Racing toward the right answers: Treating gram-negative bacterial infections

In this commentary, Infectious Disease News Editorial Board member Thomas M. File Jr., MD, professor of internal medicine at Northeast Ohio Medical University, discusses presentations at ASM Microbe 2016 on gram-negative bacterial infections, as well as recently approved therapies and agents currently in the pipeline that have been developed to treat them.

Several presentations at the inaugural ASM Microbe 2016 conference focused attention on serious gram-negative bacterial infections, which account for the majority of infections in ICUs. Infections by antibiotic-resistant, gram-negative pathogens are growing in prevalence, and although the majority of these infections occur in the hospital, a rising number are acquired in the community. The CDC has listed carbapenem-resistant Enterobacteriaceae, extended-spectrum beta-lactamase–producing Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa and Acinetobacter as serious or urgent threats. In the past, because these pathogens were perceived to be restricted to the hospital, and particularly to older and more fragile patients, they received much less press than gram-positive pathogens such as MRSA.

Inappropriate antibiotic therapy is a major risk factor for serious gram-negative bacterial infections, which are associated with increased mortality. Yet these infections are difficult to treat. When faced with a patient in septic shock, it is important that clinicians initiate appropriate antibiotic therapy rapidly. A 2006 study by Kumar and colleagues demonstrated that with each 1-hour delay in initiating treatment, mortality increases by 12%. Thus, clinicians managing gram-negative infections have to choose the right antibiotic in a short amount of time.

Important aspects of a prudent treatment approach

A prudent treatment strategy comprises early empiric therapy with broad-spectrum antibiotics, followed by de-escalation and targeted therapy once pathogens are identified. At a satellite symposium, George Sakoulas, MD, of Sharp Healthcare, and David P. Nicolau, PharmD, of Hartford Hospital, and I highlighted aspects of this strategy that warrant particular attention. In choosing antibiotic regimens, clinicians must account for patients’ immune status, the severity of their illness, previous colonization by multidrug-resistant (MDR) pathogens, previous antibiotic exposure, and infection trends in the ICU or hospital.

Thomas M. File Jr., MD

Thomas M. File Jr.

Choosing the right drug is not enough, however. Patients also need the right dose, exposure and treatment duration. Jason A. Roberts, PhD, of the University of Queensland, discussed the Defining Antibiotic Levels in Intensive Care Unit Patients (DALI) study, published in Clinical Infectious Diseases in 2014, which showed that 16% of patients did not achieve 50% fT>MIC and that these patients were 32% less likely to have a positive clinical outcome. Moreover, pharmacokinetic (PK) profiles vary among patients. Although several in vitro studies support PK and pharmacodynamic (PD)-based dosing, they define antibiotic activity based on maximum inhibitory concentration, rather than mutant preventive concentration. Moreover, clinical data are scarce. Dosing and exposure to antibiotics can be affected by altered renal function and dialysis. Therapeutic drug monitoring might be useful, but its clinical utility is still under investigation.

Tools to treat these infections

Rapid molecular tools can identify pathogens within 24 hours and at lower inoculums, compared with the 3 days required for standard culture-based methods. Catherine C. Bulik, PharmD, of the Institute for Clinical Pharmacodynamics, presented a mobile app, PK-PD Compass, which can aid clinicians in selecting the appropriate drugs, dose and treatment duration based on PK/PD parameters. According to a data review for 134 patients and 71 users, 78% of users chose a regimen with a 90% or higher probability.

Two recently approved antibiotic regimens, Zerbaxa (ceftolozane/tazobactam, Merck) and Avycaz (ceftazidime/avibactam, Allergan), continue to be effective against serious gram-negative bacterial infections. Michael D. Huband, MS, of JMI Laboratories, presented in vitro data on activity of ceftolozane/tazobactam against resistant gram-negative isolates collected from U.S. medical centers in 2015. Compared with ceftazidime, cefepime, piperacillin/tazobactam and meropenem, ceftolozane/tazobactam was more potent, with a susceptibility rate of 98% against P. aeruginosa overall and at least 80% against MDR and extensively drug-resistant (XDR) strains. Against Enterobacteriaceae, ceftolozane/tazobactam had a susceptibility rate of 94.3% overall and 57.6% of MDR isolates. This combination was more potent than all noncarbapenem beta-lactams tested. Philippe Lagacé-Wiens, MD, of Diagnostic Services of Manitoba, presented in vitro data on activity of ceftolozane/tazobactam against resistant gram-negative bacterial isolates collected from 15 Canadian hospitals. This combination was particularly potent against P. aeruginosa, with susceptibility rates of 98.5% overall, 89.2% against ceftazidime-resistant strains, 93% against meropenem-resistant strains, and 92% against piperacillin/tazobactam-resistant strains. Enterobacteriaceae and A. baumannii strains were also susceptible to ceftolozane/tazobactam. Lagacé-Wiens called Enterobacter cloacae strains, particularly those resistant to ceftriaxone or ertapenem, the “Achilles’ heel” of this agent.

Mariana Castanheira, PhD, MSc, of JMI Laboratories, presented in vitro data demonstrating the potency of ceftazidime/avibactam against 11 resistant Enterobacteriaceae strains, with susceptibility rates of at least 97% at the FDA breakpoint criteria. Among four other antimicrobial agents, only tigecycline and colistin had susceptibility rates higher than 80%. Helio S. Sader, MD, PhD, also of JMI Laboratories, presented in vitro data demonstrating the potency of ceftazidime/avibactam against resistant strains of Pseudomonas, with a susceptibility rate of 96.7% at the FDA breakpoint of no more than 8 µg/mL, compared with susceptibility rates ranging from 79.9% to 84.5% for ceftazidime alone, cefepime, piperacillin/tazobactam, and meropenem. Ceftazidime/avibactam retained activity against MDR and XDR strains, with susceptibility rates of 79.8% against MDR strains and 71.5% against XDR strains. In comparison, susceptibility rates for ceftazidime alone, piperacillin/tazobactam, and meropenem were 21.8% or less for MDR isolates and 9.2% or less for XDR strains.

Larry Tsai, MD, of Tetraphase Pharmaceuticals, presented the phase 3 IGNITE2 trial, which evaluated IV administration of the broad-spectrum antibiotic eravacycline (Tetraphase Pharmaceuticals) for at least 3 days for complicated urinary tract infection (cUTI), with transition to oral administration as clinically indicated. Although the trial did not achieve its primary endpoint of noninferiority compared with levofloxacin, a subgroup analysis found that response rates were higher for eravacycline than for levofloxacin among patients with levofloxacin-resistant infections (53.8% vs. 36.5%, difference = 17.3%, 95% CI, 2.1, 31.8) and among those who stayed on IV administration for 7 days (58.8% vs 48.2%, difference = 10.7%, 95% CI, 8.5, 29.0). Amanda Paschke, MD, of Merck Research Laboratories, presented a phase 2 dose-ranging study demonstrating that IV administration of imipenem/cilastatin plus relebactam, a new beta-lactamase inhibitor (BLI), was noninferior to IMI alone in patients with cUTI.

Several posters and presentations also described in vitro and in vivo efficacy data for agents at even earlier stages in the pipeline. Sachin Bhagwat, PhD, MSc, of Wockhardt Research Center, discussed WCK 5222 (zidebactam) — a beta-lactam enhancer that has received qualified infectious disease product designation from the FDA. David Livermore, PhD, of Public Health England, presented WCK 4234, a new BLI that is active against Class A, C, and D beta-lactamases (triple-class BLI), with activity against resistance mediated by OXA carbapenemases including in A. baumannii. Huband and Bhagwat also presented data for WCK 5999 (WCK 4234 plus meropenem), which demonstrated an effect for KPCs, derepressed AmpC P. aeruginosa, and OXA carbapenemases. Ruben Tommasi, PhD, of Entasis Therapeutics, discussed activity of another triple-class BLI, ETX2514, in combination with imipenem or sulbactam, and Troy Lister, PhD, of Spero Therapeutics, summarized in vitro and in vivo data on SPR741, a novel polymixin that permeates the outer membrane of gram-negative bacteria and thereby potentiates the activity of more than 24 antibiotics from various classes, without the nephrotoxicity seen with other polymixins. Finally, Maria Mojica, MS, of Case Western Reserve University, presented a study demonstrating efficacy of aztreonam/avibactam, a novel combination inhibiting class A and B beta-lactamases, against resistant Stenotrophomonas maltophilia — a particular concern in patients with cystic fibrosis.

The recently approved therapies, along with those making their way through the developmental pipeline, offer hope for the future. With these drugs and closer attention to patient characteristics and the timing, dosage and duration of antibiotic therapy, serious gram-negative bacterial infections may become less formidable in the future.


Bulik CC, et al. The integration of pharmacokinetics-pharmacodynamics (Pk-Pd) and the practice of antimicrobial stewardship through an educational mobile application. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Castanheira M, et al. Ceftazidime-avibactam (CAZ-AVI) activity tested against eleven Enterobacteriaceae (ENT) species producing KPC enzymes. Presented at: ASM Microbe; June 16-20, 2016; Boston.

File TM, Jr. A closer look at the burden and epidemiology of gram-negative bacterial infections. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Huband MD, et al. Activity of ceftolozane/tazobactam against drug-resistant gram-negative pathogens collected from US medical centers in 2015. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Huband MD, et al. Antibacterial activity of WCK 5999 tested against contemporary Enterobacteriaceae (ENT) isolates from a worldwide surveillance program (2015). Presented at: ASM Microbe; June 16-20, 2016; Boston.

Huband MD, et al. In vitro activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae isolates collected from medical centers in the USA (2015). Presented at: ASM Microbe; June 16-20, 2016; Boston.

Kumar A, et al. J Infect Dis. 2006;193:251-258.

Lagacé-Wiens P, et al. In vitro activity of ceftolozane-tazobactam (C/T) against gram-negative pathogens isolated from patients in Canadian hospitals in 2011-2015. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Mojica MF, et al. Aztreonam-avibactam: a novel combination effective against clinical isolates of Stenotrophomonas maltophilia. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Mushtaq S, et al. WCK 4234, a novel diazabicyclooctane, overcoming OXA-carbapenemases in Enterobacteriaceae, Pseudomonas, and Acinetobacter. Presented at: ASM Microbe; June 16-20, 2016; Boston.

New agents discovery summary session 89: early new antimicrobial agents. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Nicolau DP. Optimizing therapy for infections caused by gram-negative bacteria. Presented at: ASM Microbe; June 16-20, 2016; Boston.

O’Donnell J, et al. LB-117 / LB-117 - In Vitro and In Vivo Efficacy of the Novel β-lactamase Inhibitor ETX2514 Combined with Sulbactam Against Multidrug Resistant Acinetobacter baumannii. Presented at: ASM Microbe; June 16-20, 2016; Boston

Roberts JA. Optimized PK/PD: can it reduce resistance? Presented at: ASM Microbe; June 16-20, 2016; Boston.

Roberts JA, et al. Clin Infect Dis. 2014;doi:10.1093/cid/ciu027.

Sader HS, et al. Activity of ceftazidime-avibactam tested against clinical isolates of antimicrobial resistant Pseudomonas aeruginosa (PSA) isolates from United States (USA) medical centers (2012-2014). Presented at: ASM Microbe; June 16-20, 2016; Boston.

Sakoulas G. Making the right choice: identifying and treating serious gram-negative infections. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Sims M, et al. Phase 2 study of relebactam (REL) + imipenem/cilastatin (IMI) vs IMI alone in subjects with complicated urinary tract infection (cUTI). Presented at: ASM Microbe; June 16-20, 2016; Boston.

Takalkar SS, et al. WCK 5999 (carbapenem-WCK 4234): eradication of KPC-expressing K. pneumonia (KP-KPC), derepressed AmpCP. aeruginosa (PA-AmpC) and OXA carbapenemase-expressing A. baumannii (Ab-OXA) in neutropenic mouse lung and thigh infection models. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Tsai L, et al. Intravenous eravacycline with transition to oral therapy for treatment of complicated urinary tract infections (cUTI) including pyelonephritis: results from a randomized, double-blind, multicenter, phase 3 trial (Ignite2). Presented at: ASM Microbe; June 16-20, 2016; Boston.

Disclosure: File reports receiving research grants from Cempra and Nabriva, and consulting for Cempra, Melinta, Merck, Motif Bio, Paratek, Pfizer and Tetraphase. 

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