Novel antibiotics in the management of multidrug-resistant organisms: Real-world evidence

Antimicrobial resistance is a global crisis. In 2019, antimicrobial-resistant bacterial pathogens directly caused 1.27 million deaths worldwide. [Lancet 2022;399:629-655] In particular, carbapenem-resistant gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae and carbapenem-resistant Acinetobacter baumannii cause infections that are particularly difficult to treat. This was the main focus of the Pfizer-organized Meet-the-expert session with Professor Yehuda Carmeli, Professor of Medicine at Sackler Medical School, Tel Aviv University, and Founder and Head of Israeli National Institute for Antibiotic Resistance and Infection Control, Tel Aviv Medical Center, Israel. Dr Lee Tau Hong, infectious disease physician at Mount Elizabeth Hospital, Singapore, chaired the session.

Global spread of CRE associated with high case fatality rates
“The incidence of carbapenem-resistant Enterobacteriaceae (CRE) has increased worldwide. Epidemiological data show that carbapenem-resistant Klebsiella pneumoniae has spread globally, reaching a moderately high level in Southeast Asia. Even more concerning is the spread of carbapenem-resistant Escherichia coli (E. coli), as it is more prevalent in the community and causes numerically more infections than Klebsiella, a nosocomial pathogen,” said Carmeli. [https://resistancemap.cddep.org/AntibioticResistance.php]

“The prevalence of CRE and the carbapenemase species involved are highly dependent upon the geographic region. A decade ago, countries were affected pre-dominantly by a single carbapenemase, and dissemination between countries could be traced. However, the epidemiology of CRE has evolved rapidly. Now, most places have a mixture of carbapenemases, a mixture of species, and different modes of transmission (ie, plasmid, clonal, or transposon). [Lancet Infect Dis 2013;13:785-796; Front Microbiol 2019;10:1823],” he added.

Infections caused by CRE are associated with crude mortality rates of up to 70 percent, presenting a major public health threat. [Infect Control Hosp Epidemiol 2017;38:580-594] Observational studies have shown that infections with carbapenem-resistant Klebsiella pneumoniae result in excess mortality rates compared with controls, Carmeli pointed out. [Infect Control Hosp Epidemiol 2008;29:1099-1106; Clin Microbiol Infect 2016;22:513-519]

Older treatment options for CRE
“Up until 2015, few treatment agents were available for CRE, namely colistin, tigecycline, fosfomycin, and high-dose meropenem, as well as combinations of the above,” listed Carmeli. “However, the use of these older agents has been limited due to efficacy and/or toxicity concerns.”

“Tigecycline does not reach the pharmacokinetic or pharmacodynamic parameters against most multidrug-resistant gram-negative bacteria in most clinical sites that are commonly affected by CRE. [Medicine (Baltimore) 2016;95(11):e3126] It is not indicated for bacteraemia, nosocomial pneumonia, or urinary tract infections, and is mainly reserved for patients with relatively mild, mixed infections in the soft tissue or intra-abdominal areas,” he elaborated. “Colistin was licensed in the 1950s and deemed too toxic for clinical use in the 1970s, owing to high rates of nephrotoxicity and neurotoxicity. It re-emerged as a last-resort antibiotic in the mid-1990s against MDR gram-negative pathogens. However, it is difficult to test for susceptibility to colistin, and bacterial resistance against colistin has emerged following its resurgence.”

Combination therapy
Combination therapy with two or more agents is often attempted as a strategy to optimize outcomes. However, combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of infections caused by carbapenem-resistant pathogens. [Lancet Infect Dis 2018;18:391-400; NEJM Evid 2023;2(1).doi:10.1056/EVIDoa2200131]

Combination therapy of colistin and carbapenem did not improve clinical outcomes or survival rates for adults with infections caused by carbapenem-resistant or carbapenemase-producing gram-negative bacteria vs colistin alone. There was no significant difference in all-cause mortality between patients who received colistin therapy and those who received combination therapy at 14 days after randomization (64/198 [32 percent] vs 70/208 [34 percent]) and 28 days (86/198 [43 percent] vs 94/208 [45 percent]). (Figure 1) No survival benefit was observed (log-rank p=0.66), nor were there any significant differences for all defined secondary outcomes. [Lancet Infect Dis 2018;18:391-400]

The PROSPECT Working Group also published recommendations to reduce pain after laparoscopic cholecystectomy. Paracetamol and NSAIDs are recommended before or during operation with dexamethasone, while opioids are reserved for rescue analgesia only. Gabapentinoids, intraperitoneal local anaesthetic, and transversus abdominis plane blocks are not recommended unless basic analgesia is not possible. [Br J Anaesth 2018;121:787-803]

High-dose carbapenems
High-dose, extended infusion meropenem may be used to treat non-carbapenemase-producing CREs, as data suggest that target time over MIC can be achieved for isolates with MIC up to 8. However, extended infusion meropenem is not recommended for carbapenemase-producing isolates, as heteroresistance and inoculum effect make it difficult to obtain an exact MIC measurement for carbapenemase-producing Enterobacteriaceae (CPE). [Antimicrob Agents Chemother 2015;59:5014-5017]

Recent treatment options for CRE
More recently, several new agents with activity against certain carbapenem-resistant pathogens have been approved for clinical use or are reaching late-stage clinical development. They include ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol. Meropenem-vaborbactam, imipenem/cilastatin-relebactam, and cefiderocol are not registered in Singapore.

Ceftazidime-avibactam
Ceftazidime-avibactam has a broad spectrum of activity against various MDR gram-negative bacteria, with activity against ESBL, AmpC, KPC, and OXA-48 Enterobacteriaceae, as well as AmpC Pseudomonas. [Microb Drug Resist 2021;27:342-349]

Ceftazidime-avibactam has been evaluated in seven prospective pivotal studies encompassing urinary tract infections, pneumonia, and complicated intra-abdominal infections, namely, RECLAIM 1, 2, and 3, RECAPTURE 1 and 2, REPRISE and REPROVE trials. Some of these trials included multi-drug resistant Enterobacterales (ESBL-producing, AmpC-overexpressing, or carbapenemase-producing strains). In these studies, the clinical cure rate was higher in the ceftazidime-avibactam arm for the carbapenemase-producing strains. [Clin Infect Dis 2016;62:1380-1389; Clin Infect Dis 2016;63:754-762; Lancet Infect Dis 2016;16:661-673; Lancet Infect Dis 2018;18:285-295]

More recently, the CAVICOR study, the largest comparative series of real-world data of patients with CPE infections treated with ceftazidime-avibactam or the best available therapy (BAT), showed that patients on ceftazidime-avibactam had higher clinical cure rates and microbiological response, as well as a 59 percent risk reduction in 30-day mortality vs those on BAT consisting mainly of gentamicin, colistin, tigecycline, and fosfomycin. (Table 2) [J Antimicrob Chemother 2022;77:1452-1460]

“In a genomic surveillance study in Singapore of carbapenem-resistant Klebsiella pneumoniae, KPC was the predominant carbapenemase (n=235, 40.9 percent), followed by OXA-48-like carbapenemase (22.3 percent) and NDM (16.2 percent). [Microbiol Spectr 2022;26;10:e0095722] While ceftazidime-avibactam does not work against NDM, it is the preferred agent for KPC and OXA-48, which represent the majority of carbapenem-resistant Klebsiella pneumoniae strains in Singapore,” Carmeli said.

“Empirical therapy should consider the type of microorganism, site of infection, patient’s history and condition, the local epidemiologic data, and pharmacokinetic properties of the antibiotics,” he advised.

Take-home messages
·       CRE has spread worldwide, and its epidemiology is changing fast.
·       Combination therapy of meropenem and colistin was not superior to colistin alone in improving outcomes or survival rates for adults with infections caused by carbapenem-resistant or carbapenemase-producing gram-negative bacteria.
·       Novel agents improve the outcome of patients with serious CRE infections.
        ❖   The CAVICOR study has shown that patients on ceftazidime-avibactam have higher clinical cure rates and microbiological percent risk reduction in 30-day mortality than those on best available therapy.
·       Empirical therapy should be decided based on the local epidemiology of the pathogens and mechanisms of resistance, as well as the patient’s individual characteristics.