Activity of Meropenem-Vaborbactam against Bacterial Isolates Causing Pneumonia in Patients in U.S. Hospitals during 2014 to 2018

Meropenem-vaborbactam is approved to treat hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), in Europe. Meropenem-vaborbactam activity was evaluated against 3,193 Pseudomonas aeruginosa and 4,790 Enterobacterales isolates causing pneumonia, including VAP, in hospitalized patients in the United States. Susceptibility testing was performed by using the broth microdilution method, and all carbapenem-resistant isolates were submitted for whole-genome sequencing.

Isolates that met the CRE criteria were submitted for whole-genome sequencing and analysis as previously described (13). Carbapenemase-encoding genes were detected in 53.4% (70/131) of CRE isolates, and this finding corroborates those from previous national studies (11,12). Klebsiella pneumoniae carbapenemase (KPC; 94.2% [66/70]) remained the most frequent carbapenemase detected among carbapenemaseproducing Enterobacterales (CPE) isolates causing PHP (Table 2). Unlike other carbapenemase enzymes that have been infrequently reported in U.S. hospitals, KPCproducing isolates have been reported in every U.S. state, though the endemicity of KPC-producing bacteria within the United States remains focused in regional hot spots (4,12,14). In this study, approximately two-thirds of the KPC-producing Enterobacterales isolates detected were from the Middle Atlantic region, although these isolates were also observed in most U.S. census divisions. Meropenem-vaborbactam (MIC 50/90 , 0.03/0.5 mg/liter) was 512-fold more active than meropenem (MIC 50/90 , 16/Ͼ32 mg/ liter) against KPC-producing isolates based on MIC 50 values. These findings are in agreement with previous results where the combination of vaborbactam reduces meropenem MIC values Ͼ64-fold for CPE isolates (15)(16)(17).
All KPC-producing isolates were inhibited by meropenem-vaborbactam regardless of the KPC variant produced. KPC-3 (n ϭ 42; 60.9% of all CPE) was more common than KPC-2 (n ϭ 24; 34.8%) and was disseminated among 6 Enterobacterales species from all U.S. census divisions except West North Central, East South Central, and West South Central ( Vaborbactam is a potent inhibitor of serine ␤-lactamases, but the agent lacks activity against metallo-␤-lactamases (MBLs) and class D carbapenemase (19). In addition to No carbapenemase genes were observed in 61 CRE isolates (46.6%), and meropenem-vaborbactam was the only agent tested to inhibit 100% of these isolates. Tigecycline, colistin, and amikacin were active against 98.4%, 75.4%, and 68.9%, respectively. Limited activity was observed for all ␤-lactams agents, including meropenem (MIC 50/90 , 8/Ͼ32 mg/liter; 4.9% susceptible). Resistance mechanisms other than carbapenemase production, such as lack of major porins and overexpression of AcrAB-TolC efflux pumps combined with extended spectrum cephalosporinases or AmpC production, are well known causes of meropenem resistance. Some of those, in addition to an increase in the bla KPC gene copy number, were described to possibly affect meropenem-vaborbactam activity (19,20). However, these mechanisms can be overcome by targeting in vivo exposures that maximize the efficacy of the meropenemvaborbactam combination. Recently completed clinical trials demonstrated that these target exposures appear to be achievable due to the excellent safety profiles of both meropenem and vaborbactam (21)(22)(23).  Results of the phase 3 clinical trial (Tango II) to evaluate the safety, efficacy, and tolerability of meropenem-vaborbactam monotherapy in treating patients with serious CRE infections versus best available therapy (BAT) were very encouraging (23). Patients randomized to the meropenem-vaborbactam arm received 7 to 14 days of treatment as monotherapy (2 g-2 g) via intravenous infusion over 3 h every 8 h, and BAT therapy included polymyxins, carbapenems, aminoglycosides, or tigecycline as monotherapy or in combination and ceftazidime-avibactam monotherapy. Day 28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) for meropenem-vaborbactam and BAT, respectively. Although only 5 patients with HAP/VAP were included, meropenem-vaborbactam is a promising ␤-lactam/␤-lactam-inhibitor combination for treating pathogens causing HAP and VAP, including CRE infections, and this combination compound gained EMA approval for these indications (24).
The findings of this study, where meropenem-vaborbactam, aminoglycosides, carbapenems, and tigecycline were the only agents displaying susceptibility rates Ͼ90% against 4,790 Enterobacterales isolates, reinforce the challenges to improve care for patients with HAP/VAP, for which delayed and inadequate treatments have been associated with increased rates of morbidity and mortality (25,26). Similar results were observed when these agents were tested against a worldwide collection of Enterobacterales recovered from different infection sources (12). The emergence and widespread geography of CRE isolates have added considerable challenges to treating severe infections, and mortality rates are as high as 40% to 50% (27)(28)(29). Therapeutic options to treat CRE HAP/VAP infections are limited, and traditionally, agents from either the polymyxin or aminoglycoside classes have been recommended in combined therapy, usually with carbapenem-containing regimens (1,26,30,31). However, studies have shown that colistin, tigecycline, and gentamicin have poor lung penetration, whereas carbapenems have good distribution in lungs, achieving clinically relevant concentrations (26,32). In fact, herein, only meropenem-vaborbactam (98.5%) and tigecycline (96.9%) displayed Ͼ90% susceptibility rates against CRE isolates causing PHP.
P. aeruginosa isolates were recovered from 3,193 PHP, including 545 isolates deemed to cause VAP. Overall, 89.5% of P. aeruginosa isolates were inhibited at the meropenem-vaborbactam susceptible breakpoint established by EUCAST (Յ8 mg/liter) compared to 76.4% susceptible to meropenem alone (at Յ2 mg/liter) (Tables 1 and 2 ). However, colistin and aminoglycoside therapy raise concerns on ensuring that therapeutic and nontoxic levels will be delivered to the patient (23). Similar susceptibility rates were observed between P. aeruginosa isolates recovered from patients with PHP and VAP (Table 1).
Facing the epidemic of multidrug-resistant Gram-negative bacilli, carbapenems have become the most empirically prescribed ␤-lactams in intensive care units for HAP/VAP in many geographic regions (35,36). However, the meropenem standard dosage (1 g every 8 h, 30-min infusion) used to treat P. aeruginosa infections showed lower coverage (76.4% susceptible) against these isolates than the coverage observed by meropenem-vaborbactam (89.5% susceptible) when the approved dosage (2 g-2 g via intravenous [i.v.] infusion over 3 h every 8 h) and current EUCAST breakpoints were applied (37).
In summary, meropenem-vaborbactam was very active against a large collection of Enterobacterales isolates recovered from PHP and VAP in 31 U.S. hospitals over a 4-year period. This collection included CRE isolates that were resistant to many comparator agents but mostly (Ͼ99%) susceptible to meropenem-vaborbactam. Meropenemvaborbactam was also active against P. aeruginosa isolates that were resistant to many antipseudomonal agents and had high MDR and XDR rates. This combination agent may be considered an effective alternative for the treatment of HAP/VAP infections in U.S. hospitals when the FDA approves that indication.