The combination meropenem-vaborbactam has not been evaluated in vitro against gram-positive organisms, but retains the gram-positive activity of meropenem; however, it has limited coverage against methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, and Enterococcus faecium [23,24,25].
Meropenem and vaborbactam individually have minimal and no activity, respectively, against KPC isolates ; however, the combination meropenem-vaborbactam is highly effective against gram-negative Enterobacterales, particularly those with KPC enzymes. This has been demonstrated by in vivo animal studies . Moreover, several studies have evaluated meropenem-vaborbactam efficacy against clinical strains using reference broth microdilution techniques. Vaborbactam is a narrow-spectrum beta-lactamase inhibitor, which does not infer any additional protection against Class C/AmpC hyper production, which tends to cause resistance in Pseudomonas. However, one in vitro study suggested that vaborbactam may enhance activity against Pseudomonas aeruginosa, although the full findings have not yet been published . Of note, meropenem-vaborbactam has no improved activity against Acinetobacter baumannii and is not effective against the metallo-beta-lactamase (MBL) (Class B)-containing Enterobacterales [17, 27, 28].
Castanheira et al. evaluated the effectiveness of meropenem-vaborbactam against 315 clinical isolates of serine carbapenemase-producing Enterobacterales collected over a period of 13 years from multiple countries . The long time interval and geographic variety were purposely chosen to diversify the test population. The majority of the isolates evaluated were K. pneumoniae (66%), and the most common resistance genes detected among the Enterobacterales were blaKPC-2 (46%) and blaKPC-3 (37%). When the isolates were tested alone against meropenem, only 2.2% of the entire collection were susceptible at the CLSI (Clinical & Laboratory Standards Institute) breakpoint of ≤ 1 for meropenem . The combination of meropenem (≤ 2 µg/ml) with increasing concentrations of vaborbactam ranging from 4 to 32 µg/ml inhibited 90.2–98.1% of the isolates tested. Vaborbactam increased the activity of meropenem by at least 64 fold. When focusing on KPC-producing isolates, meropenem-vaborbactam with an inhibitor concentration of 8 µg/ml inhibited 96.6% K.pneumoniae and 100% Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Serratia marcescens, and Citrobacter freundii isolates. In addition, 98.7% of isolates that carried additional beta-lactamases were suppressed with the combination. Of the seven isolates that exhibited intrinsic resistance to meropenem-vaborbactam MICs ≥ 16 µg/ml, four carried MBLs for VIM in addition to KPC, and the remaining three isolates showed alterations in expression of outer membrane porin (OMP) and efflux pump mechanisms (Table 1).
Optimal vaborbactam concentration was 8 µg/ml, based on in vitro activity achieving adequate susceptibility at 97.8% of the tested isolates. Increasing dose did not achieve significantly higher susceptibility. More importantly, this concentration is roughly equivalent to the concentration of the FDA-approved dose of 2 g for vaborbactam (Table 2).
Subsequently, Castenheira et al. published a larger study that evaluated 14,304 worldwide contemporary gram-negative clinical isolates against meropenem-vaborbactam and comparator antibiotics . The isolates were collected in 2014 from 82 hospitals as part of the SENTRY Antimicrobial Surveillance Program and included isolates that carried different resistance mechanisms so that some of the isolates were carbapenem resistant while others were multidrug resistant (MDR), including resistance to colistin and/or tigecycline. Meropenem effectively inhibited activity of 97.3% of Enterobacterales isolates tested at ≤ 1 µg/ml. This value increased to 99.1% when the same isolates were tested against meropenem-vaborbactam at the same concentration and 99.6% for a concentration of ≤ 8 µg/ml. There were 265 CRE isolates in this cohort, of which the majority (79.6%) were K. pneumoniae. One hundred thirty-five of the 265 screened CRE isolates carried blaKPC genes. Meropenem-vaborbactam had the most activity of the β-lactam agents tested against these CRE isolates and inhibited 84.2% of isolates at ≤ 8 µg/ml, and against comparator agents high susceptibility rates were seen: amikacin (56.2%) and colistin (70.3%). Only tigecycline had higher susceptibility at 99.2% (Fig. 1).
The meropenem-vaborbactam MIC50/MIC90 for MDR isolates was 0.03/1 µg/ml and for extensively drug-resistant (XDR) isolates was 0.5/32 µg/ml. Meropenem-vaborbactam at ≤ 8 µg/ml inhibited 96.5% of MDR isolates and 82% of XDR isolates. Similar to the previous analysis, the study confirmed that meropenem-vaborbactam has limited activity against MBLs. Among the 15.5% of the CRE isolates that contained MBLs, approximately two-thirds had the NDM-1 gene. OXA-48 also accounted for 10.2% of the CRE isolates. Meropenem-vaborbactam was most effective in strains from the US and least effective in strains from Asia–Pacific countries, likely due to the region's higher prevalence of MBLs. There were only seven isolates carrying carbapenemases from the Asia–Pacific region.
The same investigators utilized a 2015 worldwide collection of 11,559 Enterobacterales isolates to evaluate meropenem-vaborbactam activity, finding that meropenem-vaborbactam demonstrated enhanced activity against CRE and KPC producers compared to other antibiotics . Meropenem alone inhibited 96.9% of all the Enterobacterales tested, which increased to 99.3% when the isolates were tested against the combination of meropenem-vaborbactam. Overall, 97% of K. pneumoniae isolates were inhibited by meropenem-vaborbactam. Of the 330 CRE isolates in the cohort, the majority (80.6%) were K. pneumoniae, 88.5% had carbapenemase genes, 15.7% had MBL genes, and 13.3% had OXA-48 genes. Meropenem-vaborbactam at ≤ 4/8 µg/ml inhibited 73.9% of the CRE Enterobacterales and only 31.4% of the non-KPC gene CRE isolates. The one KPC isolate (0.5%) that was not inhibited by meropenem-vaborbactam contained a porin mutation.
Lapuebla et al. evaluated 4500 gram-negative clinical isolates from 11 New York City hospitals against meropenem-vaborbactam, meropenem, and other antibiotics . Meropenem-vaborbactam had strong in vitro activity against E. coli, Enterobacter spp., and K. pneumoniae and enhanced activity in KPC-producing CR isolates. Among E. coli isolates blaKPC was the only carbapenemase gene detected, and all isolates were susceptible to meropenem-vaborbactam at ≤ 8 µg/ml. Eighty-eight percent of K. pneumoniae isolates were susceptible to meropenem, and 99.8% were susceptible to meropenem-vaborbactam (with a vaborbactam concentration of 8 µg/ml). Meropenem-vaborbactam had activity against 119/121 (98.3%) of the KPC K. pneumoniae strains. In addition, 26 K. pneumoniae isolates with known resistance mechanisms expressing blaKPC, acrB, and ompK36 were tested; only 2 (both with decreased expression of ompK36) had elevated MIC > 64 µg/ml to meropenem, which decreased to 1 and 2 with the addition of vaborbactam. All 211 isolates of Enterobacter species, 7 of which had the blaKPC gene, were sensitive to the combination of meropenem-vaborbactam. Evaluation of A. baumannii and P. aeruginosa revealed no significant change among the non-susceptible meropenem isolates when tested against meropenem-vaborbactam, which was expected.
Combination meropenem-vaborbactam retains the anaerobic activity of meropenem .