Combination antibiotic therapy for multidrug-resistant, gram-negative bacteria

17 March, 2022

Professor Wang-Huei Sheng
Division of Infectious Diseases
Department of Internal Medicine
National Taiwan University Hospital
Taipei, Taiwan
Director, School of Medicine
College of Medicine
National Taiwan University
Taipei, Taiwan

The recent emergence of multidrug-resistant (MDR) pathogens poses significant challenges to treatment of bacterial infections and represents a major global health concern.¹ In the case of MDR gram-negative bacteria (MDR-GNB), treatment options are limited, warranting multiple ongoing studies to investigate new agents and combinations to target MDR pathogens in both hospital-linked and community-acquired bacterial infections.²

Professor Wang-Huei shares insights on identifying target populations for combination antimicrobial treatment of the most prevalent MDR-GNB infections, and the optimisation of these treatments to combat the rapid surge in MDR strains.

Q1: What are the key risk factors for MDR gram-negative bacterial infections?

Multidrug-resistant gram-negative bacterial infections significantly contribute to morbidity and mortality and remains a major threat for human health. The commonly reported risk factors for MDR-GNB infections include underlying co-morbidities (diabetes mellitus, liver cirrhosis, chronic lung diseases, cancers, chronic renal diseases include dialysis); immune suppression (cancer chemotherapy, steroid use, transplantation); interventions (surgery, intravascular or urinary catheterizations, mechanical ventilation); prior broad-spectrum antimicrobial use or carriage of MDR-GNB; and prior stay at intensive care units, or prolonged hospital stay³.

Q2: Please indicate your antimicrobial selection criteria (mono- or combination therapy) for the current challenging-to-treat, gram-negative pathogens, including carbapenem-resistant strains. How do these criteria change by infection type and severity, or for high-risk patients including those with comorbidities or previous antibiotic use?

Antimicrobial selection for infections caused by MDR-GNB remains a major challenge. Initiation of inappropriate therapy in critical ill patients with sepsis caused by GNB may lead to longer hospital stay and increased costs. Effective treatment should be initiated as soon as possible to reduce the probability of unfavourable outcomes. Antimicrobial selection for managing MDR-GNB infections is usually based on local epidemiology and resistance pattern (hospital antibiograms), host risk for multiple drug resistance, infection severity, and laboratory microbiological results. Combination therapy, such as beta-lactams plus non-beta-lactams (such as aminoglycosides, fluoroquinolones, polymyxins, tigecycline/eravacycline) are a common regimen for MDR-GNB (including carbapenem-resistant strains)³. In addition, novel agents such as meropenem/vaborbactam or ceftazidime/avibactam, cefiderocol are recommended for infections caused by carbapenem-resistant Enterobacteriaceae. It is not yet established if combination antimicrobial therapy is more efficacious than monotherapy for infections with GNB. Appropriate regimens will be selected depending upon infection type (bloodstream infection, ventilator-associated pneumonia), severity of infection (sepsis or septic shock), comorbidities and previous antibiotic use.

Q3: In patients eligible for combination treatment, which subgroup(s) are more likely to respond to β-lactam+fluoroquinolone versus macrolide+fluoroquinolone treatment; and what factor(s) dictate your choice of fluoroquinolone in the combination?

Combination therapy with beta-lactams and fluoroquinolones have shown to be associated with a reduction in mortality in severely ill patients with infections caused by Pseudomonas aeruginosa or pneumococcal infections (especially for septicemia, hospital-acquired pneumonia or ventilator associated pneumonia)⁴. Host risk of severity and GNB infections, local epidemiology, individual hospital antibiograms, macrolide resistant rate for atypical pathogen (such as Mycoplasma) are major factors that dictate the choice of fluoroquinolone versus of macrolide combination. Therefore, combination therapy with beta-lactams and fluoroquinolones for profoundly neutropenic patients, intensive care unit patients, patients with ventilator-associated pneumonia, or septic patients with significantly elevated severity-of-illness scores is suggested. Fluoroquinolones with anti-pseudomonal activity, such as levofloxacin and ciprofloxacin, are preferred for those patients who had risk or documented with Pseudomonas aeruginosa infections.

Q4: What are some of the perceived challenges with combination treatment with fluoroquinolones (e.g., cross-resistance between different fluoroquinolones, dose selection etc)?

Unnecessary addition of a second antimicrobial agent to treat GNB infections may lead to increased antimicrobial resistance, adverse effects, and costs. The common perceived challenges with combination treatment with fluoroquinolones are cross-resistance between different fluoroquinolones, lack of optimal dose for pharmacokinetic/pharmacodynamics, drug-interaction, or adverse events (such as concurrent use with QTc-prolongation agents may lead to arrhythmia).

Q5: Based on existing evidence, which other enzyme inhibitor+β-lactam/macrolide combinations are potentially promising treatments for MDR pathogens?

Novel beta-lactamase inhibitor combinations, such as ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactum demonstrated good activities against KPC- or OXA-48-like carbapenemase producing Enterobacteriaceae. Aztreonam/avibactum might both be active against metallo-beta-lactamases producing MDR-GNB. Certain strains of MDR- Enterobacteriaceae, Pseudomonas aeruginosa or Acinetobacter baumannii might remain susceptible to piperacillin/tazobactum or cefoperazone/sulbactam.