Pre-admission antibiotics for suspected cases of meningococcal disease

  • Review
  • Intervention

Authors


Abstract

Background

Meningococcal disease can lead to death or disability within hours after onset. Pre-admission antibiotics aim to reduce the risk of serious disease and death by preventing delays in starting therapy before confirmation of the diagnosis.

Objectives

To study the effectiveness and safety of pre-admission antibiotics versus no pre-admission antibiotics or placebo, and different pre-admission antibiotic regimens in decreasing mortality, clinical failure and morbidity in people suspected of meningococcal disease.

Search methods

We updated searches of CENTRAL (2013, Issue 4), MEDLINE (1966 to April week 4, 2013), EMBASE (1980 to May 2013), Web of Science (1985 to May 2013), CAB Abstracts (1985 to May 2013), LILACS (1982 to May 2013) and prospective trials registries to May 2013.

Selection criteria

Randomised controlled trials (RCTs) or quasi-RCTs comparing antibiotics versus placebo or no intervention, in people with suspected meningococcal infection, or different antibiotics administered before admission to hospital or confirmation of the diagnosis.

Data collection and analysis

Two review authors independently assessed trial quality and extracted data from the search results. We calculated the risk ratio (RR) and 95% confidence interval (CI) for dichotomous data. We included only one trial so data synthesis was not performed. We assessed the overall quality of the evidence using the GRADE approach.

Main results

We found no RCTs that compared pre-admission antibiotics versus no pre-admission antibiotics or placebo. One open-label, non-inferiority RCT, conducted during an epidemic in Niger, evaluated a single dose of intramuscular ceftriaxone versus a single dose of intramuscular long-acting (oily) chloramphenicol. Ceftriaxone was not inferior to chloramphenicol in reducing mortality (RR 1.2, 95% CI 0.6 to 2.6; N = 503; 308 confirmed meningococcal meningitis; 26 deaths; moderate-quality evidence), clinical failures (RR 0.8, 95% CI 0.3 to 2.2; N = 477, 18 clinical failures; moderate-quality evidence) or neurological sequelae (RR 1.3, 95% CI 0.6 to 2.6; N = 477; 29 with sequelae; low-quality evidence). No adverse effects of treatment were reported. Estimated treatment costs were similar. No data were available on disease burden due to sequelae.

Authors' conclusions

We found no reliable evidence to support or refute the use of pre-admission antibiotics for suspected cases of non-severe meningococcal disease. Evidence of moderate quality from one RCT indicated that single intramuscular injections of ceftriaxone and long-acting chloramphenicol were equally effective, safe and economical in reducing serious outcomes. The choice between these antibiotics would be based on affordability, availability and patterns of antibiotic resistance.

Further RCTs comparing different pre-admission antibiotics, accompanied by intensive supportive measures, are ethically justifiable in participants with severe illness, and are needed to provide reliable evidence in different clinical settings.

Plain language summary

Pre-admission antibiotics for suspected cases of meningococcal disease

Meningococcal disease is a contagious, bacterial disease caused by Neisseria meningitidis (N. meningitidis) that, if not treated early, can rapidly lead to death or disabling consequences such as visual, hearing and intellectual impairments.

Administering antibiotics as soon as the condition is suspected and before the diagnosis is confirmed, has been advocated to prevent death and disabling consequences. However, this might result in treating people without the disease with unnecessary antibiotics.

This review update evaluated the effectiveness and safety of pre-admission antibiotics versus no pre-admission antibiotics or placebo and different pre-admission antibiotic regimens in preventing death, lack of clinical improvement and disabling consequences in those suspected to have meningococcal disease.

We found no randomised controlled trials comparing pre-admission antibiotics with placebo or no intervention (up to date 3 May 2013). We identified one well conducted trial in Niger, Africa during an epidemic of meningococcal disease in 2005 including 510 adults and children older than two months, suspected to have meningococcal disease but who were not severely ill. They were randomised to receive a single injection of either ceftriaxone (a newer antibiotic) (251 participants) or a long-acting form of chloramphenicol (an older antibiotic) (259 participants) before confirming the diagnosis. Médecins Sans Frontières sponsored this study.

Both antibiotics were effective in preventing death over the first 72 hours in 477 (95%) of the 503 evaluable participants. In the 308 participants with confirmed meningococcal disease, 154/160 (96%) given the newer antibiotic and 143/148 (95.5%) given the older antibiotic survived. Similar proportions with confirmed disease given the newer antibiotic (3/160; 2%) and the older antibiotic (2/148; 2%) did not show a clinical improvement. Those developing disabling consequences with the newer antibiotic (14/154;9%) and with the older antibiotic (9/143; 6%) were similar. However, larger trials from other parts of the world are needed to be fully confident that the two treatments are equally effective. No serious adverse events were reported with either antibiotic.

Due to the serious complications of meningococcal disease, it would be difficult, for ethical reasons, to undertake randomised controlled trials comparing the use of antibiotics as soon as the diagnosis is suspected versus no antibiotics. Further trials comparing different antibiotics in suspected meningococcal disease, especially in more severe forms, will provide insights that could help prevent death and the serious consequences of this disease.

Summary of findings(Explanation)

Summary of findings for the main comparison. Cephalosporin versus long-acting (oily) chloramphenicol compared in people suspected to have meningococcal disease
  1. 1Basis of the assumed risk: control group risk.
    2Effect estimate: consistent with non-inferiority of ceftriaxone versus chloramphenicol.
    3No serious study limitations: block randomised using off-site computer-generated codes in blocks of 20; allocation concealed in numbered, sealed, opaque envelopes; recruitment was by personnel not involved in generating random sequence; baseline variables matched in intervention arms; open-label trial but outcome was objective; outcomes completely and adequately reported; no other biases.
    4No serious inconsistency: results for all participants and in subgroups were consistent.
    5Serious imprecision: sample size was estimated to demonstrate non-inferiority for the primary outcome and not for neurological sequelae (secondary outcome). A sample size of 175 individuals with confirmed meningococcal meningitis per group (350 total) was needed for the primary outcome with a one-sided 5% significance level, 80% power and assuming 10% drop-outs. Only 308 participants were confirmed to have meningococcal meningitis; thus trial may be under-powered to detect non-inferiority for neurological outcomes. Downgraded by 1.
    6No serious imprecision: trial was adequately powered to demonstrate non-inferiority. Not downgraded.
    7Publication bias unlikely: search for trials was comprehensive. Not downgraded.
    8Parallel-group, open-label, non-inferiority trial.
    9Serious indirectness: trial excluded infants, pregnant or breastfeeding women, and those with serious illness (in non-reactive coma or with convulsions). Downgraded by 1.
    10Clinical failure: composite of: a) state of consciousness remaining severely altered (Glasgow coma score < 11 at 24 h or < 13 at 48 h), b) no improvement in the state of consciousness since 0 h, c) appearance or worsened neurological symptoms since 0 h, d) repeated or persistent convulsions, or e) axillary temperature above 38.5 degrees Celsius in the absence of other evident infectious pathological changes.
    11Neurological sequelae: judged on gross clinical abnormality.
    12Serious indirectness: follow-up was too short to detect neurological sequelae adequately. Downgraded by 1.
    13No serious imprecision: sample size of 350 required to demonstrate non-inferiority for primary outcome, but sample size adequately powered to demonstrate non-inferiority for this secondary outcome as well. Not downgraded.

What are the effects of cephalosporin versus long-acting (oily) chloramphenicol in people suspected to have meningococcal disease?
Patient or population: people suspected to have meningococcal disease (adults and children)
Settings: primary care centres in a low-income country in Africa during an epidemic
Intervention: intramuscular ceftriaxone (100 mg/kg; max 4 g) single dose
Comparison: long-acting (oily) chloramphenicol (100 mg/kg; max 3 g) single dose
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
long-acting (oily) chloramphenicol intramuscular ceftriaxone
Death - in all participants - short-term
Follow-up: 72 hours
47 per 1000 1 57 per 1000
(27 to 120)
RR 1.21
(0.57 to 2.56)2
503
(1 study8)
⊕⊕⊕⊝
moderate 3,4,5,6,7
All outcomes in this table are from one trial (Nathan 2005) that randomised 510 participants to either intervention
Death - in confirmed cases of meningococcal meningitis (subgroup)
Follow-up: 72 hours
34 per 1000 1 38 per 1000
(12 to 121)
RR 1.11
(0.35 to 3.56)2
308
(1 study8)
⊕⊕⊕⊝
moderate 3,4,6,7
 
Clinical failure - in all participants - short-term
Composite clinical criteria10
Follow-up: 24 to 48 hours
41 per 1000 1 34 per 1000
(13 to 84)
OR 0.83
(0.32 to 2.15)2
477
(1 study8)
⊕⊕⊕⊝
moderate 3,4,6,7,9
 
Clinical failure - in confirmed cases of meningococcal meningitis (subgroup)
Composite clinical criteria10
Follow-up: 24 to 48 hours
14 per 1000 1 19 per 1000
(3 to 107)
OR 1.39
(0.23 to 8.47)2
308
(1 study8)
⊕⊕⊕⊝
moderate 3,4,6,7,9
 
Neurological sequelae - in all participants- short-term
Clinical assessment11
Follow-up: 72 hours
53 per 1000 1 68 per 1000
(33 to 139)
RR 1.29
(0.63 to 2.62)2
477
(1 study8)
⊕⊕⊝⊝
low 3,4,7,9,12,13
 
Neurological sequelae - in confirmed cases of meningococcal meningitis (subgroup)
Clinical assesment11
Follow-up: 72 hours
63 per 1000 1 91 per 1000
(41 to 203)
RR 1.44
(0.65 to 3.23)
297
(1 study8)
⊕⊝⊝⊝
very low 3,4,5,7,9,12
 
Adverse events- short-term
Follow-up: 72 hours
See commentSee commentNot estimable0
(1 study8)
See commentNo adverse events detected with either intervention
*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; OR: odds ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

This is an update of a Cochrane review first published in the Cochrane Database of Systematic Reviews 2008, Issue 1 (Sudarsanam 2008) and updated in 2011 (Sudarsanam 2011).

Description of the condition

Meningococcal disease is a contagious, bacterial disease caused by Neisseria meningitidis (N. meningitidis). N. meningitidis strains are classified primarily into serogroups based on the type of polysaccharide capsule expressed. While 13 serogroups have been described  (A, B, C, D, 29E, H, I, K, L, Y, W-135, X and Z), most of the disease is caused by strains belonging to serogroups A, B, C, X, Y and W-135 (Hill 2010). Serogroups B and C account for most of the cases in Europe and the Americas (Al-Tawfiq 2010). Serogroups A and C are responsible for most of the cases in Asia and Africa (Schwartz 1989; Sinclair 2010). In the African 'meningitis belt' that extends from Ethiopia in the east to Senegal in the west, newer strains of serogroup A meningococcal disease have occurred in epidemic form that have posed a recurrent threat to public health, and rates of meningococcal disease in this region are several times higher than in high-income countries (WHO 2007).

In a systematic review of 132 studies published between 1980 to 2008 that reported on the incidence of disabling sequelae of bacterial meningitis in 18,183 adult and child survivors of bacterial meningitis, Haemophilus influenzae (H. influenzae) type b (Hib) was the most common cause of bacterial meningitis (35.5%), with pneumococcus accounting for 19.6%, meningococcus for 16.4% and other pathogens accounting for 12% (Edmond 2010). However, the relative frequency of disease caused by N. meningitidis has increased in recent years due to the widespread and successful use of an effective vaccine for H. influenzae B and a conjugate vaccine for Streptococcus pneumoniae (S. pneumoniae), leaving N. meningitidis as the most common cause of bacterial meningitis, particularly in some parts of Africa where surveys indicate that N. meningitidis was responsible for 60% to 70% of cases of meningitis (Hsu 2009; WHO 2010). Meningococcal disease is commonest in children (due to waning maternal antibody levels), adolescents and young adults (WHO 2010).

Up to 5% to 10% of a population may be asymptomatic carriers of N. meningitidis, in whom the bacteria are harmless commensals of the nasopharyngeal mucosa (WHO 2010). Meningococcal disease is caused by a combination of bacterial virulence factors (particularly the ability to express capsules) and host susceptibility; including age, prior viral infection, overcrowding, smoking, co-infections and genetic polymorphisms (Hill 2010; Stephens 2007). Meningococcal disease is spread by person-to-person contact through respiratory droplets from infected people. Meningococcal disease attack rates can be as high as 100 to 800 cases per 100,000 but individual communities have, on occasion, reported rates as high as 1000 per 100,000 (WHO 2004). In 1996, the largest outbreak ever reported occurred in the 'meningitis belt'; the total number of cases was over 250,000 with 25,000 reported deaths (Rosenstein 2001).

Mortality

The onset of symptoms of meningococcal disease is sudden and death can follow within hours (Borg 2009; Hackett 2002; Perea-Milla 2009). It is estimated that around 50,000 people, mostly children and young adults, die every year from among the approximately 500,000 cases of meningococcal disease reported annually (Granoff 2009). Case fatality rates from invasive meningococcal disease are usually in the range of 10% to 15%, but mortality rates depend on the type and severity of invasive disease, and are greatest in patients with meningococcaemia, fulminant septicaemia and shock (50% to 60%), followed by those with meningitis and associated septicaemia (up to 25%), and are lowest for meningitis without sepsis (< 5%) (Borg 2009; Ferguson 2002; Hill 2010).

Meningococcal disease differs from other Gram-negative bacterial infections by the release of lipopolysaccharide endotoxins and vesicles that cause rapidly progressing skin haemorrhage and necrosis, disseminated intravascular coagulation (DIC) and shock (Brandtzaeg 2005). Other meningococcal virulence factors have been identified such as capsular polysaccharides (serogroups A, B, C, W-135, Y and X), and a number of surface-expressed adhesive proteins, including factor H-binding protein (fHbp), Opa and Opc, that contribute to the ability to avoid innate immune responses and which aid adherence to mucosal surfaces (Hill 2010; Rouphael 2012; Schneider 2006; Stephens 2007). Capsules of N. meningitidis help with transmission and colonisation and the ability to express and modify capsule is associated with its epidemic potential (Stephens 2007).

Sequelae

There is significant resultant morbidity in 10% to 15% of survivors (Baraff 1993; Borg 2009); from reports published between 1988 to 2008 the pooled median risk (and inter-quartile range) of developing at least one major sequela after hospital discharge in people with invasive meningococcal disease was 7.2% (4.3% to 11.2%) (Edmond 2010). The risk of major sequelae is greatest in the African and South-east Asian regions and in low-income countries (Edmond 2010; Ramakrishnan 2009). Major sequelae are permanent neurological defects caused by pathophysiological inflammatory responses during infections. These involve increased blood-brain barrier (BBB) permeability; a large compartmentalised inflammatory response in the subarachnoid space, with pronounced increase in concentrations of tumour necrosis factor α (TNF-α), interleukins, chemokines and other mediators; and increased resistance to the outflow of cerebrospinal fluid and oedema of the brain leading to elevated intracranial pressure and alterations in cerebral blood flow (Hill 2010; Stephens 2007; Tunkel 1993). The alteration in the permeability of the BBB is caused in part by inflammatory mediators such as matrix metalloproteinases (particularly MMP-8), leading to disassembly of brain microvascular endothelial cell junction components and cell adhesion during meningococcal infection (Schubert-Unkmeir 2010).

The resultant neurological deficits include hearing loss or deafness (most common), vision defects, speech disorders, amputation of limbs or digits and scarring of skin (due to extensive necrosis), hydrocephalus, mental retardation, spasticity, paralysis and seizures, and present a long-term and serious challenge for families with limited means to care for a disabled child, especially in resource-poor settings (Borg 2009; Edmond 2010; Ramakrishnan 2009; WHO 2004). Prevalence estimates of these sequelae do not account for the increased mortality or social drift further down the socio-economic ladder, in those with such disabilities, particularly in low-income families and in resource-poor settings; leading to under-estimates of prevalence in surveys of post-meningitis sequelae (Edmond 2010). Even in high-income countries, impaired cognitive functions and behavioural sequelae result in impairments in many areas of social, educational, occupational functioning and quality of life after bacterial meningitis (Borg 2009).

These estimates of the sequelae of invasive meningococcal disease also do not account for deaths that might have occurred before admission to hospital; due to difficulties in establishing a clinical diagnosis, lack of clinical suspicion in areas not prone to epidemics and delays in instituting effective treatment in areas with health systems unable to respond to these needs. Meningococcal disease has many clinical manifestations and is often difficult to differentiate from common, less serious illnesses. The infectious syndromes associated with meningococcaemia include meningitis, bacteraemia, meningococcaemia, pneumonia, epiglottitis, otitis and focal diseases such as urethritis, conjunctivitis, arthritis and pericarditis (Stephens 2007). Clinical suspicion of meningococcal infection may vary with the geographic locale of the study, the age group of the patients being studied (children or adults) and the criteria used for clinical diagnosis of meningococcal disease. Meningococcal disease is suspected when there is a characteristic skin rash, headache, weakness, fever, vomiting and depressed sensorium, with or without evidence of sepsis (Hahné 2006; Harnden 2006).

Diagnosis

The definitive diagnosis of meningococcal infection requires isolation of N. meningitidis (a Gram-negative intracellular diplococcus that ferments glucose and maltose) from a sterile body fluid such as blood; cerebrospinal fluid (CSF); synovial, pleural or pericardial fluids. In meningococcal meningitis, sterilisation of the CSF occurs rapidly (within two hours) after the instigation of antibiotics (Kanegaye 2001). Culture confirmation occurs in only a third of clinically diagnosed cases, yet meningococcal DNA can be detected in 88% of admission blood samples from the same patients, and molecular techniques using polymerase chain reaction (PCR) on the CSF are informative, even after starting antibiotics (Hackett 2002). PCR of the blood is highly specific for N. meningococcus, can be used for subgroup and serotyping, and may even be of prognostic significance; quantitative PCR reveals higher bacterial DNA load to be associated with greater severity of illness (El Bashir 2003) and greater risk of mortality (Hackett 2002). PCR is more sensitive than culture, particularly in the context of pre-admission treatment. The NICE guideline (NICE 2010) recommends that blood real-time PCR should be done to confirm a diagnosis of meningococcal disease; and that CSF should also be submitted for PCR if the CSF culture is negative. However, these techniques may not be readily available in resource-poor settings.

Description of the intervention

The use of antibiotics has dramatically reduced the mortality due to meningococcal disease. Once diagnosis is confirmed, crystalline penicillin is commonly given intravenously every four to six hours for 7 to 10 days in individuals not at risk of anaphylaxis. Rates of bacterial penicillin resistance vary. In areas where penicillin resistance predominates, third-generation cephalosporins such as cefotaxime and ceftriaxone are recommended by the SIGN guidelines (SIGN 2008) and the NICE guidelines (NICE 2010), respectively. However, quinolones are not approved for routine paediatric usage and ceftriaxone requires parenteral administration (Girgis 1998). Sulphonamides are now rarely used, as intermediate resistance to these drugs is reported from some areas (Eickhoff 1965). Oral macrolide and beta-lactam antibiotics are also effective in treating invasive meningococcal disease and averting mortality, though their routine use in suspected cases of invasive meningococcal disease may be dependant on 'indication bias' (bias in initiating oral versus parenteral or no antibiotics due to perceptions of mild to moderate, as opposed to severe, illness severity) (Perea-Milla 2009). A Cochrane review studied osmotic agents for bacterial meningitis and found no benefit (Wall 2013). As review by Li 2011 is currently evaluating the role of anti-cytokine and anti-endotoxin therapies for patients with suspected or proven meningococcal disease.

The efficacy of short courses of ceftriaxone and oily chloramphenicol has been demonstrated in the treatment of meningococcal meningitis in adults (El Filali 1993). In one epidemic, a single intramuscular injection of an oily suspension of long-acting chloramphenicol proved as effective as a five-day course of crystalline penicillin (WHO 1995). Chloramphenicol is bactericidal for N. meningitidis and penetrates the BBB more effectively than do beta-lactam antibiotics (Pecoul 1991). Intravenous (IV) cefotaxime plus either ampicillin or amoxacillin are recommended in children under three years of age (NICE 2010). Cefotaxime or ceftriaxone, often combined with vancomycin, are also used in high-income countries until the causative agent has been identified (Stephens 2007). A systematic review did not reveal important differences between third-generation cephalosporins or conventional antibiotics in averting death or deafness in people with bacterial meningitis (Prasad 2007).

A recent Cochrane review (Zalmanovici 2011) found that rifampicin, ciprofloxacin, ceftriaxone or penicillin are effective for prophylaxis, with rifampicin resistance being an issue, as mentioned above.

How the intervention might work

The aim of pre-admission antibiotic therapy is to reduce the risk of serious disease by preventing delays in starting therapy. This delay may occur if confirmation of meningococcus is sought before instigation of therapy. It is believed that if treatment is begun early, the severe complications and mortality due to the disease may be avoided or minimised, by preventing or reducing the effects of the systemic inflammatory response of the body, including reduced inflammatory cytokines and chemokines, and endotoxin production; and also lead to a reduction in bacterial proliferation (Brandtzaeg 1989; Kanegaye 2001; Wang 2000). Preventing meningococcal shock is dependent on reducing endotoxin levels and meningococcal bacterial load (Hackett 2002), and given that meningococcaemia is a rapidly progressive disease, with an estimated doubling time of meningococci of 30 to 40 minutes (Stephens 2007), the time available for early administration of antibiotics is limited.

With this in mind, the concept of empiric antibiotic use based on clinical suspicion, before a confirmed bacteriological diagnosis is made; or the 'pre-admission' use of antibiotics prescribed or administered by the doctor in first contact with the patient, has been found effective in reducing mortality and complications due to meningococcal disease in observational studies (Hahné 2006; Perea-Milla 2009; Strang 1992; Wang 2000). 

Why it is important to do this review

Standard policy in many countries (Hahné 2006), backed by recommendations from professional associations, mandates the initiation of antibiotics, particularly penicillin, once criteria for bacterial meningitis are met. Some contend that instigating antibiotic therapy requires that the prior collection of CSF for bacterial confirmation or the use of PCR of the CSF; though there is a lack of consensus on the need for confirmation of the diagnosis before starting antibiotics (Hahné 2006). The NICE guideline states that children with suspected meningitis and meningococcal disease should have a lumbar puncture unless specifically contraindicated (NICE 2010).

However, it is not clear whether treating all suspected cases is associated with improved outcomes, since the effects of confounding are difficult to interpret in the observational studies supporting this view (Hahné 2006; Harnden 2006; Keeley 2006; Sorensen 1998).

We did not identify any trial comparing pre-admission antibiotics to no antibiotic prior to confirmation of meningococcal meningitis. We identified one trial that demonstrated the non-inferiority of a single dose of intramuscular ceftriaxone versus a single dose of intramuscular long-acting (oily) chloramphenicol in reducing serious outcomes.

This review update sought additional trials assessing the use of antibiotic therapy in suspected cases of meningococcal disease, and those that compared different classes of antibiotics used for this infection, before confirmation of the diagnosis.

Objectives

To study the effectiveness and safety of pre-admission antibiotics versus no pre-admission antibiotics or placebo, and different pre-admission antibiotic regimens in decreasing mortality, clinical failure and morbidity in people suspected of meningococcal disease.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) or quasi-RCTs.

Types of participants

People of all ages who were suspected to have meningococcal infection in whom antibiotics were started presumptively before confirmation of the diagnosis, or transfer to hospital.

Trials which looked at treatment of 'meningitis' or 'bacterial meningitis', where it may not have been possible to distinguish the results that applied to meningococcal disease, were treated as having 'suspected meningococcal infection'.

Types of interventions

  1. Antibiotic treatment versus placebo or no intervention.

  2. Any antibiotic versus another antibiotic from a different class.

  3. Combinations of antibiotics versus another antibiotic or combinations of other antibiotics.

Pre-admission antibiotic treatment refers to use of antibiotic treatment for an initial dose, or doses, by any route before the diagnosis is confirmed.

Types of outcome measures

Primary outcomes
  1. Mortality: death before reaching hospital, in hospital, or within a month of discharge or leaving the hospital.

  2. Lack of clinical improvement: as defined by individual trials.

  3. Morbidity: persistent neurological defects in the form of vision and hearing loss, speech disorders, persistent cognitive or intellectual impairment, and paralysis, or any other recorded persistent neurological defects.

Secondary outcomes
  1. Burden of disease: on the family, individual or the caregiver; as reported using a validated scale or measure.

  2. Adverse events: antibiotic-related clinical adverse effects.

  3. Economic costs of the intervention: if reported as done alongside the conduct of included RCTs.

We grouped morbidity, among primary outcomes, and all secondary outcomes by time. We defined 'short-term' as less than six weeks; 'medium-term' as over six weeks to six months; and 'long-term' as more than six months after the onset of symptoms subsequently confirmed to be due to meningococcal meningitis.

Search methods for identification of studies

Electronic searches

For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 4, part of The Cochrane Library, www.thecochranelibrary.com (accessed 6 May 2013), which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to April week 4, 2013), EMBASE (1980 to May 2013), Web of Science (1985 to May 2013), CAB Abstracts (1985 to May 2013) and LILACS (1982 to May 2013). See Appendix 1 for details of previous searches.

We used the following search terms to search MEDLINE and CENTRAL. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity-maximising version (2008 revision); Ovid format (Lefebvre 2011). The search strategy was adapted for EMBASE (Appendix 2), Web of Science (Appendix 3), LILACS (Appendix 4) and CAB Abstracts (Appendix 5). We applied no language or publication restrictions.

The PRISMA figure summarises this process Figure 1.

Figure 1.

Study flow diagram.

MEDLINE (OVID)

1 exp Meningococcal Infections/
2 exp Neisseria meningitidis/
3 (neisseria adj2 mening*).tw.
4 meningococc*.tw.
5 Meningitis/
6 meningit*.tw.
7 or/1-6
8 exp Anti-Bacterial Agents/
9 antibiotic*.tw,nm.
10 (penicillin* or cefotaxim* or ampicillin* or sulfa* or ciprofloxacin* or norfloxacin* or ofloxacin* or quinol* or fluoroquinol* or fluoro-quinol* or ceftriaxon* or rifampi* or azithromyci* or minocyclin* or macrolid* or cephalosporin*).tw,nm.
11 or/8-10
12 Patient Admission/
13 (patient* adj2 (admis* or admit*)).tw.
14 ((pre or before or prior or previous) adj2 hospital*).tw.
15 ((previous or prior or before) adj (admit* or admiss*)).tw.
16 (preadmit* or pre admit* or pre-admit* or preadmiss* or pre admiss* or pre-admiss*).tw.
17 empiric.tw.
18 or/12-17
19 7 and 11 and 18

Searching other resources

In addition, we searched the WHO International Clinical Trials Registry Platform (WHO ICTRP) Search Portal (http://apps.who.int/trialsearch/default.aspx), ClinicalTrials.gov (http://clinicaltrials.gov) and the ISRCTN register (http://www.controlled-trials.com/isrctn/search.html) for ongoing and completed clinical trials, using the search terms 'meningococcal' AND 'meningitis' (searched on 3 May 2013). We searched the references of all identified studies, as well as major reviews, for additional studies.

Data collection and analysis

Selection of studies

Two review authors (TS, PR) independently inspected each reference identified by the electronic searches and applied the inclusion criteria. Two review authors (TS, PR) independently inspected the full article when trials were possibly relevant but where further details were necessary for confirmation that inclusion criteria were met, and in cases of disagreement. A third review author (PT) was consulted when disagreements persisted. We discarded reports that were clearly irrelevant. We recorded studies on pre-admission antibiotics that did not fulfil the inclusion criteria along with the reasons for their exclusion in the Characteristics of excluded studies table.

Data extraction and management

Two review authors (TS, PR) independently extracted data. The data extraction was discussed, decisions documented and, where necessary, we contacted the trial authors for clarification. A third review author (PT) independently checked the extracted data.

We extracted, checked and recorded the following data.

  1. Characteristics of trials: design, date, location and setting of trial; publication status; sponsor of trial (specified, known or unknown); duration of follow-up.

  2. Characteristics of participants: age; number of participants in each group; gender, setting, location.

  3. Characteristics of interventions: type of antibiotics; dose, mode of administration, schedule; length of treatment and follow-up.

  4. Characteristics of outcome measures: we recorded data for events listed under Types of outcome measures for each intervention arm.

  5. For economic analyses, key items of resource use (costs) and outcomes (beneficial and adverse), cost per unit of effort, quality adjusted life years (QALYs), or cost-benefit analyses (resource inputs and effects of alternative interventions expressed in monetary units), if detailed in trial reports. If available, we would have recorded the following: analytic perspective adopted (for example, societal; national/sub-national; third party payer; institution); time horizon for both costs (resource use) and effects (beneficial and adverse effects); and sources of resource use, unit costs and (if applicable) effects and benefit valuation data (Campbell Collaboration 2008).

Assessment of risk of bias in included studies

Two review authors (TS, PR) independently assessed included studies for the risk of bias using The Cochrane Collaboration's 'Risk of bias' assessment tool (Higgins 2011a) on the following six domains: sequence generation, allocation concealment, blinding or masking, incomplete outcome data, selective outcome reporting and other biases. A third review author (PT) checked this assessment.

We assigned a judgement for each of these six domains regarding the risk of bias as low risk of bias, high risk of bias or unclear risk of bias when judgements could not be reliably made due to lack of information in the report or after contacting the trial authors. We used the criteria summarised in Table 8.5.c of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a) to make judgements, and recorded these assessments in the standard 'Risk of bias' tables in RevMan 5 (RevMan 2012). We presented these evaluations in the 'Risk of bias' summary figure (Figure 2) and discussed them further in the results section under Risk of bias in included studies. We incorporated these judgements in assessing limitations in study design for critical and important outcomes in the Summary of findings for the main comparison.

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for Nathan 2005.

Measures of treatment effect

Only one study fulfilled the inclusion criteria and we analysed dichotomous data from this trial by calculating the risk ratio (RR) and 95% confidence intervals (CI) for each outcome.

Unit of analysis issues

There were no non-standard designs used in the single included trial.

Had more trials been included in this review and had the included trials randomised participants by clusters, such as villages or health centres, and had the results been adjusted for clustering, we would have combined the adjusted measures of effects of these cluster-randomised trials. If results had not been adjusted for clustering, we would have attempted to adjust the results for clustering, by multiplying the standard errors of the estimates by the square root of the design effect (where the design effect is calculated as DEff = 1 + (M - 1) ICC, where M is the average cluster size and ICC is the intra-cluster coefficient). If this was not possible, we would not have combined them in a meta-analysis, but would have presented the results in an additional table.

If time-to-event outcomes had been reported, we would have extract the estimates of the log hazard ratio and its standard error. If standard errors had been unavailable we would have extracted alternative statistics such as confidence intervals or P values.

Dealing with missing data

We contacted trial authors for missing data. We planned to exclude any trial with more than 20% unexplained drop-outs in any arm. However, the included trial reported reasons for drop-outs and the trial authors provided supplementary information. The data were adequately presented and the report provided intention-to-treat and per-protocol analyses data, as well as a participant flow diagram in a sufficiently detailed manner as to facilitate data retrieval.

We extracted data to allow an intention-to-treat (ITT) analysis in which all randomised participants were analysed in the groups to which they were originally assigned. If there was a discrepancy in the number randomised and the numbers analysed in each treatment group, we calculated the percentage loss to follow-up in each group and reported this information. If unexplained drop-outs exceeded 10% in either group, we would have assigned the worst outcome to those lost to follow-up for dichotomous outcomes (except for mortality) and assessed the impact of this in sensitivity analyses with the results of completers.

For continuous outcomes, if provided and where possible, we would have calculated missing standard deviations from other available data such as standard errors (Higgins 2011b). However, we would not have imputed missing values in order to present these in the analyses. We would not have made any assumptions about loss to follow-up for continuous data and would have analysed results for those who completed the trial.

Assessment of heterogeneity

Had additional trials been included, we would have supplemented the inspection of the graphical display of results for non-overlapping CIs among individual trials with the Mantel-Haenszel Chi2 test of heterogeneity. Since this test has low power to detect heterogeneity, a significance level less than 0.10 would have been interpreted as evidence of heterogeneity.

In addition, we would have quantified inconsistency across studies and its impact on the meta-analysis by examining the value of the I2 statistic to estimate the percentage of variability due to inter-trial variability rather than random error. We would have interpreted an I2 statistic of 50% or greater as indicating substantial levels of heterogeneity (Higgins 2003).

Assessment of reporting biases

Had there been sufficient studies (at least 10), we would have used a funnel plot of treatment effect against its standard error (as a measure of study size) to assess possible publication bias or small study effects.

Data synthesis

Since only one trial fulfilled the inclusion criteria, we present the risk ratio and 95% Cl for the pre-specified outcomes from this trial.

Had there been more trials, we would have pooled data for dichotomous outcomes using the inverse variance fixed-effect model; if heterogeneity was deemed substantial, we would have used the random-effects model.

For continuous data such as care-giver burden or quality of life assessments measured in similar ways, we had planned to calculate the difference in means weighted by the inverse of the variance. We would have used the standardised mean difference to pool results if continuous outcome data assessing similar outcomes were measured in different ways. If the distribution of the outcome data was significantly skewed and the studies were small, we would have looked for a suitable normalisation method or requested more appropriate summaries of the data from the investigators.

Subgroup analysis and investigation of heterogeneity

We would have evaluated the pooled results from additional studies that used comparable participants, interventions, methods and outcomes for evidence of significant heterogeneity that would have precluded a reliable interpretation of a common 'average' effect of the combined effects of the interventions.

Had the I2 statistic exceeded 75% and had there been no explanations for this inconsistency (see below) in the effects of interventions across trials, we would have presented the results in a forest plot without pooling data.

We anticipated between-trial variations in the following situations and therefore intended to subgroup analyses when:

  1. baseline risk levels (severity of infection) differed between trials;

  2. trials presented results for people with suspected versus confirmed meningococcal meningitis; analysing the results separately allows for evaluating the effects of differences in these proportions across trials and the effects of different indices of suspicion for bacterial meningitis during and outside of epidemic settings;

  3. trials differed by levels of health service delivery (low-income versus moderate to high-income settings);

  4. trials differed by duration of follow-up (short-term (< six weeks); medium-term (six weeks to six months); long-term (> than six months).

If subgroups appeared to differ in the effects of interventions, as evident by non-overlapping Cls, we would have performed formal tests for subgroup differences using the methods described in Higgins 2011b, which are possible in RevMan 2012 when the inverse variance method is used to pool dichotomous data.

Sensitivity analysis

We had also planned to perform sensitivity analyses to assess the robustness of the findings to different aspects of the risk of bias among included trials and to evaluate the assumptions made in ITT and completer analyses.

Summarising and interpreting results

We used the GRADE approach to interpret findings (Schünemann 2011) and used GRADE Profiler (GRADE 2004) to import data from RevMan 5.2 (RevMan 2012) to create Summary of findings for the main comparison for the sole comparison of different pre-admission antibiotics included in this review. This table provides information concerning the overall quality of the evidence from the trial, the magnitude of effect of the interventions examined, and the sum of available data on all primary outcomes and the secondary outcome of adverse effects of the antibiotics. We used this summary to guide our conclusions and recommendations.

Results

Description of studies

Results of the search

Our original search retrieved 136 reports. Of these, we obtained hard copies of 30 potentially eligible trials. Only Nathan 2005 met the inclusion criteria. The search also retrieved a systematic review on the same topic (Hahné 2006) that was published while the first version of this review was underway. Hahné 2006 included 14 cohort studies but did not include any RCTs. Another review of observational studies (Leclerc 2001) looked at seven trials and again did not include any RCTs.

The updated search in June 2010 retrieved 46 records, only one of which was relevant to this review. It was a retrospective analysis that controlled for the effects of indication bias in prescribing antibiotics by using propensity scores to evaluate the effects of pre-admission antibiotics in preventing deaths due to meningococcal disease during an epidemic in Spain (Perea-Milla 2009). This is listed in the Characteristics of excluded studies table.

The updated searches in May 2013 retrieved 125 records, from which no trials relevant to this review were identified (Figure 1).

Included studies

Our protocol predefined participants as those with suspected cases of meningococcal meningitis awaiting transfer to hospital and randomised to treatment before confirmation of diagnosis. The trial by Nathan 2005, funded by Médecins Sans Frontières, was conducted between March and April 2003 in Niger, during an epidemic of meningococcal infection, and recruited people with suspected meningococcal meningitis from one of eight peripheral health centres, as well from a regional hospital at Zinder, Niger.

Clarifications from the trial authors revealed that anyone presenting with suspected meningitis to any site included in the study, who met the inclusion criteria, was invited to participate. If informed consent was obtained, a lumbar puncture was conducted (along with a rapid diagnostic test for malaria) and the patient was then randomised to the interventions. Patients remained at the site to which they had initially presented (and had received the intervention) for a minimum of 72 hours of follow-up. If a second treatment dose was required, or if an alternative treatment was necessary, these too were administered at the original site. No transfer of patients between sites occurred. Of the 510 patients originally included in the study, 97 (19%) were recruited at the National Hospital in Zinder and 41 (8%) at a district hospital in Matameye. The trial authors clarified that the hospital in Matameye was a hospital by name, but had no medical facilities beyond those of the other health centres. The remaining 372 (73%) were treated in peripheral health centres.

We felt that as 81% of patients were treated in what were effectively peripheral health centres, and since participants were randomised to the interventions before confirmation of diagnosis, the data from this trial could be used without biasing our review's stated objectives.

The sample size in this trial was chosen to show non-inferiority between the two groups (less than 10% difference in the failure rate between the two groups at 72 hours) for the primary outcome of treatment failure (death at 72 hours or clinical failure). Most patients (˜ 55% to 57%) were in the five to 14 years age group, with 31% under the age of five years but greater than two months old. The trial evaluated the effects of a single intramuscular dose of ceftriaxone (a third-generation cephalosporin) and a single dose of oily chloramphenicol (long-acting, intramuscular, chloramphenicol), in patients suspected of having meningococcal disease. This trial is further described in the Characteristics of included studies table.

Excluded studies

Thirty-one studies are described in the Characteristics of excluded studies table. We excluded nine as they randomised only proven, not suspected cases of meningitis (Barson 1985; Congeni 1984; del Rio 1983; Kavaliotis 1989; Martin 1990; Molyneux 2011; Pecoul 1991; Rodriguez 1986; Schaad 1990). The other two (Girgis 1989; Wald 1995) were RCTs of the effects of dexamethasone in children with proven bacterial meningitis with both groups receiving antibiotics. A report (Harnden 2006) of mortality following pre-admission antibiotics in suspected meningococcal meningitis was a retrospective case-control study. Perea-Milla 2009 was also a retrospective case-control study adjusted for indication bias. Riordan 2001 was a prospective cohort where the intervention being studied was the effect of training on 'door to needle time' for giving antibiotics. Most other studies were observational case-control, case series or review articles.

Risk of bias in included studies

We found no RCTs or quasi-RCTs comparing pre-admission antibiotics for suspected meningococcal infection versus placebo, or no intervention. The trial by Nathan 2005, comparing two antibiotics, had the following characteristics.

Allocation

This trial used off-site computer-generated codes in blocks of 20. Sealed, numbered, opaque envelopes containing the description of the allocated intervention were delivered to each intervention site in lots of 50 to be opened sequentially by on-site study physicians who, after obtaining consent and a sample of CSF for diagnostic confirmation, administered the intervention. The study investigators involved in random sequence generation were not involved in recruitment of the study participants.

Blinding

The study physicians were not blinded to the interventions once participants were allocated. However, the pre-stated outcomes were objective and unlikely to be influenced by assessor bias.

Incomplete outcome data

There were 510 participants randomised: 251 to receive ceftriaxone and 259 to receive chloramphenicol. Three participants left the treatment facility in the ceftriaxone arm and four in the chloramphenicol arm within the 72 hours of follow-up. Reasons were not provided but it would be difficult to assume that they had poor outcomes. Data on these participants were not included in the ITT analysis reported by the trial authors, but the numbers were few and not different in both arms, so we used data provided in the ITT analysis in the report for evaluating outcomes. Data on those in whom bacteriologic confirmation of meningococcal meningitis was done, provided in the report, were also used as presented.

Selective reporting

The trial protocol was not available, nor did the report have any identification to suggest that it had been prospectively registered in a publicly accessible database. However, the trial reported all pre-stated and expected outcomes and appeared free of selective reporting.

Other potential sources of bias

We identified no other potential sources of bias.

Effects of interventions

See: Summary of findings for the main comparison Cephalosporin versus long-acting (oily) chloramphenicol compared in people suspected to have meningococcal disease

We found no trials that evaluated the effects of pre-admission antibiotics versus placebo for suspected cases of meningococcal disease.

The one included trial (Nathan 2005) screened 557 participants and randomised 510, of whom 251 were given intramuscular ceftriaxone and 259 long-acting intramuscular (oily) chloramphenicol during an epidemic of meningococcal meningitis.

Primary outcomes

1. Mortality

Data are only available for short-term outcomes, as defined in our Types of outcome measures section. At 72 hours, deaths occurred in 14 out of 247 (6%) participants in the ceftriaxone arm and in 12 out of 256 (5%) participants in the long-acting chloramphenicol arm (intention-to-treat (ITT) values from the report). Mortality did not differ significantly between the two interventions (risk ratio (RR) 1.2, 95% confidence interval (CI) 0.6 to 2.6; N = 503) (Figure 3; Analysis 1.1). A subgroup analysis of the participants who were later confirmed to have meningococcal disease also failed to show any difference in mortality in the two arms of the study (RR 1.1, 95% CI 0.4 to 3.6; N = 308). Mortality did not differ in the remaining 195 participants in the intervention arms without confirmed meningococcal meningitis (RR 1.4, 95% CI 0.5 to 3.8). Formal tests for subgroup differences were not undertaken since the confidence intervals for subgroup effects overlapped considerably.

Figure 3.

Forest plot of comparison: 1 Cephalosporin versus long-acting (oily) chloramphenicol, outcome: 1.1 Death.

There were no data on mortality before presentation to the health centres nor after discharge from the facilities, though all participants were discharged only when well.

2. Lack of clinical improvement

This composite outcome was defined as a Glasgow Coma Scale (GCS) of less than 11 at 24 hours or less than 13 at 48 hours; no improvement or worsening in the state of consciousness or neurological status, persistent convulsions and axillary temperature above 38.5° Celsius. The ITT analysis reported that clinical failure occurred in eight out of 233 participants in the ceftriaxone arm (3%) and in eight out of 244 (4%) participants in the long-acting chloramphenicol arm. Again this difference was not statistically different (RR 0.8, 95% CI 0.3 to 2.2; N = 477) (Figure 4; Analysis 1.2). The interventions did not differ in the proportions of those with clinical failure in the 308 confirmed cases of meningococcal meningitis (RR 1.4, 95% CI 0.2 to 8.5), nor in the 169 participants in whom meningococcal meningitis was not confirmed (RR 0.8, 95% CI 0.3 to 2.6). The interventions did not differ significantly in the proportions of participants requiring a second injection between 48 to 72 hours (risk difference -0.9%, 95% CI -4.7 to 3.0).

Figure 4.

Forest plot of comparison: 1 Cephalosporin versus long-acting (oily) chloramphenicol, outcome: 1.2 Clinical failure.

3. Morbidity

Neurological sequelae were recorded in 16 out of 233 (7%) participants in the ceftriaxone arm and 13 out of 244 (5%) participants in the chloramphenicol arm. Sequelae included hearing impairment in 14 participants and motor dysfunction in 15 participants (ataxia, motor deficit or both), but data for individual sequelae were not separable by intervention arms.

The incidence of sequelae did not differ significantly between interventions (RR 1.3, 95% CI 0.6 to 2.6; N = 477) among all participants using the ITT analysis in the report (Figure 5; Analysis 1.3). The incidence in those with confirmed meningococcal meningitis was also not significantly different (RR 1.4, 95% CI 0.7 to 3.2; N = 297); nor did it differ significantly in those without confirmed meningococcal meningitis (RR 0.6, 95% CI 0.1 to 3.4; N = 180).

Figure 5.

Forest plot of comparison: 1 Cephalosporin versus long-acting (oily) chloramphenicol, outcome: 1.3 Neurological sequelae.

Secondary outcomes

1. Burden of disease

No data were available on the burden of disease on the family as participants were followed up only until discharge.

2. Adverse effects

Neither intervention was associated with adverse effects.

3. Economic costs of the intervention

The trial reported that the average treatment dose used was 2 g per person for both drugs. The treatment cost per patient was estimated as USD 4 to 6 for chloramphenicol and USD 2 to 3 for ceftriaxone. No details were provided on how these costs were arrived at or of other economic issues such as resource use, etc.

Discussion

Summary of main results

Pre-admission antibiotics versus no antibiotics

Our primary question regarding the efficacy and safety of pre-admission antibiotics in decreasing mortality or morbidity in people with suspected meningococcal disease remains unanswered, since we did not find any randomised controlled trials (RCTs) comparing antibiotics versus placebo or no antibiotic in suspected cases of meningococcal meningitis and the initiation of antibiotics in the control group after confirmation of the diagnosis.

Comparison of a third-generation cephalosporin (ceftriaxone) versus long-acting chloramphenicol

The sole eligible RCT included in this review (Nathan 2005) reported that a single dose of ceftriaxone was not inferior to long-acting chloramphenicol in preventing mortality, neurological sequelae, the need for a second injection and clinical non-response (in the first 48 hours after admission), in those with suspected, and in those subsequently confirmed, to have meningococcal meningitis that were given the antibiotic at presentation to the healthcare facility during an epidemic of meningitis (Summary of findings for the main comparison). No adverse events were reported for either drug and costs were comparable.

The trial excluded very ill participants (people in an unresponsive coma and in shock), thus leaving unanswered the question on the efficacy of the schedule of treatments in such instances, and the role of supportive measures, even if antibiotics were to be given early. Even among those with a less severe illness at the start of the trial, treatment failure at 72 hours and death were significantly more likely in those with impaired consciousness prior to admission (odds ratio (OR) 5.0, 95% confidence interval (CI) 2.3 to 10.6).

This suggests that a single dose of antibiotics prior to admission may be insufficient to prevent negative outcomes in some people with moderately severe illness, perhaps due to sub-optimal dosage, the toxic effects of rapid bacteriolysis, or the absence of adequate additional interventions to combat or prevent haemodynamic imbalance, respiratory distress, renal insufficiency, dehydration or overhydration, and electrolyte imbalance (Keeley 2006). These speculations are borne out by experiences with intensive treatment of meningococcal disease elsewhere (Booy 2001), though the speculation on the toxic effects of rapid bacteriolysis due to antibiotic treatment have not been borne out uniformly by empiric enquiry (Stephens 2007).

Overall completeness and applicability of evidence

Completeness

No reliable evidence was found on the relative efficacy of giving antibiotics before confirmation of the diagnosis or withholding it until confirmation of the diagnosis.

We believe that we have identified all trials relevant to this review.

Applicability

The trial by Nathan 2005 provided evidence of moderate quality to endorse the use of a single dose of either ceftriaxone or oily chloramphenicol in reducing mortality, though the short follow-up precludes the drawing of valid conclusions regarding neurological sequelae.

The external validity of this trial is less clear. When generalising the results to settings and periods other than during epidemics, as in this trial, it is uncertain whether similar mortality and morbidity estimates would be achieved in the absence of high levels of treatment-seeking and alertness to the possibility of meningococcal meningitis that epidemics engender.

The oily suspension of chloramphenicol is ideal for use in low-income countries, due to the comparable efficacy of a single intramuscular dose, repeated, if needed, after 48 hours, to 10 days of intravenous ampicillin given four times a day (Pecoul 1991), achieved at a tenth of the cost. Widespread resistance to chloramphenicol in high-income countries limits its usefulness in these settings. However, long-acting chloramphenicol may be a useful drug of choice in low-income countries where resistance to chloramphenicol is not a major problem (Pecoul 1999) and if supply is not compromised.

Ceftriaxone was initially around six to 10 times more expensive than long-acting chloramphenicol but patent rights for ceftriaxone have expired in most countries and the generic drug costs have also fallen (Nathan 2005). Given the comparative efficacy and costs of both agents in the trial included in the review, the choice of drug for initial pre-admission antibiotic therapy would depend on the proportion of people with chloramphenicol resistance among the population in question, and the affordability of ceftriaxone at local costs. When antibiotic susceptibility testing is limited in low-income countries with emerging chloramphenicol resistance, oily chloramphenicol as the initial drug followed by ceftriaxone, if symptoms do not improve within 48 hours and bacterial meningitis is confirmed, is a possible strategy (Duke 2003). Ceftriaxone could be used as the first-line drug in the presence of widespread chloramphenicol resistance, though the emergence of resistance to ceftriaxone could also result if this use was indiscriminately. Ceftriaxone would also be preferable to chloramphenicol in situations where the suspected case of meningococcal meningitis is caused by H. influenzae or S. pneumoniae, where chloramphenicol is not as effective.

The other factor that would influence the choice of antibiotic is safety. Both drugs were considered safe in the trial by Nathan 2005.

Additional caveats need to be considered before instituting pre-admission antibiotics in areas with and without epidemic meningitis. One is the need to rule out other common infections with similar presentations, such as malaria, and meningitis due to other infective pathogens. The alarm engendered by epidemics or local outbreaks may also result in the indiscriminate use of antibiotics. Malaria was diagnosed in 44 (9%) of participants; and three cases of meningitis were due to H. influenzae and three to S. pneumoniae; moreover 133 (23%) had sterile lumbar punctures in the included trial (Nathan 2005).

The other caveat is that unless early instigation of antibiotics in suspected cases of meningococcal disease is accompanied by other measures to improve health care delivery (increased recognition and case detection, early transfer to hospital and facilities and the rapid instigation of supportive measures to manage complications of the more severe forms of the illness), the benefits of antibiotics alone are unlikely to affect mortality rates significantly (Booy 2001; NICE 2010).

Quality of the evidence

Design and quality of reporting

The trial was designed to demonstrate non-inferiority of ceftriaxone to chloramphenicol, assuming 15% of those allocated to chloramphenicol would be treatment failures, a difference of less than 10% between the interventions, a one-sided 5% significance level, 80% power and 10% loss to follow-up. The trial authors stated that they calculated the risk difference and 90% CIs of the primary and secondary outcomes and considered the difference as equivalent if the upper limit of its 90% CI was below 10%.

Non-inferiority trials present particular difficulties in design, conduct, analysis and interpretation, as do trials assessing equivalence. True equivalence is difficult to prove but the assumption of equivalence in this instance was based on the demonstration of non-inferiority initially, using one-sided 5% significance and a one-sided 90% CI. Equivalence was then assessed using a pre-stated one-sided 90% CI of less than 10% (a two-sided CI might have been more appropriate) and an ITT analysis. The design, conduct, reporting and interpretation of this trial conformed to the recommendations in the extension to the CONSORT statement for non-inferiority and equivalence trials (Piaggio 2006). The study was considered adequate in reporting randomisation, allocation concealment and attrition, and though it was an open-label trial, the risk of detection bias was considered to be low due to the objective outcomes used.

Overall quality of the evidence

The overall quality of the evidence for primary outcomes was rated as moderate and though there were no limitations in study design, the trial was downgraded for indirectness for all outcomes due to the exclusion of infants, pregnant women and those with severe disease (Summary of findings for the main comparison).

The quality of the evidence was further downgraded to low for neurological outcomes since the duration of follow-up was only 72 hours and deemed too short to detect neurological outcomes adequately. Trials that assess deficits in the longer term would enable the detection of neurological sequelae that are detected only after discharge, particularly hearing deficits and spasticity in young children, and milder cognitive deficits and behavioural changes in adolescents (Borg 2009). The methods used to detect these outcomes in Nathan 2005 were based on gross clinical evaluation and were possibly also insensitive to detect them accurately.

The trial was possibly also underpowered to demonstrate non-inferiority for neurological outcomes in confirmed cases of meningococcal meningitis, in addition the follow-up was too short, and the quality of the evidence was judged very low for this subgroup (Summary of findings for the main comparison).

Potential biases in the review process

Despite this being an important problem, the surprising lack of RCTs for our main objective is worrying. While it may suggest that we were unable to locate small trials, particularly those with inconclusive results, and indicate publication or retrieval bias, our search of multiple sources, with no language restrictions reassures us that this is unlikely. A more credible explanation is that pre-admission antibiotics have become the standard of care in many countries and hence a RCT, especially a placebo-controlled trial, may be deemed unethical.

At first reading, the sole included trial (Nathan 2005) seemed to not fulfil our inclusion criteria of 'pre-admission' use of antibiotics, since participants were those treated in health centres; written communication with trial authors confirmed that the first dose of antibiotic was administered to people suspected to have meningococcal meningitis prior to seeking confirmation of the diagnosis. They also clarified that the majority of the treatment facilities (8/9) were primary care centres and the majority of participants were treated at these centres (81%). The results of this trial also show that 195/503 randomised (39%) were not subsequently confirmed to have meningococcal meningitis on culture or by polymerase chain reaction (PCR), attesting to the actual use of antibiotics prior to disease confirmation and the suitability of this trial for inclusion in this review. None of the excluded RCTs fulfilled this definition of antibiotic use.

Agreements and disagreements with other studies or reviews

Pre-admission antibiotics versus no antibiotics

The available evidence for this comparison comes from retrospective case series, case-control and cohort studies. Considering the non-specific nature of symptoms, especially in milder cases and in young children, and the lack of sensitivity of the specific clinical signs of both Kernig and Brudzinski, in adults as well as in children (El Bashir 2003), it is likely that data from these sources are confounded by diagnostic errors and inclusion of the more severely ill (Hahné 2006; Harnden 2006; Keeley 2006; Sorensen 1998). The latter are more likely to seek help in clinic-based studies, be perceived to have meningitis by clinicians in these and in community-based studies, and to be treated with parenteral antibiotics early, leading to 'indication bias' (Perea-Milla 2009). Consequently, the often paradoxical outcomes of these observational studies, both positive and negative, are confounded by disease severity, and the proportions that received pre-admission antibiotics (Hahné 2006; Harnden 2006; Perera 2006). Similarly, observational studies of oral pre-admission antibiotics that report lower mortality and morbidity, are confounded by indication bias too; in this case the inclusion of people with less severe or non-meningococcal disease (Harnden 2006; Keeley 2006; Perea-Milla 2009).

A retrospective analysis of 848 people admitted with invasive meningococcal disease, 49 of whom died (6%), from 1995 to 2000 in 31 hospitals in Spain, used the 'propensity score' to assign patients the probability of receiving pre-hospital antibiotics prior to admission, based on clinical symptoms, and matched the 228 who had received oral antibiotics in the 48 hours prior to admission with controls who had not received pre-hospital antibiotics, again based on their propensity scores for not being thus treated (Perea-Milla 2009). Adjusted multivariate analyses indicated that pre-hospital antibiotics appeared to protect against death (OR 0.37, 95% CI 0.15 to 0.93). The propensity score technique has been equated with randomisation in situations where randomisation is difficult, and this trial attempted to adjust for the 'indication bias' that has confounded interpretation of previous observational studies. The imprecision of the effect estimate (the confidence intervals suggest a protective effect that could be clinically very important to only marginally important) is in concordance with evidence from case-control studies that indicate, on balance, that early diagnosis, early admission to hospital (within three hours) and early instigation of supportive measures are as important as the early commencement of antibiotics (Keeley 2006).

Pre-admission cephalosporins versus chloramphenicol

Previous guidance from the UK National Institute for Health and Clinical Excellence (NICE) recommended that children with suspected meningococcal disease be given parenteral antibiotics (benzylpenicillin or a third-generation cephalosporin) at the earliest opportunity (NICE 2007). The SIGN guideline on the management of invasive meningococcal disease in children and young people recommends that parenteral antibiotics (benzylpenicillin or cefotaxime) should be given as soon as invasive meningococcal disease is suspected and even before confirmation of the diagnosis is sought (SIGN 2008). The latest NICE guidance considers transfer to hospital and fluid management of greater priority than administering pre-hospital antibiotics, unless immediate transfer is not possible, or if the clinical suspicion of meningococcal meningitis is accompanied by a non-blanching rash or meningococcal septicaemia (NICE 2010). In contrast to earlier guidance, NICE 2010 recommends using ceftriaxone as first-line treatment for bacterial meningitis and meningococcal disease in children and young people older than three months of age.

An economic analysis, done from the perspective of the NHS and a socialised medicine approach, strongly suggests that ceftriaxone is the most cost-effective antibiotic for the treatment of suspected meningococcal disease or suspected meningitis in a majority of children (NICE 2010). This concurs with the cruder estimates in Nathan 2005. The NICE analyses did not take into account variations in drug prices nor any effects on health or costs arising from antibiotic resistance, both of which may vary widely in different settings. These estimates also assumed that survival is the only health-related quality of life outcome of importance with antibiotic use and did not consider other perspectives such as prevention of neurological disability and their (more difficult to estimate) consequences and associated costs and the quality adjusted life years (QALYs) lost or gained.

Authors' conclusions

Implications for practice

This review update again found no trials to provide reliable evidence to support or refute the routine use of pre-admission antibiotics for suspected cases of meningococcal disease.

The decision to start antibiotics before admission or confirmation of the diagnosis will therefore depend on local health policy. Considering the potential for serious outcomes and rapid evolution of the disease, their routine use when meningococcus meningitis is suspected appears to be supported by the balance of evidence from available observational studies that suggest that early intervention, coupled with intensive support measures, is beneficial in reducing mortality and morbidity in people suspected to have meningococcal meningitis, and particularly meningococcal septicaemia.

When symptoms are milder, false positive diagnoses are more likely and close monitoring and investigations to confirm suspicions, and investigations to rule out other infections, are especially warranted.

If antibiotics are given before confirmation of the diagnosis, the benefits may outweigh the risks inherent in their use, though this needs to be reviewed on an individual basis. Limited data from the one RCT reviewed here that excluded infants, pregnant women and those with severe illness, suggest that pre-admission antibiotics in people suspected to have meningococcal meningitis are more likely to prevent unfavourable outcomes if initiated before the onset of frequent seizures or impaired consciousness, or in the absence of concurrent infections. Early antibiotic treatment should be accompanied by better health care delivery that facilitates more rapid and accurate diagnosis, rapid transfer to hospital and the immediate initiation of intensive supportive measures.

While penicillin is commonly recommended as a pre-admission antibiotic, we found no trials of penicillin for this indication. In the sole trial of pre-admission antibiotics for meningococcal meningitis identified in this review, single intramuscular injections of ceftriaxone and long-acting chloramphenicol (with an additional dose in 24 to 48 hours, if clinical recovery was poor) were equally effective and safe in reducing mortality and morbidity in suspected and confirmed cases. Ceftriaxone may also be the cheaper alternative to penicillin (NICE 2010).

Implications for research

Meningococcal disease has serious consequences and progresses rapidly in a sizable proportion of patients. Standard policy in many countries (Hahné 2006), backed by recommendations from professional associations (MRF 2003; NICE 2010; SIGN 2008), mandates the early initiation of antibiotics, particularly penicillin or a third-generation cephalosporin, once criteria for bacterial meningitis are met.

Under these circumstances, it is unlikely that randomised, placebo-controlled trials will be conducted to answer the primary question on the efficacy and safety of instigating early antibiotic treatment versus delaying antibiotics until confirmation of the diagnosis in suspected cases of meningococcal meningitis, to prevent deaths and neurological or other disabling or disfiguring sequelae.

More accurate and early diagnosis would aid the early and appropriate use of antibiotics. Dot-ELISA using outer membrane complexes from N. meningitidis B as a target was found to be specific for serologic verification of clinically suspected meningococcal disease in patients; determination of antibody titres produced during different phases of natural infection was also possible (Belo 2010). The increased use of dip-stick rapid diagnostic tests (RDTs) that can be easily and accurately used by non-specialist healthcare personnel in basic healthcare facilities and that are comparable in diagnostic accuracy to PCR diagnosis, will obviate the need to wait till samples are confirmed in reference laboratories, and will aid the decision to institute life-saving measures early for those diagnosed with meningococcal meningitis (Chanteau 2007). They would also facilitate attempts to use scarce stocks of emergency vaccines more appropriately (Boisier 2009). However, their sensitivity would need to improve and large-scale production be stabilised to ensure less batch-to-batch variation than is currently observed (Rose 2010). Molecular testing of nasopharyngeal specimens using loop-mediated isothermal amplification (LAMP) to detect the ctrA gene involved in N. meningitidis capsular transport is a noninvasive near-patient diagnostic test that is being evaluated (Bourke 2010).

The need for placebo-controlled trials to guide decisions pertaining to the pre-hospital use of antibiotics will then have less urgency, due to the shorter times to confirmation of diagnoses.

However, RCTs comparing the efficacy and safety of different pre-admission antibiotics, particularly in comparison with penicillin, are ethically justifiable and are needed to widen the evidence-base for antibiotics available to clinicians in settings of differing resistance patterns, drug costs, availability and preferences.

Given that the majority of treatment failures and fatalities in many observational studies (Edmond 2010; Perea-Milla 2009), and the sole RCT included in this review (Nathan 2005), occurred in those with more severe manifestations of the disease at presentation, the efficacy of immediate antibiotic use needs to be evaluated alongside other immediate measures to prevent death or clinical deterioration. Nathan 2005 excluded people with established evidence of serious illness pre-randomisation, severely ill people and those in coma or shock. Including people with such characteristics in future trials may be ethically justified if coupled with measures for rapid confirmation of the diagnosis, and if other intensive supportive measures were also given to all participants, or were the focus of specific enquiry, when given along with pre-admission antibiotics.

Trials in those with less severe forms of illness are also both needed and ethically justified. An important issue is the potential for antibiotic resistance should antibiotics be indiscriminately used for this indication. Evidence for the efficacy of pre-confirmation antibiotic use is particularly important in those with suspected meningitis without indicators of severe disease, as many such cases could eventually be not due to meningitis or due to other aetiologies. Such trials should be adequately powered to detect differences in outcomes between those with and without confirmed meningococcal meningitis, and could stratify participants by levels of severity.

However, uncertainties in the speed of, and variations in, disease evolution, and the problems of identifying an ideal threshold of clinical symptoms and signs for inclusion in such trials, given the problems with sensitivity and specificity of clinical diagnostic criteria (unless replaced or supplemented by molecular or dip-stick rapid diagnostic tests) would pose ethical and logistic problems in the implementation and interpretation of such trials.

Acknowledgements

We thank Dr Nathan and Dr Kate Alberti, who gave us valuable information about their trial which was vital to this review. We gratefully acknowledge the valuable comments and suggestions on the draft protocol by Peter Morris, Linda Glennie, John Smucny, Ratana Panpanich and Sreekumaran Nair; and Anne Lyddiatt, Ratana Panpanich, Abigail Fraser, Rob Ware and Peter Morris on the initial version of the completed review. We are also grateful for the support from the editorial base of the Cochrane Acute Respiratory Infections Group, in particular the considerable copy-editing support, encouragement and, above all, patience of Liz Dooley.

Data and analyses

Download statistical data

Comparison 1. Cephalosporin versus long-acting (oily) chloramphenicol
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death1 Risk Ratio (IV, Fixed, 95% CI)Subtotals only
1.1 In all participants - short-term1503Risk Ratio (IV, Fixed, 95% CI)1.21 [0.57, 2.56]
1.2 In confirmed cases of meningococcal meningitis - short-term1308Risk Ratio (IV, Fixed, 95% CI)1.11 [0.35, 3.56]
1.3 In cases due to other causes - short-term1195Risk Ratio (IV, Fixed, 95% CI)1.42 [0.54, 3.76]
2 Clinical failure1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 In all participants - short-term1477Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.32, 2.15]
2.2 In confirmed cases of meningococcal meningitis - short-term1308Odds Ratio (M-H, Fixed, 95% CI)1.39 [0.23, 8.47]
2.3 In cases due to other causes - short-term1169Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.25, 2.58]
3 Neurological sequelae1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 In all participants - short-term1477Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.63, 2.62]
3.2 In confirmed cases of meningococcal meningitis - short-term1297Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.65, 3.23]
3.3 In cases due to other causes - short-term1180Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.12, 3.40]
Analysis 1.1.

Comparison 1 Cephalosporin versus long-acting (oily) chloramphenicol, Outcome 1 Death.

Analysis 1.2.

Comparison 1 Cephalosporin versus long-acting (oily) chloramphenicol, Outcome 2 Clinical failure.

Analysis 1.3.

Comparison 1 Cephalosporin versus long-acting (oily) chloramphenicol, Outcome 3 Neurological sequelae.

Appendices

Appendix 1. Details of previous searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (1966 to February 2007) and EMBASE (1980 to February 2007) and handsearched the references of all identified studies.

The following search terms were run over MEDLINE and CENTRAL. The MEDLINE search was combined with the search strategy designed by The Cochrane Collaboration for identifying randomised controlled trials. See Appendix 2 for the EMBASE search strategy.

MEDLINE (OVID)
1 exp MENINGOCOCCAL INFECTIONS/
2 exp Neisseria meningitides/
3 (neisseria adj mening$).mp.
4 meningococ$.mp
5 or/1-4
6 exp Anti-bacterial Agents/
7 (antibiotic$ or penicillin or cefotaxime or ampicillin$ or sulfa$ or ciprofloxacin$ or norfloxaci$ or ofloxaci$ or quinol$ or fluoroquinol$ or fluoro-quinolon$ or ceftriaxon$ or rifampi$ or azithromyci$ or minocyclin$ or macrolid$ or cephalospori$.).mp.
8 or/6-7
9 exp Patient Admission/
10 (preadmission or pre-admission).mp.
11 empiric.mp.
12 or/9-11
13 5 and 8 and 12

EMBASE (Embase.com)
#16 #6 and #10 and #15
#15 #11 or #12 or #13 or #14
#14 (empiric in ti) or (empiric in ab)
#13 (preadmission or pre-admission)in ab
#12 (preadmission or pre-admission)in ti
#11 explode 'hospital-admission' / all subheadings in DEM,DER,DRM,DRR
#10 #7 or #8 or #9
#9 (antibiotic* or penicillin or cefotaxime or ampicilli* or sulfa* or ciprofloxacin* or norfloxaci* or ofloxaci* or quinol* or fluoroquinol* or fluoro-quinolon* or ceftriaxon* or rifampi* or azithromyci* or minocyclin* or macrolid* or cephalospori*) in ab
#8 (antibiotic* or penicillin or cefotaxime or ampicilli* or sulfa* or ciprofloxacin* or norfloxaci* or ofloxaci* or quinol* or fluoroquinol* or fluoro-quinolon* or ceftriaxon* or rifampi* or azithromyci* or minocyclin* or macrolid* or cephalospori*) in ti
#7 'antibiotic-agent' / all subheadings in DEM,DER,DRM,DRR
#6 #1 or #2 or #3 or #4 or #5
#5 (neisseria adj mening*) in ab
#4 (neisseria adj mening*) in ti
#3 explode 'Neisseria-meningitidis' / all subheadings in DEM,DER,DRM,DRR
#2 (meningococcal infection* in ti) or (meningococcal infection* in ab)
#1 explode 'meningococcosis-' / all subheadings in DEM,DER,DRM,DRR

Appendix 2. EMBASE search strategy

EMBASE (Embase.com)
#31 #22 AND #30
#30 #25 NOT #29
#29 #26 NOT #28
#28 #26 AND #27
#27 'human'/de
#26 'nonhuman'/de OR 'animal'/de OR 'animal experiment'/de
#25 #23 OR #24
#24 random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR allocat*:ab,ti OR trial:ti OR (doubl* NEXT/1 blind*):ab,ti
#23 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#22 #7 AND #21
#21 #11 AND #20
#20 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19
#19 (emergenc* NEAR/3 treat*):ab,ti OR triage:ab,ti
#18 'emergency health service'/de
#17 empiric*:ab,ti
#16 preadmit*:ab,ti OR preadmis*:ab,ti OR (pre NEXT/1 (admit* OR admis*)):ab,ti
#15 ((previous OR prior OR before) NEAR/3 (admit* OR admis*)):ab,ti
#14 ((pre OR before OR prior OR previous) NEAR/5 hospital*):ab,ti
#13 ((hospital* OR patient*) NEAR/3 (admis* OR admit*)):ab,ti
#12 'hospital admission'/de
#11 #8 OR #9 OR #10
#10 penicillin*:ab,ti OR cefotaxim*:ab,ti OR ampicillin*:ab,ti OR sulfa*:ab,ti OR ciprofloxacin*:ab,ti OR norfloxacin*:ab,ti OR ofloxacin*:ab,ti OR quinol*:ab,ti OR fluoroquinol*:ab,ti OR fluoro-quinolone':ab,ti OR ceftriaxon*:ab,ti OR rifampi*:ab,ti OR azithromyci*:ab,ti OR minocyclin*:ab,ti OR macrolid*:ab,ti OR cephalosporin*:ab,ti
#9 antibiotic*:ab,ti
#8 'antibiotic agent'/exp
#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6
#6 meningococc*:ab,ti OR meningit*:ab,ti OR (neisseria NEAR/2 mening*):ab,ti OR 'n. meningitidis':ab,ti
#5 'neisseria meningitidis'/de
#4 'meningitis'/de
#3 'bacterial meningitis'/de
#2 'epidemic meningitis'/de
#1 'meningococcosis'/exp

Appendix 3. Web of Science (Thomson Reuters) search strategy

# 3 35

#2 AND #1

Databases=SCI-EXPANDED, CPCI-S, CCR-EXPANDED, IC Timespan=1985-2012

Lemmatization=Off  

# 2 1,009,501

Title=(trial) OR Topic=(random* or placebo* or ((singl* or doubl*) NEXT/1 blind*))

Databases=SCI-EXPANDED, CPCI-S, CCR-EXPANDED, IC Timespan=1985-2012

Lemmatization=Off  

# 1 491

Topic=(meningococcal OR "Neisseria meningitidis" OR "N. meningitidis" OR meningitis) AND Topic=(antibiotic* OR penicillin* OR cefotaxim* OR ampicillin* OR sulfa* OR ciprofloxacin* OR norfloxacin* OR ofloxacin* OR quinol* OR fluoroquinol* OR fluoro-quinol* OR ceftriaxon* OR rifampi* OR azithromycin* OR minocyclin* OR macrolid* OR cephalosporin*) AND Topic=(pre-admit* OR pre-admis* OR preadmit* OR pre-admis* OR empiric* OR ((patient or previous or prior or before) NEAR/3 (admit* or admis*)) OR ((pre or before or prior or previous) NEAR/5 hospital*))

Databases=SCI-EXPANDED, CPCI-S, CCR-EXPANDED, IC Timespan=1985-2012

Lemmatization=Off  

Appendix 4. LILACS (BIREME) search strategy

Search > (MH:"Meningococcal Infections" OR "Infecciones Meningocócicas" OR "Infecções Meningocócicas" OR MH:C01.252.400.625.549$ OR MH:"Neisseria meningitidis" OR MH:B03.440.400.425.550.550.641$ OR MH:B03.660.075.525.520.500$ OR "Neisseria meningitidis" OR "N. meningitidis" OR meningit$ OR meningococ$ OR MH:Meningitis OR MH:"Meningitis, Bacterial" OR "Meningitis Bacteriana" OR "Meningite Bacteriana" OR "Bacterial Meningitis" OR MH:"Meningitis, Meningococcal" OR "Meningitis Meningocócica" OR "Meningite Meningocócica" OR "Meningitis Meningocóccica" OR "Meningite Meningocóccica") AND (MH:"Anti-Bacterial Agents" OR antibacter$ OR antibiotic$ OR Antibióticos OR Antibacterianos OR MH:D27.505.954.122.085$ OR penicillin$ OR cefotaxim$ OR ampicillin$ OR sulfa$ OR ciprofloxacin$ OR norfloxacin$ OR ofloxacin$ OR quinol$ OR fluoroquinol$ OR fluoro-quinol$ OR ceftriaxon$ OR rifampi$ OR azithromycin$ minocyclin$ OR macrolid$ OR cephalosporin$) > clinical_trials

Appendix 5. CAB Abstracts (Thomson Reuters) search strategy

# 3 7

#2 AND #1

Databases=CAB Abstracts Timespan=1985-2012

Lemmatization=Off  

# 2 8,358

Title=(trial) AND Topic=((random* or placebo* or ((singl* or doubl*) NEXT/1 blind*)))

Databases=CAB Abstracts Timespan=1985-2012

Lemmatization=Off  

# 1 1,314

Topic=((meningococcal OR "Neisseria meningitidis" OR "N. meningitidis" OR meningitis)) AND Topic=(antibiotic* OR penicillin* OR cefotaxim* OR ampicillin* OR sulfa* OR ciprofloxacin* OR norfloxacin* OR ofloxacin* OR quinol* OR fluoroquinol* OR fluoro-quinol* OR ceftriaxon* OR rifampi* OR azithromycin* OR minocyclin* OR macrolid* OR cephalosporin*)

Databases=CAB Abstracts Timespan=1985-2012

Lemmatization=Off  

What's new

DateEventDescription
3 May 2013New citation required but conclusions have not changedThe conclusions remain unchanged.
3 May 2013New search has been performedWe updated our searches and identified 45 records. We excluded one new trial (Molyneux 2011).

History

DateEventDescription
4 June 2010New search has been performedSearch updated; no new trials found.
22 February 2007New search has been performedSearches conducted. Review published Issue 1, 2008.

Contributions of authors

Thambu Sudarsanam (TS) and Priscilla Rupali (PR) wrote the initial draft of the protocol, selected trials, assessed quality, entered data for the review and screened studies for the review updates.
TS wrote the draft of the earlier version of the review and of the updates.
Prathap Tharyan (PT) modified the draft of the protocol, checked extracted data, checked study quality, wrote the final version of the initial review, updated the background, methods and discussion sections, completed the 'Risk of bias' tables, created the 'Summary of findings' table and wrote the final version of the 2007 review update, and checked study selection and the 2007 update.
Ooriapadickal Cherian Abraham (OCA) and Kurien Thomas (KT) helped modify the protocol and all authors approved the final version of the review and the review updates.

Declarations of interest

None known.

Sources of support

Internal sources

  • Christian Medical College Hospital, Vellore, India.

    Salaries and logistic support for all authors

  • South Asian Cochrane Network & Centre, India.

    Support for study retrieval and training

External sources

  • Indian Council of Medical Research, India.

    Funding support for the Prof. BV Moses & ICMR Centre for Advanced Research & Training in Evidence-Informed Healthcare that hosts the South Asian Cochrane Centre

  • Effective Healthcare Research Consortium, UK.

    Prof. Tharyan is a programme partner of this consortium that is funded by DFID, UK and led by Prof. Paul Garner, International Health Group, Liverpool School of Tropical Medicine, UK; this consortium funds, in part, the capacity-building activities of the South Asian Cochrane Centre.

Differences between protocol and review

2013 update

None.

2010 update

Since the publication of the review, newer methods were introduced with the release of RevMan 5.2 (RevMan 2012) and were incorporated with this update. These include a more detailed description of methods, such as the 'Risk of bias' assessments and the 'Summary of findings' tables. These also stimulated other changes during this update to evaluate better the outcomes in the context of potential biases and confounders and other contextual factors that were not immediately apparent nor considered in the original review.

1. Outcomes

For this update of the review, we also included the proportion of people with confirmed diagnosis of meningococcal meningitis among those randomised, as subgroups in the analyses of primary and secondary outcomes. This omission was an oversight in the initial review, as this analysis enables an exploration of the efficacy of pre-admission antibiotics in confirmed meningococcal meningitis versus that due to other organisms such as H. influenzae or S. pneumoniae, or in those without a bacterial aetiology for their presenting symptoms. Since overall mortality is also of importance from a public health perspective in recommending particular antibiotics, and not just that due to meningococcal disease, this exploration was introduced to inform our conclusions better of their relative efficacy in the two subgroups.

In addition, comparisons of trials with short durations of follow-up, as in the included trial in this review, and those that assess deficits in the longer term, if identified by future updates, would enable comparison of the development of neurological sequelae that are detected only after discharge, particularly hearing deficits and spasticity in young children and milder cognitive deficits and behavioural changes in adolescents (Borg 2009), which may differ in those with meningitis due to meningococcus and those without.

We also included the outcome of lack of clinical improvement as a subgroup for this purpose in this update. The results for this outcome were presented in the previous version of this review, though this outcome had not been explicitly pre-stated in the protocol. Additional subgroups introduced were levels of severity and low-income versus moderate to high-income settings, though no data were available for this review; both are factors that can impact the outcomes independent of the kind of antibiotic used prior to confirmation of the diagnosis.

In this updated review, we used the ITT data provided in the trial report and did not attribute a poor outcome to the seven drop-outs in the first 72 hours after randomisation as we had done in the first version, since it did not seem reasonable to do so. The results are only marginally different between the two approaches.

We also included the economic costs provided in the report for this update, which had not be used in the original review.

2. Methods

We expanded on the sections describing methods for dealing with missing data and unit of analysis issues and, as stated above, subgroup analyses and explorations of heterogeneity. We added a section on summarising findings.

While these were done after knowledge of the results of Nathan 2005, they were necessitated by the newer methods incorporated with RevMan 5.2 (RevMan 2012) and will better inform interpretation of results and conclusions, should future updates include other trials.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Nathan 2005

  1. a

    CFS: cerebrospinal fluid
    GCS: Glasgow Coma Scale
    IM: intramuscular
    IV: intravenous
    LA: long-acting
    PCR: polymerase chain reaction
    RCT: randomised controlled trial

Methods

Randomised, open-label, parallel-group, non-inferiority trial

Period of study: between March to April 2003

Participants

Number randomised: 510

Age: children and adults > 2 months of age (< 5 years 33%; 5 to 14 years 57%; > 15 years 12%)

Gender: 54% male

Included: sudden onset of fever or history of fever in the previous 24 hours associated with at least 1 of the following symptoms: neck stiffness, impaired consciousness, or petechial rash for patients older than 1 year; or bulging fontanel, axial hypotonia, upwardly turned gaze or petechial rash for patients younger than 1 year

Excluded: < 2 months of age; allergy to study drug; coma; shock; pregnant women; recurrent meningitis; severely ill patients

Diagnosis meningococcal meningitis confirmed by: CSF white blood cell count of more than 50 cells per mL and a biological confirmation of N meningitidis  meningitis by:

  • pathogen identification in the CSF by Gram staining

  • presence of soluble antigens in the CSF detected by direct agglutination test (Pastorex, Bio-rad Laboratories, CA, USA)

  • pathogen identification in CSF culture or

  • detection of bacterial DNA of pathogen by PCR

Interventions

Intervention

Ceftriaxone 100 mg/kg (max 4 g) IM at 0 hour, 1 dose (N = 251)
Control

LA chloramphenicol 100 mg/kg (max 3 g) IM at 0 hour, 1 dose (N = 259)

No concomitant steroids were used

Outcomes

Outcomes used:

  1. Death at 72 hours in all participants and in those with confirmed diagnosis

  2. Death within 72 hours

  3. Clinical failure at 72 hours in all participants and in those with confirmed diagnosis (see notes for definition of clinical failure)

  4. Clinical failure between 24 hours and 48 hours needing a second injection

  5. Neurological sequelae (short-term - 72 hours)

  6. Drug-related adverse effects

  7. Treatment costs per person for chloramphenicol and ceftriaxone in USD $

Outcomes not used:

  1. Treatment failure, defined by: death or clinical failure at 72 hours

  2. Risk of treatment failure at 72 hours analysed for baseline characteristics

Outcomes not available:

  1. Burden of disease on the family and the caregiver

Notes

Setting: Niger during an epidemic; 8 primary healthcare centres and Zinder regional hospital. Individuals with suspected disease represented more than 90% of those attending health facilities during the study

Clinical failure: GCS < 11 at 24 hours/< 13 at 48 hours; no change in GCS from baseline; worsening of neurological deficits/new deficits; increase in convulsions; fever > 38.5 °C after 24 to 48 hours

Exact treatment protocol:

1. Ceftriaxone: 100 mg/kg (max 4 g) IM at 0 hour 1 dose; if clinical failure at 24 to 48 hours then repeat dose at 75 mg/kg

2. LA chloramphenicol: 100 mg/kg (max 3 g) IM at 0 hour 1 dose: if clinical failure at 24 to 48 hours then repeat dose at 100 mg/kg

(19/259 of those given LA chloramphenicol and 16/251 of those given ceftriaxone were given a second injection).

If clinical failure at 72 hours then ceftriaxone 100 mg/kg/day IV for a minimum of 4 days as rescue therapy

Sample size estimation for non-inferiority: based on estimated proportion of treatment failure in the chloramphenicol group of 15% and a difference of less than 10% between the 2 groups (beyond which non-inferiority could not be proven)

The difference in risk between interventions for primary and secondary outcomes was regarded as equivalent if the upper limit of its 90% CI was below 10%

Analyses: primary and secondary endpoints were analysed according to:

1. intention-to-treat principles (all individuals with suspected disease included); 251 in ceftriaxone arm and 259 in chloramphenicol arm (4 and 3 in the respective arms left the facility before 72 hours)

2. per-protocol principles (restricted to individuals with confirmed meningococcal meningitis without any additional infection or concomitant antibiotic therapy; 148/256 (58%) in the chloramphenicol arm; 160/247 (65%) in the ceftriaxone arm

Data were not provided for proportions with antibiotic resistance in intervention arms

Sponsor: Médecins Sans Frontières (MSF), Paris

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Block randomisation was done with a computer-generated list".

Comment: communication with trial authors clarified that randomisation was done in blocks of 20

Allocation concealment (selection bias)Low risk

Quote: "At inclusion (0 h), medical doctors who were assigned to the study obtained CSF samples by lumbar puncture, undertook a rapid test for malaria diagnosis (Optimal, Diamed, Switzerland), and randomly assigned patients"

Quote: "the treatment group was allocated with individually sealed envelopes"

Quote: "Principal investigators undertook the randomisation in Paris before the trial began. They did not assign patients to treatment groups in the field"

Comment: additional information from the trial authors clarified that serially numbered, opaque envelopes were distributed in blocks to inclusion sites (for example, 1 to 50 to one site, 51 to 100 to a second site). The study physicians opened the envelopes sequentially and allocated the interventions

Comment: although interventions were not given blind, allocation appears to have been concealed till the administration of interventions

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "Because of field conditions, our trial was not masked; the vials had different appearances and the treating doctors were not masked to which treatment was given."

Comment: the trial was open-label but the outcomes evaluated were objective; allocation was concealed, and therefore the review authors do not feel this introduced selection nor detection bias

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "Of the 557 patients screened, 510 were randomly assigned to receive ceftriaxone or chloramphenicol. Of these individuals, 47 (9%) were excluded because they were ineligible and another seven (1%) were lost to follow-up after treatment allocation".

Comment: 4/251 in the ceftriaxone arm and 3/259 in the chloramphenicol arm who left the facility before 72 hours were not included in the 'intention-to-treat' analysis by trial authors. The review authors feel this is a reasonable interpretation to explain these drop-outs for the primary outcomes of this review. The original version of this review used a revised intention-to-treat analysis of these drop-outs considering them to have had the worst outcome for primary and secondary outcomes; the results of the 2 analyses do not significantly differ

Comment: 160/247 in the ceftriaxone arm and 148/256 in the chloramphenicol arm who were included in the ITT analyses were confirmed to have meningococcal meningitis and were included in the per-protocol analysis. The 87 and 108 participants in the respective arms did not have the suspected diagnosis confirmed. The differences in confirmed cases for primary and secondary outcomes excluded clinically and statistically important differences between interventions

Quote: "Patients in clinical failure at 72 h were followed through to complete recovery. Although the risk of relapse after discharge was regarded as low and all patients were advised to return to the clinic in the event of clinical deterioration, no patients returned during the study period."

Comment: unlikely to introduce bias as both drugs were associated with very low relapse rates in other observational studies done in the region with longer follow-up periods

Selective reporting (reporting bias)Low riskComment: all pre-specified outcomes were reported
Other biasLow riskComment: no other sources of bias were apparent

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    CFS: cerebrospinal fluid
    PCR: polymerase chain reaction
    RCT: randomised controlled trial

Barquet 1997Design: prospective population-based study
Barquet 1999Design: population-based cohort study
Barson 1985Design: RCT
Patients: confirmed cases of meningitis based in a hospital. 10% patients in each group - ceftriaxone and ampicillin and chloramphenicol had pre-admission antibiotics and data regarding outcomes were not separately available
Bohr 1983Design: retrospective chart review
BSSI 1995Design: retrospective case series
Cartwright 1992Design: retrospective case review
Congeni 1984Design: RCT
Participants: only those with CSF confirmed meningitis. Those not confirmed by CSF culture were excluded
del Rio 1983Design: mentioned as randomised but methods not described
Participants: only confirmed cases of meningitis - excluded as not 'pre-admission' antibiotics
Gedde-Dahl 1990Review article
Girgis 1989Design: RCT
Patients: patients with meningitis randomised to receive dexamethasone or no dexamethasone - both groups received ampicillin and chloramphenicol
Gunn 1996Design: review of cases in a district programme
Harnden 2006Design: case-control study
Jolly 2001Design: prospective, non-controlled study in a health district
Kavaliotis 1989Design: RCT
Patients: proven cases with meningitis
Leclerc 2001Design: a meta-analysis of observational studies
Martin 1990Design: RCT
Patients: children with proven bacterial meningitis
Molyneux 2011

Design: RCT

Patients: proven meningitis

Intervention: 5 days of ceftriaxone

Control: 10 days of ceftriaxone

Newcombe 1997Design: laboratory-based PCR study
Noorgard 2002Design: cohort study
Pecoul 1991Design: RCT
Patients: children with proven meningitis; clinical suspicion with CSF microbiology suggestive of meningitis or CSF cell counts > 5000/cu mm
Perea-Milla 2009Design: retrospective analysis adjusted for indication bias by using propensity scores of risk factors to predict mortality
Quagliarello 2003Review article
Riordan 2001Design: not a RCT - cohort of the effect of training on 'door to needle time'
Rodriguez 1986Design: ? RCT
Patients: only confirmed cases of meningitis included
Roord 2001Review article
Roznovsky 2003Design: description of confirmed cases only
Schaad 1990Design: RCT
Patients: only confirmed cases were included
Sorensen 1998Design: 16-year historical follow-up
Strang 1992Design: retrospective case-control study
Wald 1995Design: RCT
Patients: children with proven bacterial meningitis
Intervention: dexamethasone versus placebo. Both groups received antibiotics
Wylie 1997Design: description of cases

Ancillary