The treatment of Carbapenem-Resistant Gram-Negative Bacterial Infections: A Comprehensive Review
Introduction
Antimicrobial resistance (AMR), encompassing multidrug resistance (MDR), extensively drug resistance (XDR), and pan-drug resistance (PDR), poses a significant global health threat. Carbapenem-resistant Gram-negative bacilli (CRGNB) or carbapenem-resistant organisms (CRO) are defined as Gram-negative bacilli or organisms resistant to any carbapenem, documented to produce a carbapenemase or carrying a carbapenemase gene. This includes carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Acinetobacter baumannii (CRAB). CRGNB infections are associated with high morbidity and mortality, and the World Health Organization (WHO) designated CRE, CRPA, and CRAB as "critical-priority" pathogens in the global priority list of antibiotic-resistant bacteria as early as 2017. Carbapenem resistance is a critical and escalating global concern.
Global Prevalence and Impact
Data from EARS-Net, collected between January 1, 2015, and December 31, 2015, estimated 671,689 infections with antibiotic-resistant bacteria, with 67.9% of total disability-adjusted life-years (DALYs) per 100,000 caused by infections with four resistant bacteria: third-generation cephalosporin-resistant Escherichia coli, meticillin-resistant Staphylococcus aureus (MRSA), CRPA, and third-generation cephalosporin-resistant Klebsiella pneumoniae. The CRO rate was 29 cases per 100,000 population in Alameda County, USA, with a significant increase over a 2-year period. Surveillance results in China showed a rising detection rate of carbapenem-resistant Klebsiella pneumoniae (CRKP) from 3.0% in 2005 to 20.9% in 2017. Between June 2019 and February 2021, CRKP was detected in 333 ICUs across 52 countries, affecting 2,600 patients with hospital-acquired bloodstream infections (HA-BSI).
Global Mortality and Resistance Trends
Worldwide, carbapenem resistance-related deaths rose from 619,000 in 1990 to 1,030,000 in 2021, while directly attributed deaths increased from 127,000 to 216,000 over the same period. In 2019, CRAB caused 50,000-100,000 deaths globally. The CRACKLE-2 cohort study reported a 19% unadjusted 30-day all-cause mortality rate and a 22% unadjusted 90-day all-cause mortality rate among patients with CRKP infections from June 2017 to November 2018.
Polymyxins: A Viable Treatment Option
CRKP, CRAB, and CRPA are common CRGNB sensitive to polymyxins. Polymyxins, often used in combination with carbapenems, tigecycline, fosfomycin, and sulbactam, have shown efficacy in treating CRGNB infections. This article explores the types, safety, and efficacy of polymyxins.
Types of Polymyxins
Polymyxins are cyclic polypeptide antibiotics, primarily consisting of five types: A, B, C, D, and E. Only polymyxin B (PMB) and polymyxin E, with similar structures, are clinically used. The common formulations are polymyxin B sulfate and colistin sulfate/colistin methanesulfonate (CMS). Polymyxin E and PMB differ in the amino acid of the peptide ring (R2 group), with phenylalanine in PMB and leucine in colistin.
Pharmacokinetics and Dosing
CMS is primarily excreted via the kidneys, with a variable half-life of 2-12 hours. The active metabolite, polymyxin E, is mostly reabsorbed by renal tubules, with only 1% excreted via the kidneys. PMB is also largely reabsorbed, with 4% excreted via the kidneys. Therapeutic colistin concentrations may be challenging for patients with normal renal function due to rapid CMS clearance. PMB requires an initial loading dose of 2.0-2.5 mg/kg, followed by a maintenance dose of 2.5-3 mg/kg per day in two divided doses.
Mechanism of Action
Polymyxins are bactericidal, disrupting bacterial cell membranes, leading to cell lysis. They interact with negatively charged lipid A of lipopolysaccharide (LPS) on the bacterial cell membrane, increasing membrane permeability. This interaction causes the leakage of small molecules, resulting in bacterial swelling, dissolution, and death. Polymyxins also have hydrophobic regions that interact with LPS, further increasing membrane permeability. They can induce the fusion of the inner and outer membranes, leading to phospholipid loss and cell death.
Efficacy of Polymyxins
PMB and Polymyxin E
PMB and polymyxin E are effective against CRGNB infections. A Brazilian study found no significant difference in 30-day mortality between PMB and CMS in treating BSIs. Another study reported higher clinical response and microbiological eradication rates in the CMS group, but discrepancies in dosing regimens may account for divergent outcomes. Meta-analysis showed no significant difference in unadjusted mortality between CMS and PMB.
Monotherapy vs. Combination Therapy
Polymyxins can be administered as monotherapy or in combination with other antibiotics. However, studies indicate no advantage of combination therapy over monotherapy. A study in 2017 showed lower mortality in patients receiving CMS combination therapy in the high-risk group but no advantage in the low-risk group. Randomized controlled trials found no significant differences in mortality, clinical failure, microbiological cure, or adverse events between CMS monotherapy and combination therapy.
Intravenous Polymyxins Alone vs. Combination with Nebulization
Nebulized polymyxins can increase drug concentrations in alveolar epithelial lining fluid. Current evidence suggests considering nebulized polymyxins for ventilator-associated pneumonia (VAP) caused by susceptible CRGNB. Treatment-associated bronchospasm requires careful monitoring. Colistin sulfate and CMS can be used for nebulization, but colistin sulfate is associated with higher bronchospasm frequency. Nebulized polymyxins may be a reasonable adjunctive therapy for VAP, but definitive evidence is pending.
Polymyxins vs. Other Antibiotics
Polymyxins show varying efficacy compared to other antibiotics in treating CRGNB infections. Ceftazidime-avibactam has shown superior clinical and microbiological efficacy and reduced acute kidney injury compared to PMB in CRE infections. However, mortality outcomes remain comparable. A meta-analysis found significantly lower 30-day mortality, higher clinical cure rates, and microbiological eradication rates with ceftazidime-avibactam compared to polymyxins.
Safety of Polymyxins
Polymyxins have a narrow therapeutic window, with major adverse reactions including neurotoxicity and nephrotoxicity. CMS and PMB are cytotoxic to renal tubular cells, leading to acute tubular necrosis. Nephrotoxicity is associated with higher doses and longer treatment durations, with an overall incidence rate of 0-55%. A study reported a 44.9% nephrotoxicity incidence in CMS-treated patients, with higher mortality and dialysis rates.
Conclusion and Future Perspectives
The bacterial resistance situation is severe, posing a significant health threat. Polymyxins, both CMS and PMB, can treat CRGNB infections. No efficacy advantage of PMB over polymyxin E has been demonstrated, and combination therapy is not superior to monotherapy. The combination of nebulized and intravenous polymyxins can improve microbial eradication and clinical cure rates. Polymyxins do not confer a clear survival benefit compared to other antibiotics. Close attention should be paid to resistance emergence during treatment. With high mortality in polymyxin-treated infections, ideal drugs remain elusive. Therapeutic drug monitoring of polymyxins is rapidly evolving, becoming a cornerstone of precision medicine. Future efforts should focus on developing predictive models for polymyxin efficacy and safety to identify beneficial patients while avoiding injury.
