Antibiotics for secondary peritonitis in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
1. The primary aim of this review will be to assess the adequacy of the antibiotic regimens in eradicating initial sepsis and the need for subsequent interventions to eradicate peritoneal sepsis. As part of the review, mortality associated with the initial pathology will be also be assessed and correlated to the efficacy of the different antibiotic regimens.
2. Patients with peritonitis frequently undergo surgery to treat the cause of infection, and a secondary objective is to identify whether certain systemic antibiotic regimens reduce post‐operative infection rates and post‐operative stay. Wound, urinary and chest infection rates will be specifically examined, together with an evaluation of the success of antibiotic regimens in adequate source control, most specifically the need for subsequent interventions to eradicate peritoneal sepsis.
3. Certain antibiotics, particularly the aminoglycosides, have higher toxicity compared to the others. We would aim to elucidate and compare the various adverse events relating to the regimens used.
Background
Secondary peritonitis, which is defined as inflammation of the peritoneum secondary to perforation of a hollow viscus or transmural necrosis of gastrointestinal tract, is associated with a high mortality rate (Wittmann 1996; Bosscha 1999; Tellado 2000; Mulier 2003). To serve as an example, patients with large bowel perforation have mortality rates varying from 20% to 60% (Wittmann 1990; Christou 1993; Ohmann 1993; Mc Lauchlan 1995; Pacelli 1996). These severe abdominal infections are accompanied by a high level of sepsis, endotoxin production and systemic inflammatory response syndrome (SIRS), which often results in multiple organ failure (Bohnen 1983).
Surgical eradication of the infectious focus (source control) is the most important prerequisite for a successful treatment (Tellado 2000; Schein 2002). Timely surgical intervention aims to eliminate the source of contamination, reduce the microbial inoculum and prevent the development of persistent sepsis (Bosscha 1999).
Judicious use of appropriate antibiotics in peritonitis serves as an adjunctive treatment to surgical intervention (Bohnen 1992). Antibiotic therapy was first introduced in the 1960s, however mortality did not improve until better understanding of the pathophysiology of these infections, screening techniques, intensive care and resuscitation, and use of appropriate antimicrobial drugs were developed in the 1990s (Tellado 2000). Even the best antimicrobial agent, however, has little efficacy if used without an effort to gain adequate source control .
The polymicrobial nature of the gastrointestinal tract demands use of antibiotics which cover aerobic, facultative anaerobic enterobacteriaceae and anaerobic organisms, particularly Bacteroides fragilis (Nichols 1992). The current practice of early empirical administration of antibiotics targeted against these bacteria is well established (Bohnen 1992; Holzheimer 2001; Mazuski 2002a; Mazuski 2002b). These have been accomplished by a number of regimens either in single or combinations of antimicrobials. There is, however, no strong evidence to identify one regimen as being more efficacious to another and at the same time has the least acceptable side‐effects. Recent reviews on antibiotics and intra‐abdominal infections (Holzheimer 2001; Mazuski 2002a) have further highlighted these problems and the inadequacies where current evidence is lacking.
Treatment failure is often associated with the cause and extent of the initial infection as well as the response of the host to that infection. Useful tools for identifying patients at increased risk of adverse outcome following the insult are the APACHE II (Knaus 1985) and POSSUM severity scoring system (Jones 1992; Copeland 2003). Identifying these high risk patients will often guide the clinician towards a more aggressive approach and use of broader spectrum antimicrobial regimens. However, the latter may put this particular group of patients at an increased risk of toxicity from these agents.
The course of the disease is thus influenced by the physiological reserve of the patient, perioperative optimisation, the severity of the underlying pathology, success of the operation and subsequent management and complications. These factors generate controversy concerning the optimal antibiotic therapy.
There have been a vast expansion and development in antibiotic regimens over the last decade, many of which are costly. This review is therefore strategically timed and will aim to scrutinise the clinical cost‐effectiveness and toxicity of the regimens and provide the evidence required for guiding practitioners in treating secondary peritonitis with systemic parenteral antibiotics.
Objectives
1. The primary aim of this review will be to assess the adequacy of the antibiotic regimens in eradicating initial sepsis and the need for subsequent interventions to eradicate peritoneal sepsis. As part of the review, mortality associated with the initial pathology will be also be assessed and correlated to the efficacy of the different antibiotic regimens.
2. Patients with peritonitis frequently undergo surgery to treat the cause of infection, and a secondary objective is to identify whether certain systemic antibiotic regimens reduce post‐operative infection rates and post‐operative stay. Wound, urinary and chest infection rates will be specifically examined, together with an evaluation of the success of antibiotic regimens in adequate source control, most specifically the need for subsequent interventions to eradicate peritoneal sepsis.
3. Certain antibiotics, particularly the aminoglycosides, have higher toxicity compared to the others. We would aim to elucidate and compare the various adverse events relating to the regimens used.
Methods
Criteria for considering studies for this review
Types of studies
Acceptable randomised controlled trials and controlled clinical trials (where treatment allocations were randomised using coin flips, odd‐even numbers, case record number, days of the week, or other such pseudo‐ or quasi random processes) (Clarke 2003) in which treatment with one antibiotic agent or regimen was compared to another or placebo in patients with secondary peritonitis.
Types of participants
Trials including adult patients with secondary peritonitis diagnosed clinically or at surgery, requiring a course of antibiotic treatment will be entered into the review.
Patients with peritonitis will be divided into aetiological or risk‐assessed subgroups, where possible:
1. Faecal
2. Ischaemia
3. Biliary and pancreatic
4. Upper gastrointestinal
5. APACHE II / POSSUM score range
Gynaecological causes of peritonitis will not be reviewed, nor will trials of antibiotics in appendicitis unless the patients presented with 2+ quadrant peritonitis. Patients with peritonitis secondary to continuous ambulatory peritoneal dialysis or peritonitis secondary to trauma will similarly be excluded as these patients have different disease patterns and microbial flora.
Types of interventions
Trials comparing one antibiotic agent or regimen versus another or placebo for treatment of secondary peritonitis will be recruited for this review.
Types of outcome measures
The primary aims of the review will be to assess the efficacy of the antibiotic regimens in eradicating the initial sepsis and reducing mortality.
This review will also assess these secondary aims:
1. Wound infection.
2. Post‐operative intra abdominal abscess.
3. Respiratory and urinary tract infections.
4. Adverse events related to antibiotic therapy.
5. Failure rate in terms of change of antibiotics and re‐operation.
6. Cost effectiveness.
All definitions will be standardised whenever possible.
Search methods for identification of studies
See: Collaborative Review Group search strategy.
The following bibliographic databases will be searched to identify relevant primary studies:
Latest issue of The Cochrane Central Register of Controlled Trials (CENTRAL).
MEDLINE from 1966 to present date.
EMBASE from 1980 to present date.
Cochrane Colorectal Cancer Group specialised register SR‐COLOCA.
The following search strategy will be used to search the databases:
#1 Periton$
#2 Abdo$
#3 Intra‐abdo$
#4 Intraabdo$
#5 #2 or #3 or #4
#6 Infect$
#7 Sep$
#8 #6 or #7
#9 #5 and #8
#10 #1 or #9
#11 Antibio$
#12 Antimicro$
#13 Anti‐infect$
#14 Drug therapy
#15 #11 or #12 or #13 or #14
#16 #10 and #15
1. Trials examining treatment of primary bacterial peritonitis, antibiotics prophylaxis and peritonitis as a result of continuous ambulatory peritoneal dialysis will not be included. Antifungal therapies, topical antibiotics and antiseptic agents will be similarly excluded.
Trials that fulfill the eligibility criteria will be recruited regardless of language.
2. Two independent assessors for inclusion will evaluate all identified trials from the search. Identified and included studies will be further examined for additional studies from the reference list.
3. Authors of technical reports and conference proceedings, and pharmaceutical companies will be contacted to seek additional unpublished studies that would potentially fulfill the eligibility criteria.
Data collection and analysis
Study selection:
Two independent reviewers will conduct a methodical search of the databases according to the search strategy specified. Trials will be considered for review if they fulfil the following inclusion criteria:
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randomised control trials or controlled clinical trials where one regimen of antibiotics versus another or placebo is used to treat secondary peritonitis.
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adult patients.
The following exclusion criteria will be used:
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trials involving peritonitis as a result of spontaneous, gynaecological, traumatic and continuous ambulatory peritoneal dialysis related causes will be excluded from this review.
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studies involving paediatric patients (<16 years of age ) will also be excluded.
The reviewers will use the title, keyword and abstract of the citations retrieved to consider the studies for inclusion. A third reviewer will further assess trials that do not fully meet the criteria of this review for possible inclusion. At this stage, any disagreement as to the suitability of the trials will be resolved by discussion among all five reviewers. Where a trial has been identified, the full paper will be obtained and inspected independently by two reviewers.
Quality assessment:
The methodology of identified studies will be assessed by two independent reviewers. Trials fulfilling the eligibility criteria will be assessed for quality using the following characteristics:
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concealment of allocation sequence will be classified as adequate, unclear, inadequate or not used as recommended by the Cochrane Handbook (Clarke 2003).
Allocation according to computer generated numbers, sequentially numbered sealed envelopes, shuffles, etc are considered truly random, whereas, randomisation according to date of birth, case record number, day of the week, etc, are considered inadequate. When studies do not report any concealment approach, concealment would be considered unclear.
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blinding of physicians and outcome assessors
Adequacy of efforts to make treatment and control arms indistinguishable to prevent performance and detection bias will be assessed.
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patient attrition
Efforts will be made to assess the way trials handle losses of participants (e.g. withdrawals, dropouts, protocol deviation) and the use of intention‐to‐treat analysis.
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patient stratification and external validity
Presence of patient stratification according to well established severity scores such as APACHE II and POSSUM will be scrutinised as this will aid in facilitating the external validity of the trials (Egger 2001).
Collection of data
Data collection will be standardised by means of specially developed forms and double checked by a second independent reviewer. The data collected will be divided into the following study characteristics:
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methods
Details of the randomisation method will be recorded according to the classification used in RevMan and suggested by the Cochrane Handbook (Clarke 2003). Duration of the study and follow up time, type of blinding used and methods employed to avoid attrition bias will be retrieved.
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participants
Data with regards to patient numbers in relation to power calculations, age, gender distribution, severity of illness and attempts at patient stratification using severity scoring systems such as APACHE II and POSSUM will be recorded.
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interventions
Details of blinding, type, length, dose and timing of antibiotics administration will be noted. Length of antibiotic administration will be documented as mean and standard deviation.
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outcome measures and results
Primary outcome measures ‐ in terms of mortality rate and interventional success. Interventional success will be documented as either clinical or bacteriological success. Failure rate will be quantified either as re‐operation or change of antibiotic regimen.
Secondary outcome measures ‐ such as wound and super‐ infection, adverse events and length of hospital stay.
Synthesis of data
The data collected will be analysed using intention‐to‐treat analysis. The statistical package (MetaView of RevMan) provided by the Cochrane Collaboration will be used. For dichotomous outcome (death or survival), the impact of the intervention will be expressed as odds ratio together with 95% confidence intervals. Continuous outcomes will be compared using weighted mean difference. The following data will be extracted to perform subgroup analysis:
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APACHE II / POSSUM score.
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duration of antibiotic administration.
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aetiology of secondary peritonitis.
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toxicity / side‐effects.
Antimicrobial regimens will be grouped according to their molecular class. Each arm of each controlled study refers to a specific regimen / dosage pattern. All studies where the antibiotics under comparison are assigned to the same set of regimen / dosage pattern will be pooled.
Tables of comparison will include the following outcomes:
Primary aims:
1) Death for any cause.
2) Success / failure rate (in terms of re‐operation and change of antibiotics).
Secondary aims:
1) Postoperative wound infections (discharge of pus or necessity for additional interventions).
2) Postoperative intra‐abdominal infection (clinical or imaging studies).
3) Bacterial eradication (comparison of intra‐ and post‐operative cultures).
4) Adverse drug effects (this will be divided into minor symptoms such as rashes, and abnormal blood results; moderate symptoms and severe symptoms such as renal failure, deafness).
Potential effects of publication bias on the results of the meta‐analysis will be assessed from a funnel graph of the sample size plotted against the odds ratio. Heterogeneity in the results of the trials will be assessed using a Chi‐square test of heterogeneity (p<0.1). Data will be pooled using the random effects model.
In addition, multivariate regression models will be calculated.
Cost‐effectiveness
Where possible, cost effectiveness of each regimen will be appraised, for example, by examination of frequency of administration of antibiotics.
