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What the MERINO Study Results Mean for the Future of Antibiotic Resistance

Monday, November 26, 2018  
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Lakyn Husinka, Doctor of Pharmacy Candidate 2019, Duquesne university School of Pharmacy

 

 Background

            In today’s medical society, there is increasing concern against the growth of resistant bacteria leading to an extinction of superior antibiotic medications. These resistant Gram- negative bacteria express extended spectrum β-lactamase (ESBL) enzymes rendering current classes such as penicillins and cephalosporins ineffective. Significant morbidity and mortality up to 20% can be seen in some patients infected with either ESBL- producing Escherichia coli or Klebsiella pneumoniae.1 The most common resistance shown by these bacteria strains is to third generation cephalosporins such as ceftriaxone.2 Due to lack of susceptible antibiotics, carbapenems are considered first line treatment in the ESBL bloodstream infections. Carbapenems, such as meropenem, can be considered “big gun” antibiotics that have the capability to cover a broad spectrum of organisms. However, as with any bacteria, resistance can develop after being exposed to any medication for an extended period. As the growth of carbapenem-resistant enterobacteriaceae (CRE) increases, there is a growing question for our next therapeutic step, as well as how we can preserve the antibiotics that we currently have on hand.

            The MERINO study was designed to find a potential “carbapenem-sparing” therapy in the use of ceftriaxone non-susceptible E coli or K pneumoniae. Due to its current mechanism of action as a β-lactamase inhibitor, tazobactam has been considered a possible therapeutic selection for ESBL organisms.3,4 Moreover, it is estimated that more than 50% of E. Coli and K. pneumonia resistant to ceftriaxone is still susceptible to piperacillin-tazobactam.1 Therefore, the use of piperacillin-tazobactam (Zosyn®) was studied as a noninferior treatment to meropenem in the use of ESBL bloodstream infections.

Method

            The international, multicentered trial took place over two and a half years and across nine countries including Australia, Canada, New Zealand, and South Africa. Included patients had to be legal adults with a blood culture positive for either E. coli or K. pneumoniae that was both non-susceptible to ceftriaxone and susceptible to both meropenem and piperacillin-tazobactam. Those excluded from the study were allergic to either of the test medications, had a remining lifespan of less than 96 predicted hours, were not being treated with a curative intent, or were pregnant. Additionally, patients could only be enrolled in the study once regardless of whether or not they were infected again during the trial’s time frame.

 Patients were separated into four groups based on pathogen strain as and severity of disease. They were randomized in a 1:1 ratio into either receiving meropenem 1 gm every 8 hours or piperacillin-tazobactam 4.5 gms every 6 hours for bacteremia with a minimum duration of four days until a max of two weeks. Proper dosing protocols were followed resulting in appropriate patient specific renal dosing. Initiation of therapy had to be started within 72 hours of blood culture results. The use of prior empiric treatment or de-escalation therapy was site specific. Clinical data was collected for the first five days and patients were followed for up to 30 days post randomization.

Results

            The MERINO trial screened 1,646 patients resulting in a total of 379 patients being included in the final analysis. Overall baseline characteristics between treatment groups were similar except for an increase in diabetes patients in the meropenem group and an increased number of immune compromised patients in the piperacillin-tazobactam group. The primary outcome of comparing 30-day mortality among the two treatment groups post bloodstream infection eradication were accessed using a 1-sided 97.5% confidence interval. Noninferiority would be established if a 5% margin was not crossed.2,3 An intent to treat analysis was conducted which included any patient who received at lead one dose of treatment. The piperacillin- tazobactam treatment group had 23 of 187 patients (12.3%) meet a 30-day all-cause mortality as compared to the 7 of 191 (3.7%) of the meropenem group [CI, -α to 14.5%].3 A calculated number needed to harm of 12 was determined.2

            This trial also addressed multiple secondary outcomes. Microbiological resolution by the end of day 4 of treatment was determined in 68.4% of piperacillin-tazobactam patients and 74.6% of meropenem patients (P =0.19). Although not significant, symptoms of infection were resolved a day earlier in the piperacillin-tazobactam group than the meropenem group.3 Both groups showed low rates of carbapenem resistant organisms in follow up cultures. Differences in C. difficile occurrence were not significant.

Discussion

            Based on the results from this trial, piperacillin-tazobactam cannot be defined as noninferior to meropenem and therefore is not supported as “carbapenem-sparing” therapy. The trial itself was terminated early due to potential result of harm since noninferiority was unlikely to be established even if the trial was continued to term.

Study Strengths

            Analysis of this study was completed as need to treat but also supported through a per protocol analysis. Furthermore, the study was conducted throughout multiple countries and health care systems to give generalizability to allow for adaption to other acute care settings. Although baseline characteristics among both treatment groups were similar, the differences gave bias towards the use of piperacillin-tazobactam. In addition to those already described, the meropenem group had an increased difference in APACHE II score (+3) that put these patients at an increased risk of hospital death.3 The piperacillin-tazobactam group also had a shorter time span of culture results to initiation of therapy allowing for coverage sooner as compared to the meropenem group.

Study Limitations

            Limitations were identified including a lag time of blood cultures and susceptibility tests resulting in variations of empiric therapy. Therefore, some patients received the opposite treatment as empiric therapy allowing for adulteration of accurate therapeutic results. De-escalation also allowed patients to receive the opposite medication as step down therapy. Both therapeutic changes could have favored a noninferiority outcome for the piperacillin-tazobactam group. Specifically, for the piperacillin-tazobactam group, almost 14% received empiric therapy with meropenem before starting the treatment therapy and slightly over 20% received meropenem after the initial four days of studied treatment.2

            Another limitation is the lack of blinding leading to possible selection bias. Prescribers were also enrolled in the trial in addition to their patients which allowed the prescribers possible control of choosing which patients they felt should be candidates for the study. Confirmation bias could have also been present if a physician was skeptical about the use of piperacillin-tazobactam for resistant organisms in a specific patient and switched them to meropenem after initial therapy. Finally, the number of patients needed to achieve an 80% power while including a 10% drop out rate was a total of 454 patients which was not reached in this trial population leading to a potential Type II error.1 However, based on the trials result, even if the calculated power had been met changes in result would likely not have occurred.

Clinical Importance

            Until the MERINO trial there had not been any randomized controlled trials that looked specifically into finding other treatment options for ceftriaxone resistant Gram-negative organisms.1 In previous studies, post hoc analysis looking at empiric and definitive therapies were unsuccessful in finding carbapenems superior for ESBL- producing E coli treatment as compared to β-lactamase β-lactam inhibitors (BLBLI) although they were shown to have lower mortality.1,5 The outcomes of the MERINO trial confirm that current first line therapy of carbapenems is appropriate for enterobacteriaceae blood stream infections. However, due to a growing increase in carbapenem-resistant organisms over recent years, it is now more than ever important to only use carbapenems in appropriate treatment circumstances when other susceptible antibiotics are lacking.

            Growth in resistance against carbapenems would leave us with last line options and eventually completely defenseless against mutating organisms. Previous studies focused on carbapenem- resistant enterobacteriaceae have reported mortality rates up to 50%.6 As carbapenem MICs increase, both worsening outcomes and an increased risk of death are observed.6 Resistant organism not only weaken antibiotic use but also increase health care cost by billions of dollars due to increased hospitalizations and combination therapies.7,8 Therefore, while it is important to continue developing new antibiotics, reassessing antibiotics currently on the market is just as important financially. Although piperacillin-tazobactam failed to be determined as a noninferior medication, there are still newer BLBLIs that could be reviewed as well. New studies reviewing extended infusion piperacillin-tazobactam or non- carbapenems step down therapies should also be conducted for possible decrease in carbapenem exposure.2 It is also important to potentially decrease antibiotics use by increasing practices that can lead to a reduction in infection rates warranting less therapeutic courses.6

Take Away

            Increasing antibiotic resistance through the growth of ESBL or CRE organisms is leading to an overall decrease in viable therapeutic options. However, based on the results of the MERINO trial, carbapenems hold superior to the use of piperacillin-tazobactam for the treatment of ceftriaxone-resistant infections.

References

1.       Harris PN, Peleg AY, Iredell J, et al. Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial. Trials. 2015;16:24. Published 2015 Jan 27. doi:10.1186/s13063-014-0541-9

2.        Hayden MK, Won SY. Carbapenem- Sparing Therapy for Extended Sectrum B-Lactamase- Producing E coli and Klebsiella pneumoniae Bloodstream Infection. JAMA. 2018;320(10):979-982.

3.        Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH. Effect of Piperacillin-Tazobactam vs Meropenem on 30- Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance. JAMA. 2018;320(10):984-994.

4.        National Center for Biotechnology Information. PubChem Compound Database; CID=123630, https://pubchem.ncbi.nlm.nih.gov/compound/123630 (accessed Nov. 12, 2018).

5.       Rodriguez-Bano J, Navarro MD, Retamer P, Pascual A, Picon E. β-Lactam/β-Lactam Inhibitor Combinations for the Treatment of Bacteremia Due to Extended-Spectrum β-Lactamase–Producing Escherichia coli: A Post Hoc Analysis of Prospective Cohorts. Clinical Infectious Diseases. 2012;54(2):167-174.

6.       CDC. Guidance for Control of Carbapenem-Resistant Enterobacteriaceae. 2012 CRE Toolkit. https://www.cdc.gov/hai/pdfs/cre/CRE-guidance-508.pdf 

7.        van Duin D, Kaye KS, Neuner EA, Bonomo RA. Carbapenem-resistant Enterobacteriaceae: a review of treatment and outcomes. Diagn Microbiol Infect Dis. 2013;75(2):115-20.

8.        Infectious Diseases Society of America (IDSA), Spellberg B, Blaser M, et al. Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis. 2011;52 Suppl 5(Suppl 5):S397-428.

                                                                 


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