TITLE: Carbapenems for Multi-Drug Resistant Infections: A Review of Clinical and Cost- Effectiveness

DATE: 27 July 2016

CONTEXT AND POLICY ISSUES

The global increase in prevalence of multi-drug resistant (MDR) pathogens is causing significant issues in today’s healthcare systems, including increasing morbidity, mortality, and healthcare- associated costs.1 Resistance mechanisms, such as through extended-spectrum beta- lactamases or AmpC beta-lactamases, often provide pathogens with resistance against commonly used broad-spectrum antibiotics, such as third-generation cephalosporins or penicillins.2 These antibiotics are also often reserved only for the treatment of MDR organisms in order to reduce resistance rates against the dwindling pool of antibiotic alternatives available.

Carbapenems, one of the most broad-spectrum agents in the penicillin antibiotic class, are often used empirically in infections that are high risk for multi-drug resistant bacteria, or definitively to treat organisms with resistance to other antibiotics.3 Empiric therapy is defined as treating a patient without prior knowledge of the causative organism or sensitivities, while definitive therapy is treatment based on the determined causative agent and its sensitivities. Carbapenems are considered active against many gram-positive and gram-negative aerobic and anaerobic bacteria.3 Carbapenems are unique from other penicillins in that they have high stability against certain β-lactamases, making them ideal for infections with organisms that are resistant to other penicillins due to certain β-lactamases.3

Unfortunately, uncertainty exists regarding which of the limited number of options available to treat MDR infections, such as carbapenems and beta-lactam/beta-lactamase inhibitors (BLBLIs), would be optimally appropriate, efficacious and safe in patients. Other areas of uncertainty include the differences between various carbapenems, and between certain populations who are at high-risk for poor outcomes, such as in patients with meningitis or febrile neutropenia. Of special interest is the clinical efficacy (e.g. clinical or microbiological cure, mortality), safety (e.g. antimicrobial resistance rates, seizures, treatment-related complications), and cost-effectiveness outcomes.

Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to provide a list of sources of the best evidence on the topic that the Canadian Agency for Drugs and Technologies in Health (CADTH) could identify using all reasonable efforts within the time allow ed. Rapid responses should be considered along w ith other ty pes of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report.

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The objectives of this study are to review the comparative efficacy, safety, and cost- effectiveness of various carbapenems and BLBLIs in specific, high-risk patient populations.

RESEARCH QUESTIONS

1. What is the comparative clinical effectiveness of imipenem versus meropenem in patients with central nervous system infection?

2. What is the comparative clinical effectiveness of meropenem 500 milligrams every 6 hours versus meropenem 1 gram every 8 hours in patients with multi-drug resistant infection?

3. What is the comparative clinical effectiveness of carbapenems versus beta-lactam/beta- lactamase inhibitor combination treatment in patients with infections due to AmpC beta- lactamase-producing bacteria?

4. What is the comparative clinical effectiveness of carbapenems versus beta-lactam/beta- lactamase inhibitor combination treatment in patients with infections due to extended- spectrum beta-lactamase producing bacteria?

5. What is the clinical effectiveness of carbapenems versus piperacillin/tazobactam or cefepime in patients with febrile neutropenia?

6. What is the cost-effectiveness of ertapenem versus meropenem for the treatment of multi- drug resistant infections in hospital inpatients?

KEY FINDINGS

Evidence from mostly poor quality trials and systematic reviews revealed that the comparative clinical efficacy and safety of carbapenems and other broad-spectrum antibiotics for multi-drug resistant organisms and patients at high risk for multi-drug resistant organisms is inconsistent and inconclusive. Though the clinical evidence is poor, good antimicrobial stewardship practices support the judicious use of carbapenems, and pharmacokinetic data supports the use of smaller dose, shorter interval regimens of meropenem.

No economic evaluations could be identified to assess the comparative cost-effectiveness of ertapenem to meropenem.

METHODS

Literature Search Methods

A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type, except for research question #6, where an economic studies filter was applied. Where possible, retrieval was limited to the human population. The search was limited to English language documents published between January 1, 2006 and June 24, 2016 for questions #1, #2, #5 and #6. For question #3 and #4, the search was limited to English language documents published between January 1, 2011 and June 24, 2016.

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Rapid Response reports are organized so that the evidence for each research question is presented separately.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria Population Patients of any age with: Q1: Central nervous system infection Q2: multi-drug resistant infection Q3: Infections due to AmpC beta-lactamase-producing bacteria Q4: Infections due to extended-spectrum beta-lactamase producing bacteria Q5: Febrile neutropenia Q6: In the hospital setting Intervention Q1: Imipenem Q2: Meropenem Q3 to 5: Carbapenems Q6: Ertapenem Comparator Q1 and 6: Meropenem Q2: Meropenem 1g q8h Q3 and 4: Beta-lactamase/beta-lactamase inhibitor combination treatment Q5: Piperacillin/tazobactam or cefepime Outcomes Q1 to 5: Clinical effectiveness (e.g. treatment success [clinical or microbiological cure], rate of infection, mortality, relapse rates) Q1 to 5: Harms (e.g. rate of antimicrobial resistance [carbapenem- resistant Enterobacteriaceae], seizure, treatment complications Q6: Cost-effectiveness outcomes Study Designs Health technology assessments (HTA), systematic reviews (SR), meta-analyses (MA), randomized controlled trials (RCTs), non- randomized studies, economic evaluations

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, were published prior to 2006 for Q1, Q2, Q5, and Q6, were published prior to 2011 for Q3 and Q4, or if they were reference in a selected systematic review. Studies were also excluded if they included combination therapy comparators.

Critical Appraisal of Individual Studies

The included systematic reviews were critically appraised using the Assessment of Multiple Systematic Reviews (AMSTAR) tool.4 Randomized and non-randomized studies were critically

Carbapenems for MDR Infections 3

appraised using the Downs and Black instrument.5 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described, narratively.

SUMMARY OF EVIDENCE

Quantity of Research Available

A total of 703 citations were identified in the literature search. Following screening of titles and abstracts, 654 citations were excluded and 49 potentially relevant reports from the electronic search were retrieved for full-text review. Nine potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, 37 publications were excluded for various reasons, while 21 publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection.

Summary of Study Characteristics

Details on study characteristics, critical appraisal, and findings can be found in Appendices 2, 3 and 4.

Study Design

Overall, Five systematic reviews,6-10 four randomized controlled trials (RCT),11-14 one post-hoc analysis of pooled results from two phase II trials,15 and 11 retrospective cohort trials16-26 met the inclusion criteria. No evidence-based health technology assessments or economic evaluations were identified.

What is the comparative clinical effectiveness of imipenem versus meropenem in patients with central nervous system infection?

Country of Origin

The one study identified was conducted at a single center in Spain.16

Patient Population

The one study identified for this research question was comprised of adult patients with diagnosed brain abscesses.16 The mean age ± standard deviation (SD) in the imipenem group was 37.5 ± 19.3 years, and was 50 ±15.9 years in the meropenem group.16 Both groups were approximately 80% male, but the imipenem group had a higher percentage of patients with a Glasgow Coma Scale GCS < 7, at 27.3%, relative to the meropenem group, 12%.16

Interventions and Comparators

The one trial identified compared imipenem, meropenem, and cefotaxime with metronidazole.16

Outcomes Measured

The one trial measured clinical cure, neurosurgery, relapse, seizure, and mortality rates as outcomes.16

Carbapenems for MDR Infections 4

What is the comparative clinical effectiveness of meropenem 500 milligrams every 6 hours versus meropenem 1 gram every 8 hours in patients with multi-drug resistant infection?

Country of Origin

One systematic review, conducted by a group in Canada, was found for this research question.6 The systematic review included three studies that were from the USA.6 The systematic review included trials published between 1950 to September 2009.6

Patient Population

The one systematic review did not thoroughly describe the patient populations of the three included trials, and a specific patient population of interest was not reported.6 One of the three trials included any patient who had received one of the comparators of interest.6 These patients had a relatively low severity of illness, at an Acute Physiology and Chronic Health Evaluation (APACHE) score of approximately 15.6 Another trial was a historical control trial comparing patient outcomes before and after changing meropenem to a lower dose but higher frequency regimen. The last included trial recruited adult patients with febrile neutropenia who had failed or were intolerant to cefepime.6

Interventions and Comparators

The one identified systematic review assessed trials comparing different dosing of meropenem.6

Outcomes Measured

The one systematic review identified reported the following relevant outcomes: clinical success rate, microbiologic success rate, infection-related length of stay, and in-hospital mortality rate.6

What is the comparative clinical effectiveness of carbapenems versus beta-lactam/beta- lactamase inhibitor combination treatment in patients with infections due to AmpC beta- lactamase-producing bacteria?

Country of Origin

One systematic review was found for this research question, and included trials published between January 1980 and August 2015.7 The systematic review was conducted by individuals from Australia, USA, and South Korea.7 Four included studies came from the USA, two from Australia, and one each from Spain, Switzerland, Canada, South Korea, and Taiwan.7

Patient Population

The one systematic review included adult patients with bacteremia by a gram-negative bacteria with confirmed AmpC beta-lacatamase.7 With the exception of one trial which included adult and pediatric patients, all other trials only included adult patients.7 The majority of trials consisted of patients who had malignancies or were immunocompromised.7

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Interventions and Comparators

The one systematic review identified for this question compared carbapenems against either BLBLIs, cefepime, or fluoroquinolones.7

Outcomes Measured

The only outcome measured reported in this review and relevant to the research questions was all-cause mortality.7

What is the comparative clinical effectiveness of carbapenems versus beta-lactam/beta- lactamase inhibitor combination treatment in patients with infections due to extended-spectrum beta-lactamase producing bacteria?

Country of Origin

Two systematic reviews were found for this research question.8,9 One systematic review, by a group in Israel, included many studies conducted in centers in several different countries published up to June 2014.8 This systematic review did not provide an earlier date as a limit for the literature search.8 Thirteen trials included patients from the USA, while four trials included centers from Canada.8 Other trials included in this systematic review included centers from Asian countries (i.e. predominantly Japan, but also including the Phillipines and Israel), European countries (e.g. Switzerland, Turkey, Sweden, Germany), and South Africa.8 The other systematic review, by individuals from Greece and the USA, included nine trials with centers in Asia, six in Europe, four in North or South America, one in South Africa, and one international, all published before January 2012.9 This systematic review also did not provide an earlier date as a limit for the literature search.9

One of the phase II trials included in the post-hoc analysis was conducted in centers in the USA, Argentina, Russia, Georgia, and Serbia.15 The other phase II trial was in Guatemala, India, Jordan, Lebanon, and the USA.15

Of the six non-randomized trials, two studies each were conducted in Singapore and internationally, and one study each was conducted in Taiwan and the USA.

Patient Population

In one systematic review, trials with adult or pediatric patients could be included, but also trials that allowed other antibiotics to be used in the different treatment comparator groups, so as long as they were applied equally to all groups.8 Interest in a specific subgroup of patients with ESBL-producing organisms was determined ad-hoc, but lack of reporting from the studies regarding patient-specific data of etiologic organisms precluded this analysis.8 Instead, the authors conducted an analysis of patients at higher risk for ESBL-producing organisms, namely patients with P. aeruginosa infections, febrile neutropenia, and nosocomial infections. The mean age of the studies ranged from approximately 7 to 85 years old.8 The other systematic review included trials of adult patients with ESBL-producing Enterobacteriaciae bacteremia infections.9 The majority of included trials included high proportions of patients with malignancies, or diabetes mellitus.9

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The six non-randomized, retrospective trials included patients with infections with documented ESBL-producing organisms, or from organisms that were non-susceptible to third-generation cephalosporins. The one trial that included patients with organisms that had resistance to third- generation cephalosporins did not test for the specific mechanism of resistance, so other mechanisms of resistance may have been present, such as AmpC beta-lactamases.18 The majority of patients were adult, and had infections with ESBL-producing E. coli, K. pneumoniae, or P. mirabilis.17-22 Five of the six trials had a mean age range from 70 to 78 years old,17-20,22 while the sixth trial had a mean age of 48 years old.21 The last included study pooled the data of two phase II trials and assessed patient-specific data regarding the etiologic pathogen of infection and its mechanism of resistance.15 One of the two trials assessed adult patients with complicated urinary tract infections, and the other assessed adult patients with complicated intra-abdominal infections.15 The patients of both trials had a mean age of 47 years old.15

Interventions and Comparators

One of the two systematic reviews identified compared carbapenems against BLBLIs,8 while the other compared carbapenems against non-carbapenems, which included a BLBLI group.9 All of the non-randomized trials compared carbapenems (i.e. meropenem, imipenem, ertapenem) against BLBLIs (i.e. piperacillin/tazobactam, amoxicillin/clavulanate, ceftazidime/avibactam).17-22

Outcomes Measured

One systematic review measured mortality, and clinical failure in the P. aeruginosa, neutropenic fever, and nosocomial infection subgroups.8 The other systematic review only assessed all- cause mortality.9

The pooled-results analysis of the two Phase II trials assessed a “clinically favourable response” as an outcome.15

Of the six non-randomized trials, clinical cure was reported by one trial,17 a mortality outcome by all six trials,17-22 hospital length of stay by one trial,18 relapse by two trials,18,19 and resolution of systemic inflammatory response syndrome (SIRS) by one trial.18 Two studies reported safety outcomes (i.e. C. difficile infection and isolation of a MDR organism).18,19

What is the clinical effectiveness of carbapenems versus piperacillin/tazobactam or cefepime in patients with febrile neutropenia?

Country of Origin

One systematic review was identified for this research question. The systematic review was conducted by individuals from the UK and Israel, and for the relevant outcomes, four included trials were conducted in Turkey, one included trial was conducted in the USA, France, Sweden, Germany, Korea, Sweden, the UK, and Spain each.10 Trials were included if published between 1966 and August 2010.10

All four of the identified RCTs were related to this research question.11-14 One RCT was conducted in China,11 while the other three were conducted in Japan.12-14

Of the four non-randomized, retrospective cohort studies, one trial was conducted in the USA, Australia, Turkey, and China each.11,23,24,26

Carbapenems for MDR Infections 7

Patient Population

The one systematic review identified included pediatric and adult patients with febrile neutropenia.10 The four RCTs were all exclusively in adult patients with febrile neutropenia, with three RCTs in patients with hematologic disease and one RCT with patients with lung cancer.11- 14 In the remaining four non-randomized, retrospective cohort trials, two were exclusively in adult patients,23,26 and the other two were in pediatric patients.24,25 The median or mean age ranged from 60 months old to 70 years old.11-13,23-25 Two trials did not report detailed patient characteristics.14,26

Interventions and Comparators

The systematic review had a large number of comparisons, including between carbapenems and either cefepime or piperacillin/tazobactam.10 The trials not included in the systematic review studied comparisons including carbapenems (i.e. meropenem, imipenem/cilastatin, panipenem/betamiron) against either cefepime or piperacillin/tazobactam. 11-14,23-26

Outcomes Measured

The systematic review assessed all-cause mortality, infection-related mortality, clinical failure and microbiological failure.10 It also assessed broad class comparisons for C. difficile infections.10

Three RCTs reported clinical success,11,13,14 two reported defervescence,11,12 two reported mortality outcomes,11,13 and one reported recovery from febrile neutropenia.12 All four RCTs reported adverse events as an outcome.11-14

Of the four non-randomized trials, two trials did not report an efficacy outcome, and only reported C. difficile infection rates.25,26 The other two trials reported clinical success, mortality, and adverse events.23,24 One of these two trials also reported length of hospitalization.24

What is the cost-effectiveness of ertapenem versus meropenem for the treatment of multi-drug resistant infections in hospital inpatients?

No evidence was identified for this research question.

Summary of Critical Appraisal

For question 1, the quality of the study was low.16 The trial was a retrospective cohort study, and the comparator arm was mostly comprised of patients who were started on piperacillin/tazobactam prior to a preference change to carbapenems.16 The proportion or number of patients from each group prior to and after this preference change was not provided. The study had a small sample size, several baseline characteristic differences between groups (e.g. imipenem group had more patients with GCS score < 7, multiple abscesses, and were younger), and no specified primary outcome, with analyses done on several different outcomes which were not clearly specified in the methods section.16 Seizure rate was not adjusted for confounders.16 The lower limit of the 95% confidence interval was also close to 1, leaving open the possibility that any confounders could influence the results, making the results not statistically significant.16

Carbapenems for MDR Infections 8

The systematic review, which included three retrospective cohort studies, identified for question 2 was of low quality.6 A comprehensive literature search including three databases was conducted.6 Potential limitations include lack of description of an a priori design, no reported duplication of study selection and data extraction, no reported search of the grey literature, no assessment of publication bias, study quality or heterogeneity, multiple outcomes reported with no clear primary outcome, and low number of trials.6

The systematic review identified for question 3 was recent, the literature search was comprehensive with triplicate study selection and data extraction, the quality of studies was assessed, and a random effects model was used.7 However, only observational prospective and retrospective cohort studies were included, and no assessment of publication bias was reported.7

One of the systematic reviews for question 4 only included high quality studies (i.e. RCTs) and had a comprehensive literature search, but a fixed-effects model was used, and the RCTs identified did not report on the specific population of patients with ESBL-producing bacterial infections.8 A fixed effects model assumes that the patient populations between studies are similar enough to not significantly alter the results, meaning the results are more likely to be statistically different than with a random effects model. The generalizability of the results from this systematic review are limited since only data on patient subgroups at high risk for ESBL infections was reported.8 The other systematic review was mainly comprised of lower quality trials (i.e. observational, retrospective cohort trials).9 Other limitations include detection of publication bias via funnel plot, and search of the grey literature was not reported.9 Strengths of this trial include a comprehensive literature search with two databases and duplicate study selection and data extraction, quality assessment of the included trials, and use of a random effects model.9

The other trials found for question 4 were generally of low quality. Six of the seven identified trials were retrospective cohort trials,17-22 with one trial calculating the required sample size to detect a clinically important difference.18 The seventh trial was a pooled analysis of two phase II RCTs, specifically of the patients with confirmed infections of ESBL-producing bacteria.15 The two included trials were in different patient populations in terms of types of infections, the outcome reported was heterogeneous between trials, and the total sample size was small.15 The sample sizes of the included studies ranged from 40 to 627 patients and most had significant imbalances in baseline characteristics between treatment arms.17-22 One of these trials exclusively included patients with resistance to cefotaxime, which would have included organisms with any resistance mechanism including ESBL or AmpC, among others, limiting the generalizability of the results to specifically ESBL-producing or AmpC producing organisms.18 However, all trials except for the pooled analysis identified and adjusted results for confounders.17-22 Two trials had an adverse event as an outcome,18,19 the remainder did not report safety.

In question 5, the identified systematic review was of high quality.10 It only included RCTs, a comprehensive literature search, including the grey literature, was done, study characteristics and quality assessment was completed, and publication bias was assessed.10 Limitations include single investigator study selection, a fixed effects model being used, and a small number of RCTs for the outcomes of interest for this question.10 The four RCTs identified for this question were of moderate quality.11-14 The methodology for all trials was well-described.11-14 One trial did not include a power calculation.11 Two trials had a power calculation and met the

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required sample size to power their results,12,13 while one did not have an adequate sample size.14 Two of the RCTs were open-label,13,14 and the other two did not report blinding.11,12 The external validity of the trials is also limited, due to all four trials having been conducted in Asian countries (3 in Japan, 1 in China).11-14 The four non-randomized studies were all retrospective cohort trials.23-26 Two of these trial focused on C. difficile infection rates, which is a strength given that most trials assess adverse drug events as an exploratory outcome.25,26 None of the trials reported a power calculation, and two of the trials did not identify or adjust results for confounders.23-26

Summary of Findings

What is the comparative clinical effectiveness of imipenem versus meropenem in patients with central nervous system infection?

One single center, retrospective cohort trial was identified.16 The trial did not show a statistically significant difference between imipenem or meropenem in treating brain abscesses in terms of clinical cure, neurosurgery, brain abscess relapse or mortality rates.16 The trial did show a higher seizure frequency with imipenem (31.8%) compared against meropenem (8.0%) (P = 0.03, odds ratio [OR] 6.57, 95% confidence interval [CI]; 1.04 to 52.8).16

What is the comparative clinical effectiveness of meropenem 500 milligrams every 6 hours versus meropenem 1 gram every 8 hours in patients with multi-drug resistant infection?

The systematic review identified this question did not provide an analysis of pooled results.6 The qualitative summary of the studies did not report any statistically significant benefits with administering meropenem as smaller doses with shorter intervals in terms of clinical success rates, microbiologic success rates, infection-related length of stay, or in-hospital mortality rates.6

What is the comparative clinical effectiveness of carbapenems versus beta-lactam/beta- lactamase inhibitor combination treatment in patients with infections due to AmpC beta- lactamase-producing bacteria?

One systematic review was identified for this question.7 It did not identify any statistically significant differences between carbapenems or BLBLIs for definitive or empiric therapy in terms of all-cause mortality.7 After adjusting for age, sex, and illness severity, the difference for definitive therapy all-cause mortality was still not statistically significant.7 The authors report that not enough patient-level data was present to adjust for confounders for empiric therapy.7

What is the comparative clinical effectiveness of carbapenems versus beta-lactam/beta- lactamase inhibitor combination treatment in patients with infections due to extended-spectrum beta-lactamase producing bacteria?

The first of two systematic reviews did not identify any trials for inclusion that explicitly determined the mechanism of resistance, thus an analysis of patients with ESBL-producing organisms could not be done.8 Instead, the authors analyzed subgroups of patients more likely to have ESBL-producing organisms (i.e. P. aeruginosa infection, neutropenic fever, and nosocomial infection).8 In these subgroups, no difference in mortality or clinical failure was seen between carbapenems and BLBLIs.8 The second systematic review only assessed a single outcome, all-cause mortality, and also found no statistically significant differences between carbapenems and BLBLIs.9

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Three trials did not show a statistically significant difference in any outcome, such as mortality, clinical response, isolation of resistant organism, relapse infection, or hospital length of stay.17,18,22 One trial with pooled results from 2 phase II trials did not conduct any statistical analyses, but the authors noted that the results between the two groups were similar.15 One of the trials found a statistically significant increase in the acquisition of a MDR organism with carbapenems (adjusted OR 3.32, 95% CI; 1.12 to 9.87).19 Two other trials found a statistically significant increase in mortality, one with 90-day mortality (adjusted OR 7.9, 95% CI; 1.2 to 53) and the other with 14-day mortality (adjusted hazard ratio [HR] 1.92, 95% CI 1.07 to 3.45), with piperacillin/tazobactam use.20,21

What is the clinical effectiveness of carbapenems versus piperacillin/tazobactam or cefepime in patients with febrile neutropenia?

One systematic review was identified.10 No statistically significant difference was detected between carbapenems and piperacillin/tazobactam or cefepime in regards to all-cause mortality, infection-related mortality, clinical failure, or microbiological failure in patients with febrile neutropenia.10

One RCT compared a carbapenem (i.e. imipenem/cilastatin) against piperacillin/tazobactam.11 The trial found that imipenem/cilastatin was associated with a statistically significant increase in rate of defervescence at 48 h after initiation of empiric antibiotic therapy, success at end of therapy without change of initial antibiotics, and GI adverse events.11 Survival rate and other adverse events were not different between the two groups.11 Three RCTs compared a carbapenem against cefepime.12-14 Two of the three RCTs did not find any differences between treatment groups in clinical outcomes, such as rate of defervescence, recovery from febrile neutropenia, and adverse events.12,14 Neither of these trials assessed mortality.12,14 The last RCT identified that carbapenems were associated with a statistically significant benefit in 30-day mortality relative to cephalosporins, which included both cefozopran and cefepime (1% vs 6%, respectively, P = 0.02).13 Furthermore, a subgroup analysis in patients with febrile neutropenia for > 7 days had lower response rates with cefepime (46%) relative to imipenem/cilastatin (79%) or meropenem (74%, P = 0.01 between all arms).13

Of the non-randomized trials, two reported on C. difficile infection rates.25,26 Both reported a statistically significant increase in C. difficile infection rates with use of cefepime.25,26 One of the other two trials did not find a statistically significant difference between imipenem and piperacillin/tazobactam in regards to successful treatment without regimen modification at 72h, 28-day mortality, or C. difficile infection rates, despite finding that use of piperacillin/tazobactam was had a higher rate of antibiotic regimen modification relative to imipenem use (62% and 31%, respectively, P < 0.01).23 The other non-randomized trial did not find any statistically significant differences in terms of treatment success, median duration of hospitalization, or mortality.24

What is the cost-effectiveness of ertapenem versus meropenem for the treatment of multi-drug resistant infections in hospital inpatients?

No studies on the cost-effectiveness of ertapenem compared with meropenem for the treatment of multi-drug resistant infections were identified.

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Limitations

The robustness of evidence for each of the 6 questions is limited due to the nature of the available evidence. Major limitations impacting the results include small sample sizes, lack of adjustment for confounders, poor study quality and methodology, and heterogeneous inter- and intra-patient populations and results. The four higher quality trials (i.e. RCTs) were all found in regards to the effectiveness of carbapenems for patients with febrile neutropenia, and only two reported a power calculation and met an adequate sample size based on their power calculation. The majority of the non-randomized trial did not include a power calculation, and due to small sample sizes, the trials were unlikely to be of an adequate size to power their results. External validity in the systematic reviews is also generally impaired due to the small number of studies available for each comparison. Furthermore, most of the literature with neutral findings concluded that the investigated treatment arms are likely equivalent or non- inferior. However, these conclusions cannot be relied upon because the majority of trials were not designed as equivalence or non-inferiority trials.

Importantly, questions 3, 4 and 5 included a larger number of trials, or a systematic review including a larger number of trials. One non-randomized trial was identified for question 1, one systematic review including three non-randomized studies for question 2, and no evidence was identified regarding the cost-effectiveness of ertapenem versus meropenem for the treatment of MDR infections.. The poor quality of evidence and the small number of trials available for these questions greatly limit the ability to draw any definitive conclusions regarding carbapenem use.

CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING

Use of meropenem or imipenem in brain abscesses, a type of CNS infection, produced similar clinical efficacy results, but imipenem was associated with a statistically significantly greater seizure frequency relative to meropenem. However, several aforementioned limitations prevent being able to conclude that meropenem is just as efficacious as imipenem, but safer in regards to seizures in all CNS infections. Given that the current evidence for selecting between carbapenems in CNS infections is limited, either meropenem or imipenem remain options. Meropenem may be preferable in light of evidence, albeit poor, that imipenem may result in an increased risk for seizures. Further larger, RCTs comparing the two carbapenems are required to make definitive conclusions regarding efficacy and safety in CNS infections.

The comparative efficacy and safety of alternative, smaller dose and shorter interval dosing of meropenem compared to higher dose, more extended interval dosing were similar in regards to clinical efficacy outcomes as no statistically significant differences were seen. However, safety outcomes were not reported. Similar to the evidence for carbapenem use in CNS infections, the significant limitations to the evidence prevent the ability to draw the conclusion that both treatment regimens are equivalent or non-inferior to each other, especially in patients with MDR infections. Though the evidence regarding clinical outcomes is limited, pharmacokinetic data suggests that the use of smaller dose, shorter interval dosing regimens are feasible and theoretically just as efficacious as higher dose, longer interval dosing regimens.6

There is a considerably larger pool of evidence for the treatment of AmpC beta-lactamase- producing and extended-spectrum beta-lactamase producing bacterial infection. The systematic reviews and pooled-analyses did not find any differences between piperacillin/tazobactam or carbanem therapy, though safety was not assessed as an outcome. Overall between the systematic reviews and lower quality trials, significant heterogeneity was seen for inter- and

Carbapenems for MDR Infections 12

intra- study patient populations, reported outcomes, and results, greatly limiting the interpretability of the results as a whole. Given the lack of consistent results, limitations to the current evidence, and rising incidence of MDR infections, the practice of using broad-spectrum antibiotics based on good antimicrobial stewardship practices (e.g. appropriate empiric use based on local susceptibility patterns, stepping down therapy when appropriate) is a reasonable option in place of selection of an antibiotic for preferential use in the setting of MDR infections. Larger and better designed trials are required to draw definite conclusions regarding efficacy and safety of carbapenems against other broad-spectrum antibiotics in AmpC- or ESBL- producing bacterial infections.

The evidence for comparative efficacy and safety between carbapenems and either piperacillin/tazobactam or cefepime also demonstrated heterogeneous results. Though no differences were seen in mortality between any of the comparisons of interest, clinical efficacy ranged from benefits seen with carbapenems over comparators to no significant differences between groups. Safety outcomes were also heterogeneous between studies. One systematic review indicates that cefepime may be associated with a greater risk for developing C. difficile infections, which is corroborated by some of the lower quality evidence. However, other trials, including RCTs and retrospective cohort trials, suggest that there are no differences in any adverse events between groups, or carbapenems cause more GI adverse events than piperacillin/tazobactam. Similar to other research questions examined here, larger and better designed trials and meta-analyses are required to be able to draw more definite conclusions.

Conclusions cannot be drawn for the cost-effectiveness comparison between ertapenem and meropenem since no relevant evidence-based economic evaluations were identified.

PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

Carbapenems for MDR Infections 13

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7. Harris PN, Wei JY, Shen AW, Abdile AA, Paynter S, Huxley RR, et al. Carbapenems versus alternative antibiotics for the treatment of bloodstream infections caused by Enterobacter, Citrobacter or Serratia species: a systematic review with meta-analysis. J Antimicrob Chemother. 2016 Feb;71(2):296-306.

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9. Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum beta-lactamases: a systematic review and meta-analysis. J Antimicrob Chemother [Internet]. 2012 Dec [cited 2016 Jul 4];67(12):2793-803. Available from: http://jac.oxfordjournals.org/content/67/12/2793.full.pdf+html

10. Paul M, Yahav D, Bivas A, Fraser A, Leibovici L. Anti-pseudomonal beta-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of beta-lactams. Cochrane Database Syst Rev. 2010;(11):CD005197.

11. Jing Y, Li J, Yuan L, Zhao X, Wang Q, Yu L, et al. Piperacillin-tazobactam vs. imipenem- cilastatin as empirical therapy in hematopoietic stem cell transplantation recipients with febrile neutropenia. Clin Transplant. 2016 Mar;30(3):263-9.

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12. Fujita M, Matsumoto T, Inoue Y, Wataya H, Takayama K, Ishida M, et al. The efficacy and safety of cefepime or meropenem in the treatment of febrile neutropenia in patients with lung cancer. A randomized phase II study. J Infect Chemother. 2016 Apr;22(4):235-9.

13. Nakane T, Tamura K, Hino M, Tamaki T, Yoshida I, Fukushima T, et al. Cefozopran, meropenem, or imipenem-cilastatin compared with cefepime as empirical therapy in febrile neutropenic adult patients: a multicenter prospective randomized trial. J Infect Chemother. 2015 Jan;21(1):16-22.

14. Nakagawa Y, Suzuki K, Ohta K, Hino M, Ohyashiki K, Kanamaru A, et al. Prospective randomized study of cefepime, panipenem, or meropenem monotherapy for patients with hematological disorders and febrile neutropenia. J Infect Chemother. 2013 Feb;19(1):103- 11.

15. Mendes RE, Castanheira M, Gasink L, Stone GG, Nichols WW, Flamm RK, et al. Beta- lactamase characterization of gram-negative pathogens recovered from patients enrolled in the phase 2 trials for ceftazidime-avibactam: clinical efficacies analyzed against subsets of molecularly characterized isolates. Antimicrob Agents Chemother [Internet]. 2015 Dec 14 [cited 2016 Jul 4];60(3):1328-35. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775982/pdf/zac1328.pdf

16. Martin-Canal G, Saavedra A, Asensi JM, Suarez-Zarracina T, Rodriguez-Guardado A, Bustillo E, et al. Meropenem monotherapy is as effective as and safer than imipenem to treat brain abscesses. Int J Antimicrob Agents. 2010 Mar;35(3):301-4.

17. Gutierrez-Gutierrez B, Perez-Galera S, Salamanca E, de Cueto M, Calbo E, Almirante B, et al. A multinational, preregistered cohort study of beta-lactam/beta-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-beta- lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016 Jul;60(7):4159-69.

18. Harris PN, Yin M, Jureen R, Chew J, Ali J, Paynter S, et al. Comparable outcomes for beta-lactam/beta-lactamase inhibitor combinations and carbapenems in definitive treatment of bloodstream infections caused by cefotaxime-resistant Escherichia coli or Klebsiella pneumoniae. Antimicrob Resist Infect Control [Internet]. 2015 May 1 [cited 2016 Jul 4];4:14. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414382/pdf/13756_2015_Article_55.pdf

19. Ng TM, Khong WX, Harris PN, De PP, Chow A, Tambyah PA, et al. Empiric piperacillin- tazobactam versus carbapenems in the treatment of bacteraemia due to extended- spectrum beta-lactamase-producing Enterobacteriaceae. PLoS One [Internet]. 2016 Apr 22 [cited 2016 Jul 4];11(4):e0153696. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841518/pdf/pone.0153696.pdf

20. Ofer-Friedman H, Shefler C, Sharma S, Tirosh A, Tal-Jasper R, Kandipalli D, et al. Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae. Infect Control Hosp Epidemiol. 2015 Aug;36(8):981-5.

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21. Tamma PD, Han JH, Rock C, Harris AD, Lautenbach E, Hsu AJ, et al. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum beta-lactamase bacteremia. Clin Infect Dis [Internet]. 2015 May 1 [cited 2016 Jul 4];60(9):1319-25. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462658/pdf/civ003.pdf

22. Tsai HY, Chen YH, Tang HJ, Huang CC, Liao CH, Chu FY, et al. Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum beta-lactamase-producing Proteus mirabilis. Diagn Microbiol Infect Dis. 2014 Nov;80(3):222-6.

23. Roohullah A, Moniwa A, Wood C, Humble M, Balm M, Carter J, et al. Imipenem versus piperacillin/tazobactam for empiric treatment of neutropenic fever in adults. Intern Med J. 2013 Oct;43(10):1151-4.

24. Sezgin G, Acipayam C, Ozkan A, Bayram I, Tanyeli A. Meropenem versus piperacillin- tazobactam as empiric therapy for febrile neutropenia in pediatric oncology patients. Asian Pac J Cancer Prev. 2014;15(11):4549-53.

25. Fisher BT, Sammons JS, Li Y, de Blank P, Seif AE, Huang YS, et al. Variation in risk of hospital-onset Clostridium difficile infection across beta-lactam antibiotics in children with new-onset acute lymphoblastic leukemia. J Pediatric Infect Dis Soc [Internet]. 2014 Dec [cited 2016 Jul 4];3(4):329-35. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854370/pdf/piu008.pdf

26. Muldoon EG, Epstein L, Logvinenko T, Murray S, Doron SI, Snydman DR. The impact of cefepime as first line therapy for neutropenic fever on Clostridium difficile rates among hematology and oncology patients. Anaerobe [Internet]. 2013 Dec [cited 2016 Jul 4];24:79-81. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876480/pdf/nihms532447.pdf

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APPENDIX 1: Selection of Included Studies

703 citations identified from electronic literature search and screened

654 citations excluded

49 potentially relevant articles retrieved for scrutiny (full text, if available)

9 potentially relevant reports retrieved from other sources (grey literature, hand search)

58 potentially relevant reports (full text)

37 reports excluded: -irrelevant population (n = 10) -irrelevant intervention and/or comparator (n = 4) -already included in at least one of the selected systematic reviews (n = 11) -other (review articles, editorials) (n = 12)

21 reports included in review

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APPENDIX 2: Characteristics of Included Publications

Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses First Types and Population Intervention Comparator(s) Clinical Author, numbers of Characteristics Outcomes, Publication primary Length of Year, studies Follow-Up Country included Research Question 2: Comparative clinical efficacy between meropenem dosing in MDR infections) Perrott,6 Trials relevant Patient Meropenem Meropenem Clinical success 2010, to research population alternative, traditional rate Canada question: characteristics small-dose, dosing not well short-interval (1 g q8h or 1 g Microbiologic Retrospective described regimens q12h if renal success rate cohort (500 mg q6h, insufficiency) n = 1 One study had or 500 mg q8h Infection-related patients with if renal length of stay Retrospective relatively low insufficiency) cohort with severity of Time to historical illness infection control (APACHE resolution n = 2 scores ~15) Treatment One study had failure rate patients with neutropenic In-hospital fever after mortality cefepime failure or intolerance Meropenem- related length of stay Research Question 3 and 4: Comparative clinical efficacy between carbapenems and BLBLIs in AmpC beta-lactamase-producing and extended-spectrum beta-lactamase producing bacteria Harris,7 Prospective Adult, Broad- Carbapenems All-cause 2016, cohort hospitalized spectrum mortality Australia, n = 5 patients with BLBLI agents USA, South blood stream Time to follow- Korea Retrospective infections OR up as defined cohort caused by by each n = 6 gram-negative Cefepime individual study, bacteria with and 30 day chromosomally OR mortality used if encoded AmpC several follow- -lactamase Fluoroquinolon up times es reported Shiber,8 RCTs Patients, adult Any BLBLI Any All-cause 2015, Israel n = 31 or child, being carbapenem mortality treated for sepsis. Other Clinical failure antibiotics could be used but only if applied equally to both

Carbapenems for MDR Infections 18

Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses First Types and Population Intervention Comparator(s) Clinical Author, numbers of Characteristics Outcomes, Publication primary Length of Year, studies Follow-Up Country included treatment groups

No data was found specifically in patients with ESBL infections Vardakas,9 Retrospective Patients any Carbapenems BLBLIs All-cause 2012, cohort age with mortality Greece, n = 16 community-, OR USA hospital-, and Case-control healthcare- Non-BLBLIs n = 1 associated bacteremia OR Prospective being treated cohort empirically or Fluoroquinolone n = 3 definitively for s ESBL-positive Post-hoc Enterobacteriac OR analysis of eae prospective Cephalosporins cohort data n = 2 OR

All other alternatives Research Question 5: Comparative clinical efficacy between carbapenems and piperacillin/tazobactam or cefepime in febrile neutropenia Paul,10 2010, RCTs Febrile Carbapenems Other beta- All-cause 30- Israel, UK n = 44 neutropenic lactams, day mortality RCTs of cancer patients. including carbapenem Interventions cefepime, and Clinical failure vs cefepime had to be equal piperacillin/ n = 8 – no other tazobactam Microbiological antibiotics were failure RCTs of allowed except carbapenem for Infection- vs piperacillin/ glycopeptides, related tazobactam which were mortality n = 5 required in both treatment arms APACHE = Acute Physiology and Chronic Health Evaluation; BLBLI = beta-lactam beta-lactamase inhibitor; ESBL = extended- spectrum beta-lactamases; q6h = every 6 hours; q8h = every 8 hours; RCT = randomized controlled trial; UK = United Kingdom; USA = United States of America

Carbapenems for MDR Infections 19

Table A2: Characteristics of Included Clinical Studies First Author, Population, Number Intervention(s) Comparator(s) Clinical Outcomes Publication of patients (N) Year, Country, Study Design, Length of Study Research Question 1: Comparative clinical efficacy between meropenem and imipenem for central nervous system infections Martin-Canal,16 Adult patients Meropenem Imipenem Clinical cure 2010, Spain diagnosed with brain abscess. Prior to year OR Neurosurgery Single-center, 2000, patients were retrospective started on antibiotics Cefotaxime + Relapse cohort based on preference of metronidazole infectious disease Seizures Duration not consultant. After year specified 2000, most patients were treated with carbapenem and neurosurgery.

N = 59 Research Question 3 and 4: Comparative clinical efficacy between carbapenems and BLBLIs in AmpC beta-lactamase-producing and extended-spectrum beta-lactamase producing bacteria Guti rrez- Patients with clinically BLBLIs (i.e. Carbapenems Clinical response at Guti rrez,17 significant amoxicillin/clavul (i.e. imipenem, day 14 2016, Spain, monomicrobial anate, meropenem, Italy, Canada, bloodstream infection piperacillin/tazob doripenem, 30-day mortality Turkey, due to ESBL- actam, ertapenem) Germany, Enterobacteriaceae and ampicillin/sulbac Greece, USA, received monotherapy tam) Israel, South antibiotics as therapy Africa, Taiwan, Australia, Empirical therapy Argentina cohort n = 365 Multicenter, retrospective Targeted therapy cohort cohort n = 601 30 days Global cohort (i.e. to assess patients who switched therapies) n = 627 Harris,18 2015, Adult patients, ≥21 Piperacillin/tazo Meropenem, Days to resolution Singapore years old, with one bactam, or ertapenem, or of SIRS positive monomicrobial amoxicillin/clavul imipenem as Single center, blood culture for E. coli anate as definitive therapy All-cause mortality retrospective or Klebsiella spp. which definitive cohort were cefotaxime non- therapy Identification of susceptible, but carbapenem or At least 30 days piperacillin/tazobactam piperacillin/tazobact

Carbapenems for MDR Infections 20

Table A2: Characteristics of Included Clinical Studies First Author, Population, Number Intervention(s) Comparator(s) Clinical Outcomes Publication of patients (N) Year, Country, Study Design, Length of Study and until and meropenem am resistant resolution of susceptible. organisms or C. SIRS difficile within 30 N = 47 days

Microbiological relapse

Length of hospital stay post first positive blood culture Mendes,15 2015, Adult patients, age 18 – Ceftazidime/avib Imipenem/cilastat Favourable Guatemala, 90 years, diagnosed actam in response, as India, Jordan, with cUTI or cIAI that defined by each Lebanon, USA, were microbiologically OR OR trial: Bulgaria, evaluable (i.e. patients France, India, that had bacterial Ceftazidime/avib Meropenem cUTI trial: Poland, isolates available for actam + eradication of all Romania, resistance mechanism metronidazole pathogens from Russia testing) urine and blood

Pooled results N = 192 cIAI trial: complete from two phase resolution or II clinical trials significant improvement of cUTI trial: 6 – 9 signs/symptoms of days after last infection with no dose of antibiotic requirements for cIAI trial: 7 – 14 additional days after last antimicrobial dose of antibiotic therapy Ng,19 2016, Patients with E. coli and Empiric Empiric 30-day mortality Singapore K. pneumoniae piperacillin/tazob carbapenem (i.e. bacteremia actam imipenem, 30-day incidence of Dual-center, ertapenem, or multi-drug resistant retrospective N = 151 meropenem) organisms cohort Relapsed At least 30 days, bacteremia and up to discharge or death Ofer-Friedman,20 Adult patients, > 18 Carbapenem Piperacillin/tazob In-hospital mortality 2015, Israel, years old, with ESBL (i.e. ertapenem, actam USA bloodstream infections imipenem, 30-day mortality (i.e. monomicrobial meropenem,

Carbapenems for MDR Infections 21

Table A2: Characteristics of Included Clinical Studies First Author, Population, Number Intervention(s) Comparator(s) Clinical Outcomes Publication of patients (N) Year, Country, Study Design, Length of Study Dual-center, blood isolations of doripenem) 90-day mortality retrospective ESBL-producing E. coli, cohort K. pneumonia, P. Length of hospital mirabilis) of nonurinary stay from culture to 90 days origin discharge

N = 79 Total days in ICU from culture to discharge Tamma,21 2015, Patients with ESBL- Empiric therapy Empiric therapy 14-day mortality USA producing organisms piperacillin/tazob with carbapenem (i.e. E. coli, K. actam, then Single-center, pneumoniae, K. switched to retrospective oxytoca, P. mirabilis) carbapenem cohort isolated from after ESBL- bloodstream producing 14 days organism N = 213 isolated Tsai,22 2014, Adult patients, aged ≥ Carbapenem Piperacillin/tazob 30-day mortality Taiwan 18 years old, with actam bacteremia due to In-hospital mortality Multicenter, ESBL-producing P. OR retrospective mirabilis cohort Other antibiotics N = 40 30 days Research Question 5: Comparative clinical efficacy between carbapenems and piperacillin/tazobactam or cefepime in febrile neutropenia Jing,11 2016, Patients with acute Imipenem/cilast Piperacillin/tazob Defervescence China leukemia, lymphoma atin actam after initial empiric and other antibiotic for 48h Dual-center, hematological diseases prospective, scheduled for Clinical success at randomized myeloablative end of therapy hematopoetic stem cell Patients transplantation Adverse reactions followed 48 h for primary These patients did not outcome, and up have neutropenic fever to treatment at study entry, but were success or randomize to receive death. Duration therapy if febrile not reported. neutropenia occurred

N = 123 patients with febrile neutropenia

Carbapenems for MDR Infections 22

Table A2: Characteristics of Included Clinical Studies First Author, Population, Number Intervention(s) Comparator(s) Clinical Outcomes Publication of patients (N) Year, Country, Study Design, Length of Study Fujita,12 2016, Febrile neutropenic Meropenem Cefepime Rate of Japan patients ≥ 20 years old defervescence for 5 with lung cancer and consecutive days Multicenter, chemotherapy induced prospective, neutropenia Defervescense randomized rates at 72 h, day 7, N = 38 day 14 14 days Adverse reactions

Nakane,13 2015, Febrile neutropenic Meropenem Cefepime Clinical efficacy Japan patients, ≥ 16 years old, OR with hematologic Imipenem/cilast 30-day mortality Multicenter. disease or cancer who atin Randomized, had not undergone OR Adverse events open-label, non- allogeneic stem cell Cefozopran inferiority transplantation

30 days N = 376

Nakagawa,14 Febrile neutropenic Panipenem/beta Cefepime Clinical efficacy 2013, Japan patients, ≥ 16 years old, miprom (based on with hematopoietic subjective Multicenter, disease without proven OR assessment of randomized, infection clinical open-label Meropenem improvement and N = 255 laboratory values) 30 days Adverse events

Roohullah,23 Patients, ≥ 16 years Piperacillin/tazo Imipenem Successful 2013, New old, with neutropenic bactam treatment without Zealand fever and an underlying regimen hematological disorder modification at 72 h Single center, retrospective N = 105 28-day mortality cohort, with historical control C. difficile rate

Up to death or Antibiotic therapy discharge modification

Sezgin,24 2014, Patients < 18 years old Meropenem Piperacillin/tazob Clinical success Turkey with febrile neutropenia actam who had been treated Antibiotic therapy Retrospective for hemato-oncological modification cohort malignancies

Carbapenems for MDR Infections 23

Table A2: Characteristics of Included Clinical Studies First Author, Population, Number Intervention(s) Comparator(s) Clinical Outcomes Publication of patients (N) Year, Country, Study Design, Length of Study Treatment failure Up to treatment N = 136 patients (defined as addition failure or Patients could be of other success recruited more than antimicrobial or once if > 1 febrile death) neutropenic episode N = 284 episodes Fisher,25 2014, Newly diagnosed ALL Carbapenems Cefepime, OR Diagnosis of CDI USA patients, aged 1 year to (imipenem and anti- (incidence) < 19 years, treated at meropenem) pseudomonal Multicenter, pediatric institutions penicillins retrospective contributing data to the (piperacillin, cohort Pediatric Health piperacillin/tazob Information System actam, ticarcillin, Up to 180 days ticarcillin/clavulan after ALL N= 8268 ate), OR diagnosis ceftazidime Muldoon,26 Patients in the Cefepime as Meropenem as CDI rate 2013, USA hematology and initial empiric initial empiric oncology ward therapy for therapy for Single center, neutropenic neutropenic fever retrospective N = N/A fever cohort with historical control

Data collected monthly over three years BLBLI = beta-lactam beta-lactamase inhibitor; CDI = C. difficile infection; cIAI = complicated intra-abdominal infection; cUTI = complicated urinary tract infection; ESBL = extended-spectrum beta-lactamases; RCT = randomized controlled trial; SIRS = systemic inflammatory response syndrome; USA = United States of America

Carbapenems for MDR Infections 24

APPENDIX 3: Critical Appraisal of Included Publications Table A3: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR4 Strengths Limitations Research Question 2: Comparative clinical efficacy between meropenem dosing in MDR infections) Perrot6  Comprehensive literature search performed  Multiple outcomes; no clear, single primary  Authors do not have any apparent conflicts of outcome interest  Qualitative systematic review; no pooled, quantitative results  No statement on grey literature results  A priori design not provided  Number of data extractors not reported  List of studies not provided  Aggregate characteristics of included studies not provided  Scientific quality of studies not reported, no assessment of heterogeneity  Publication bias not assessed  Studies included were all relatively small and retrospective  Small number of studies included  Heterogeneous patient populations  True incidence of MDR organisms unclear

Research Question 3 and 4: Comparative clinical efficacy between carbapenems and BLBLIs in AmpC beta-lactamase-producing and extended-spectrum beta-lactamase producing bacteria Harris7  A priori design provided, triplicate study  Only 3 studies provided enough information for selection and data extraction, and adjustment with definitive therapy. No studies comprehensive literature search performed provided enough information for adjustment  Quality of studies assessed using Newcastle- with empiric therapy Ottawa score, and heterogeneity was reported  Reason for high heterogeneity with 2 outlier  Authors had no reported conflict of interests studies is unclear  Random effects model used  Most studies included did not primarily study AmpC-producing organisms or carbapenems vs BLBLIs  No explicit statement on grey literature results  Publication bias not reported  No RCTs included, only retrospective and prospective cohort studies Shiber8  A priori design provided, duplicate study  No data on actual ESBL infections selection and data extraction, and  Analyses for ESBL infection subgroup was comprehensive literature search performed done using neutropenic fever and nosocomial  Grey literature search performed and included infections subgroups due to likely higher  Risk of bias assessed using domain-based relative rate of ESBL-positive infections approach  Study quality not assessed  Symmetrical funnel-plot  Heterogeneity not provided for subgroup  List of studies and characteristics provided analyses  No reported conflicts of interest or funding  Fixed-effect model used

Carbapenems for MDR Infections 25

Table A3: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR4 Strengths Limitations Vardakas9  A priori design provided, duplicate data  No explicit statement regarding grey literature extraction  Significant heterogeneity within and between  Two databases used for literature search trials (e.g. concomitant antibiotics used, patient  List and characteristics of studies provided populations)  Quality of studies assessed using Newcastle-  Publication bias detected via funnel plot Ottawa scale  One author has received funding from  Random effects model used pharmaceutical companies  All authors except 1 did not have any reported  Some patients on initial piperacillin/tazobactam conflicts of interest, and funding was not therapy were eventually switched to required for this study carbapenems (but ITT analysis was conducted)  Other resistance mechanisms not accounted for  Many non-randomized trials, many potential confounders (e.g. severity of infection, bacterial etiology) not accounted for Research Question 5: Comparative clinical efficacy between carbapenems and piperacillin/tazobactam or cefepime in febrile neutropenia Paul10  A priori design provided, duplicate data  Single investigator study selection extraction  Fixed effects model used  Grey literature searched  Small number of RCTs for specific outcome  Comprehensive literature search performed comparisons of carbapenems vs cefepime and  Characteristics of included studies provided piperacillin/tazobactam  Quality of studies assessed via investigator  Conclusions for adverse drug event/reaction judgement comparisons are generalized into antibiotic  Publication bias assessed via investigator class comparisons instead of specific antibiotic judgement comparisons  No reported conflicts of interests AMSTAR = Assessing the Methodological Quality of Systematic Review s; BLBLI = beta-lactam beta-lactamase inhibitor; ESBL = extended-spectrum beta-lactamase; ITT = intention-to-treat; MDR = multi-drug resistant organism

Table A4: Strengths and Limitations of Included Trials using Downs and Black5 Strengths Limitations Research Question 1: Comparative clinical efficacy between meropenem and imipenem for central nervous system infections Martin-Canal16  Patient characteristics, and interventions  Main outcomes not well described until results, clearly described several outcomes without a specified primary  Statistical tests appropriate outcome  Confounders identified and results adjusted for  No power calculation confounders  Small sample size  Estimates of random variability and exact  Retrospective cohort with partial historical probability values provided control  No reported funding or conflicts of interest  Significant baseline characteristic differences (e.g. imipenem group had younger patients)  Statistical tests missing in neurosurgery outcome

Carbapenems for MDR Infections 26

Table A4: Strengths and Limitations of Included Trials using Downs and Black5 Strengths Limitations Research Question 3 and 4: Comparative clinical efficacy between carbapenems and BLBLIs in AmpC beta-lactamase-producing and extended-spectrum beta-lactamase producing bacteria Guti rrez- Guti rrez17  Main outcomes, patient characteristics, and  Non-inferiority objectives described, but non- interventions clearly described inferiority analysis and margin were not used  Statistical tests appropriate, propensity scores,  Adverse events not reported sensitivity analyses, and multivariate logistic  Retrospective cohort regression used to control for confounding  Power calculation not done  Estimates of random variability and exact  Cohorts included not mutually exclusive probability values provided  Relatively large sample size and international population

Harris18  Objectives, main outcomes, patient  Mechanism of resistance not specified, but characteristics, and interventions clearly ESBL or AmpC resistance inferred from described resistance to cefotaxime  Confounders identified and adjusted for  Only E. coli and K. pneumoniae included in  Statistical tests appropriate study  Estimates of random variability and exact  Older population, median age 77 years old probability values provided  Power calculation only done on length of  Monotherapy comparisons hospital stay, study was underpowered to detect a difference in most outcomes due to small sample size  Multiple outcome measures, no defined primary outcome  Retrospective cohort

Mendes15  Main outcomes, patient characteristics, and  Pooled results of different outcomes and interventions clearly described infection from two trials  Mechanisms of resistance reported  Only patients who were “microbiologically  Results well described evaluable” were included in the analysis  Patient characteristics not well described, other than microbiological profile  Confounders not identified, results not adjusted for any confounders  No statistical tests done to compare results, power calculation not done  Small sample size  Estimates of random variability and exact probability values not provided  Funding provided from a pharmaceutical company  Metronidazole used in cIAI BLBLI group  Post-hoc analysis, small sample size  Studies included were not non-inferiority trials and confidence intervals of original results were wide

Carbapenems for MDR Infections 27

Table A4: Strengths and Limitations of Included Trials using Downs and Black5 Strengths Limitations Ng19  Objectives, main outcomes, patient  Retrospective cohort characteristics, and interventions clearly  Imbalances in baseline demographics (e.g. described carbapenem group less likely to have health-  Confounders identified, and results adjusted for care associated risk factors and an unknown confounders source of bacteremia)  Statistical tests appropriate  No power calculation  Estimates of random variability and exact  Multiple outcomes, no primary outcome probability values provided identified  Relatively large sample size  Only empiric therapy assessed  Mostly UTI  Elderly patients (median ~78 years old)

Ofer-Friedman20  Objectives, main outcomes, patient  Baseline characteristic comparisons between characteristics, and interventions clearly groups not provided described  Adjusting for confounders only reported on one  Confounders identified but not fully reported. outcome, poor description of results Results adjusted for confounders  Small numbers of patients, and imbalance of  Monotherapy comparisons patients between groups (69 patients in carbapenem group, 10 patients in piperacillin/tazobactam group)  High mortality rate  Retrospective cohort  Differences in therapy between definitive and empiric not reported

Tamma21  Objectives, main outcomes, patient  All patients received carbapenems after ESBL characteristics, and interventions clearly organism isolated described  Retrospective cohort study  Monotherapy comparisons  Power calculation not done  ITT analysis  Majority infectious source from central line  Statistical tests appropriate catheter, urinary tract, or intra-abdominal  Estimates of random variability and exact  Baseline characteristic differences: probability values provided piperacillin/tazobactam group less likely to be  Relatively large cohort immunocompromised and more likely to have  Confounders identified and results adjusted for underlying structural lung disease confounders  Safety data not reported  No reported conflicts of interest

Tsai22  Objectives, main outcomes, patient  Older population, mean age 74.1 years characteristics, and interventions clearly  Retrospective cohort described  Small sample size  Confounders identified and results adjusted for  Majority of patients had urinary tract source of confounders infection  No reported conflicts of interest  Inappropriate statistical tests for multiple between group comparisons

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Table A4: Strengths and Limitations of Included Trials using Downs and Black5 Strengths Limitations  Several significant between group baseline characteristic differences (e.g. source of infection, severity of illness)  Safety not reported  Results do not differentiate between empiric and definitive therapy, all patients receiving at least 48 hours of an in vitro active drug were analyzed

Research Question 5: Comparative clinical efficacy between carbapenems and piperacillin/tazobactam or cefepime in febrile neutropenia Jing11  Objectives, main outcomes, patient  Confounders not identified and results not characteristics, and interventions clearly adjusted for any potential confounders described  Chinese patients undergoing stem cell  Statistical tests appropriate transplantation  Adverse events reported  Blinding not reported  Exact probability values provided  Small sample size, no power calculation  ITT analysis  Many between group baseline characteristic differences  Many results not presented quantitatively, no tables for results

Fujita12  Objectives, main outcomes, patient  Blinding not reported characteristics, and interventions clearly  Specific population – only lung cancer patients described  Results were not adjusted for confounders  Randomized, prospective, active-comparator  Small sample size trial  Power calculation done, adequate sample size  Chi-squared test appropriate  No significant conflicts of interests  Probability values and estimates of random variability provided  Adverse events reported

Nakane13  Objectives, main outcomes, patient  Open-label characteristics, and interventions clearly  Fisher’s exact test used for multiple described comparisons between groups  Power calculation done and met sample size  Confounders, such as bacterial etiology and G-  Randomized, prospective, active-comparator CSF use, were not adjusted for trial  Three authors received funding from  Per protocol and a mITT done for non- pharmaceutical companies inferiority analysis and post-therapy modification, respectively  Non-inferiority margin of 10%  Stratified analyses based on severity of febrile neutropenia

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Table A4: Strengths and Limitations of Included Trials using Downs and Black5 Strengths Limitations Nakagawa14  Objectives, main outcomes, patient  Clinical efficacy was mostly determined characteristics, and interventions clearly subjectively described  Clinical efficacy on days 14 and 30 were mITT  Power calculation done – groups included patients whose empiric  Randomized, prospective, active-comparator therapy was changed on day 3 trial  Did not meet required sample size for adequate power  Short duration of study  Some baseline differences in underlying disease (more malignant lymphoma in meropenem group)  Multiple comparisons between groups analyzed using chi-squared and Fisher’s exact tests  Open-label Roohullah23  Objectives, patient characteristics, and  Retrospective, historical control interventions clearly described  Potential confounders were not identified or  Statistical analyses appropriate adjusted for  No conflicts of interest or funding  No power calculation  Small sample size  Multiple outcomes assessed  Main outcomes not clearly described  Limited safety outcomes reported Sezgin24  Objectives, main outcomes, patient  Retrospective cohort study, unclear if single or characteristics, and interventions clearly multicenter described  Patients could enter the study more than once  Main findings, and actual probability values  Multiple outcomes, no clear primary outcome clearly described  No identification or adjustment for potential confounders  Patients in meropenem group were younger than in the piperacillin/tazobactam group (p = 0.04)  No power calculation Fisher25  Objectives, main outcome, patient  Not specifically in patients with febrile characteristics, and interventions clearly neutropenia, but in patients where anti- described pseudomonal β-lactam antibiotics are  Confounders identified commonly used for febrile neutropenia  Main findings, and actual probability values  Large database data, data may not be accurate clearly described  Patient population specifically pediatric ALL  Multivariate adjustment done on several patients relevant confounder  No power calculation  Patients recruited over same time period  Not a head-to-head comparison  No conflicts of interests due to funding of the  One author has received funding in the past trial from Pfizer Pharmaceuticals for work with piperacillin/tazobactam

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Table A4: Strengths and Limitations of Included Trials using Downs and Black5 Strengths Limitations Muldoon26  Objectives, outcome clearly defined,  No patient characteristics, single-center data  Probability values provided  Only 1 outcome described  Statistical tests appropriate  Other adverse events not reported  Case mix index and other antibiotics used were the only other variables used in the model  Retrospective, historic control  Two interventions – second intervention was change to a laboratory test with higher sensitivity for detecting C. difficile infection (resulted in higher rate post-laboratory test change)  No power calculation BLBLI = beta-lactam beta-lactamase inhibitor; cIAI = complicated intra-abdominal infection; ESBL = extended-spectrum beta- lactamase; G-CSF = granulocyte-colony stimulating factor; ITT = intention-to-treat; mITT = modified intention-to-treat; UTI = urinary tract infection

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APPENDIX 4: Main Study Findings and Author’s Conclusions

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions Research Question 1: Comparative clinical efficacy between meropenem and imipenem for central nervous system infections Martin-Canal, 201016 Clinical cure “Meropenem, although the most expensive Meropenem: 96.0% regimen, induced fewer seizures with slightly better Imipenem: 81.8% clinical efficacy than imipenem and so may prove to p = 0.17 be a better choice to treat this neurological infection.” (p. 304) Neurosurgery Meropenem: 84.0% Imipenem: 77.3% No statistical tests done between these two groups

Relapse Meropenem: 12% Imipenem: 31.8% p = 0.1

Seizures Meropenem: 8.0% Imipenem: 36.4% p = 0.03 OR 6.57, 95% CI 1.04 – 52.8

Mortality Meropenem vs imipenem p = 0.13 HR and 95% CI not provided for this comparison Research Question 2: Comparative clinical efficacy between meropenem dosing in MDR infections) Perrot, 20106 Clinical success rate*  “Overall, the practice of administering Alternative dosing: 78% meropenem as smaller doses with shorter Traditional dosing: 82% intervals appears to provide p = 0.86 pharmacodynamics target attainment rates and clinical outcomes similar to those with Alternative dosing: 92% traditional dosing, with potential Traditional dosing: 91% pharmacoeconomic benefit.” (p. 560) p = 0.72  “Small doses with shorter interval dosing also Microbiologic success rate provide pharmacoeconomic benefits and Alternative dosing: 63% similar clinical outcomes.” (p. 562) Traditional dosing: 79% p = 0.33

Infection-related length of stay Alternative dosing: 14 days Traditional dosing: 13 days p = 0.97

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Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions In-hospital mortality rate* Alternative dosing: 11.5% Traditional dosing: 8% p = 0.24

Alternative dosing: 6.9% Traditional dosing: 6.2% p = 0.82

*Two studies reported this outcome Research Question 3 and 4: Comparative clinical efficacy between carbapenems and BLBLIs in AmpC beta-lactamase-producing and extended-spectrum beta-lactamase producing bacteria Harris, 20167 Definitive therapy:  “Crude mortality data would suggest that no Crude all-cause mortality significant differences exist between BLBLIs or Carbapenems: 13.5% cefepime when used for empirical or definitive BLBLIs: 17.9% therapy.” (p. 305) 2 OR 0.87, 95% CI 0.32 – 2.36, I = 65.5%  “When compared to carbapenems, no Adjusted* all-cause mortality differences in the use of non-carbapenem Carbapenems: 14.5% agents as definitive therapy were found in BLBLIs: 11.1% studies where patient-level data were available OR 0.94, 95% CI 0.22 – 4.12 to adjust for potential confounders. Given clear *Adjusted for age, sex, and illness severity limitations of the current evidence base, we believe randomized controlled trials are Empiric therapy: warranted to clarify these uncertainties.” (p. Crude all-cause mortality: 305) Carbapenems: 20.6% BLBLIs: 10.3% 2 OR 0.48, 95% CI 0.14 – 1.60, I = 33%

Sensitivity analysis removing the two studies with outlier results changed I2 = 0%, and unadjusted pooled effect estimate was in favour of BLBLIs OR 0.45, 95% CI 0.21 – 1.00

Shiber, 20158

RR < 1 favours BLBLIs  “Subgroup analyses of patients more likely to have had infections caused by ESBL-producing Pseudomonas aeruginosa subgroup bacteria did not reveal an advantage from Mortality using carbapenems.” (p. 45) NR  “Our analysis joins that of the overview of all Clinical failure observational studies, showing no advantage RR 1.06, 95% CI 0.84 – 1.34 of carbapenems over [BLBLIs] in the treatment of sepsis. (p. 45) Neutropenic fever subgroup Mortality RR 0.88, 95% CI 0.56 – 1.37

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Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions Clinical failure RR 1.01, 95% CI 0.89 – 1.14

Nosocomial infection subgroup Mortality RR 1.10, 95% CI 0.86 – 1.41

Clinical failure RR 0.98, 95% CI 0.86 – 1.12

Vardakas, 20129

RR < 1 = increased risk of mortality for BLBLIS  “In conclusion, carbapenems may be considered the treatment of choice for the All-cause mortality empirical treatment of patients with ESBL- RR 0.91, 95% CI 0.66 – 1.25 producing Enterobacteriaceae bacteremia. [BLBLIs] may provide an appropriate, alternative treatment option, and – at least in some settings- can be used as carbapenem- sparing antibiotics.” (p. 2801 – 2)

Guti rrez- Guti rrez, 201617 Empirical therapy cohort  “Until the results of randomized control trials Cure/improvement rates at day 14 are available, these data are the best evidence Carbapenems: 78.9% to support the use of BLBLIs with in vitro BLBLIs: 80.0% activity as alternatives to carbapenems for the p = 0.81 treatment of [bloodstream infections] due to ESBL-E, which may have significant Adjusted OR for cure/improvement rates at day 14 implications for avoidance of the overuse of for BLBLIs vs carbapenems carbapenems.” (p. 4167) OR 1.37, 95% CI 0.69 – 2.76

30-day mortality rates Carbapenems: 20% BLBLIs: 17.6% p = 0.6

Adjusted OR for 30-day mortality rates for BLBLIs vs carbapenems OR 0.55, 95% CI 0.25 – 1.18

Targeted therapy cohort Cure/improvement rates at day 14 Carbapenems: 90.2% BLBLIs: 85.5% p = 0.22

Adjusted OR for cure/improvement rates at day 14 for BLBLIs vs carbapenems OR 1.61, 95% CI 0.58 – 4.86

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Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions 30-day mortality rates Carbapenems: 9.8% BLBLIs: 13.9% p = 0.28

Adjusted OR for 30-day mortality rates for BLBLIs vs carbapenems OR 0.59, 95% CI 0.19 – 1.71

Harris, 201518 Isolation of carbapenem resistant organism  “In this retrospective study, comparable Carbapenems: 4.3% outcomes were seen for patients given BLBLIs: 4.2% definitive treatment with BLBLIs or p = 1.0 carbapenems for bloodstream infections caused by cefotaxime non-susceptible E. coli C. difficile infection or K. pneumoniae in terms of all-cause Carbapenems: 13.0% mortality, resolution of SIRS, length of stay, or BLBLIs: 8.3% bacteraemia relapse. There were also no p = 0.67 significant differences in subsequent infection or colonization with a multi-resistant organism Relapsed bloodstream infection or C. difficile infection.” (p. 8) Carbapenems: 0% BLBLIs: 2% p = 0.23

BLBLIs vs carbapenems: 30-day mortality Crude: HR 0.47, 95% CI 0.09 – 2.59 Adjusted*: HR 0.91, 95% CI 0.13 – 6.28

Resolution of SIRS Crude: HR 1.19, 95% CI 0.44 – 3.19 Adjusted*: HR 0.91, 95% CI 0.32 – 2.59

Hospital discharge Crude: HR .74, 95% CI 0.38 – 1.41 Adjusted*: HR 0.62, 95% CI 0.27 – 1.42

*Adjusted for ICU admission, infecting organism, Pitt score Mendes, 201515

Pooled results:  “...the efficacy of ceftazidime-avibactam was Favourable response for Enterobacteriaceae similar to that of carbapenems for treatment of positive for resistant mechanisms cUTI and cIAI caused by ESBL organisms.” (p. Ceftazidime/avibactam: 85.7% 1334) Carbapenem: 80%

Favourable response for nonfermenting-gram negative bacteria Ceftazidime/avibactam: 85.7% Carbapenem: 100%

Carbapenems for MDR Infections 35

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions Monotherapy results (i.e. only cUTI results) Favourable response for Enterobacteriaceae positive for resistant mechanisms Ceftazidime/avibactam: 72.7% Carbapenems: 61.5%

Favourable response for resistant E. coli Ceftazidime/avibactam: 75% Carbapenems: 66.7%

Statistical analyses not reported Ng, 201619

Empiric therapy  “In conclusion, the use of empiric [piperacillin/tazobactam] in the treatment of Piperacillin/tazobactam vs carbapenem ESBL-producing E. coli or K. pneumoniae 30-day Mortality bacteremia in a cohort with mainly urinary tract Carbapenem: 29.8% infections was not associated with higher 30- Piperacillin/tazobactam: 30.9% day mortality compared with empiric p = 0.89 carbapenems. “ (p. 9) Adjusted OR: 1.00, 95% CI 0.45 – 2.17

Carbapenem vs piperacillin/tazobactam Acquisition of MDR organism Crude OR 4.05, 95% CI 1.52 – 10.76 Adjusted OR 3.32, 95% CI 1.12 – 9.87

Relapsed bacteremia Carbapenem: 15.8% Piperacillin/tazobactam: 3.2% p = 0.05 Adjusted OR: 6.84, 95% CI 0.81 – 58.3 Ofer-Friedman, 201520

90-day mortality  “To conclucde, in this small retrospective Piperacillin/tazobactam: 80% cohort study among adults, receiving Carbapenems: 48% piperacillin/tazobactam as opposed to p = 0.05 carbapenems was independently associated Crude OR: 4.5, 95% CI 1.01 – 34 with 90-day mortality, following an ESBL Adjusted OR 7.9, 95% CI 1.2 - 53 bloodstream infection of nonurinary origin.” (p. 984) 30-day mortality Piperacillin/tazobactam: 60% Carbapenems: 34% p = 0.1

Among survivors, being a piperacillin/tazobactam case associated with increased length of stay, increased ICU length of stay, and deterioration in functional status. Results were not qualitatively or quantitatively described further

Carbapenems for MDR Infections 36

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions Tamma, 201521

14-day mortality  “Our results suggest that carbapenems should Piperacillin/tazobactam: 17% be used a preferred therapy for patients Carbapenem: 8% suspected to have ESBL bacteremia.” (p. Crude HR 1.78, 95% CI 1.00 - 3.13 1323) Adjusted* HR 1.92, 95% CI 1.07 – 3.45  “For patients at high risk of invasive ESBL *Inverse probability-weighted sample with infections, early carbapenem therapy should be additional adjustment for age, Pitt score, and ICU- considered.” (p. 1324) level care Tsai, 201422

30-day mortality  “In conclusion, among the patients with ESBL- Carbapenems: 14.3% producing P. mirabilis bacteremia, carbapenem Piperacillin/tazobactam: 23.1% therapy tends to be associated with a lower 30- p = 0.65 day crude mortality rate than Piperacillin/tazobactam vs carbapenems: piperacillin/tazobactam therapy.” (p. 226) Crude OR 1.80, 95% CI 0.30 – 10.64 Adjusted* OR 4.38, 95% CI 0.35 – 54.90

In-hospital mortality Carbapenems: 19.1% Piperacillin/tazobactam: 30.8% p = 0.68

Sepsis-related mortality Carbapenems: 14.3% Piperacillin/tazobactam: 15.4% p = 0.348

*Adjusted for non-fatal underlying disease, Pitt score > 4 points Research Question 5: Comparative clinical efficacy between carbapenems and piperacillin/tazobactam or cefepime in febrile neutropenia Paul, 201010 Carbapenems vs cefepime  “Carbapenems showed similar all-cause mortality and a lower rate of clinical failure…” All-cause mortality (n = 8) (p. 14) OR 0.84, 95% CI 0.52 – 1.37, I2 = 0%  “Based on this review, cefepime should not be Infection-related mortality (n = 5) used for patients with febrile neutropenia. 2 OR 1.17, 95% CI 0.46 – 3.00, I = 0% Piperacillin-tazobactam should be the preferred beta-lactam for use as single agent, with or Clinical failure (n = 7) without a glycopeptide, in settings where 2 OR 1.08, 95% CI 0.91 – 1.28, I = 34% resistance of Gram-negative bacteria to piperacillin-tazobactam is not prevalent.” (p. Microbiological failure (n = 5) 14) 2 OR 1.01, 95% CI 0.77 – 1.32, I = 19%  “[Carbapenems] can be used, considering that Carbapenems vs piperacillin/tazobactam the carbapenems are associated with a higher rate of antibiotic-associated and Clostridium difficile-associated diarrhea.” (p. 14)

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Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions All-cause mortality (n = 4) OR 2.19, 95% CI 1.05 – 4.57, I2 = 39%

Infection-related mortality (n = 2) OR 2.71, 95% CI 0.11 – 64.65, I2 = N/A

Clinical failure (n = 5) OR 0.93, 95% CI 0.80 – 1.07, I2 = 51%

Microbiological failure (n = 2) OR 1.09, 95% CI 0.88 – 1.35, I2 = 62% Jing11

Defervescence rate within 48 h after initiation of  “Although [imipenem/cilastatin] had more empiric antibiotic therapy gastrointestinal side effects than Piperacillin/tazobactam: 75.4% [piperacllin/tazobactam], [imipenem/cilastatin] Imipenem/cilastatin: 95.2% was more effective than p = 0.002 [piperacillin/tazobactam] as an initial empiric antibiotic in the [hematopoetic stem cell Success rate at end of therapy without change in transplantation] setting.” (p. 268) initial empiric antibiotic Piperacillin/tazobactam: 55.7% Imipenem/cilastatin: 85.5% p = 0.001

Survival rate Piperacillin/tazobactam: 96.7% Imipenem/cilastatin: 98.4%

Adverse events GI events: Piperacillin/tazobactam: 16% Imipenem/cilastatin: 32% p = 0.045 Difference in other adverse events not statistically significant Fujita12

Rate of defervescence for 5 consecutive days  “We found no statistically significant difference Cefepime: 17.65% in the efficacy and safety of [cefepime or Meropenem: 38.1% meropenem]. Although the population of the p = 0.167 present study [is] small, our results indicated that either [cefepime] or [meropenem] could be Recover from FN without change in therapy or used in the treatment of [febrile neutropenia] serious complications ion lung cancer patients.” (p. 239) Cefepime: 94.12% Meropenem: 85.71% p = 0.389

Adverse events rate Cefepime: 33.33% Meropenem: 45.83% p = 0.491

Carbapenems for MDR Infections 38

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions Nakane13

Clinical efficacy on day 7 relative to cefepime  “In conclusion, our results indicate that Per-protocol analysis: cefepime, cefozopran, meropenem, and Cefepime: 66%, imipenem/cilastatin are well tolerated and Imipenem/cilastatin: 72% effective when administered as an initial Difference in proportions: 5.7%, 95% CI -8.1 to empirical treatment to febrile neutropenic adult 19% patients with hematological disease or Meropenem: 65% cancer….although [only] Difference in proportions: -0.7%, 95% CI -15 – 13% imipenem/cilastatin…showed non-inferiority to cefepime at day 7.” (p. 21) 30-day mortality Cephalosporins: 6% Carbapenems: 1% p = 0.02

Discontinuation due to adverse event Cefepime: 4.3% Imipenem/cilastatin: 2.1% Meropenem: 0% p = 0.23

Subgroup analyses of duration of neutropenia: Response rates for more than 7 days: Cefepime: 46% Imipnem/cilastatin: 79% Meropenem: 74% Between all groups analysis p = 0.01

Nakagawa14

Clinical efficacy on day 3  “Panipenem/betamipron, meropenem, and Cefepime: 34.9% cefepime all had similar efficacy rates.” (p. 108) Panipenem/betamipron: 32.5% Meropenem: 31.5%  “…it may be reasonable to use fourth- Cefepime vs panipenem/betamipron p = 0.746 generation cephem antimicrobials such as Cefepime vs meropenem p = 0.631 [cefepime] and carbapenem antibiotics…as first line therapy for [febrile neutropenia].” (p. Clinical efficacy on day 7 110) Cefepime: 57% Panipenem/betamipron: 57.5% Meropenem: 62.9% Cefepime vs panipenem/betamipron p = 1.000 Cefepime vs meropenem p = 0.422

Clinical efficacy on day 14 Cefepime: 76.7% Panipenem/betamipron: 83.8% Meropenem: 79.8% Cefepime vs panipenem/betamipron p = 0.258 Cefepime vs meropenem p = 0.627

Carbapenems for MDR Infections 39

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions Clinical efficacy on day 30 Cefepime: 82.4% Panipenem/betamipron: 87.5% Meropenem: 84.1% Cefepime vs panipenem/betamipron p = 0.357 Cefepime vs meropenem p = 0.760

Total incidence of adverse drug reactions Cefepime: 4.3% Panipenem/betamipron: 6.3% Meropenem: 9.0% No statistical tests were conducted to analyze the differences between groups. All adverse drug reactions were considered mild. Roohullah23

Successful treatment without regimen modification  “In summary, this retrospective study found no at 72h change in clinical outcome among adult Imipenem: 33% haematology patients with neutropenic fever Piperacillin/tazobactam: 35% following a change of empirir first-line antibiotic p = 1.00 treatment from imipenem to [piperacillin/tazobactam].” (p. 1153) Antibiotic regimen modified Imipenem: 31%  “…clinical outcomes were equivalent, with a Piperacillin/tazobactam: 62% trend towards fewer C. difficile infections.” (p. p < 0.01 1153)

28-day mortality Imipenem: 4% Piperacillin/tazobactam: 3% p = 1.00

C. difficile infection Imipenem: 11% Piperacillin/tazobactam: 2% p = 0.08 Sezgin, 201424

Success without modification  “In conclusion, in this retrospective study Meropenem: 68% monotherapy with meropenem or Piperacillin/tazobactam: 32% [piperacillin/tazobactam] was found to be p = 0.58 equally effective and safe for the initial treatment of febrile neutropenia.” (p. 4552) Success with modification Meropenem: 71% Piperacillin/tazobactam: 29% P = 0.58

Median duration of hospitalization Meropenem: 8 days (range 1 – 80) Piperacillin/tazobactam: 8 days (range 3 – 38) p = 0.43

Carbapenems for MDR Infections 40

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions Mortality Data not given, but no statistical difference between groups p = 0.87

Adverse reactions No adverse reactions were observed

Fisher, 201425

HR for developing CDI after Exposure to: “Among anti-pseudomonal agents, cefepime and Cefepime adjusted* HR 1.07, 95% CI 1.02 - 1.12 ceftazidime were each independently associated Carbapenems adjusted* HR 0.98, 95% CI 0.93 – with CDI, raising questions about the optimal 1.04 antibiotic choice for management of febrile neutropenia.” (p. 334) Muldoon, 201326

CDI rate with meropenem as empiric therapy  “This study shows that there may be an 0.45/1000 patient days association between increased cefepime use for empiric neutropenic fever and CDI rates.” CDI rate with cefepime as empiric therapy (p. 3) 2.59/1000 patient days

Change in rate of CDI + 0.3/1000 patient days per month post-empiric therapy change to cefepime p = 0.008 95% CI = 95% confidence interval; BLBLI = beta-lactam beta-lactamase inhibitor; CDI = C. difficile infection; cIAI = complicated intra-abdominal infection; cUTI = complicating urinary tract infection; ESBL = extended-spectrum beta-lactamase; GI = gastrointestinal; HR = hazards ratio; NR = not reported; OR = odds ratio; RR = relative risk; SIRS = systemic inflammatory response syndrome

Carbapenems for MDR Infections 41