title: carbapenems for multi-drug resistant infections: a ... · q6: cost-effectiveness outcomes...

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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.

Carbapenems for MDR Infections 2

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.


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


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


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


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


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


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


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


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


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.


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


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

http://www.cadth.ca/


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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

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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

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

703 citations identified from electronic literature search and

screened


APPENDIX 2: Characteristics of Included Publications

Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses

First

Author, Publication

Year,

Country

Types and

numbers of primary studies

included

Population

Characteristics

Intervention Comparator(s) Clinical

Outcomes, Length of Follow-Up

Research Question 2: Comparative clinical efficacy between meropenem dosing in MDR infections)

Perrott,6

2010,

Canada

Trials relevant to research

question: Retrospective

cohort n = 1

Retrospective cohort with historical

control n = 2

Patient population

characteristics not well described

One study had patients with

relatively low severity of illness

(APACHE scores ~15)

One study had patients with neutropenic

fever after cefepime failure or intolerance

Meropenem alternative,

small-dose, short-interval regimens

(500 mg q6h, or 500 mg q8h if renal

insufficiency)

Meropenem traditional

dosing (1 g q8h or 1 g q12h if renal

insufficiency)

Clinical success rate

Microbiologic success rate

Infection-related length of stay

Time to infection

resolution Treatment

failure rate In-hospital

mortality 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

2016, Australia, USA, South

Korea

Prospective

cohort n = 5

Retrospective cohort n = 6

Adult,

hospitalized patients with blood stream

infections caused by gram-negative

bacteria with chromosomally encoded AmpC

-lactamase

Broad-

spectrum BLBLI agents

OR Cefepime

OR

Fluoroquinolones

Carbapenems All-cause

mortality Time to follow-

up as defined by each individual study,

and 30 day mortality used if several follow-

up times reported

Shiber,8

2015, Israel RCTs n = 31

Patients, adult or child, being

treated for sepsis. Other antibiotics could

be used but only if applied equally to both

Any BLBLI Any carbapenem

All-cause mortality

Clinical failure


Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses

First Author,

Publication

Year, Country

Types and numbers of

primary

studies included

Population Characteristics

Intervention Comparator(s) Clinical Outcomes, Length of

Follow-Up

treatment groups

No data was found

specifically in patients with ESBL infections

Vardakas,9

2012, Greece, USA

Retrospective

cohort n = 16

Case-control n = 1

Prospective cohort n = 3

Post-hoc analysis of prospective

cohort data n = 2

Patients any

age with community-, hospital-, and

healthcare-associated bacteremia

being treated empirically or definitively for

ESBL-positive Enterobacteriaceae

Carbapenems BLBLIs

OR

Non-BLBLIs OR

Fluoroquinolones

OR Cephalosporins

OR

All other alternatives

All-cause

mortality

Research Question 5: Comparative clinical efficacy between carbapenems and piperacillin/tazobactam or cefepime in febrile neutropenia

Paul,10

2010,

Israel, UK

RCTs

n = 44 RCTs of carbapenem

vs cefepime n = 8

RCTs of carbapenem vs piperacillin/

tazobactam n = 5

Febrile

neutropenic cancer patients. Interventions

had to be equal – no other antibiotics were

allowed except for glycopeptides,

which were required in both treatment arms

Carbapenems Other beta-

lactams, including cefepime, and

piperacillin/ tazobactam

All-cause 30-

day mortality Clinical failure

Microbiological failure

Infection-related

mortality

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


Table A2: Characteristics of Included Clinical Studies

First Author, Publication

Year, Country,

Study Design, Length of

Study

Population, Number of patients (N)

Intervention(s) Comparator(s) Clinical Outcomes

Research Question 1: Comparative clinical efficacy between meropenem and imipenem for central

nervous system infections

Martin-Canal,16

2010, Spain

Single-center, retrospective cohort

Duration not specified

Adult patients diagnosed with brain abscess. Prior to year

2000, patients were started on antibiotics based on preference of

infectious disease consultant. After year 2000, most patients

were treated with carbapenem and neurosurgery.

N = 59

Meropenem Imipenem

OR

Cefotaxime + metronidazole

Clinical cure Neurosurgery

Relapse

Seizures


Guti rrez- Guti rrez,

17

2016, Spain,

Italy, Canada, Turkey, Germany,

Greece, USA, Israel, South Africa, Taiwan,

Australia, Argentina

Multicenter, retrospective cohort

30 days

Patients with clinically significant

monomicrobial bloodstream infection due to ESBL- Enterobacteriaceae and received monotherapy antibiotics as therapy

Empirical therapy cohort

n = 365 Targeted therapy

cohort n = 601

Global cohort (i.e. to assess patients who switched therapies)

n = 627

BLBLIs (i.e. amoxicillin/clavul

anate, piperacillin/tazobactam,

ampicillin/sulbactam)

Carbapenems (i.e. imipenem,

meropenem, doripenem, ertapenem)

Clinical response at day 14

30-day mortality

Harris,18

2015, Singapore

Single center, retrospective cohort

At least 30 days

Adult patients, ≥21 years old, with one positive monomicrobial

blood culture for E. coli or Klebsiella spp. which were cefotaxime non-

susceptible, but piperacillin/tazobactam

Piperacillin/tazobactam, or amoxicillin/clavul

anate as definitive therapy

Meropenem, ertapenem, or imipenem as

definitive therapy

Days to resolution of SIRS

All-cause mortality Identification of

carbapenem or piperacillin/tazobact




Year, Country,


Study



and until

resolution of SIRS

and meropenem

susceptible. N = 47

am resistant

organisms or C. difficile within 30 days

Microbiological relapse

Length of hospital stay post first

positive blood culture

Mendes,15

2015, Guatemala,

India, Jordan, Lebanon, USA, Bulgaria,

France, India, Poland, Romania, Russia

Pooled results from two phase

II clinical trials cUTI trial: 6 – 9

days after last dose of antibiotic cIAI trial: 7 – 14

days after last dose of antibiotic

Adult patients, age 18 – 90 years, diagnosed

with cUTI or cIAI that were microbiologically evaluable (i.e. patients

that had bacterial isolates available for resistance mechanism testing)

N = 192

Ceftazidime/avibactam

OR

Ceftazidime/avibactam + metronidazole

Imipenem/cilastatin

OR

Meropenem

Favourable response, as

defined by each trial:

cUTI trial: eradication of all pathogens from urine and blood

cIAI trial: complete resolution or

significant improvement of signs/symptoms of

infection with no requirements for additional

antimicrobial therapy

Ng,19

2016, Singapore

Dual-center, retrospective

cohort At least 30 days,

and up to discharge or death

Patients with E. coli and K. pneumoniae

bacteremia N = 151

Empiric piperacillin/tazob

actam

Empiric carbapenem (i.e.

imipenem, ertapenem, or meropenem)

30-day mortality

30-day incidence of multi-drug resistant organisms

Relapsed bacteremia

Ofer-Friedman,20

2015, Israel, USA

Adult patients, > 18

years old, with ESBL bloodstream infections (i.e. monomicrobial

Carbapenem

(i.e. ertapenem, imipenem, meropenem,

Piperacillin/tazob

actam

In-hospital mortality

30-day mortality




Year, Country,


Study



Dual-center,

retrospective cohort

90 days

blood isolations of

ESBL-producing E. coli, K. pneumonia, P. mirabilis) of nonurinary

origin N = 79

doripenem) 90-day mortality

Length of hospital stay from culture to

discharge Total days in ICU

from culture to discharge

Tamma,21

2015, USA

Single-center, retrospective

cohort 14 days

Patients with ESBL-producing organisms

(i.e. E. coli, K. pneumoniae, K. oxytoca, P. mirabilis)

isolated from bloodstream

N = 213

Empiric therapy piperacillin/tazob

actam, then switched to carbapenem

after ESBL-producing organism

isolated

Empiric therapy with carbapenem

14-day mortality

Tsai,22

2014,

Taiwan Multicenter,


30 days

Adult patients, aged ≥

18 years old, with bacteremia due to ESBL-producing P.

mirabilis N = 40

Carbapenem Piperacillin/tazob

actam OR

Other antibiotics

30-day mortality

In-hospital mortality


Jing,11

2016, China

Dual-center, prospective,

randomized Patients

followed 48 h for primary outcome, and up

to treatment success or death. Duration

not reported.

Patients with acute leukemia, lymphoma

and other hematological diseases scheduled for

myeloablative hematopoetic stem cell transplantation

These patients did not have neutropenic fever

at study entry, but were randomize to receive therapy if febrile

neutropenia occurred N = 123 patients with

febrile neutropenia

Imipenem/cilastatin

Piperacillin/tazobactam

Defervescence after initial empiric

antibiotic for 48h Clinical success at

end of therapy Adverse reactions




Year, Country,


Study



Fujita,12

2016,

Japan Multicenter,

prospective, randomized

14 days

Febrile neutropenic

patients ≥ 20 years old with lung cancer and chemotherapy induced

neutropenia N = 38

Meropenem Cefepime Rate of

defervescence for 5 consecutive days

Defervescense rates at 72 h, day 7, day 14

Adverse reactions

Nakane,13

2015,

Japan Multicenter.

Randomized, open-label, non-inferiority

30 days

Febrile neutropenic

patients, ≥ 16 years old, with hematologic disease or cancer who

had not undergone allogeneic stem cell transplantation

N = 376

Meropenem

OR Imipenem/cilastatin

OR Cefozopran

Cefepime Clinical efficacy

30-day mortality

Adverse events

Nakagawa,14

2013, Japan

Multicenter, randomized,

open-label 30 days

Febrile neutropenic patients, ≥ 16 years old,

with hematopoietic disease without proven infection

N = 255

Panipenem/betamiprom

OR

Meropenem

Cefepime Clinical efficacy (based on

subjective assessment of clinical

improvement and laboratory values)

Adverse events

Roohullah,23

2013, New

Zealand Single center,

retrospective cohort, with historical control

Up to death or discharge

Patients, ≥ 16 years old, with neutropenic

fever and an underlying hematological disorder

N = 105

Piperacillin/tazobactam

Imipenem Successful treatment without

regimen modification at 72 h

28-day mortality C. difficile rate

Antibiotic therapy modification

Sezgin,24

2014, Turkey

Retrospective cohort

Patients < 18 years old with febrile neutropenia who had been treated

for hemato-oncological malignancies

Meropenem Piperacillin/tazobactam

Clinical success Antibiotic therapy

modification




Year, Country,


Study



Up to treatment failure or success

N = 136 patients Patients could be recruited more than

once if > 1 febrile neutropenic episode N = 284 episodes

Treatment failure

(defined as addition of other antimicrobial or

death)

Fisher,25

2014,

USA Multicenter,


Up to 180 days after ALL diagnosis

Newly diagnosed ALL

patients, aged 1 year to < 19 years, treated at pediatric institutions

contributing data to the Pediatric Health Information System

N= 8268

Carbapenems

(imipenem and meropenem)

Cefepime, OR

anti-pseudomonal penicillins

(piperacillin, piperacillin/tazobactam, ticarcillin,

ticarcillin/clavulanate), OR ceftazidime

Diagnosis of CDI

(incidence)

Muldoon,26

2013, USA

Single center, retrospective

cohort with historical control

Data collected monthly over three years

Patients in the hematology and

oncology ward N = N/A

Cefepime as initial empiric

therapy for neutropenic fever

Meropenem as initial empiric

therapy for neutropenic fever

CDI rate

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


APPENDIX 3: Critical Appraisal of Included Publications

Table A3: Strengths and Limitations of Systematic Reviews and Meta-Analyses using

AMSTAR4 Strengths Limitations


Perrot6

Comprehensive literature search performed

Authors do not have any apparent conflicts of interest

Multiple outcomes; no clear, single primary

outcome

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


Harris7

A priori design provided, triplicate study

selection and data extraction, and comprehensive literature search performed

Quality of studies assessed using Newcastle-

Ottawa score, and heterogeneity was reported

Authors had no reported conflict of interests

Random effects model used

Only 3 studies provided enough information for

adjustment with definitive therapy. No studies provided enough information for adjustment with empiric therapy

Reason for high heterogeneity with 2 outlier studies is unclear

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 selection and data extraction, and comprehensive literature search performed

Grey literature search performed and included

Risk of bias assessed using domain-based approach

Symmetrical funnel-plot

List of studies and characteristics provided

No reported conflicts of interest or funding

No data on actual ESBL infections

Analyses for ESBL infection subgroup was done using neutropenic fever and nosocomial

infections subgroups due to likely higher relative rate of ESBL-positive infections

Study quality not assessed

Heterogeneity not provided for subgroup analyses

Fixed-effect model used


Table A3: Strengths and Limitations of Systematic Reviews and Meta-Analyses using

AMSTAR4 Strengths Limitations

Vardakas9

A priori design provided, duplicate data extraction

Two databases used for literature search

List and characteristics of studies provided

Quality of studies assessed using Newcastle-Ottawa scale

Random effects model used

All authors except 1 did not have any reported conflicts of interest, and funding was not required for this study

No explicit statement regarding grey literature

Significant heterogeneity within and between trials (e.g. concomitant antibiotics used, patient

populations)

Publication bias detected via funnel plot

One author has received funding from

pharmaceutical companies

Some patients on initial piperacillin/tazobactam therapy were eventually switched to 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


Paul10

A priori design provided, duplicate data extraction

Grey literature searched

Comprehensive literature search performed

Characteristics of included studies provided

Quality of studies assessed via investigator

judgement

Publication bias assessed via investigator judgement

No reported conflicts of interests

Single investigator study selection

Fixed effects model used

Small number of RCTs for specific outcome comparisons of carbapenems vs cefepime and piperacillin/tazobactam

Conclusions for adverse drug event/reaction comparisons are generalized into antibiotic class comparisons instead of specific antibiotic comparisons

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 clearly described

Statistical tests appropriate

Confounders identified and results adjusted for confounders

Estimates of random variability and exact probability values provided

No reported funding or conflicts of interest

Main outcomes not well described until results, several outcomes without a specified primary outcome

No power calculation

Small sample size

Retrospective cohort with partial historical control

Significant baseline characteristic differences (e.g. imipenem group had younger patients)

Statistical tests missing in neurosurgery

outcome



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 interventions clearly described

Statistical tests appropriate, propensity scores, sensitivity analyses, and multivariate logistic

regression used to control for confounding


Relatively large sample size and international population

Non-inferiority objectives described, but non-inferiority analysis and margin were not used

Adverse events not reported


Power calculation not done

Cohorts included not mutually exclusive

Harris18

Objectives, main outcomes, patient

characteristics, and interventions clearly described

Confounders identified and adjusted for



Monotherapy comparisons

Mechanism of resistance not specified, but

ESBL or AmpC resistance inferred from resistance to cefotaxime

Only E. coli and K. pneumoniae included in study

Older population, median age 77 years old

Power calculation only done on length of hospital stay, study was underpowered to

detect a difference in most outcomes due to small sample size

Multiple outcome measures, no defined primary outcome


Mendes15

Main outcomes, patient characteristics, and interventions clearly described

Mechanisms of resistance reported

Results well described

Pooled results of different outcomes and infection from two trials

Only patients who were “microbiologically 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



Strengths Limitations Ng

19

Objectives, main outcomes, patient characteristics, and interventions clearly

described

Confounders identified, and results adjusted for confounders



Relatively large sample size


Imbalances in baseline demographics (e.g.

carbapenem group less likely to have health-care associated risk factors and an unknown source of bacteremia)


Multiple outcomes, no primary outcome identified

Only empiric therapy assessed

Mostly UTI

Elderly patients (median ~78 years old)

Ofer-Friedman20


described

Confounders identified but not fully reported. Results adjusted for confounders


Baseline characteristic comparisons between groups not provided

Adjusting for confounders only reported on one outcome, poor description of results

Small numbers of patients, and imbalance of patients between groups (69 patients in

carbapenem group, 10 patients in piperacillin/tazobactam group)

High mortality rate


Differences in therapy between definitive and empiric not reported

Tamma21




ITT analysis



Relatively large cohort

Confounders identified and results adjusted for confounders

No reported conflicts of interest

All patients received carbapenems after ESBL

organism isolated

Retrospective cohort study

Power calculation not done

Majority infectious source from central line

catheter, urinary tract, or intra-abdominal

Baseline characteristic differences: piperacillin/tazobactam group less likely to be

immunocompromised and more likely to have underlying structural lung disease

Safety data not reported

Tsai22

Objectives, main outcomes, patient characteristics, and interventions clearly described

Confounders identified and results adjusted for

confounders

No reported conflicts of interest

Older population, mean age 74.1 years


Small sample size

Majority of patients had urinary tract source of infection

Inappropriate statistical tests for multiple between group comparisons



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 Jing

11



Adverse events reported

Exact probability values provided

ITT analysis

Confounders not identified and results not adjusted for any potential confounders

Chinese patients undergoing stem cell

transplantation

Blinding not reported

Small sample size, no power calculation

Many between group baseline characteristic

differences

Many results not presented quantitatively, no tables for results

Fujita12



Randomized, prospective, active-comparator

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

Blinding not reported

Specific population – only lung cancer patients

Results were not adjusted for confounders

Small sample size

Nakane13



Power calculation done and met sample size

Randomized, prospective, active-comparator trial

Per protocol and a mITT done for non-inferiority analysis and post-therapy

modification, respectively

Non-inferiority margin of 10%

Stratified analyses based on severity of febrile neutropenia

Open-label

Fisher’s exact test used for multiple comparisons between groups

Confounders, such as bacterial etiology and G-CSF use, were not adjusted for

Three authors received funding from pharmaceutical companies



Strengths Limitations Nakagawa

14


described

Power calculation done

Randomized, prospective, active-comparator trial

Clinical efficacy was mostly determined subjectively

Clinical efficacy on days 14 and 30 were mITT – groups included patients whose empiric therapy was changed on day 3

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 interventions clearly described

Statistical analyses appropriate

No conflicts of interest or funding

Retrospective, historical control

Potential confounders were not identified or adjusted for


Small sample size

Multiple outcomes assessed

Main outcomes not clearly described

Limited safety outcomes reported

Sezgin24


Main findings, and actual probability values clearly described

Retrospective cohort study, unclear if single or multicenter

Patients could enter the study more than once

Multiple outcomes, no clear primary outcome

No identification or adjustment for potential confounders

Patients in meropenem group were younger than in the piperacillin/tazobactam group (p =

0.04)


Fisher25

Objectives, main outcome, patient characteristics, and interventions clearly

described

Confounders identified

Main findings, and actual probability values clearly described

Multivariate adjustment done on several relevant confounder

Patients recruited over same time period

No conflicts of interests due to funding of the

trial

Not specifically in patients with febrile neutropenia, but in patients where anti-

pseudomonal β-lactam antibiotics are commonly used for febrile neutropenia

Large database data, data may not be accurate

Patient population specifically pediatric ALL

patients


Not a head-to-head comparison

One author has received funding in the past

from Pfizer Pharmaceuticals for work with piperacillin/tazobactam



Strengths Limitations Muldoon

26

Objectives, outcome clearly defined,

Probability values provided


No patient characteristics, single-center data

Only 1 outcome described

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 = modif ied intention-to-treat; UTI = urinary

tract infection


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: 96.0%

Imipenem: 81.8% p = 0.17

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

“Meropenem, although the most expensive regimen, induced fewer seizures with slightly better

clinical efficacy than imipenem and so may prove to be a better choice to treat this neurological infection.” (p. 304)


Perrot, 20106

Clinical success rate*

Alternative dosing: 78% Traditional dosing: 82% p = 0.86

Alternative dosing: 92% Traditional dosing: 91%

p = 0.72 Microbiologic success rate

Alternative dosing: 63% Traditional dosing: 79% p = 0.33

Infection-related length of stay Alternative dosing: 14 days

Traditional dosing: 13 days p = 0.97

“Overall, the practice of administering

meropenem as smaller doses with shorter intervals appears to provide pharmacodynamics target attainment rates and

clinical outcomes similar to those with traditional dosing, with potential pharmacoeconomic benefit.” (p. 560)

“Small doses with shorter interval dosing also provide pharmacoeconomic benefits and

similar clinical outcomes.” (p. 562)


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


Harris, 20167

Definitive therapy:

Crude all-cause mortality Carbapenems: 13.5% BLBLIs: 17.9%

OR 0.87, 95% CI 0.32 – 2.36, I2 = 65.5%

Adjusted* all-cause mortality

Carbapenems: 14.5% BLBLIs: 11.1% OR 0.94, 95% CI 0.22 – 4.12

*Adjusted for age, sex, and illness severity Empiric therapy:

Crude all-cause mortality: Carbapenems: 20.6% BLBLIs: 10.3%

OR 0.48, 95% CI 0.14 – 1.60, I2 = 33%

“Crude mortality data would suggest that no

significant differences exist between BLBLIs or cefepime when used for empirical or definitive therapy.” (p. 305)

“When compared to carbapenems, no differences in the use of non-carbapenem

agents as definitive therapy were found in studies where patient-level data were available to adjust for potential confounders. Given clear limitations of the current evidence base, we

believe randomized controlled trials are warranted to clarify these uncertainties.” (p. 305)

Sensitivity analysis removing the two studies with outlier results changed I

2 = 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

Pseudomonas aeruginosa subgroup Mortality

NR Clinical failure

RR 1.06, 95% CI 0.84 – 1.34 Neutropenic fever subgroup

Mortality RR 0.88, 95% CI 0.56 – 1.37

“Subgroup analyses of patients more likely to

have had infections caused by ESBL-producing bacteria did not reveal an advantage from using carbapenems.” (p. 45)

“Our analysis joins that of the overview of all observational studies, showing no advantage

of carbapenems over [BLBLIs] in the treatment of sepsis. (p. 45)


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 All-cause mortality

RR 0.91, 95% CI 0.66 – 1.25

“In conclusion, carbapenems may be considered

title: carbapenems for multi-drug resistant infections: a ... · q6: cost-effectiveness outcomes...

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