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Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections

  1. Jennifer R Shiu1,
  2. Erica Wang2,
  3. Aaron M Tejani3,*,
  4. Michael Wasdell4

Editorial Group: Cochrane Injuries Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 13 SEP 2012

DOI: 10.1002/14651858.CD008481.pub2


How to Cite

Shiu JR, Wang E, Tejani AM, Wasdell M. Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD008481. DOI: 10.1002/14651858.CD008481.pub2.

Author Information

  1. 1

    Alberta Health Services, Edmonton, Canada

  2. 2

    Interior Health Authority, Kelowna General Hospital, Kelowna, Canada

  3. 3

    University of British Columbia, Therapeutics Initiative, Vancouver, BC, Canada

  4. 4

    Bridgepoint Collaboratory for Research and Innovation Bridgepoint Health, Toronto, Canada

*Aaron M Tejani, Therapeutics Initiative, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Aaron.Tejani@fraserhealth.ca.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 28 MAR 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

 
Summary of findings for the main comparison. Continuous versus Intermittent Antibiotic Infusions for Treatment of Severe Bacterial Infections

Continuous versus Intermittent Antibiotic Infusions for Treatment of Severe Bacterial Infections

Patients: Adults with Severe Bacterial Infections
Setting: Hospital
Intervention: Continuous Antibiotic Infusions
Comparison: Intermittent Antibiotic Infusions

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)

Assumed riskCorresponding risk

Intermittent antibiotic InfusionsContinuous antibiotic Infusions

All-cause mortality131 per 1000116 per 1000
(88 to 157)
RR 0.89
(0.67 to 1.20)
1241
(19 studies)
⊕⊕⊕⊝
moderate

Infection recurrence19 per 100024 per 1000
(7 to 81)
RR 1.22
(0.35 to 4.19)
398
(8 studies)
⊕⊕⊝⊝
low

Clinical cure584 per 1000608 per 1000
(555 to 660)
RR 1.04
(0.95 to 1.13)
975
(15 studies)
⊕⊕⊝⊝
low

Super-infection49 per 100053 per 1000
(29 to 95)
RR 1.08
(0.60 to 1.94)
813
(12 studies)
⊕⊕⊝⊝
low

Serious adverse events48 per 100065 per 1000
(38 to 110)
RR 1.36
(0.80 to 2.30)
871
(10 studies)
⊕⊕⊝⊝
low

Withdrawal due to adverse events7 per 100014 per 1000
(4 to 54)
RR 2.03
(0.52 to 7.95)
871
(10 studies)
⊕⊕⊝⊝
low

Adverse events441 per 1000450 per 1000
(415 to 494)
RR 1.02
(0.94 to 1.12)
575
(5 studies)
⊕⊝⊝⊝
very low

*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; RR: Risk 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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Description of the condition

Intravenous broad–spectrum antibiotics are indicated for the treatment of severe community–acquired or healthcare–associated infection. However, the emergence of multiple–drug resistant infections caused by organisms such as Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecium, Enterococcus faecalis, and Enterobacteriaceae is growing worldwide (Rosenthal 2012; Ghafourian 2011; Meyer 2011; Neidell 2012). Such antimicrobial–resistant infections have been associated with poor outcomes, such as increases in length of hospital stay, healthcare costs, and mortality (Sunenshine 2007; Neidell 2012). Despite this growing problem, few novel antibiotics have been developed in recent years; therefore, alternative dosing strategies have been investigated to improve clinical efficacy while ensuring tolerability. To optimise the pharmacokinetic and pharmacodynamic properties of antibiotics, dosing strategies such as continuous or extended intravenous antibiotic infusions have been compared with traditional intermittent intravenous antibiotic dosing.

 

Description of the intervention

Antibiotics are divided into categories on the basis of the pharmacokinetic and pharmacodynamic parameters associated with antibacterial efficacy. Although these bacterial kill characteristics have been determined most often from in vitro studies, this information remains important in optimising antibiotic clinical efficacy. For example, aminoglycosides, fluoroquinolones, and metronidazole are classified as concentration–dependent antibiotics, for which efficacy is determined by peak plasma drug concentration over minimum inhibitory concentration (Cmax/MIC) (Roberts 2006; Craig 1998; Moore 1987). Conversely, beta–lactams, carbapenems, clindamycin, linezolid, and clarithromycin are time–dependent or concentration–independent antibiotics for which the time the drug serum concentration remains above the minimum inhibitory concentration (T > MIC) is the best predictor of efficacy (Roberts 2006; McKinnon 2008; Craig 1998; van Zanten 2009). Although it is commonly accepted that antibiotics are divided into two main classifications, some antimicrobials exhibit more complex bacterial kill characteristics. Fluoroquinolones, azithromycin, glycopeptides, and tetracyclines are concentration–dependent antibiotics with time dependence, for which efficacy is best predicted by the area under the serum concentration–time curve during 24 hours over the minimum inhibitory concentration (AUC24/MIC) (Roberts 2006; Craig 1998).

Studies evaluating the efficacy of continuous or extended antibiotic infusions generally involve time–dependent antibiotics (Buck 2005; Roberts 2008; Roberts 2009a). Several time–dependent antibiotics are known to have a short half-life; therefore, concern has arisen that the drug serum concentration will drop below the minimum inhibitory concentration (MIC) before the next scheduled intermittent infusion (Lipman 2001). To optimise antibiotic kill characteristics, extended (> 3-hour intermittent infusions) or continuous (24-hour fixed–rate infusions) administration is thought to prolong T > MIC and to improve clinical efficacy (Tamma 2011; Lodise 2006). Although T > MIC targets vary between antibiotic classes (20% to 40% carbapenems, 50^ to 60% penicillins, 60% to 70% cephalosporins, 50% to 60% monobactams) (Craig 1998; Drusano 2004), improved clinical cure rates and bacteriologic eradication were observed in critically ill participants when T > MIC was maintained at 100% (McKinnon 2008). It has also been suggested in comparison with intermittent infusions of vancomycin and beta–lactams, continuous infusions may reduce time to achieve therapeutic drug serum concentrations (Roberts 2008). In contrast, for concentration–dependent antibiotics that exhibit post–antibiotic effects, it is not known whether extended or continuous infusions would be of additional benefit because large, infrequent infusions would maximize Cmax/MIC, resulting in peak efficacy. However, for select concentration-dependent antibiotics in which efficacy is also characterized by AUC24/MIC (e.g. fluoroquinolones), extended or continuous infusions may result in favourable clinical outcomes.

 

Why it is important to do this review

Previous reviews have suggested that continuous or extended infusion of time–dependent antibiotics results in more favourable pharmacodynamic outcomes. A systematic review of 17 randomised clinical trials performed by Kasiakou et al compared the pharmacokinetic and pharmacodynamic parameters of intermittent and continuous infusions of time–dependent antibiotics in hospitalised adults and in healthy volunteers (Kasiakou 2005a). It was found that the mean Cmax of the intermittent infusion group was 5.5 times greater than the steady–state serum concentration (Css) of the continuous infusion group (range 1.9 to 11.2). Additionally, the Css of the continuous infusion group was 5.8 times higher than the trough serum concentration (Cmin) of the intermittent infusion group (range 1.2 to 15.6). Investigators also observed that the T > MIC was longer in the continuous infusion group in three of the six studies included.

Although it is of theoretical advantage to administer time–dependent antibiotics by continuous or extended infusion, several systematic reviews investigating this issue have not confirmed these proposed clinical benefits. A meta–analysis of nine randomised controlled trials (RCTs) performed by Kasiakou et al to compare continuous versus intermittent administration of beta–lactams, aminoglycosides, and vancomycin showed no difference in clinical failure (odds ratio (OR) 0.73, 95% CI 0.53 to 1.01) or mortality (OR 0.89, 95% CI 0.48 to 1.64) (Kasiakou 2005b). However, a subgroup analysis of those RCTs that used the same daily antibiotic dose in both intervention groups showed reduced clinical failure in the continuous infusion arm (OR 0.70, 95% CI 0.50 to 0.98) (Kasiakou 2005b). A systematic review of 14 RCTs conducted by Tamma et al in hospitalised patients showed that prolonged beta–lactam infusions rather than intermittent infusions did not affect mortality (n = 982, RR 0.92, 95% CI 0.61 to 1.37) or clinical cure (n = 1380, RR 1.00, 95% CI 0.94 to 1.06) (Tamma 2011). Another systematic review of 14 RCTs including 846 hospitalised patients from 9 countries also showed that continuous or extended infusion beta–lactam infusions versus bolus dosing led to no improvement in clinical cure (n = 745, OR 1.04, 95% CI 0.74 to 1.46, P = 0.83) or mortality (n = 541, OR 1.00, 95% CI 0.48 to 2.06, P = 1.00) (Roberts 2009a). These systematic reviews were generally well conducted; however, they were limited by small sample sizes, clinical heterogeneity in participants and infections studied, and study designs that were not blind.

Investigators reported some improvement in pharmacodynamic outcomes with weak evidence supporting clinical benefits of continuous or extended infusion antibiotics. Therefore, the purpose of this review will be to determine whether any advantage is derived from using this alternative dosing strategy rather than conventional dosing strategies in patients with severe infection. In addition to evaluating clinical and safety outcomes of continuous versus intermittent dosing of time–dependent antibiotics, this review will be extended to include concentration–dependent antibiotics.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

To compare the clinical efficacy and safety of continuous intravenous administration of concentration-dependent and time-dependent antibiotics with traditional intermittent intravenous administration in patients with severe acute bacterial infection. Continuous intravenous infusions included extended and continuous infusions. Severe acute infection was defined as any infection requiring intravenous antibiotics.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Open-label or blinded parallel-group RCTs comparing continuous versus intermittent intravenous infusions of the same antibiotic were included. Cross-over studies were excluded.

 

Types of participants

Study participants were male or non-pregnant female adults (18 years or older) with a bacterial infection requiring intravenous antibiotic therapy. Investigators considered different infections in this review, and no restrictions were placed on the anatomical site of infection, participant baseline risk, or co-morbid conditions.

 

Types of interventions

Included studies compared continuous versus intermittent infusions of the same intravenous antibiotic. Both time-dependent and concentration-dependent antibiotics were included.

 

Types of outcome measures

 

Primary outcomes

  • All-cause mortality.
  • Infection recurrence within 14 days of resolution of primary infection.

 

Secondary outcomes

  • Clinical cure (any pre-defined criteria specific to the infection being studied that address signs and symptoms of infection, such as fever, leukocyte counts, bacterial culture results, vital signs and visual signs or symptoms of infection, such as sputum production or inflammation, redness, or size of skin lesion).

  • Secondary/super-infections post-therapy (new infection with different organisms from those observed in the primary infection).

  • Safety:
    • Number of participants who experienced at least one serious adverse event (results in death, is life threatening, places the participant at immediate risk of death, requires or prolongs hospitalisation, causes permanent/significant disability or incapacity, or is another condition that investigators judge to represent significant hazards).
    • Number of participants who withdrew as the result of adverse events.
    • Number of participants with at least one adverse event.

 

Search methods for identification of studies

The searches were not restricted by date, language, or publication status.

 

Electronic searches

The following electronic databases were searched;

  • Cochrane Injuries Group Specialised Register (13 September 2012).
  • Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library) 2012, Issue 8 of 12.
  • MEDLINE (OvidSP) 1946 to September Week 1 2012.
  • EMBASE (OvidSP) 1980 to 2012 Week 37.
  • CINAHL (EBSCO) (1982 to September 2012).
  • ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to 13 September 2012).
  • ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (1990 to 13 September 2012).

Searches were based on the MEDLINE search strategy reported in the protocol, and amendments were made, when necessary, to adapt it for the other databases. All search strategies are reported in full in Appendix 1.

 

Searching other resources

A manual search of reference lists of all relevant material was performed to identify additional potentially eligible studies. The Internet was searched using the Google search engine (www.google.com), with selected terms from the MEDLINE strategy, to identify any further unpublished or grey literature. An online clinical trials register (www.clinicaltrials.gov) was searched for completed and ongoing trials, and authors were contacted for information about ongoing or recently completed trials.

 

Data collection and analysis

The Injuries Group Trials Search Co-ordinator conducted the search using the methods described and collated the results before sending them to the authors. The review was conducted according to the previously published protocol (Yu 2010).

 

Selection of studies

Four independent authors (JS, EW, AT, MW) screened the titles and abstracts of the search results. Studies not meeting the pre-defined inclusion criteria were excluded. Reasons for excluding studies that seemed to meet the inclusion criteria, but then were subsequently excluded, were documented. Studies that met the inclusion criteria were further examined. The full text of all studies that were potentially relevant was retrieved and, where necessary, was translated into English. Studies with more than one publication were examined closely to ensure that each study was counted only once, and that multiple references were included by study.

 

Data extraction and management

Three independent authors (JS, EW, AT) used a pre-formed standardised data extraction sheet to record study characteristics and outcomes considered for this review. All data were cross-checked, and differences were resolved with further examination until a consensus was reached. The data extracted from each study included the following:

  • Participant characteristics (e.g. gender, age, ethnicity, co-morbid conditions).
  • Methods (e.g. random allocation procedures; allocation concealment; blinding of participants, healthcare providers, and outcome assessors).
  • Losses to follow-up, how they were handled, and follow-up duration.
  • Interventions (including antibiotic used, dose, and duration).
  • Outcome measures as listed previously.

All data were collected, regardless of compliance or completion of follow-up, to allow for an intention-to-treat analysis.

 

Assessment of risk of bias in included studies

Three independent authors (JS, EW, AT) assessed the methodological quality of each study using the following parameters as an evaluation tool and transcribed information from each included study into the 'Risk of bias' tables. Criteria for assessing risk of bias included evaluating the sequence generation, allocation concealment, blinding, management of incomplete data, selective outcome reporting, and other potential threats to the validity of the studies (Higgins 2009).

 

Sequence generation

Was sequence generation adequate?

  • Low risk of bias: A random component of sequence generation is described (e.g. computer-generated random sequence, random number table).
  • High risk of bias: A non-random component of sequence generation is described (e.g. allocation by clinician's judgement, allocation by participant's preference, sequence generated by admission date).
  • Unclear: insufficient information to conclude 'low risk of bias' or 'high risk of bias.'

 

Allocation concealment

Was allocation concealment adequate?

  • Low risk of bias: Participants and investigators enrolling participants could not predict assignment (e.g. sequentially numbered opaque sealed envelopes, telephone randomisation).
  • High risk of bias: Participants and investigators enrolling participants could predict assignment (e.g. unsealed envelopes, alternation).
  • Unclear: Information is insufficient to allow conclusion of 'low risk of bias' or 'high risk of bias.'

 

Blinding of participants, personnel, and outcome assessors

Was blinding of individuals involved in the study (participants, personnel, and outcome assessors) to the treatment allocation adequate?

  • Low risk of bias—any of the following:
    • No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
    • Blinding of participants and key study personnel ensured; unlikely that the blinding could have been broken.
    • Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others unlikely to introduce bias.
  • High risk of bias—any of the following:
    • No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.
    • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.
    • Either participants or some key study personnel were not blinded, and the non-blinding of others is likely to introduce bias.
  • Unclear: insufficient information allow conclusion of 'low risk of bias' or 'high risk of bias.'

 

Incomplete outcome data

Were incomplete outcome data adequately addressed?

  • Low risk of bias-any of the following:
    • No missing outcome data.
    • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).
    • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.
    • For dichotomous outcomes data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.
    • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size.
    • Missing data have been imputed using appropriate method.
  • High risk of bias-any of the following:
    • Reason for missing outcome data likely to be related to true outcome, with imbalance in numbers of or reasons for missing data across intervention groups.
    • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate.
    • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size.
    • 'As-treated' analysis done with substantial departure of the intervention received from that assigned at randomisation.
    • Potentially inappropriate application of simple imputation.
  • Unclear: insufficient reporting of attrition/exclusions to conclude 'low risk of bias' or 'high risk of bias'

 

Selective outcome reporting

Are reports of the study free of selective outcome reporting?

  • Low risk of bias-any of the following:
    • Study protocol is available and all pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way.
    • Study protocol is not available, but it is clear that published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
  • High risk of bias-any of the following:
    • Not all pre-specified primary outcomes of the study have been reported.
    • One or more primary outcomes are reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not pre-specified.
    • One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).
    • One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis.
    • Study report fails to include results for a key outcome that would be expected to have been reported for such a study.
  • Unclear: information is insufficient to allow investigators to conclude 'low risk of bias' or 'high risk of bias'

 

Other potential threats to validity

Was the study free from other problems that could put it at risk of bias?

  • Low risk of bias: Study appears to be free from other sources of bias.
  • High risk of bias: One or more important risks of bias are included (e.g. extreme baseline imbalance).
  • Unclear: Information is insufficient to allow investigators to assess whether there is an important risk of bias.

An overall assessment of the level of bias in the included trials was performed to determine the reliability and validity of the data.

 

Measures of treatment effect

All outcomes were dichotomous; therefore, the measure of treatment effect calculated was risk ratio (RR) with an associated 95% confidence interval (95% CI) using a random-effects model. A random-effects model was conducted for all analyses to account for the underlying heterogeneity of included studies, in which different participant populations, antibiotics, and infections were studied. Also, most of the studies were small; therefore, it was thought that a random-effects model would be less likely to diminish the importance of an observed effect because the weights assigned to each study would be more balanced.

 

Unit of analysis issues

The participant was the unit of analysis. Data from all randomly assigned participants were used for analyses. Scenarios in which censoring or exclusion of data was possible and whether results were presented as the total number of events or the total number of participants with a first event were examined closely. Authors of the studies were contacted regarding any ambiguity.

 

Dealing with missing data

Authors of the studies were contacted via e-mail to clarify and provide any missing data.

 

Assessment of heterogeneity

The I2 statistic and the Chi2 test were used to test for heterogeneity in the included studies. The threshold for the I2 statistic was > 50% for important heterogeneity to be considered. The threshold for the Chi2 statistic was P < 0.10 for important heterogeneity to be considered. When heterogeneity was detected (Chi2 test value of P < 0.10 or I2 > 50%), a random-effects model was used to confirm whether a statistically significant difference between the effects of continuous infusion and those of intermittent infusion could be noted. Clinical and methodological sources of heterogeneity were investigated, including baseline risk factors for outcome measures, study duration, age, race, and sex distribution of participants across studies.

Initially, a fixed-effect meta-analysis was planned because the default for all analyses and a random-effects model would be used only when heterogeneity was detected. However, a random-effects model was used as the default because a large number of small studies with between-study heterogeneity (e.g. different infections and antibiotics between studies) were used. Fixed-effect analyses were conducted to determine if there were differences between models because it is possible that small positive studies may drive the meta-analysis to look more positive as small studies may be given more weight when a random-effects model is used.

 

Assessment of reporting biases

Funnel plots were produced to detect potential publication bias. Any asymmetry noted in the plot was investigated to identify possible reasons for the asymmetry (i.e. true heterogeneity of treatment effect, play of chance, poor methodology in included studies).

 

Data synthesis

Review Manager 5 (RevMan 2008) was used to perform all data syntheses and analyses. Risk ratios for dichotomous clinical outcomes were calculated and are presented with 95% confidence intervals. GRADEpro (GRADEpro 2008) was used to generate the 'summary of findings' table.

 

Subgroup analysis and investigation of heterogeneity

Any heterogeneity detected was investigated for possible reasons (Higgins 2003). Aspects of trials assessed included antibiotic choice, infections being treated, use of other open-label antibiotics, and dose/duration of antibiotic therapy. A subgroup analysis of trials that included septic participants versus non-septic participants was conducted to determine whether differences in effect were based on this variable.

 

Sensitivity analysis

Sensitivity analyses were performed for primary outcomes only. Sensitivity analyses were performed to determine the impact of the presence or absence of appropriate allocation concealment procedures on all-cause mortality and infection recurrence effect estimates. Sensitivity analyses were also performed to determine the impact of trials studying extended interval infusions compared with intermittent infusions and the impact of the use of other open-label antibiotics in studies.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

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

 

Results of the search

The searches conducted in January 2010 identified 2935 records and 6 additional records from other sources. After removal of 1133 duplicate records, 1808 records were screened. The titles and abstracts for these results were screened by four appraisers; initially, 1752 studies were excluded for not meeting the pre-defined inclusion criteria. The full texts of the remaining 56 potentially eligible studies were retrieved for further assessment. Of 56 potentially eligible studies, 26 studies met the pre–specified inclusion criteria and were included in this review (Figure 1). Two trials were translated from French into English. However, only a partial translation of 1 trial from Japanese into English could be obtained. An updated search conducted in September 2012 identified 326 records and 3 additional records from other sources. After removal of 102 duplicate records, 227 records were screened and 4 full text articles were retrieved for further assessment. Of the 4 potentially eligible studies, 3 studies were included in this review (Figure 1). No trials from the updated search required translation into English. A total of 29 studies were included in this review from searches conducted in January 2010 and September 2012. A search of an online clinical trials register (www.clinicaltrials.gov) and the Internet identified 8 ongoing studies as of November 2012 that may meet inclusion criteria for this review.

 FigureFigure 1. Continuous vs intermittent study flow diagram.

 

Included studies

Of the 29 included studies, 25 studies compared continuous antibiotic infusions with traditional intermittent infusions, and 4 studies compared extended antibiotic infusions with intermittent infusions. Hospitalised patients were studied in the 29 included trials, and 19 of these trials studied patients admitted to a critical care unit. The population size of each study ranged from 7 to 262 patients; 4 studies had a study sample size greater than 100 patients. The studies included adults between the ages of 18 and 80 years, with the exception of one trial (Feld 1977), which included patients aged 15 years and older. This trial was included in the analysis because the median participant age was 43 to 46 years; therefore, it was thought that very few patients younger than 18 years participated in the study. The percentage of males in the included studies ranged from 43% to 82%. 

Types of infections studied in the included trials were pneumonia (n = 16), septicemia (n = 13), urinary tract infection (n = 3), skin and soft tissue infection (n = 2), peritonitis (n = 2), acute exacerbation of chronic obstructive pulmonary disease (n = 2), acute exacerbation of chronic bronchitis (n = 1), fever of unknown origin (n = 1), cholangitis (n = 1), sinusitis (n = 1), perirectal infection (n = 1), intra–abdominal or periappendiceal abscess (n = 1), complicated perforated diverticulitis (n = 1), shock lung (n = 1), endocarditis (n = 1), melioidosis (n = 1), catheter-related infection (n = 1), mediastinitis (n = 1), post-operative surgical infection (n = 1), and meningitis or central nervous system infection (n = 1).  Organisms isolated included Enterococcus faecalis, Enterococcus faecium, coagulase-negativeStaphylococcus (CoNS), Staphylococcus aureus, methicillin–resistantStaphylococcus aureus (MRSA), Burkholderia, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacteriaceae, Proteus mirabilis, Citrobacter, Serratia marcescens, Acinetobacter, Clostridium, Haemophilus influenzae, Aeromonas, Moraxella catarrhalis, Morganella morganii, Enterobacter, Salmonella, Streptococcus viridans, Streptococcus milleri, Streptococcus mitis, Streptococcus pneumoniae, Stenotrophomonas, Bacteroides, and Peptostreptococcus. Antibiotics studied included ceftazidime (n = 8), piperacillin-tazobactam (n = 5), meropenem (n = 3), tobramycin (n = 2), piperacillin (n = 1), linezolid (n = 1), carbenicillin (n = 1), cefamandole (n = 1), temocillin (n = 1), sisomicin (n = 1), cefepime (n = 1), cefoperazone (n = 1), ceftriaxone (n = 1), imipenem (n = 1), cefotaxime (n = 1), gentamicin (n = 1), and vancomycin (n = 1). Open–label antibiotics were permitted in 17 studies, although the remaining included studies did not indicate whether any additional antibiotics were permitted. Antibiotic treatment duration ranged from 4 to 14 days. Follow-up duration ranged from 24 hours to 28 days but was not reported in 18 studies.

Of studies meeting inclusion criteria, 3 studies (Lipman 1999; Nicolau 1999a; Nicolau 1999b) did not report any outcome data. One study (Bodey 1979) reported outcomes expressed as episodes and not by participant. This unit of analysis issue could not be reconciled. Therefore, 4 studies that met inclusion criteria did not contribute data to this meta-analysis.

 

Excluded studies

Of 60 potentially eligible studies, 31 were excluded after closer examination by 4 independent study appraisers. Studies excluded were cross-over studies (n = 10), were not randomised (n = 9), used prophylactic antibiotics (n = 3), and included healthy volunteers (n = 2), pharmacoeconomic or cost-effectiveness analyses (n = 2), pharmacokinetic/pharmacodynamic analyses of already included studies (n = 1), letters to the editor (n = 1), case reports (n = 1), uncontrolled (n = 1), or preliminary analyses of an already included study (n = 1).

 

Risk of bias in included studies

Most included studies were judged to be at unclear or high risk of bias with regard to randomisation sequence generation, allocation concealment, blinding, management of incomplete outcome data, selective outcome reporting, and other potential threats to validity (86%, 76%, 97%, 69%, 76%, and 90% of studies, respectively). No studies were judged to be at low risk of bias for all methodological quality items assessed.

See 'Risk of bias' tables and 'Risk of bias' graphs (Figure 2, Figure 3) for additional details regarding evaluation of the included studies.

 FigureFigure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
 FigureFigure 3. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

 

Allocation

Generation of randomisation sequence

Four trials (Cousson 2005; Lipman 1999; Roberts 2007; Wysocki 2001) adequately described generation of allocation sequence procedures and were judged to be at low risk of bias. Four trials (Nicolau 1999b; Nicolau 2001; Rafati 2006; Roberts 2009c) did not describe randomisation methods or generation of allocation sequence methods and were judged to have an unclear risk of bias. The remaining 21 studies were randomised, but randomisation methods were not reported or could not be translated into English, and these studies were judged to have an unclear risk of bias. For additional details, refer to information presented in 'Risk of bias' tables.

Allocation concealment

Six studies (Chytra 2012; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Wysocki 2001) used sealed, opaque envelopes to conceal randomisation allocation and were judged to be at low risk of bias. Five trials (Adembri 2008; Bodey 1979; Buck 2005; Feld 1984; Sakka 2007) used sealed envelopes to conceal randomisation allocation, but opacity of envelopes was not described, and these studies were judged to be at unclear risk of bias. Allocation concealment was not clear in 1 study (Okimoto 2009) because only a partial translation from Japanese into English was available. The remaining 17 studies did not describe allocation concealment methods and were judged to be at unclear risk of bias. For additional details, refer to information presented in 'Risk of bias' tables.

 

Blinding

Fourteen studies (Adembri 2008; Buck 2005; Chytra 2012; DeJongh 2008; Georges 2005; Lau 2006; Lubasch 2003; Nicolau 2001; Pedeboscq 2001; Roberts 2009b; Roberts 2009c; Roberts 2010; van Zanten 2007; Wysocki 2001) were not blind and were judged to be at high risk of bias. One study (Nicolau 1999a) was single blind and was judged to be at high risk of bias. Another study (Roberts 2007) was double blind and was judged to be at low risk of bias. Blinding was not clear in 1 study (Okimoto 2009) because only a partial translation from Japanese into English was available. The remaining 12 studies did not comment on blinding and were judged to be at unclear risk of bias. For additional details, refer to information presented in 'Risk of bias' tables.

 

Incomplete outcome data

Participants were lost to follow-up or were censored in 12 trials (Angus 2000; Chytra 2012; DeJongh 2008; Feld 1977; Feld 1984; Georges 2005; Hanes 2000; Lau 2006; Lubasch 2003; Nicolau 1999a; Nicolau 2001; Wysocki 2001) and were judged to be at unclear or high risk of bias. One trial (Adembri 2008) included participants who did not complete the study and was judged to be at unclear risk of bias. Two studies (Bodey 1979; van Zanten 2007) did not report all pre–specified outcomes for all participants and were judged to be at high risk of bias. Nine studies (Buck 2005; Cousson 2005; Lagast 1983; Nicolau 1999b; Okimoto 2009; Rafati 2006; Roberts 2007; Roberts 2009c; Roberts 2010) yielded complete outcome data and were judged to be at low risk of bias. Five studies (Lipman 1999; Pedeboscq 2001; Roberts 2009b;Sakka 2007; Wright 1979) did not report on attrition bias and were judged to be at unclear risk of bias. For additional details, refer to information presented in 'Risk of bias' tables.

The corresponding authors of 25 studies were contacted via e-mail to clarify and provide missing outcome data. Nine authors replied with the requested missing data, which were incorporated into the analyses. Five authors stated that the requested missing data were no longer available, and the remaining authors did not respond.

No authors of the 8 ongoing studies were contacted, and no data from these unpublished or ongoing trials were included, because it was not clear from the current information provided whether these trials will meet inclusion criteria for this review. When the full texts of these studies become available, they will be considered for future updates.

It is important to note that a substantial amount of information was not available for the pre-specified outcome measures of this review. Data from all 29 RCTS were not reported for any outcome measures. See table below.


OutcomeNumber of trials reporting outcomes (of a total of 29 possible trials)

All-cause mortality19

Infection recurrence8

Clinical cure15

Super-infection12

Adverse events5

Serious adverse events10

Withdrawal due to adverse events10



 

Selective reporting

Seven studies (Adembri 2008; Chytra 2012; Cousson 2005; Feld 1977; Lubasch 2003; Pedeboscq 2001; Roberts 2007) reported all pre–specified outcomes and were judged to be at low risk of bias. Seven studies (Angus 2000; DeJongh 2008; Georges 2005; Lipman 1999; Nicolau 1999a; Sakka 2007; Wright 1979) reported outcomes that were not pre–specified and were judged to be at unclear or high risk of bias. Five studies (Hanes 2000; Lagast 1983; Lau 2006; Nicolau 1999b; van Zanten 2007) did not report all pre–specified outcomes and were judged to be at unclear or high risk of bias. Three studies (Bodey 1979; Feld 1984; Wysocki 2001) did not report the total numbers of participants or participants in each group and were judged to be at high or unclear risk of bias. Five studies (Nicolau 2001; Rafati 2006; Roberts 2009b; Roberts 2009c; Roberts 2010) did not describe methods, including outcomes, and were judged to be at unclear risk of bias. One study (Buck 2005) did not assess clinical outcomes and was judged to be at unclear risk of bias. Selective reporting was not clear in 1 study (Okimoto 2009) because only a partial translation from Japanese into English was available. For additional details, refer to information presented in 'Risk of bias' tables.

 

Other potential sources of bias

No other potential sources of bias were identified in 3 studies (Angus 2000; Feld 1977; Rafati 2006), which were judged to be at low risk of bias. Other potential sources of bias were not clear in 1 study (Okimoto 2009) because only a partial translation from Japanese into English was available. The remaining 25 studies included participant baseline imbalances, unclear use of open–label antibiotics, or pharmaceutical company funding and were judged to be at unclear or high risk of bias. For additional details, refer to information presented in 'Risk of bias' tables.

 

Effects of interventions

See:  Summary of findings for the main comparison Continuous versus Intermittent Antibiotic Infusions for Treatment of Severe Bacterial Infections

Intention-to-treat analyses were conducted for all outcomes using the total numbers of participants randomly assigned to each intervention for each included study. All analyses were conduced using a random-effects model and a fixed-effect model. One difference between the 2 models in the subgroup analysis of septic versus non-septic participants reporting clinical cure data was noted. However, no differences between the 2 models were observed in all other analyses, suggesting no bias due to small study effects.

Worst-case scenarios were conducted for primary and secondary outcomes for participants lost to follow-up or censored. Analyses were conducted only when exact numbers of missing participants were known.

All–cause mortality ( Analysis 1.1)

Nineteen studies reported mortality data (Adembri 2008; Angus 2000; Chytra 2012; Cousson 2005; DeJongh 2008; Feld 1977; Georges 2005; Lagast 1983; Lau 2006; Pedeboscq 2001; Rafati 2006; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Sakka 2007; van Zanten 2007; Wright 1979; Wysocki 2001). No statistically significant differences in all–cause mortality were noted when time–dependent antibiotics and concentration–dependent antibiotics were analysed together (n = 1241, pooled relative risk (RR) 0.89, 95% CI 0.67 to 1.20, P = 0.45). No evidence of statistical heterogeneity was found (Chi2 = 13.86, degrees of freedom (df) = 15, P = 0.54; I2 = 0%).

Seventeen studies compared time–dependent antibiotics (Adembri 2008; Angus 2000; Chytra 2012; Cousson 2005; DeJongh 2008; Georges 2005; Lagast 1983; Lau 2006; Pedeboscq 2001; Rafati 2006; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Sakka 2007; van Zanten 2007; Wysocki 2001). No statistically significant differences in all–cause mortality were reported with time–dependent antibiotics (n = 1085, RR 0.87, 95% CI 0.62 to 1.22, P = 0.42).  No evidence of statistical heterogeneity was obtained (Chi2 = 13.47, df = 13, P = 0.41; I2 = 4%).

Two studies compared concentration–dependent antibiotics (Feld 1977; Wright 1979). No statistically significant differences in all–cause mortality were found with concentration–dependent antibiotics (n = 156, RR 1.10, 95% CI 0.50 to 2.40, P = 0.82). No evidence of statistical heterogeneity was noted (Chi2 = 0.09, df = 1, P = 0.76; I2 = 0%).

When the worst–case scenario was calculated for time-dependent and concentration-dependent antibiotics, when all missing participants were assumed to have died, no statistically significant differences in all–cause mortality were observed (n = 1241, RR 0.94, 95% CI 0.80 to 1.11, P = 0.49).

Infection recurrence within 14 days of resolution of primary infection ( Analysis 1.2)

Eight studies reported infection recurrence data; all of these trials compared time–dependent antibiotics (DeJongh 2008; Lagast 1983; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; van Zanten 2007; Wysocki 2001). No statistically significant differences in infection recurrence (n = 398, RR 1.22, 95% CI 0.35 to 4.19, P = 0.76) were described, and no evidence of statistical heterogeneity was found (Chi2 = 0.37, df = 2, P = 0.83; I2 = 0%).

When the worst–case scenario was calculated for time-dependent antibiotics, and when all missing participants were assumed to have infection recurrence, no statistically significant differences in infection recurrence were observed (n = 398, RR 0.88, 95% CI 0.46 to 1.66, P = 0.69).

Clinical cure ( Analysis 1.3)

Fifteen studies reported clinical cure; all of these studies compared time–dependent antibiotics (Adembri 2008; Buck 2005; Chytra 2012; Cousson 2005; DeJongh 2008; Georges 2005; Lau 2006; Lubasch 2003; Nicolau 2001; Okimoto 2009; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; van Zanten 2007). No statistically significant differences in clinical cure were reported (n = 975, RR 1.00, 95% CI 0.93 to 1.08, P = 0.98). No evidence of statistical heterogeneity was found (Chi2 = 13.72, df = 14, P = 0.47; I2 = 0%).

A worst-case scenario is not estimable because it is already assumed that all missing participants did not attain clinical cure.

Superinfections post–therapy ( Analysis 1.4)

Twelve studies reported secondary super-infections post–therapy (Chytra 2012; DeJongh 2008; Feld 1977; Feld 1984; Georges 2005; Hanes 2000; Nicolau 2001; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Wysocki 2001). No statistically significant differences in superinfections post–therapy when time–dependent antibiotics and concentration–dependent antibiotics were analysed together (n = 813, RR 1.08, 95% CI 0.60 to 1.94, P = 0.79). No evidence of statistical heterogeneity was found (Chi2 = 3.64, df = 6, P = 0.73; I2 = 0%).

Ten studies reported secondary super-infections in studies comparing time–dependent antibiotics (Chytra 2012; DeJongh 2008; Georges 2005; Hanes 2000; Nicolau 2001; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Wysocki 2001). No statistically significant differences in super-infections with time–dependent antibiotics were reported (n = 623, RR 0.98, 95% CI 0.53 to 1.83, P = 0.95). No evidence of statistical heterogeneity was found (Chi2 = 2.81, df = 4, P = 0.59; I2 = 0%).

Two studies reported secondary super-infections when concentration–dependent antibiotics were compared (Feld 1977; Feld 1984). No statistically significant differences in secondary super-infections were seen with concentration–dependent antibiotics (n = 190, RR 2.20, 95% CI 0.41 to 11.70, P = 0.36). No evidence of statistical heterogeneity was found (Chi2 = 0.05, df = 1, P = 0.82; I2 = 0%).

When the worst–case scenario was calculated for time-dependent and concentration-dependent antibiotics, and when all missing participants were assumed to have secondary super-infections, no statistically significant differences in infection recurrence were reported (n = 813, RR 1.01, 95% CI 0.73 to 1.40, P = 0.96).

Serious adverse events ( Analysis 1.5)

Ten studies reported serious adverse events; all of these studies were conducted to compare time–dependent antibiotics (Chytra 2012; Cousson 2005; DeJongh 2008; Lau 2006; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; van Zanten 2007; Wysocki 2001). No statistically significant differences in participants experiencing at least one serious adverse event were observed (n = 871, RR 1.36, 95% CI 0.80 to 2.30, P = 0.26), and no evidence of statistical heterogeneity was found (Chi2 = 1.00, df = 1, P = 0.32; I2 = 0%).

When the worst–case scenario was calculated for time-dependent antibiotics, and when all missing participants were assumed to have had a serious adverse event, no statistically significant differences in serious adverse events were noted (n = 871, RR 1.04, 95% CI 0.67 to 1.62, P = 0.85).

Withdrawals due to adverse events ( Analysis 1.6)

Ten studies reported withdrawals due to adverse events; all of these studies compared time–dependent antibiotics (Chytra 2012; Cousson 2005; DeJongh 2008; Lau 2006; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; van Zanten 2007; Wysocki 2001). No statistically significant differences in withdrawals due to adverse events were described (n = 871, RR 2.03, 95% CI 0.52 to 7.95, P = 0.31). Statistical heterogeneity could not be calculated because only one study reported participant withdrawals due to adverse events.

When the worst–case scenario was calculated, and when all missing participants were assumed to have withdrawn because of an adverse event, no statistically significant differences in withdrawals due to adverse events were seen (n = 871, RR 0.99, 95% CI 0.66 to 1.50, P = 0.98).

Adverse events ( Analysis 1.7)

Five studies reported adverse events; all of these studies were performed to compare time–dependent antibiotics (Chytra 2012; Lau 2006; Roberts 2007; Roberts 2009c; Roberts 2010). No statistically significant differences in adverse events were observed (n = 575, RR 1.02, 95% CI 0.94 to 1.12, P = 0.63), and no evidence of statistical heterogeneity was found (Chi2 = 0.37, df = 1, P = 0.54; I2 = 0%). 

When the worst-case scenario was calculated, in which all missing participants were assumed to have had an adverse event, no statistically significant differences in adverse events were noted (n = 575, RR 1.02, 95% CI 0.94 to 1.12, P = 0.60).

Subgroup analysis: septic versus non–septic participants

Twenty studies included participants with sepsis (met criteria for systemic inflammatory response syndrome with a documented or suspected infection and/or critically unwell admitted to an intensive care unit) (Adembri 2008; Angus 2000; Chytra 2012; Cousson 2005; DeJongh 2008; Georges 2005; Hanes 2000; Lipman 1999; Nicolau 1999a; Nicolau 1999b; Nicolau 2001; Pedeboscq 2001; Rafati 2006; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Sakka 2007; Wright 1979; Wysocki 2001).

Fifteen studies reported mortality in septic participants (Adembri 2008; Angus 2000; Chytra 2012; Cousson 2005; DeJongh 2008; Georges 2005; Pedeboscq 2001; Rafati 2006; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Sakka 2007; Wright 1979; Wysocki 2001). No statistically significant differences in all–cause mortality were reported when time–dependent antibiotics and concentration–dependent antibiotics were analysed together (n = 721, RR 0.82, 95% CI 0.59 to 1.13, P = 0.23). Four studies reported mortality in non–septic participants (Feld 1977; Lagast 1983; Lau 2006; van Zanten 2007). No statistically significant differences in all–cause mortality were noted when time–dependent antibiotics and concentration–dependent antibiotics were analysed together (n = 520, RR 1.32, 95% CI 0.67 to 2.61, P = 0.43).

Six studies reported infection recurrence in septic participants; all of these trials were conducted to compare time–dependent antibiotics (DeJongh 2008; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Wysocki 2001). No statistically significant differences in infection recurrence were observed (n = 260, RR 2.90, 95% CI 0.12 to 68.33, P = 0.51). Two studies reported infection recurrence in non–septic participants; all of these trials compared time–dependent antibiotics (Lagast 1983; van Zanten 2007). No statistically significant differences in infection recurrence were described (n = 138, RR 1.04, 95% CI 0.27 to 3.99, P = 0.95).

Ten studies reported clinical cure in septic participants; all of these studies compared time–dependent antibiotics (Adembri 2008; Chytra 2012; Cousson 2005; DeJongh 2008; Georges 2005; Nicolau 2001; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010). No statistically significant differences in clinical cure were reported (n = 465, RR 1.17, 95% CI 0.99 to 1.37, P = 0.06) when a random-effects model was used. However, a statistically significant difference favouring intermittent antibiotic infusions was seen when a fixed-effect model was used (n = 465, RR 1.26, 95% CI 1.02 to 1.55, P = 0.03). Five studies reported clinical cure in non–septic participants; all of these trials compared time–dependent antibiotics (Buck 2005; Lau 2006; Lubasch 2003; Okimoto 2009; van Zanten 2007). No statistically significant differences in clinical cure were observed (n = 510, RR 0.96, 95% CI 0.89 to 1.04, P = 0.36).

Ten studies reported super-infection in septic participants; all of these studies compared time-dependent antibiotics (Chytra 2012; DeJongh 2008; Georges 2005; Hanes 2000; Nicolau 2001; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Wysocki 2001). No statistically significant differences in super-infection were described (n = 623, RR 0.98, 95% CI 0.53 to 1.83, P = 0.95). Two studies reported super-infection in non–septic participants; all of these studies compared concentration-dependent antibiotics (Feld 1977; Feld 1984). No statistically significant differences in super-infection were reported (n = 190, RR 2.20, 95% CI 0.41 to 11.70, P = 0.36).

Eight studies addressed serious adverse events and withdrawals due to adverse events in septic participants; all of these compared time-dependent antibiotics (Chytra 2012; Cousson 2005; DeJongh 2008; Roberts 2007; Roberts 2009b; Roberts 2009c; Roberts 2010; Wysocki 2001). However, no serious adverse events or withdrawals due to adverse events were recorded in these studies; therefore, comparison with non–septic participants could not be performed. 

Four studies reported adverse events in septic participants; all of these studies compared time-dependent antibiotics (Chytra 2012; Roberts 2007; Roberts 2009c; Roberts 2010). No statistically significant differences in adverse events were observed (n = 313, RR 0.83, 95% CI 0.37 to 1.85, P = 0.66). One study, which compared time-dependent antibiotics, reported adverse events in non-septic participants (Lau 2006). No statistically significant differences in adverse events were noted (n = 262, RR 1.02, 95% CI 0.94 to 1.12, P = 0.60).

Sensitivity analysis

When studies that did not report allocation concealment procedures were removed from analysis, no statistically significant differences in all–cause mortality were reported (n = 521, RR 1.00, 95% CI 0.63 to 1.58, P = 1.00) nor were differences in infection recurrence described (n = 243, RR 2.90, 95% CI 0.12 to 68.33, P = 0.51).

When studies that compared extended interval infusions with intermittent infusions were removed from analysis, no statistically significant differences in all–cause mortality (n = 1187, RR 0.90, 95% CI 0.65 to 1.25, P = 0.53) or infection recurrence were found (n = 398, RR 1.22, 95% CI 0.35 to 4.19, P = 0.76).

When studies that stated that open–label antibiotics were permitted were removed from analysis, no statistically significant differences in all–cause mortality (n = 546, RR 1.37, 95% CI 0.71 to 2.67, P = 0.35) or infection recurrence were described (n = 164, RR 1.04, 95% CI 0.27 to 3.99, P = 0.95).

The Feld 1977 study included some participants younger than 18 years; therefore, it was removed from analysis. When removed, no statistically significant differences in all-cause mortality were seen (n = 1121, RR 0.87, 95% CI 0.64 to 1.18, P = 0.37). This study did not contribute data to the infection recurrence outcome.

The Lau 2006 and Lubasch 2003 studies reported clinical success as a composite outcome of clinical cure and clinical improvement, and these studies were removed from the analysis. When they were removed, no statistically significant differences in clinical cure were reported (n = 632, RR 1.06, 95% CI 0.94 to 1.19, P = 0.36).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Summary of main results

No differences in all–cause mortality, infection recurrence, clinical cure, or super-infection post–therapy were found between continuous antibiotic infusions and intermittent antibiotic infusions. Nor were differences reported when safety outcomes (serious adverse events, withdrawals due to adverse events, and adverse events) were compared. When comparisons between time–dependent and concentration–dependent antibiotics were made, no differences in all–cause mortality or super-infection post–therapy were noted.

Subgroup analyses revealed no differences in all–cause mortality, infection recurrence, or super-infection post–therapy when septic or critical care participants were compared with non–septic participants. A difference was observed in the subgroup analyses of clinical cure in septic versus non-septic participants. However, this result was not robust because it was not observed in both random-effects and fixed-effect models. Additionally, this result is difficult to interpret because clinical cure was a subjective outcome, and no standard definition was used in the included studies. Clinical cure was defined by clinician judgement as improvement in signs and symptoms of infection, which included assessment of some or all of the following factors: bacteriological eradication, leukocyte counts, vital signs, inflammation, and sputum production. In addition, clinical success was defined as a composite outcome of clinical cure and clinical improvement in two studies. Therefore, it cannot be concluded from these data that greater clinical cure was seen in the intermittent antibiotic infusion group. It is also unclear whether any clinically meaningful differences in clinical cure were noted between continuous antibiotic infusions and intermittent antibiotic infusions because of identified risks of bias due to outcome subjectivity and lack of a robust statistical finding.

No differences between continuous and intermittent antibiotic infusions were reported for any sensitivity analyses performed.

 

Overall completeness and applicability of evidence

A wide range of antibiotics, infections, and organisms were included in this review, and this may allow the results to be broadly generalized. Although continuous infusions are thought to optimise the pharmacokinetic and pharmacodynamic parameters of time–dependent antibiotics, both time–dependent and concentration–dependent antibiotics were included in this analysis, because there is some thought that a lower total daily antibiotic dose could be used during continuous infusions (Nicolau 1996). This would affect the peak concentration and the area under the curve (estimate of drug exposure) for a drug; therefore, concentration–dependent antibiotics were included to investigate whether any adverse clinical outcomes or effects related to continuous infusions of concentration–dependent antibiotics were noted. Additionally, because the continuous infusion of concentration–dependent antibiotics has not been widely studied, it is not clear whether this dosing strategy would be beneficial or harmful to patients. The results of this study are applicable only to hospitalised patients and may not be applied to outpatient parenteral therapy programs based on the types of patients and settings of trials included in this review.  

Several other concerns surround the applicability of these results. One concern is the heterogeneous definition of clinical cure in each study. Measuring an outcome such as clinical cure is especially difficult when clinicians or outcome assessors are not blinded, which was the case in most of the studies included in this review. Also, the use of open–label antibiotics in many of the studies may bias the effect of the intervention to show no difference. However, it would be unethical to limit antibiotic use in patients with severe bacterial infection. Another factor not considered in this review was pathogen susceptibility. It is possible that a difference between interventions was not observed as more highly susceptible pathogens were studied. Outcomes would theoretically be more similar between groups if the pathogens were highly susceptible (i.e. organisms were very sensitive to the effects of study antibiotics) because any suitable antibiotic would be effective no matter the dosing strategy. It could be hypothesized that continuous antibiotic infusions would be of greater benefit in cases of less susceptible organisms. Other confounding factors are the numerous other therapeutic interventions in hospitalised and critically ill patients (such as fluid resuscitation, vasopressor and inotrope use, and blood transfusion) that could also have a substantial impact on mortality, infection recurrence, and clinical cure. This is an important issue despite the fact that only randomised studies were included, because the validity of randomisation is affected by the small size of the included studies.

Although all of the trials included were randomised, it is of note that most of the studies had small participant populations. Generally, fewer than 100 participants were included in each study, and in one case, as few as seven participants were included. This is a potential problem because it raises the issue of whether the pooling of small studies for this review has sufficient power to detect a difference between continuous and intermittent antibiotic infusions. It is not clear whether the sample size as a result of pooling would be able to detect differences between the two antibiotic dosing strategies. This becomes an important issue when the safety outcomes of this review are interpreted because only two studies analysed reported participants experiencing an adverse effect or a serious adverse event, and only one study reported participant withdrawal due to an adverse event. This potential under–reporting of safety outcomes makes it difficult to assess the safety of continuous antibiotic infusions and intermittent antibiotic infusions in severe bacterial infection.   

Furthermore, for each outcome, the calculated effect estimates in this review are associated with wide confidence intervals and show no particular consistent trend in beneficial or harmful effects with either continuous or intermittent administration. If data were available for outcomes from the trials that did not report on these outcomes, more precise effect estimates could have been calculated and could possibly show advantages or disadvantages for either continuous or intermittent antibiotic administration. It is important to refrain from concluding that outcomes for continuous and intermittent administration are equal, given the quantity of missing information and the possibility that the meta-analyses are underpowered.   

In addition to the limitations already described, many logistical concerns have been raised regarding the administration of continuous infusion antibiotics. Some beta–lactams, such as carbapenems, are thought to be too unstable for continuous infusion (Viaene 2002). Continuous infusion pumps may increase nursing workload and may limit patient mobility on medical wards, and additional intravenous lines may be required if the antibiotic chosen is not compatible with other medications (Ariano 2010). Extending the infusion also occupies an intravenous line that may be essential for other therapies, especially in critically ill patients who have limited intravenous access. As well, it is not known whether continuous infusions would result in increased dosing and administration errors by physicians, pharmacists, and nursing staff. However, several studies have suggested that continuous infusion of antibiotics is more cost–effective compared with intermittent infusions (McNabb 2001; Florea 2003; Hitt 1997; Grant 2002). Although intermittent antibiotic infusions are the current standard of therapy, some disadvantages merit consideration. Intermittent antibiotic infusions may increase nursing workload for those antibiotics that require multiple daily doses compared with continuous infusion pumps. In the preparation of these multiple antibiotic doses, the chance of dispensing and mixing errors by pharmacy and nursing staff may be increased. Intermittent infusions typically also result in higher peak concentrations of antibiotics, which could lead to an increase in adverse effects related to drug toxicity. Finally, intermittent antibiotic infusions could put the patient at increased infection risk compared with continuous infusions because more frequent access to intravenous lines is required to give multiple daily doses of antibiotics.

 

Quality of the evidence

The quality of evidence included in this review was very low to moderate according to GRADE considerations (GRADEpro 2008; Balshem 2011; Guyatt 2011). Although all 29 studies were randomised, procedures for both generation of the randomisation sequence and allocation concealment were described in only two studies. Only two studies were blinded, and the remaining studies were not blinded, or blinding was not reported and the studies appeared to be unblinded as judged by the authors. Additionally, accounting of missing participants and missing outcomes was not well described in the studies reviewed. It is interesting to note that many included studies were published before the CONSORT guidelines for reporting of RCTs were available.

 

Potential biases in the review process

This review had a focused objective and used a systematic search strategy to identify studies for potential inclusion. Biases in the review process were minimized by using pre–defined inclusion and exclusion criteria for study selection and standardized data extraction forms to gather data and appraise studies. Although no evidence of statistical heterogeneity was observed for all outcomes studied, several potential sources of heterogeneity (such as variation in outcomes studied, open–label antibiotic use, infection type, and patient co–morbidities) should be considered. Also, the potential for publication bias exists, although the funnel plots for all–cause mortality, infection recurrence, clinical cure, and super-infection do not seem to indicate this (Figure 4, Figure 5, Figure 6, Figure 7). Publication bias increases the potential for adverse events, serious adverse events, and withdrawals due to adverse events as a result of the fact that funnel plots could not be analysed because the number of trials reporting these outcomes was insufficient.

 FigureFigure 4. Funnel plot of comparison: continuous vs intermittent antibiotic infusions, outcome. All-cause mortality.
 FigureFigure 5. Funnel plot of comparison: continuous vs intermittent antibiotic infusions. Outcome: infection recurrence.
 FigureFigure 6. Funnel plot of comparison: continuous vs intermittent antibiotic infusions. Outcome: clinical cure.
 FigureFigure 7. Funnel plot of comparison: continuous vs intermittent antibiotic infusions. Outcome: super-infection.

 

Agreements and disagreements with other studies or reviews

This systematic review is consistent with previously published reviews. A meta–analysis of nine RCTs did not show any statistically significant differences in mortality (OR 0.89, 95% CI 0.48 to 1.64) (Kasiakou 2005b). A potential explanation for the similarity of results is that seven of the nine RCTs in the Kasiakou et al study also met inclusion criteria for this review. The remaining two studies were excluded from this review because one study was a cost-effectiveness re-analysis of an already included study, and the other study included nonーrandomly assigned participants. Moreover, four of the five RCTs that reported mortality data were included in this review. Similar antibiotics, such as beta–lactams, aminoglycosides, and vancomycin, were compared in both reviews. Similar participant populations, such as critical care participants, were compared in both reviews. Although no differences in mortality were reported by Kasiakou et al, these authors still concluded that continuous antibiotic infusions have a clinical advantage compared with intermittent infusions. This conclusion was based on a subgroup analysis in which only trials comparing the same total antibiotic dose showed that clinical failure rates were lower in the continuous infusion group (OR 0.70, 95% CI 0.50 to 0.98) (Kasiakou 2005b). Conversely, a difference favouring intermittent antibiotic infusions for clinical cure in septic participants was observed in this review. However, as has been discussed, the difference observed was not a robust statistical finding. A larger systematic review of 14 RCTs conducted by Roberts et al also did not find any differences in mortality (OR 1.00, 95% CI 0.48 to 2.06) or clinical cure (OR 1.04, 95% CI 0.74 to 1.46) (Roberts 2009a). Again, this similarity is likely related to the fact that 13 of the 14 RCTs in the review by Roberts et al are included in this review. The remaining study was not included in this review because it was not randomised. Therefore, both reviews had similar patient populations, study settings, and antibiotics studied. Tamma et al compared only beta–lactam continuous infusions versus intermittent infusions when conducting another systematic review of 14 RCTs. Similar to this review, Tamma et al did not find any differences in mortality (RR 0.92, 95% CI 0.61 to 1.37) or clinical cure (RR 1.00, 95% CI 0.94 to 1.06) (Tamma 2011). Once again, with 12 of the 14 RCTs included in both reviews, this consistency is likely explained. The remaining 2 studies were not included in this review because 1 study was not randomised, and the other study compared different antibiotics, which was an exclusion criterion for this review.

Generally, those studies that have shown a trend toward improved outcomes with continuous infusion antibiotics were investigating more resistant organisms in critically ill participants. A cohort study performed by Lodise et al compared 194 participants with a mean APACHE II score of 16, who received piperacillin-tazobactam extended infusions versus intermittent infusions to treat Pseudomonas aeruginosa (Lodise 2007). Lodise et al found that participants with an APACHE II score > 17 receiving piperacillin-tazobactam extended infusions had a statistically significant benefit in 14–day mortality (P = 0.04) (Lodise 2007). However, when the overall 14–day mortality was calculated, no statistically significant difference was noted (P = 0.17) (Lodise 2007). Therefore, it could be hypothesized that continuous antibiotic infusions provide clinically meaningful benefit only in the critically ill. However, the subgroup analysis comparing septic or critically ill participants with non–septic participants in this review did not find any differences except for clinical cure in septic participants, which was not robust. A potential explanation for this is that all studies included in this review were RCTs, and the Lodise et al study was a nonーrandomly assigned retrospective cohort.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

No differences in mortality, infection recurrence, clinical cure, and super-infection post–therapy were found when continuous infusions of intravenous antibiotics were compared with traditional intermittent antibiotic infusions. However, the wide confidence intervals suggest that beneficial or harmful effects cannot be ruled out for all outcomes. Although no evidence of statistical heterogeneity was found, some clinically meaningful heterogeneity between studies is likely and should be considered. Also, no differences in safety outcomes between the two interventions were apparent. Because several trials did not report data for clinically important outcomes, and because confidence intervals for effect estimates were wide, it is possible that the analyses in this review are underpowered because of lack of data. Therefore, the current available evidence is insufficient to recommend the widespread adoption of continuous infusion antibiotics in the place of standard intermittent antibiotic infusions.

 
Implications for research

Large, prospective randomised trials looking at additional outcomes, such as length of hospital stay, and reporting on all outcomes of interest as outlined in this review, would add to the findings of this review. It would also be helpful if these large trials were conducted with concurrent pharmacokinetic and pharmacodynamic studies. Trials investigating the effects of continuous infusion antibiotics in critically ill participants should be considered, because this population is theoretically more likely to benefit from this alternate dosing strategy based on subgroup data from previous retrospective studies. It is also not clear whether there would be additional therapeutic efficacy if continuous antibiotic infusions were used to treat more resistant organisms. Additional pharmacoeconomic studies are required to confirm whether there are other reasons to support the use of continuous infusion antibiotics.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

We would like to thank the Cochrane Injuries Group for its support in the preparation of the protocol and review. We would also like to thank Ivane Stephanie Yu for contributions to search result screening and data extraction.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Continuous vs intermittent

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality191241Risk Ratio (M-H, Random, 95% CI)0.89 [0.67, 1.20]

    1.1 Time-dependent antibiotics
171085Risk Ratio (M-H, Random, 95% CI)0.87 [0.62, 1.22]

    1.2 Concentration-dependent antibiotics
2156Risk Ratio (M-H, Random, 95% CI)1.10 [0.50, 2.40]

 2 Infection recurrence8Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Time-dependent antibiotics
8398Risk Ratio (M-H, Random, 95% CI)1.22 [0.35, 4.19]

 3 Clinical Cure15Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Time-dependent antibiotics
15975Risk Ratio (M-H, Random, 95% CI)1.00 [0.93, 1.08]

 4 Superinfection12813Risk Ratio (M-H, Random, 95% CI)1.08 [0.60, 1.94]

    4.1 Time-dependent antibiotics
10623Risk Ratio (M-H, Random, 95% CI)0.98 [0.53, 1.83]

    4.2 Concentration-dependent antibiotics
2190Risk Ratio (M-H, Random, 95% CI)2.20 [0.41, 11.70]

 5 Serious Adverse Events10Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Time-dependent antibiotics
10871Risk Ratio (M-H, Random, 95% CI)1.36 [0.80, 2.30]

 6 Withdrawal due to Adverse Events10Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Time-dependent antibiotics
10871Risk Ratio (M-H, Random, 95% CI)2.03 [0.52, 7.95]

 7 Adverse Events5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 Time-dependent antibiotics
5575Risk Ratio (M-H, Random, 95% CI)1.02 [0.94, 1.12]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Appendix 1. Search strategy

Cochrane Injuries Group Specialised Register
(anti-biotic* or antibiotic* or anti-infect* or antiinfect* or antibacteria* or anti-bacteria* or microbicide* or anti-microbi* or antimicrobi*) AND (infusion* or intravenous* or drip or drips) AND (infection* or infectious or Sepsis or pneumonia* or mening*) AND ((drug* and schedule*) or continuous* or discontinu* or intermittent* or interval*)

Cochrane Central Register of Controlled Trials (The Cochrane Library)
#1MeSH descriptor Anti-Infective Agents explode all trees with qualifier: AD
#2MeSH descriptor Anti-Bacterial Agents explode all trees with qualifier: AD
#3(anti-biotic* or antibiotic* or anti-infect* antiinfect* or antibacteria* or anti-bacteria*)
#4(microbicide* or anti-microbi* or antimicrobi* or microbi*)
#5(beta-lactam* or betalactam* or B-lactam* or aminoglycoside* or vancomycin)
#6(#1 OR #2 OR #3 OR #4 OR #5)
#7MeSH descriptor Infusions, Intravenous explode all trees
#8(infusion* or intravenous* or drip or drips)
#9 MeSH descriptor Infection explode all trees
#10 MeSH descriptor Soft Tissue Infections explode all trees
#11 MeSH descriptor Pneumonia, Viral explode all trees
#12 MeSH descriptor Meningitis explode all trees
#13 MeSH descriptor Urinary Tract Infections explode all trees
#14 MeSH descriptor Sepsis explode all trees
#15 (infected or infection* or infectious or infectious disease* or (infect* near disease*))
#16 (Sepsis or pneumonia* or mening*)
#17 (urine or urinary tract) near3 (infect*)
#18 ((skin or soft tissue) near3 infect*)
#19 (#7 OR #8)
#20 (#9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18)
#21 (#19 AND #20)
#22 (#6 AND #21)
#23 MeSH descriptor Drug Administration Schedule explode all trees
#24 (continuous* or discontinu* or intermittent* or interval*)
#25 (#23 OR #24)
#26 (#22 AND #25)

MEDLINE (OvidSP)
1.exp anti-infective agents/ad [Administration & Dosage]
2.exp anti-bacterial agents/ad [Administration & Dosage]
3.(anti-biotic* or antibiotic* or anti-infect* antiinfect* or antibacteria* or anti-bacteria*).ab,ti.
4.(microbicide* or anti-microbi* or antimicrobi* or microbi*).ab,ti.
5.(beta-lactam* or betalactam* or B-lactam* or aminoglycoside* or vancomycin).ab,ti.
6.or/1-5
7.exp Infusions, Intravenous/
8.(infusion* or intravenous* or drip or drips).ab,ti.
9.7 or 8
10.6 and 9
11.exp Infection/
12.exp Soft Tissue Infections/
13.exp Pneumonia, Viral/
14.exp Meningitis/
15.exp Urinary Tract Infections/
16.exp Sepsis/
17.(infected or infection* or infectious or infectious?disease* or (infect* adj disease*)).ab,ti.
18.(Sepsis or pneumonia* or mening*).ab,ti.
19.((urine or urinary tract) adj3 infect*).ab,ti.
20.((skin or soft tissue) adj3 infect*).ab,ti.
21.or/11-20
22.10 and 21
23.(continuous* or discontinu* or intermittent* or interval*).ab,ti.
24.exp Drug administration schedule/
25.23 or 24
26.22 and 25
27.randomi?ed.ab,ti.
28.randomized controlled trial.pt.
29.controlled clinical trial.pt.
30.placebo.ab.
31.clinical trials as topic.sh.
32.randomly.ab.
33.trial.ti.
34.27 or 28 or 29 or 30 or 31 or 32 or 33
35.(animals not (humans and animals)).sh.
36.34 not 35
37.26 and 36

EMBASE (OvidSP)
1.exp antibiotic agent/ad, do [Drug Administration, Drug Dose]
2.exp antiinfective agent/ad, do [Drug Administration, Drug Dose]
3.(anti-biotic* or antibiotic* or anti-infect* antiinfect* or antibacteria* or anti-bacteria*).ab,ti.
4.(microbicide* or anti-microbi* or antimicrobi* or microbi*).ab,ti.
5.(beta-lactam* or betalactam* or B-lactam* or aminoglycoside* or vancomycin).ab,ti.
6.or/1-5
7.exp intravenous drug administration/
8.(infusion* or intravenous* or drip or drips).ab,ti.
9.7 or 8
10.6 and 9
11.exp Infection/
12.exp infection control/
13.exp Soft Tissue Infection/
14.exp pneumonia/
15.exp virus pneumonia/
16.exp Meningitis/
17.exp virus meningitis/
18.exp Urinary Tract Infection/
19.exp intrauterine infection/
20.exp Sepsis/
21.(infected or infection* or infectious or infectious?disease* or (infect* adj disease*)).ab,ti.
22.(Sepsis or pneumonia* or mening*).ab,ti.
23.((urine or urinary tract) adj3 infect*).ab,ti.
24.((skin or soft tissue) adj3 infect*).ab,ti.
25.or/11-24
26.10 and 25
27.(continuous* or discontinu* or intermittent* or interval*).ab,ti.
28."dosage schedule comparison"/
29.exp drug intermittent therapy/
30.27 or 28 or 29
31.26 and 30
32.exp Randomized Controlled Trial/
33.exp controlled clinical trial/
34.randomi?ed.ab,ti.
35.placebo.ab.
36.*Clinical Trial/
37.randomly.ab.
38.trial.ti.
39.32 or 33 or 34 or 35 or 36 or 37 or 38
40.exp animal/ not (exp human/ and exp animal/)
41.39 not 40
42.31 and 41

CINAHL (EBSCOhost)
S25 S13 and S24
S24 S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23
S23 skin infect* or soft tissue infect*
S22 urine infec* or urinary tract infec*
S21 Sepsis or pneumonia* or mening*
S20 infected or infection* or infectious or infectious disease*
S19 (MH "Sepsis+")
S18 (MH "Urinary Tract Infections+")
S17 (MH "Meningitis+")
S16 (MH "Pneumonia, Viral") Interface -
S15 (MH "Soft Tissue Infections")
S14 (MH "Infection+")
S13 S9 and S12
S12 S10 or S11
S11 (continuous* or discontinu* or intermittent* or interval*)
S10 (MH "Drug Administration Schedule")
S9 S5 and S8
S8 S6 or S7
S7 (infusion* or intravenous* or drip or drips)
S6 (MH "Administration, Intravenous+") or (MH "Infusions, Intravenous")
S5 S1 or S2 or S3 or S4
S4 (beta-lactam* or betalactam* or B-lactam* or aminoglycoside* or
vancomycin)
S3 (microbicide* or anti-microbi* or antimicrobi* or microbi*) Search
S2 (anti-biotic* or antibiotic* or anti-infect* antiinfect* or antibacteria* or anti-bacteria)
S1 (MH "Antibiotics+")

ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED),
ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S)

#1 TS=(anti-biotic* or antibiotic* or anti-infect* antiinfect* or antibacteria* or anti-bacteria* or microbicide* or anti-microbi* or antimicrobi*) AND TS=(infusion* or intravenous* or drip or drips) AND TS=(infection* or infectious or Sepsis or pneumonia* or mening*) AND TS=((drug* same schedule*) or continuous* or discontinu* or intermittent* or interval*)
#2 TS=(clinical OR control* OR placebo OR random OR randomised OR randomized OR randomly OR random order OR random sequence OR random allocation OR randomly allocated OR at random) SAME TS=(trial* or group* or study or studies or placebo or controlled)
#3 #1 and #2

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

Last assessed as up-to-date: 13 September 2012.


DateEventDescription

29 May 2013AmendedCopy edits made.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

Jennifer Shiu selected trials for inclusion, extracted data, critically appraised included studies, analysed data, and wrote and revised the final report.

Erica Wang selected trials for inclusion, extracted data, critically appraised included studies, and revised the final report.

Aaron Tejani selected trials for inclusion, extracted data, critically appraised included studies, and revised the final report.

Michael Wasdell selected trials for inclusion and revised the final report.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

All authors: none known.

Aaron Tejani: no direct or indirect association with the pharmaceutical industry in the past 8 years.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

  • Revised wording of review objective.
  • Added clarification in the review objective for the term continuous intravenous infusions.
  • Added clarification that cross-over studies were excluded from the review.
  • Revised definition of adult to age 18 or older instead of older than 18 years.
  • Four independent authors (JS, EW, AT, MW) screened the titles and abstracts of the search results.
  • Data extraction and assessment of risk of bias of included studies were performed by JS, EW, and AT.
  • Default analysis was conducted with a random-effects model instead of a fixed-effect model (more conservative to assume underlying heterogeneity in included studies when different antibiotics, participant populations, and infection types were reviewed).
  • Added that GRADEpro was used to generate the 'Summary of findings' table.
  • Performed additional sensitivity analyses to determine the impact of studies using extended interval antibiotic infusions (instead of continuous infusions) and the impact of the use of open-label antibiotics.

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Adembri 2008 {published data only}
  • Adembri C, Fallani S, Cassetta MI, Arrigucci S, Ottaviano A, Pecile P, Mazzei T, De Gaudio R, Novelli A. Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion. International Journal of Antimicrobial Agents 2008;31(2):122-9.
Angus 2000 {published data only}
Bodey 1979 {published data only}
  • Bodey GP, Ketchel SJ, Rodriguez V. A randomized study of carbenicillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients. American Journal of Medicine 1979;67(4):608-16.
Buck 2005 {published data only}
  • Buck C, Bertram N, Ackermann T, Sauerbruch T, Derendorf H, Paar WD. Pharmacokinetics of piperacillin-tazobactam: intermittent dosing versus continuous infusion. International Journal of Antimicrobial Agents 2005;25(1):62-7.
Chytra 2012 {published and unpublished data}
  • Chytra I, Stepan M, Benes J, Pelnar P, Zidkova A, Bergerova T, Pradl R, Kasal E. Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial. Critical Care 2012;16:R113 (Epub ahead of print).
Cousson 2005 {published and unpublished data}
  • Cousson J, Floch T, Vernet-Garnier V, Appriou M, Petit JS, Jovenin N, Lamiable D, Hoizey G. Pharmacodynamic interest of ceftazidime continuous infusion vs intermittent bolus administration in patients with severe nosocomial pneumonia (French). Pathologie Biologie 2005;53:546-50.
DeJongh 2008 {published and unpublished data}
  • De Jongh R, Hens R, Basma V, Mouton JW, Tulkens PM, Carryn S. Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection. Journal of Antimicrobial Chemotherapy 2008;61(2):382-8.
Feld 1977 {published data only}
  • Feld R, Valdivieso M, Bodey GP, Rodriguez V. A comparative trial of sisomicin therapy by intermittent versus continuous infusion. The American Journal of the Medical Sciences 1977;274(2):179-88.
Feld 1984 {published data only}
  • Feld R, Rachlis A, Tuffnell PG, Duncan I, Moran L, Pinfold P, DeBoer G. Empiric therapy for infections in patients with granulocytopenia. Continuous v interrupted infusion of tobramycin plus cefamandole. Archives of Internal Medicine 1984;144(5):1005-10.
Georges 2005 {published data only}
  • Georges B, Conil JM, Cougot P, Decun JF, Archambaud M, Seguin T, Chabanon G, Virenque C, Houin G, Saivin S. Cefepime in critically ill patients: continuous infusion vs. an intermittent dosing regimen. International Journal of Clinical Pharmacology and Therapeutics 2005;43(8):360-9.
Hanes 2000 {published data only}
  • Hanes SD, Wood GC, Herring V, Croce MA, Fabian TC, Pritchard E, Boucher BA. Intermittent and continuous ceftazidime infusion for critically ill trauma patients. The American Journal of Surgery 2000;179(6):436-40.
Lagast 1983 {published data only}
Lau 2006 {published data only}
  • Lau WK, Mercer D, Itani KM, Nicolau DP, Kuti JL, Mansfield D, Dana A. Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection. Antimicrobial Agents and Chemotherapy 2006;50(11):3556-61.
Lipman 1999 {published data only}
Lubasch 2003 {published data only}
  • Lubasch A, Luck S, Hartmut L, Mauch H, Lorenz J, Bolcskei P, Welte T. Optimizing ceftazidime pharmacodynamics in patients with acute exacerbation of severe chronic bronchitis. Journal of Antimicrobial Chemotherapy 2003;51:659-64.
Nicolau 1999a {published data only}
  • Nicolau DP, McNabb J, Lacy MK, Li J, Quintiliani R, Nightingale CH. Pharmacokinetics and pharmacodynamics of continuous and intermittent ceftazidime during the treatment of nosocomial pneumonia. Clinical Drug Investigation 1999;18(2):133-9.
Nicolau 1999b {published data only}
  • Nicolau DP, Lacy MK, McNabb J, Quintiliani R, Nightingale CH. Pharmacokinetics of continuous and intermittent ceftazidime in intensive care unit patients with nosocomial pneumonia. Infectious Diseases in Clinical Practice 1999;8(1):45-9.
Nicolau 2001 {published data only}
  • Nicolau DP, McNabb J, Lacy MK, Quintiliani R, Nightingale CH. Continuous versus intermittent administration of ceftazidime in intensive care unit patients with nosocomial pneumonia. International Journal of Antimicrobial Agents 2001;17(6):497-504.
Okimoto 2009 {published data only}
  • Okimoto N, Ishiga M, Nanba F, Kibayashi T, Kishimoto M, Kurihara T, Honda Y, Asaoka N, Tamada S. Clinical effects of continuous infusion and intermittent infusion of meropenem on bacterial pneumonia in the elderly (Japanese). Nihon Kokyuki Gakkai Zasshi 2009;47(7):553-7.
Pedeboscq 2001 {published and unpublished data}
  • Pedeboscq S, Dubau B, Frappier S, Hernandez V, Veyssieres D, Winnock S, Pometan JP. Comparison of 2 administration protocols (continuous or discontinuous) of a time-dependent antibiotic, Tazocin (French). Pathologie Biologie (Paris) 2001;49(7):540-7.
Rafati 2006 {published data only}
  • Rafati MR, Rouini MR, Mojtahedzadeh M, Najafi A, Tavakoli H, Gholami K, Fazeli MR. Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients. International Journal of Antimicrobial Agents 2006;28(2):122-7.
Roberts 2007 {published and unpublished data}
  • Roberts JA, Boots R, Rickard CM, Thomas P, Quinn J, Roberts DM, Richards B, Lipman J. Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. Journal of Antimicrobial Chemotherapy 2007;59(2):285-91.
Roberts 2009b {published and unpublished data}
  • Roberts JA, Kirkpatrick CMJ, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. Journal of Antimicrobial Chemotherapy 2009;64(1):142-50.
Roberts 2009c {published and unpublished data}
  • Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Piperacillin penetration into tissue of critically ill patients with sepsis-bolus versus continuous administration?. Critical Care Medicine 2009;37(3):926-33.
Roberts 2010 {published and unpublished data}
  • Roberts JA, Kirkpatrick CMJ, Roberts MS, Dalley AJ, Lipman J. First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. International Journal of Antimicrobial Agents 2010;35:156-63.
Sakka 2007 {published data only}
  • Sakka SG, Glauner AK, Bulitta JB, Kinzig-Schippers M, Pfister W, Drusano GL, Sorgel F. Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial. Antimicrobial Agents and Chemotherapy 2007;51(9):3304-10.
van Zanten 2007 {published and unpublished data}
  • van Zanten ARH, Oudijk M, Nohlmans-Paulssen MKE, van der Meer YG, Girbes ARJ, Polderman KH. Continuous vs. intermittent cefotaxime administration in patients with chronic obstructive pulmonary disease and respiratory tract infections: pharmacokinetics/pharmacodynamics, bacterial susceptibility and clinical efficacy. British Journal of Clinical Pharmacology 2007;63(1):100-9.
Wright 1979 {published data only}
  • Wright JP, Potgieter PD, Forder AA, Botha P, Brinkworth G, Elisha G, Ferguson AD. Gentamicin and penicillin in the treatment of severe respiratory infections. South African Medical Journal 1979;55(6):197-200.
Wysocki 2001 {published and unpublished data}
  • Wysocki M, Delatour F, Faurisson F, Rauss A, Pean Y, Misset B, Thomas F, Timsit JF, Similowski T, Mentec H, Mier L, Dreyfuss D, and the study group. Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: prospective multicenter randomized study. Antimicrobial Agents and Chemotherapy 2001;45(9):2460-7.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Adembri 2010 {published data only}
  • Adembri C, Ristori R, Chelazzi C, Arrigucci S, Cassetta MI, De Gaudio AR, Novelli A. Cefazolin bolus and continuous administration for elective cardiac surgery: improved pharmacokinetic and pharmacodynamic parameters. Journal of Thoracic and Cardiovascular Surgery 2010;140:471-5.
Ambrose 1998 {published data only}
  • Ambrose PG, Quindliani R, Nightingale CH, Nicolau DP. Continuous vs. intermittent infusion of cefuroxime for the treatment of community-acquired pneumonia. Infectious Diseases in Clinical Practice 1998;7(9):463-70.
Benko 1996 {published data only}
  • Benko A, Cappelletty D, Kruse J, Rybak M. Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected gram-negative infections. Antimicrobial Agents and Chemotherapy 1996;40(3):691-95.
Bosso 1999 {published data only}
Buijk 2002 {published data only}
  • Buijk SLCE, Gyssens IC, Mouton JW, Van Vliet A, Verbrugh HA. Pharmacokinetics of ceftazidime in serum and peritoneal exudate during continuous versus intermittent administration to patients with severe intra-abdominal infections. Journal of Antimicrobial Chemotherapy 2002;49(1):121-8.
Burgess 2002 {published data only}
  • Burgess D, Waldrep T. Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered by continuous infusion and intermittent dosing. Clinical Therapeutics 2002;24(7):1090-1104.
DeRyke 2006 {published data only}
  • DeRyke CA, Kuti JL, Mansfield D, Dana A, Nicolau DP. Pharmacoeconomics of continuous versus intermittent infusion of piperacillin-tazobactam for the treatment of complicated intraabdominal infection. American Journal of Health System Pharmacy 2006;63(8):750-5.
Georges 1999 {published data only}
  • Georges B, Archambaud M, Saivin S, Decun J, Cougot P, Mazerolles M, Andrieu P, Suc C, Houin G, Chabanon G, Virenque C. Continuous versus intermittent cefepime infusion in critical care. Preliminary results (French). Pathologie Biologie 1999;47(5):483-85.
Grant 2002 {published data only}
  • Grant E, Kuti J, Nicolau D, Nightingale C, Quintiliani R. Clinical efficacy and pharmacoeconomics of a continuous-infusion piperacillin-tazobactam program in a large community teaching hospital. Pharmacotherapy 2002;22(4):471-83.
Hutschala 2009 {published data only}
  • Hutschala D, Kinstner C, Skhirdladze K, Thalhammer F, Muller M, Tschernko E. Influence of vancomycin on renal function in critically ill patients after cardiac surgery. Anesthesiology 2009;111:356-65.
James 1996 {published data only}
  • James J, Palmer S, Levine D, Rybak M. Comparison of conventional dosing versus continuous-infusion vancomycin therapy for patients with suspected or documented gram-positive infections. Antimicrobial Agents and Chemotherapy 1996;40(3):696-700.
Jaruratanasirikul 2002 {published data only}
Jaruratanasirikul 2005 {published data only}
  • Jaruratanasirikul S, Sriwiriyajan S, Punyo J. Comparison of the pharmacodynamics of meropenem in patients with ventilator-associated pneumonia following administration by 3-hour infusion or bolus injection. Antimicrobial Agents and Chemotherapy 2005;49(4):1337-39.
Jaruratanasirikul 2009 {published data only}
  • Jaruratanasirikul S, Sudsai T. Comparison of the pharmacodynamics of imipenem in patients with ventilator-associated pneumonia following administration by 2 or 0.5h infusion. Journal of Anitimicrobial Chemotherapy 2009;63:560-63.
Jaruratanasirikul 2010 {published data only}
  • Jaruratanasirikul S, Julamanee J, Sudsai T, Saengsuwan P, Jullangkoon M, Ingviya N, Jarumanokul R. Comparison of continuous infusion versus intermittent infusion of vancomycin in patients with methicillin-resistant Staphylococcus aureus. Journal of the Medical Association of Thailand 2010;93(2):172-6.
Kirkpatrick 2001 {published data only}
  • Kickpatrick C, Howard G, Vella-Brincat J. Comment: serum concentrations of cefuroxime after continuous infusion in coronary bypass graft patients. The Annals of Pharmacotherapy 2001;53:1295-96.
Klepser 1998 {published data only}
  • Klepser M, Patel K, Nicolau D, Quintiliani R, Nightingale C. Comparison of bactericidal activities of intermittent and continuous infusion dosing of vancomycin against methicillin-resistant staphylococcus aureus and enterococcus faecalis. Pharmacotherapy 1998;18(5):1069-74.
Kojika 2005 {published data only}
  • Kojika M, Sato N, Hakozaki M, Suzuki Y, Takahasi G, Endo S, Suzuki K, Wakabayasi G. A preliminary study of the administration of carbapenem antibiotics in sepsis patients on the basis of administration time. The Japanese Journal of Antibiotics 2005;58(5):452-7.
Langgartner 2007 {published data only}
  • Langgartner J, Lehn N, Gluck T, Herzig H, Kees F. Comparison of the pharmacokinetics of piperacillin and sulbactam during intermittent and continuous intravenous infusion. Chemotherapy 2007;53:370-77.
Li 2005 {published data only}
  • Li C, Kuti JL, Nightingale CH, Mansfield DL, Dana A, Nicolau DP. Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection. Journal of Antimicrobial Chemotherapy 2005;56(2):388-95.
Lorente 2006 {published data only}
  • Lorente L, Lorenzo L, Martin MM, Jimenez A, Mora ML. Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli. Annals of Pharmacotherapy 2006;40:219-23.
Martin 1998 {published data only}
  • Martin C, Cotin A, Giraud A, Beccani-Argeme M, Alliot P, Mallet MN, Argeme M. Comparison of concentrations of sulbactam-ampicillin administered by bolus injections or bolus plus continuous infusion in tissues of patients undergoing colorectal surgery. Antimicrobial Agents and Chemotherapy 1998;42(5):1093-97.
McNabb 2001 {published data only}
Nicasio 2007 {published data only}
Pass 2001 {published data only}
  • Pass SE, Miyagawa CI, Healy DP, Ivey TD. Serum concentrations of cefuroxime after continuous infusion in coronary bypass graft patients. Annals of Pharmacotherapy 2001;35:409-13.
Schuster 2009 {published data only}
  • Schuster KM, Wilson D, Schulman CI, Pizano LR, Ward CG, Namias N. Continuous infusion oxacillin for the treatment of burn wound cellulitis. Surgical Infections 2009;10(1):41-5.
Seguin 2009 {published data only}
  • Seguin P, Verdier M, Chanavaz C, Engrand C, Laviolle B, Donnio P, Malledant Y. Plasma and peritoneal concentration following continuous infusion of cefotaxime in patients with secondary peritonitis. Journal of Antimicrobial Chemotherapy 2009;63:564-67.
Thalhammer 1999 {published data only}
  • Thalhammer F, Traunmuller F, El Menyawi I, Frass M, Hollenstein U, Locker G, Stoiser B, Staudinger T, Thalhammer-Scherrer R, Burgmann H. Continuous infusion versus intermittent administration of meropenem in critically ill patients. Journal of Antimicrobial Chemotherapy 1999;43:523-27.
Vinks 2003 {published data only}
  • Vinks A, Hollander J, Overbeek S, Jelliffe R, Mouton J. Population pharmacokinetic analysis of nonlinear behavior of piperacillin during intermittent of continuous infusion in patients with cystic fibrosis. Antimicrobial Agents and Chemotherapy 2003;47(2):541-47.
Vuagnat 2004 {published data only}
Waltrip 2002 {published data only}
  • Waltrip T, Lewis R, Young V, Farmer M, Clayton S, Myers S, Gray L, Galandiuk S. A pilot study to determine the feasibility of continuous cefazolin infusion. Surgical Infections 2002;3(1):5-9.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Cousson 2010 {unpublished data only}
  • Cousson J, Floch T, Hoizey G, Nicolai F, Guillard T, Vernet-Garnier V. Comparison of pharmacodynamic interest of ceftazidime continuous infusion vs intermittent bolus administration in epithelial lining fluid concentrations of patients with severe nosocomial pneumonia. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (poster) 2010.
NCT00891423 {unpublished data only}
  • Johnson P. A Randomised controlled crossover pilot study of meropenem standard 30 minute infusion versus prolonged 3 hour infusion in intensive care patients. Available at http://www.clinicaltrials.gov, last updated July 2012. Accessed November 14, 2012.
NCT01158937 {unpublished data only}
  • Cortes D. Pharmacokinetic study of extended infusion meropenem in adult cystic fibrosis patients with exacerbation of pulmonary infection. Available at http://www.clinicaltrials.gov, last updated June 2012. Accessed November 14, 2012.
NCT01198925 {unpublished data only}
  • Decruyenaere J. Assessment of the optimal dosing of piperacillin-tazobactam in intensive care unit patients: extended versus continuous infusion. Available at http://www.clinicaltrials.gov, last updated July 2012. Accessed November 14, 2012.
NCT01379157 {unpublished data only}
  • Jaruratanasirikul S. The pharmacodynamics of imipenem in critically ill patients with ventilator-associated pneumonia following administration by 4h or 0.5h infusion. Available at http://www.clinicaltrials.gov, last updated December 2011. Accessed November 14, 2012.
NCT01577368 {unpublished data only}
  • Gil-Navarro MV. Efficacy and safety of piperacillin-tazobactam continuous infusion vs intermittent infusion for complicated or nosocomial Pseudomonas aeruginosa infection or suspected infection. Available at http://www.clinicaltrials.gov, last updated April 2012. Accessed November 14, 2012.
NCT01667094 {unpublished data only}
  • Peleg A. Continuous infusion anti-pseudomonal beta-lactams for the treatment of acute, infective pulmonary exacerbations in cystic fibrosis: a prospective randomised controlled trial. Available at http://www.clinicaltrials.gov, last updated August 2012. Accessed November 14, 2012.
NCT01720940 {unpublished data only}
  • Fisher D. Reducing nephrotoxicity of vancomycin: a prospective, randomised study of continuous versus intermittent infusion of vancomycin. Available at http://www.clinicaltrials.gov, last updated November 2012. Accessed November 14, 2012.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
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Craig 1998
Drusano 2004
Florea 2003
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