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Finally, new drugs for bad bugs: What’s available and what’s in the pipeline

Issue: June 2018

ByKeith S. Kaye, MD, MPH

ByOwen Albin, MD

ByTwisha S. Patel, PharmD, BCPS

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Many years ago, I worked on new and exciting antibiotics that had activity against naturally resistant organisms such as Pseudomonas and Proteus species. Some of these antibiotics were ampicillin, first-generation cephalosporins and tobramycin. We are now in a new ball game of acquired resistance, and for this report, I have turned over the job of describing some of the newer antibiotics to researchers who are in the forefront of antimicrobial resistance. – by Donald Kaye, MD, MACP

Gram-negative bacillary (GNB) resistance is increasing worldwide, leaving clinicians with challenging treatment dilemmas, given the few remaining effective antibiotic options. Three pathogens have become increasingly problematic threats: carbapenem-resistant Enterobacteriaceae (CRE), multidrug-resistant (MDR) Pseudomonas aeruginosa, and Acinetobacter species. Rates of morbidity and mortality are particularly high among patients with invasive infections caused by these pathogens. Historically, few antibiotic options existed for the treatment of these pathogens, and many of these agents — such as aminoglycosides, polymyxins and tigecycline — are associated with significant toxicities and/or suboptimal pharmacokinetic parameters.

With the passing of the Generating Antibiotic Incentives Now Act as a part of the Food and Drug Administration Safety and Innovation Act in 2012, economic incentives and expedited reviews are granted to pharmaceutical companies for Qualified Infectious Disease Products (QIDP). Three QIDP agents with expanded spectra of GNB activity have been approved by the FDA since then: Zerbaxa (ceftolozane/tazobactam, Merck), Avycaz (ceftazidime/avibactam, Allergan) and Vabomere (meropenem/vaborbactam, Melinta Therapeutics). Additionally, there are several novel agents undergoing investigation that have broad-spectrum activity. In this article, we review the antimicrobial activity, clinical efficacy and treatment niches for the newly approved agents and briefly introduce some of the antibiotics undergoing clinical investigation.

What’s available: FDA-approved agents

Ceftolozane/tazobactam: A novel cephalosporin plus an older beta-lactamase inhibitor

Ceftolozane/tazobactam, an oxyimino-aminothiazolyl cephalosporin and existing beta-lactamase inhibitor combination, was approved in late 2014 for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs). Ceftolozane/tazobactam has expanded activity against GNB, notably P. aeruginosa. In a multicenter investigation, the in vitro activity of ceftolozane/tazobactam was tested against 3,851 isolates of P. aeruginosa. At the FDA-approved clinical susceptibility breakpoint of 4 mg/L, 97% of isolates were considered susceptible to ceftolozane/tazobactam (MIC₅₀ 0.5 mg/L and MIC₉₀ 2 mg/L). Compared with other commonly used beta-lactam antibiotics, including cefepime, ceftazidime, meropenem and piperacillin/tazobactam, ceftolozane/tazobactam displayed improved activity against P. aeruginosa by more than 10%. Furthermore, among isolates that were considered MDR (defined as nonsusceptible to at least one agent in three or more antimicrobial classes), ceftolozane/tazobactam retained activity against 84%. Additionally, among isolates of P. aeruginosa that were considered extensively drug-resistant (defined as nonsusceptible to at least one agent in all but two or fewer antimicrobial classes), 76.9% maintained susceptibility. Several other studies have reported the activity of ceftolozane/tazobactam against P. aeruginosa isolates from various clinical sources and from a variety of patient populations, including those with cystic fibrosis. Collectively, these data demonstrated the superior in vitro activity of ceftolozane/tazobactam compared with other beta-lactam antibiotics for P. aeruginosa.

Ceftolozane/tazobactam is also active against Enterobacteriaceae. In a pooled analysis of 15,223 isolates of Enterobacteriaceae, 94% were susceptible to ceftolozane/tazobactam at the currently approved breakpoint of 2 mg/L (MIC₅₀ 0.25 mg/L and MIC₉₀ 1 mg/L). Ceftolozane/tazobactam also has activity against bacteria that produce extended-spectrum beta-lactamases (ESBLs). Although meropenem remained the most active beta-lactam antibiotic tested, ceftolozane/tazobactam was active against 87.5% of 1,450 isolates of ESBL-producing Enterobacteriaceae (MIC₅₀ 0.5 mg/L and MIC₉₀ 4 mg/L). Notably, ceftolozane/tazobactam does not have activity against organisms producing metallo-beta-lactamases (eg, NDM, IMP and VIM) and serine carbapenemases (eg, Klebsiella pneumoniae carbapenemase, or KPC).

The clinical efficacy of ceftolozane/tazobactam was demonstrated in two phase 3 clinical trials: ASPECT-cIAI and ASPECT-cUTI. ASPECT-cIAI was a randomized, double-blind study comparing the efficacy of ceftolozane 1 g/tazobactam 0.5 g plus metronidazole 0.5 g given every 8 hours with meropenem 1 g given every 8 hours intravenously for 4 to 14 days for the treatment of cIAI. Ceftolozane/tazobactam plus metronidazole demonstrated statistical noninferiority compared with meropenem regarding clinical cure at the test-of-cure visit in the microbiologic intention-to-treat (MITT) population (83% [323/389] vs. 87.3% [364/417]; weighted difference, –4.2%; 95% CI, –8.91 to 0.54). ASPECT-cUTI was a multinational, randomized, double-blind trial comparing the efficacy of ceftolozane 1 g/tazobactam 0.5 g administered intravenously every 8 hours with levofloxacin 750 mg given intravenously once daily for 7 days for the treatment of cUTI, including pyelonephritis. Ceftolozane/tazobactam was superior to levofloxacin with regard to composite cure rates in the microbiologically modified intention-to-treat (mMITT) population (76.9% [306/398] vs. 68.4% [275/402]; 95% CI, 2.3-14.6). The superiority of the combination drug was driven, in part, by high rates of resistance to levofloxacin among causative pathogens (27% of total population). Of those participants with levofloxacin-resistant pathogens, composite cure rates were significantly higher among patients treated with ceftolozane/tazobactam than in patients treated with levofloxacin (60% vs. 39%; 95% CI, 7.2-33.2). In a separate pooled analysis from both phase 3 studies — including only patients with infections caused by ESBL-producing Escherichia coli or K. pneumoniae — clinical cure rates were high in patients treated with ceftolozane/tazobactam (97.4%). A phase 3 randomized trial is currently being conducted to compare the efficacy of ceftolozane/tazobactam with meropenem for the treatment of ventilator-associated bacterial pneumonia (VABP) and hospital-acquired bacterial pneumonia (HABP).

Although ASPECT-cIAI and ASPECT-cUTI represent the best comparative clinical data available to date for ceftolozane/tazobactam, real-world clinical use will likely focus on treatment of MDR P. aeruginosa. Published data on the efficacy of ceftolozane/tazobactam for infection due to resistant pseudomonal infection are limited to retrospective, single-cohort, observational studies. In a larger multicenter, retrospective review of patients with infections caused by carbapenem-resistant P. aeruginosa who were treated with ceftolozane/tazobactam, 74% (n = 26) achieved treatment success. Although these data are promising, comparative data are needed to further define the role of ceftolozane/tazobactam in real-world clinical settings.

Ceftazidime/avibactam: An older cephalosporin plus a novel beta-lactamase inhibitor

Ceftazidime/avibactam, a cephalosporin and non-beta-lactam, diazabicyclooctane beta-lactamase inhibitor, was approved by the FDA in 2015 for the treatment of cUTI and cIAI. Ceftazidime/avibactam has expanded activity against Enterobacteriaceae due to the addition of avibactam, which inhibits class A (eg, ESBLs and KPCs), class C (eg, AmpC), and some class D (eg, oxacillinases) enzymes. Among 36,380 isolates of Enterobacteriaceae, almost all (> 99%) were susceptible to ceftazidime/avibactam at the FDA-approved breakpoint of 8 mg/L (MIC₅₀ 0.12 mg/L and MIC₉₀ 0.25 mg/L). Of the 513 isolates of CRE tested, 97.5% were susceptible (MIC₅₀ 0.5 mg/L and MIC₉₀ 2 mg/L) and ceftazidime/avibactam was the most active antibiotic tested (ie, more active than other beta-lactam antibiotics, aminoglycosides and tigecycline). In a separate analysis of 433 confirmed ESBL-producing Klebsiella species, more than 99% were susceptible to ceftazidime/avibactam (MIC₅₀ 0.25 mg/L and MIC₉₀ 1 mg/L). Ceftazidime/avibactam also displayed improved activity against P. aeruginosa compared with ceftazidime alone. Among 7,868 isolates, 97.1% were susceptible to ceftazidime/avibactam (MIC₅₀ 2 mg/L and MIC₉₀ 4 mg/L) compared with 84.7% that were susceptible to ceftazidime alone (MIC₅₀ 2 mg/L and MIC₉₀ 32 mg/L). Ceftazidime/avibactam does not have activity against GNB that produce metallo-beta-lactamases.

The clinical efficacy of ceftazidime/avibactam for the treatment of cUTI was first demonstrated in a phase 2 clinical trial. Although a lower dose of ceftazidime/avibactam was used in this study than in more recent phase 3 studies, microbiological response was achieved in 70.4% of patients receiving ceftazidime/avibactam and 71.4% receiving imipenem/cilastatin (difference, –1.1%; 95% CI, –27.2% to 25%). Two phase 3 clinical studies — RECLAIM 1 and 2 — were prospective, double-blind, randomized trials comparing the efficacy of ceftazidime/avibactam with meropenem for the treatment of cIAI. In RECLAIM 1/2, ceftazidime 2 g/avibactam 0.5 g plus metronidazole 0.5 g given every 8 hours was noninferior to meropenem 1 g given every 8 hours in the mMITT population, with clinical cure rates of 81.6% vs. 85.1%, respectively (difference, –3.5%; 95% CI, –8.64 to 1.58). In the trial, there was a decreased response with ceftazidime/avibactam plus metronidazole compared with meropenem in patients with moderate renal impairment. REPRISE evaluated the efficacy of ceftazidime 2 g/avibactam 0.5 g given every 8 hours compared with the best available therapy (BAT) for the treatment of cUTI or cIAI due to ceftazidime-resistant Enterobacteriaceae or P. aeruginosa. The proportion of patients with clinical cure at the test-of-cure visit was similar among those treated with ceftazidime/avibactam as compared with BAT; both were 91%.

Although REPRISE included patients with infections caused by resistant GNB, it did not evaluate the clinical efficacy of ceftazidime/avibactam for infections caused by CRE. The superior efficacy of ceftazidime/avibactam over older regimens has been demonstrated in retrospective studies evaluating the clinical outcomes of patients with CRE infection. Shields and colleagues demonstrated higher rates of clinical success in patients who received ceftazidime/avibactam compared with those who received combination therapy with a carbapenem and aminoglycoside (85% vs. 48%; P = .04) or carbapenem and colistin (85% vs. 40%; P = .009) for the treatment of bloodstream infections due to KPC-producing K. pneumoniae. In an analysis by van Duin and colleagues, 30-day all-cause in-hospital mortality was significantly lower in patients with CRE infection who received treatment with ceftazidime/avibactam compared with those who received colistin-based therapy (9% vs. 32%; P = .001). These data support the use of ceftazidime/avibactam over colistin-based therapy for the treatment of invasive infections caused by KPC-producing CRE.

Meropenem/vaborbactam: An older carbapenem plus a novel beta-lactamase inhibitor

Meropenem/vaborbactam, a carbapenem and boronic acid-based beta-lactamase inhibitor combination product was recently approved by the FDA for the treatment of cUTI, including pyelonephritis. Meropenem/vaborbactam has a broad spectrum of activity against GNB, including Enterobacteriaceae that produce class A and class C beta-lactamases. In a multicenter evaluation, 99.5% (10,374/10,426) of clinical Enterobacteriaceae isolates tested susceptible to meropenem/vaborbactam at the FDA-approved clinical breakpoint of 4 mg/L or lower. Furthermore, of 991 KPC-producing CRE, 99% (n = 981) were considered susceptible. The MIC₅₀ and MIC₉₀ of organisms producing KPC-2 (n = 610) and KPC-3 (n = 373) were 0.06 mg/L and 1 µg/mL; and 0.12 mg/L and 1 mg/L, respectively. These values are similar to the MIC₅₀ and MIC₉₀ values reported for all KPC producers studied. Although meropenem/vaborbactam has activity against nonfermenting GNB such as P. aeruginosa and Acinetobacter species, vaborbactam does not significantly potentiate meropenem activity against these organisms. In an evaluation of 2,604 isolates of P. aeruginosa, the MIC₅₀ (0.5 mg/L) and MIC₉₀ (8 mg/L) values of meropenem/vaborbactam were the same as for meropenem alone. Meropenem/vaborbactam does not have activity against GNB that produce metallo-beta-lactamases.

Two phase 3 trials investigating the efficacy of meropenem/vaborbactam have been conducted. TANGO I was a multicenter, international, randomized, double-blind, double-dummy, active-controlled trial that evaluated the safety and efficacy of meropenem/vaborbactam for the treatment of cUTI, including acute pyelonephritis. Patients received either meropenem 2 g/vaborbactam 2 g intravenously every 8 hours or piperacillin 4 g/tazobactam 0.5 g intravenously every 8 hours. Among patients with cUTI and growth of a baseline pathogen, meropenem/vaborbactam was determined to be superior to piperacillin/tazobactam based on the composite outcome of symptom improvement or resolution and microbial eradication (98.4% vs. 94%; difference, 4.5%; 95% CI, 0.7%-9.1%; P < .001 for noninferiority; P = .01 for superiority). TANGO II was a multicenter, international, randomized, prospective, open-label, comparative trial evaluating the efficacy and safety of meropenem/vaborbactam vs. BAT for CRE infection. Meropenem/vaborbactam therapy compared with BAT resulted in higher rates of clinical cure at end of therapy (64.3% vs. 33.3%; P = .04). Additional real-world data, such as data from the TANGO II trial, will help to further define the role of meropenem/vaborbactam in clinical practice.

What’s in the pipeline

Although ceftolozane/tazobactam, ceftazidime/avibactam and meropenem/vaborbactam provide clinicians with promising new treatment options, there remains a need for novel new antibiotic agents because gaps in treatment of MDR GNB persist. None of the new agents has activity against GNB that produce metallo-beta-lactamases. Additionally, these agents do not address the unmet therapeutic need for extensively drug-resistant Acinetobacter species. Furthermore, since the introduction of ceftolozane/tazobactam and ceftazidime/avibactam, the emergence of resistance to these agents — often occurring during treatment — has been documented in the literature. Resistance appears to be multifactorial, including mechanisms such as changes in outer membrane porin channel expression and mutations conferring conformational changes in the hydrolytic enzymes produced by the resistant bacteria, leading to a loss in binding affinity to the beta-lactamase inhibitor. Fortunately, several agents with novel mechanisms of action to help fill these unmet therapeutic needs are currently being investigated in phase 2 and phase 3 clinical trials (see Table).

Cefiderocol is a novel siderophore cephalosporin antibiotic with a broad range of antimicrobial activity against GNB, including Acinetobacter species, P. aeruginosa and CRE. Activity against CRE includes both KPC-producing and metallo-beta-lactamase-producing bacteria. A phase 3 trial, APEKS-cUTI, comparing the efficacy of cefiderocol to imipenem/cilastatin for the treatment of cUTI was recently completed and met noninferiority endpoints for clinical and microbiological response. Of note, CRE were not included in this phase 3 study. Instead, a separate phase 3 trial, CREDIBLE-CR, in patients with various infections caused by carbapenem-resistant pathogens is ongoing.

Plazomicin is an aminoglycoside derivative of sisomicin with expanded activity primarily against CRE, including KPC producers, some metallo-beta-lactamase producers, P. aeruginosa and Acinetobacter species. Plazomicin was synthesized to maintain activity in the presence of aminoglycoside-modifying agents. However, resistance can occur in the setting of ribosomal methyl transferase production, which is often seen in NDM-producing bacteria. Two phase 3 trials have offered promising results: EPIC and CARE. EPIC compared the efficacy of plazomicin with meropenem for the treatment of cUTI or pyelonephritis. In this study, rates of composite cure (including both clinical cure and microbiologic eradication) were significantly higher at the test-of-cure visit in the plazomicin group than in the meropenem group. CARE compared the efficacy of plazomicin with colistin, both of which were administered in combination with an additional agent (meropenem or tigecycline), for the treatment of adults who had invasive CRE infections (ie, bloodstream infection, VABP, HABP and cUTIs). The 28-day all-cause mortality rate was lower in the plazomicin-based combination treatment cohort than in the colistin-based combination treatment cohort.

Imipenem/relebactam is a carbapenem and non-beta-lactam, diazabicyclooctane beta-lactamase inhibitor with activity against KPC-producing CRE and P. aeruginosa. Two phase 2 studies evaluating the efficacy of imipenem/relebactam for the treatment of IAIs and UTIs have been completed, and phase 3 trials are ongoing.

Eravacycline is a novel, synthetic fluorocycline tetracycline with activity against CRE, including both KPC producers and metallo-beta-lactamase producers, and Acinetobacter species. Phase 3 trials evaluating the efficacy of eravacycline for the treatment of cIAI and cUTI have been conducted. Although noninferiority was established in the cIAI trial, eravacycline did not achieve noninferiority for the primary endpoint of clinical and microbiological cure in two cUTI trials.

Fosfomycin is a phosphonic acid derivative with activity against CRE, including KPC-producing and metallo-beta-lactamase-producing organisms, and variable activity against P. aeruginosa. Although oral fosfomycin is currently available for use in the United States, the IV formulation is undergoing investigation. ZEUS was a phase 3 study that compared the efficacy of IV fosfomycin with that of piperacillin/tazobactam for the treatment of cUTI, including acute pyelonephritis. In this study, fosfomycin was noninferior to piperacillin/tazobactam, with similar rates of overall success, defined as clinical cure plus microbiologic eradication.

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• For more information:
• Owen Albin, MD, is a fellow in the division of infectious diseases at the University of Michigan Medical School.
• Keith S. Kaye, MD, MPH, is a professor of internal medicine at the University of Michigan Medical School, an Infectious Disease News Editorial Board member, and president of the Society of Healthcare Epidemiology of America.
• Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.
• Twisha S. Patel, PharmD, BCPS, is a clinical infectious diseases pharmacist at Michigan Medicine and an adjunct clinical assistant professor at the University of Michigan College of Pharmacy.

Disclosures: Albin, Patel and Donald Kaye report no relevant financial disclosures. Keith Kaye reports receiving grant support from Merck and serving as a consultant for Achaogen, Allergan, Melinta Therapeutics, Merck, Shionogi and Zavante Therapeutics.