to tracheal secretions and in absence of other possible infection, or positive culture of pleural fluid. Mean time after commencing mechanical ventilation before onset of VAP: 9.3 days. 68% patients had received a prior course of antibiotics. In 97% cases, initial antibiotic therapy for VAP was appropriate. There were no significant differences in baseline characteristics between treatment groups
Exclusion criteria: failure to meet clinical and microbiological criteria, decision not to institute antibiotic therapy, duration of therapy < 6 days, death before 6th day of treatment, onset of VAP within 48 hours of admission from other centre
Interventions77 patients randomised to 8-day treatment or 12-day course on Day 8 of antibiotic therapy. Antibiotic choice was that of the attending physician; in 75/77 (97%) cases, initial antibiotic therapy was appropriate. The most commonly used antibiotics were: cefoperazone-sulbactam, carbapenem and other third-generation cephalosporins. In 51% cases, antibiotic combinations were used
Outcomes

The following outcomes were studied:

  • ITU mortality

  • VAP-related mortality

  • Clinical resolution of VAP

  • Non-resolution of VAP ("Therapeutic failure")

  • Recurrence of VAP

  • Duration of mechanical ventilation

Notes0 patients were lost to follow-up. No patient received a shorter duration of antibiotic therapy than allocated; data incomplete for patients who had antibiotics continued beyond the allocated duration
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomisation using random number table
Allocation concealment (selection bias)Low riskSealed, numbered envelopes opened sequentially
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded study
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo patients lost to follow-up
Selective reporting (reporting bias)Unclear riskUnclear. Data incomplete for patients who had antibiotics continued beyond the allocated duration
Other biasLow riskStudy appears to be free of other sources of bias

Micek 2004

MethodsSingle-centre, medical ICU from USA. Randomised controlled study comparing strategy involving discontinuation policy to decrease antibiotic administration for VAP with standard-therapy
Participants

302 patients receiving antibiotic treatment for VAP were randomised. VAP was diagnosed on the basis of: new persistent radiographic infiltrates together with one of: positive pleural culture (same organism as in sputum/tracheal aspirate), radiographic cavitation, histopathologic evidence of pneumonia, or 2 of: fever, leukocytosis and purulent tracheal aspirate or sputum. Mean age 60 years; 50% male; 29% COPD; APACHE II score 23; mean CPIS 7.1; Pseudomonas or Acinetobacter infection 11%; MRSA 20%. 25% patients had received prior antibiotics. Proportion of patients receiving appropriate initial antibiotic therapy was 94% overall. 18.6% patients were defined as "Immunosuppressed". No significant differences in baseline characteristics between groups

Exclusions: transfers to host institution because of lack of capacity at external institutions

Interventions154 patients randomised to discontinuation group; one of investigators recommended discontinuation of antibiotics to treating physician on weekdays if: non-infectious cause for radiographic infiltrates identified, signs and symptoms of active infection had resolved (in terms of temperature, white cell count, radiographic appearance, sputum characteristics and PaO2/ FiO2 ratio). 148 patients were randomised to the control group. Recommendations regarding choice of antibiotic therapy were made to both groups
Outcomes

Reported outcome measures:

  • Duration of antibiotic therapy for VAP

  • ITU mortality

  • Hospital mortality

  • Duration of ITU stay

  • Duration of hospital stay

  • Duration of mechanical ventilation

  • VAP recurrence during same ITU stay

NotesOutcome data was missing for 4 patients in the intervention group, and for 8 patients in the control group. Among intervention group, recommendations to discontinue antibiotics were given to the physicians of 142 patients (94.7%); among 88.7% of these patients antibiotics were discontinued within 48 hours of the recommendation. Trial author contacted, but no further information available
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details provided
Allocation concealment (selection bias)Unclear riskNo details provided
Blinding (performance bias and detection bias)
All outcomes
High riskIntervention involved investigators contacting the physician team
Incomplete outcome data (attrition bias)
All outcomes
High riskOutcome data missing in 12/302 (4%) cases; no information given regarding missing outcome data
Selective reporting (reporting bias)Unclear riskUnclear
Other biasLow riskThere do not appear to be other major potential sources of bias

Pontet 2007

Methods4-centre Uruguayan study, conducted December 2005 to April 2006; 2 of these centres also recruited to the study Medina 2007, but outside this time period. Unblinded, randomised controlled study comparing PCT-guided strategy for antibiotic cessation versus standard therapy for VAP
Participants81 adult patients (medical, surgical, cardiothoracic and neurosurgical; mean age 54 years, 63% male; NF-GNB 23.4%; MRSA 6.1%; Day 1 MODS 6.2; Day 1 SOFA score 4.8) with suspected VAP. VAP was diagnosed on the basis of: new and persistent radiographic infiltrates, 2 of temperature ≥ 38.5 ºC or < 36 ºC, leukocytes ≥12,000/ mm3 or ≤ 4 x103/ mm3, and BAL culture ≥ 104 cfu/ml, or positive ETA plus CPIS > 6, or micro-organism in ≥ 2 blood cultures with identical sensitivity to tracheal secretions and in absence of other possible infection, or positive culture of pleural fluid. Patients were excluded on the basis of: AIDS, leukaemia or immunosuppression. A further 14 patients were excluded after randomisation; from control group, 5 patients were excluded because of short duration of treatment (3 patients) or negative BAL (3 patients); from the PCT group, 9 patients were excluded post-randomisation because Day 1 or 2 PCT was < 0.5 ng/mL. There were no significant baseline differences between groups in terms of demographics, underlying disease or prior antibiotic administration
InterventionsIntervention: for the group receiving PCT-guided therapy; if at day 7 PCT was < 0.5 ng/ml, antibiotic discontinuation was encouraged. Duration of therapy in control group was according to pre-existing guidelines in place at each ICU. Choice of antibiotic therapy was that of the treating physician. Most commonly used antibiotics were: cephalosporins, ampicillin-sulbactam and amikacin; antibiotic combinations were used in 54.5% cases
Outcomes

Data are presented as a per-protocol analysis. The following outcome measures were reported:

  • ITU mortality

  • VAP-related ITU mortality

  • Duration of mechanical ventilation

  • Duration of ITU stay

  • Non-resolution (therapeutic failure)

  • Relapse (Day 29)

  • Super-infection (Day 29)

  • Clinical resolution

  • CPIS (Day 1, 7)

  • MODS (Day 1, 7)

  • SOFA score (Day 1, 7)

NotesAll patients in the procalcitonin group completed at least 7 days of antibiotic therapy. At Day 7, antibiotics were discontinued for all patients with procalcitonin < 0.5 ng/ml
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomisation using random number table
Allocation concealment (selection bias)Low riskSealed, numbered envelopes opened in sequence
Blinding (performance bias and detection bias)
All outcomes
High riskTreating team were made aware of assignment on Day 7, when PCT measured and communicated to PCT group
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo patients lost to follow-up
Selective reporting (reporting bias)Unclear riskUnclear
Other biasHigh riskPotential source of bias as this is a per-protocol analysis; exclusion of 9 patients with low PCT measurements in the PCT group may exclude a higher proportion of relatively well patients compared with the control group

Singh 2000

MethodsSingle-centre study from the USA. Randomised controlled trial comparing strategy of 3 days' ciprofloxacin monotherapy versus standard therapy (duration and antibiotic choice at the discretion of physician) for patients with pulmonary infiltrates but low-probability pneumonia
Participants

Study entry criteria: new-onset pulmonary infiltrate associated with possible nosocomial pneumonia. Modified Clinical Pulmonary Infection Score (CPIS) < 7 on Day 1 (suggesting low probability pneumonia)

81 adult medical and surgical ICU patients; 47 (58%) receiving mechanical ventilation; mean age 66.7 years; no data on sex. APACHE III score 41.8; mean CPIS 4.9. Prior mean duration of ICU stay 8.8 days and duration of mechanical ventilation 7.6 days. Chronic obstructive airways disease present in 27% cases. 5% patients were transplant recipients. With the exception of abnormal respiration (92% experimental group versus 71% standard-therapy group, P = 0.016), there were no significant differences in baseline characteristics between the 2 groups

Exclusions: HIV, chemotherapy-induced neutropenia, concurrent antibiotic administration (other than surgical prophylaxis), flouroquinolone allergy

Interventions

Randomised at Day 1 of episode of possible pneumonia. Intervention group (N = 39): 3 days' ciprofloxacin monotherapy. At Day 3 if CPIS < 7, antibiotics would be discontinued; if CPIS > 6, therapy would be continued, with choice of agent and duration of therapy at the discretion of treating physician, and incorporating microbiology results

Standard therapy (N = 42): choice and duration of antibiotic therapy at choice of treating physician

Outcomes

The following outcomes were reported:

  • Mortality (Day 3, 14, 30)

  • Duration of ITU stay

  • Emergence of antimicrobial resistance or superinfection (Day 28)

  • Duration of antibiotic therapy

  • Antimicrobial therapy cost

Notes

Pathogens associated with possible HAP were incompletely presented

For patients allocated to the short-course therapy, 0 patients with CPIS < 7 at Day 3 had antibiotics continued beyond 72 hours

A significant decrease in duration of therapy in "Standard therapy" group was observed with time (P = 0.0001), thought to be a result of unblinded nature of study. The study was terminated by institutional review board as it was deemed "unethical to continue study."

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation process not described
Allocation concealment (selection bias)Unclear riskRandomisation/concealment not described
Blinding (performance bias and detection bias)
All outcomes
High riskThis was an unblinded study
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)High riskThe components of the composite measure of "emergence of antimicrobial resistance or superinfection" are not reported
Other biasHigh riskStopped early by institutional review board. Results for patients managed in "experimental" group appear to have influenced management of patients subsequently allocated to "standard therapy group"

Stolz 2009a

  1. a

    APACHE II score: Acute Physiology and Chronic Health Evaluation II score
    BAL: broncho-alveolar lavage
    cfu/ml: colony-forming units per millilitre
    COPD: chronic obstructive airways disease
    CPIS: clinical pulmonary infection score
    DNR order: do not resuscitate order
    ETA: endo-tracheal aspirate
    FiO2: fraction of inspired oxygen (in a gas mixture)
    HAP: hospital-acquired pneumonia
    ICU: intensive care unit
    ITU: intensive therapy unit
    MODS: multiple organ dysfunction score
    MRSA: methicillin-resistant Staphylococcus aureus
    NF-GNB: non-fermenting Gram-negative bacilli
    ODIN: organ dysfunction and/or infection score
    PaO2: partial pressure of oxygen
    PCT: procalcitonin
    PSB: protected specimen brush
    SAPS II: Simplified Acute Physiology Score II
    SOFA score: Sequential Organ Failure Assessment score
    VAP: ventilator-associated pneumonia

MethodsThe ProVAP study, an international, multi-centre study involving 7 ICUs in USA and Switzerland. Unblinded, randomised controlled trial comparing strategy utilising serum procalcitonin measurement to guide discontinuation of antibiotics for ICU patients with VAP, with antibiotic administration according to an agreed guideline
Participants101 patients with VAP; 36% NF-GNB; 10% MRSA; mean age 56; 75% male; 27% surgical patients; 19% with chronic obstructive airways disease. Mean SAPS II score 43; ODIN score 2.1; SOFA score 7.8. Mean duration of mechanical ventilation before onset of VAP 6 days. 75% received antibiotics during the 14 days before VAP. 89% patients had CPIS ≥ 6.ODIN score was slightly higher in the control group than the procalcitonin group (2.3 versus 1.9; P = 0.042); otherwise, there were no significant differences in baseline characteristics. VAP diagnosed according to clinical criteria: new or persistent infiltrates on chest radiography with at least 2 of purulent tracheal secretions, temperature > 38 ºC, leukocyte count > 11,000/ µL or < 3000/ µL; microbiological confirmation was not an essential criterion, and indeed was absent in 27% patients. Exclusions: treatment with immunosuppressants or long-term corticosteroid treatment; or underlying immunosuppressant disorder; co-existing extrapulmonary infection
Interventions

101 patients were randomised on day of diagnosis of VAP (Day 0). Serum procalcitonin levels were measured from Day 0 to Day 10 for all patients (including patients in the control group). For the 51 patients in the intervention group, discontinuation of antibiotic therapy was encouraged according to an algorithm 72 hours (Day 2) after randomisation if PCT was < 0.5 µg/L or had decreased to 20% or less of level on Day 0

For the 50 patients randomised to the control group, procalcitonin levels were withheld, and duration of therapy was determined by treating physician

In both intervention and control groups, choice of antibiotic therapy was that of the attending physician

Outcomes

The following outcome measures were reported:

  • Mortality (Day 28)

  • In-hospital mortality

  • Duration of antibiotic therapy

  • Antibiotic-free days (Day 28)

  • Mechanical ventilation-free days (Day 28)

  • Duration of hospital stay

  • Number of ITU-free days alive (Day 28)

  • Clinical features associated with respiratory infection

  • PaO2/ FiO2

  • SOFA score

  • ODIN score

  • CPIS

NotesIt is unclear how many patients were treated with antibiotics beyond the point at which discontinuation was advocated by the protocol
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Arbitrary allocation to... treatment assignments based on sealed, opaque envelopes."
Allocation concealment (selection bias)Low risk"Treating physicians were not aware of envelope contents before randomisation."
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo patients lost to follow-up
Selective reporting (reporting bias)High riskComplete data on numbers of patients for whom physicians violate (PCT) protocol not presented
Other biasLow riskThere appear not to be other major potential sources of bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    BAL: broncho-alveolar lavage
    CPIS: clinical pulmonary infection score
    HAP: hospital-acquired pneumonia
    ICU: intensive care unit
    ITU: intensive therapy unit
    PCT: procalcitonin
    RCT: randomised controlled trial
    VAP: ventilator-associated pneumonia

Cai 2001A randomised controlled study investigating diagnostic strategies (quantitative versus qualitative culture of respiratory tract specimens) on outcome from VAP
CCCTG 2006This 2-by-2 factorial randomised controlled study aiming to compare: i. invasive and non-invasive diagnostic strategies for diagnosis of VAP, and ii. initial empiric treatment with meropenem or meropenem plus ciprofloxacin for suspected VAP. There was no significant difference in number of antibiotic-free days between groups of patients allocated to invasive or non-invasive strategies
Chastre 2003bData subsequently published in full (Chastre 2003a)
Fagon 2000This was a randomised study designed to compare strategies for diagnosis and selection of initial antimicrobial therapy of VAP, not duration of therapy. For groups of patients randomised to both invasive and non-invasive diagnostic strategies, recommended duration of therapy in the presence of positive respiratory culture (i.e. confirmed pneumonia) was 14 days
Hochreiter 2009This was a randomised controlled study comparing a strategy using serial procalcitonin (PCT) measurement to guide discontinuation of antibiotic therapy for treatment of sepsis in 110 surgical intensive care patients with standard therapy. Of these patients, 43 had "pneumonia"; it is unclear what proportion had nosocomial or community-acquired pneumonia, and what proportion of patients was receiving mechanical ventilation at time of diagnosis. Duration of antibiotic therapy was significantly shorter in the intervention (PCT-guided) group (5.9 +/- 1.7 days versus 7.9 +/- 0.5 days), but outcome data relevant to this systematic review are restricted to duration of ITU stay and hospital mortality
Ibrahim 2001Non-randomised before-and-after study investigating a clinical guideline regarding initial treatment and subsequent discontinuation of antibiotic therapy
Kim 2009This was an RCT investigating effectiveness of an antibiotic de-escalation protocol for patients with low probability of HAP (according to CPIS and culture results), published in abstract form only. It has not been possible to contact study authors for further details. It is unclear whether it was a single or multi-centre study. 109 patients (unclear whether exclusively adults or not) with HAP (diagnostic criteria not described) were randomised to the de-escalation protocol (N = 54) or standard therapy (N = 55). The protocol is not described nor relevant outcome data presented adequately for inclusion in this review. In addition, the significantly higher rate of appropriate initial antibiotic therapy in the de-escalation group represents a potential risk of bias
Kollef 2005Prospective observational study investigating application of previously described clinical guideline (Ibrahim 2001) for patients with suspected VAP, but negative quantitative BAL results
Maldonado-Ortiz 2004This multi-centre randomised controlled study from Mexico enrolled 65 patients in a study intended to evaluate a strategy of early discontinuation of empirical antibiotic therapy: it has been published in abstract form only. 31 patients were allocated to early (< 8 days) discontinuation of empirical therapy versus 34 patients to late discontinuation (> 9 days). Patient characteristics and diagnostic criteria were not described. Outcome data presented in the abstract was inadequate for the study's inclusion in this review, and contact with a trial author did not yield any further information. Furthermore, a highly significant risk of bias was identified: antibiotic discontinuation at Day 8 was higher (70.6%) among patients allocated to late discontinuation than among patients allocated to early discontinuation (67.7%)
Nobre 2008This was a randomised controlled study comparing a strategy using serial measurements of procalcitonin (PCT) to guide cessation of antibiotic therapy with standard therapy in critically ill patients with sepsis or septic shock. 79 patients were randomised, of whom a total of 47 patients had sepsis of pulmonary origin. A high proportion of patients (68%) had community-acquired sepsis. A significant proportion of patients in the PCT group (19%) had the protocol overridden to receive a longer course of antibiotics than advised by the algorithm. On intention-to-treat analysis, the difference in antibiotic days between control and intervention groups for all patients was not significant. A decision was made to exclude this study on the basis of small numbers of the subgroup of patients with suspected HAP or VAP and the lack of significant difference between groups in terms of duration of therapy
Peery 2001This was a randomised study comparing diagnostic strategies for suspected VAP. It was not designed to investigate duration of therapy; there were no protocols to guide duration of antibiotic therapy
Rello 2004This was an observational rather than a randomised controlled study. It investigated outcomes following introduction of a "De-escalation" strategy which incorporated the initial administration of broad spectrum antibiotics and subsequent simplification of antibiotic treatment with culture results: 1. changing to monotherapy in absence of Pseudomonas sp; 2. shortening therapy to < 5 days if culture negative and > 48 hours of defervescence; 3. changing from broad to narrow spectrum agent on basis of culture results
Sanchez-Nieto 1998A randomised clinical trial comparing the effects of an invasive quantitative diagnostic strategy versus a non-invasive strategy on management of and outcome from suspected VAP
Schroeder 2007This was a RCT comparing a procalcitonin-guided antibiotic discontinuation strategy with standard treatment for surgical intensive care patients with severe sepsis. The reasons for exclusion of this study are: 1. its very small size (of the 27 patients enrolled in this study, only 8 were diagnosed with pneumonia); 2. it is unclear what proportion of patients had nosocomial versus community-acquired infection; 3. of the patients with "pneumonia" it is unclear what proportion were receiving mechanical ventilation at time of diagnosis; 4. limited outcome data relevant to this systematic review are published (in-hospital mortality and duration of ICU stay)
Singh 1998Data subsequently published in full (Singh 2000)
Sole 2000A RCT to evaluate invasive versus non-invasive diagnostic methods on outcome from VAP
Stolz 2009bData subsequently published in full (Stolz 2009a)
Svoboda 2007RCT evaluating PCT-guided strategies in the management of septic illness after multiple trauma or major surgery. The study makes no reference to patients with HAP
Wolff 2003Data subsequently published in full (Chastre 2003a)

Characteristics of ongoing studies [ordered by study ID]

NCT00934011

Trial name or titleComparative study of C-reactive protein versus procalcitonin to guide antibiotic therapy in patients with severe sepsis and septic shock admitted to the Intensive Care Unit
MethodsRandomised controlled trial
ParticipantsAdult ICU patients with severe sepsis or septic shock
InterventionsCRP-guided antibiotic therapy versus procalcitonin-guided antibiotic therapy
OutcomesPrimary: duration of antibiotic therapy for first episode infection, total antibiotic days, 28-day antibiotic-free days
Starting dateSeptember 2009
Contact informationhttp://clinicaltrials.gov/ct2/show/NCT00934011
NotesNCT00934011

NCT00987818

Trial name or titleReduction of antibiotic use in the ICU: procalcitonin guided versus conventional antibiotic therapy in patients with sepsis in the ICU
MethodsRandomised controlled study
ParticipantsAdult ICU patients receiving antibiotic therapy for sepsis of suspected or proven focus of infection
InterventionsProcalcitonin-guided antibiotic therapy versus standard antibiotic therapy
OutcomesPrimary outcome: duration of antibiotic therapy; secondary outcome: 28-day mortality
Starting dateOctober 2009
Contact informationhttp://clinicaltrials.gov/ct2/show/NCT00987818
NotesNCT00987818

PASS

Trial name or titleThe procalcitonin and survival study (PASS)
MethodsA randomised multi-centre investigator-initiated trial to investigate whether procalcitonin-guided diagnostic and therapeutic strategies can improve survival in intensive care unit patients
Participants1000 critically ill patients
Interventions"Standard of care" versus "standard of care and procalcitonin-guided diagnostics and treatment of infection"
OutcomesPrimary outcome: 28-day mortality
Starting dateIn progress
Contact informationhttp://clinicaltrials.gov/ct2/show/NCT00271752
NotesNCT00271752

Pro-SEPS

Trial name or titleRandomised multicenter prospective study of procalcitonin-guided treatment on antibiotic use and outcome in severe sepsis ICU patients without obvious infection
MethodsRandomised controlled trial
ParticipantsAdult patients hospitalised in resuscitation ward, severe sepsis symptomatology, 2 or more SIRS criteria, at least one organ deficiency, no infectious aetiology
InterventionsDuration of antibiotic therapy guided by procalcitonin level versus standard care
OutcomesPrimary outcome: antibiotic treatment at day 5
Starting dateDecember 2007
Contact informationhttp://clinicaltrials.gov/ct2/show/NCT01025180
NotesNCT01025180

SAPS

Trial name or titleSafety and efficacy of procalcitonin guided antibiotic therapy in adult intensive care units (ICU's) (SAPS)
MethodsRandomised controlled trial
ParticipantsAdult ICU patients with suspected or proven infection
InterventionsProcalcitonin-guided antibiotic therapy versus standard therapy
OutcomesPrimary: 28-day mortality; consumption of antibiotics expressed as the defined daily dosage and duration of antibiotic therapy expressed in days of therapy
Starting dateNovember 2009
Contact informationhttp://clinicaltrials.gov/ct2/show/NCT01139489
NotesNCT01139489

SISPCT

  1. a

    CRP: C-reactive protein
    ICU: intensive care unit
    PCT: procalcitonin
    SIRS: Systemic Inflammatory Response Syndrome

Trial name or titlePlacebo-controlled trial of sodium selenite and procalcitonin guided antimicrobial therapy in severe sepsis (SISPCT)
MethodsProspective, randomised multi-centre 2 x 2 trial
ParticipantsAdult patients with severe sepsis or septic shock, with onset of < 24 hours
Interventions

2 x 2 trial:

1. Intravenous sodium-selenite versus placebo

2. Procalcitonin-guided antibiotic therapy versus alternative (non-PCT guided) antibiotic protocol

OutcomesPrimary outcome: 28-day mortality
Starting dateNovember 2009
Contact informationwww.clinicaltrials.gov/ct2/show/NCT00832039
NotesNCT00832039

Ancillary