Assessment of MIC Increases with Meropenem-Vaborbactam and Ceftazidime-Avibactam in TANGO II (a Phase 3 Study of the Treatment of CRE Infections)

Abstract

Background. TANGO II is a Phase 3 comparative trial of meropenem-vabor-bactam (M-V) given as monotherapy vs. best available therapy (BAT) in patients with bacteremia, cUTIs, cIAI, or HABP/VABP due to CRE. Patients in the BAT arm could receive ceftazidime-avibactam (C-A) as monotherapy. Changes in MIC in bacterial isolates to M-V or C-A recovered during monotherapy were assessed. Methods. MICs were conducted on baseline and post-baseline isolates of Enterobacteriaceae (ENT) recovered during treatment. MICs were determined using CLSI reference methods and MIC changes ≥4 were further assessed. Whole genomes of the majority of isolates were sequenced using Illumina MiSeq platform. Transcription level of various genes was determined using RT-PCR. Results. 25 patients treated with M-V and 4 treated with C-A had KPC-producing ENT. The mean days of treatment was 8.5 and 8.4 for M-V and C-A, respectively. One patient treated with M-V who carried KPC-3-producing K. pneumoniae (KP) (1/25; 4.0%) had a subsequent clinical isolate with a ≥4-fold change in M-V MIC (0.25 to 1 µg/mL), but remained susceptible after 6 days of therapy for acute pyelonephritis; the MIC increase was associated with overexpression of AcrAB, and no mutations in bla KPC-3 were observed. Two of the 4 patients treated with C-A (2/4; 50%) had a post-baseline clinical isolate of KP with ≥4-fold increase in MIC compared with the baseline isolate. In one case, the C-A MIC of the KPC-2-producing isolate increased >128-fold (0.5 to >64 µg/mL) following 7 days of therapy for a complicated intra-abdominal infection (cIAI). Resistance was associated with a point mutation in the blaKPC-2 gene leading to D179Y amino acid substitution in the enzyme, downregulation of genes encoding porins OmpK35 and OmpK36, and upregulation of the efflux operon, acrAB. In the second case, the C-A MIC of the KPC-3 producing isolate increased 8-fold (1 µg/mL to 8 µg/mL) after 14 days of therapy for cIAI; this change in MIC was associated with downregulation of ompK36 and acquisition of a plasmid-containing blaCTX-M-15 and blaOXA-1 genes. Conclusion. M-V appears to be associated with a lower incidence of in vitro MIC changes compared with C-A. Based on these findings, M-V may be a viable treatment option for infections due to KPC-producing CRE. Background. OMC is a novel aminomethylcycline antibiotic that completed Phase 3 studies as once daily oral and intravenous (IV) monotherapy for CABP (OPTIC study) and acute bacterial skin and skin structure infections (OASIS study). CABP is a common , serious infection, in which microbiological confirmation of infection is difficult and a pathogen is only identified in <10% of patients. The OPTIC study demonstrated that OMC was non-inferior to MOX at the post treatment evaluation in the microbio-logical intent-to-treat (microITT population) (89.2 vs. 87.4; 95% CI:-4.6, 8.5). Methods. The microITT population consisted of subjects in the ITT population who had at least 1 causative pathogen identified at screening through positive blood culture, adequate quality lower respiratory tract culture, positive urinary anti-gen for Legionella pneumophila or Streptococcus pneumoniae, or positive serology titers for L. pneumophila, Mycoplasma pneumoniae or Chlamydophila pneumoniae. Results. Requiring a microbiological diagnosis in the OPTIC study resulted in 49.8% (386/774) of the ITT qualifying for inclusion in the microITT. By culture methods, 24.1% had a Gram-positive pathogen, 38.1% had a Gram-negative pathogen and the majority were mono-microbial. The most frequently isolated pathogens from culture in the microITT were S. pneumoniae (13.7%), H. influenzae (12.4%), H. parainfluenzae (9.1%), Klebsiella pneumoniae (6.7%) and S. aureus (5.7%). In total, 28.3% (15/53) and 24.5% (13/53) of S. pneumoniae were macrolide resistant and multi-drug resistant, respectively. Serotype 3 was the most common S. pneu-moniae serotype. There was no correlation between OMC MIC values and clinical outcome which suggests that target exposures were achieved at the infection site. Conclusion. OMC is a novel antibiotic with potent in vitro and clinical activity against typical and atypical CABP pathogens, including multi-drug resistant S. pneumoniae.