Nationwide epidemiology of carbapenem resistant Klebsiella pneumoniae isolates from Greek hospitals, with regards to plazomicin and aminoglycoside resistance

Abstract

Background To evaluate the in vitro activities of plazomicin and comparator aminoglycosides and elucidate the underlying aminoglycoside resistance mechanisms among carbapenemase-producing K. pneumoniae isolates collected during a nationwide surveillance study in Greek hospitals. Methods Three hundred single-patient carbapenemase-producing K. pneumoniae isolates were studied, including 200 KPC-, 50 NDM-, 21 VIM-, 14 KPC & VIM-, 12 OXA-48-, two NDM & OXA- and one KPC & OXA-producing isolates. Susceptibility testing was performed by broth microdilution, and minimum inhibitory concentrations (MICs) interpreted per EUCAST breakpoints. Carbapenemase-, aminoglycoside modifying enzyme- and 16S rRNA methylase- encoding genes were detected by PCR. Results Of 300 isolates tested, 5.7% were pandrug resistant and 29.3% extensively drug resistant. Plazomicin inhibited 87.0% of the isolates at ≤2 mg/L, with MIC 50 /MIC 90 of 0.5/4 mg/L. Apramycin (a veterinary aminoglycoside) inhibited 86.7% of the isolates at ≤8 mg/L and was the second most active drug after plazomicin, followed by gentamicin (S, 43%; MIC 50 /MIC 90 , 4/> 256) and amikacin (S, 18.0%; MIC 50 /MIC 90 , 32/128). Twenty-three (7.7%) isolates (16 KPC-, 6 VIM- and one KPC & OXA-48-producers) exhibited MICs ≥64 mg/L for plazomicin, and harbored rmtB ( n = 22) or armA ( n = 1). AAC(6′)-Іb was the most common aminoglycoside modifying enzyme (84.7%), followed by AAC(3΄)-IIa (25.3%), while those two enzymes were co-produced by 21.4% of the isolates. Conclusions Plazomicin retains activity against most carbapenemase-producing K. pneumoniae isolated from Greek hospitals, with MICs consistently lower than those of the other aminoglycosides, even in the presence of aminoglycoside modifying enzymes. Dissemination of 16S- rRNA methylases in 8% of the isolates is an unwelcome event that needs strict infection control measures and rigorous stewardship interventions. Electronic supplementary material The online version of this article (10.1186/s12879-019-3801-1) contains supplementary material, which is available to authorized users.

Critical analysis of antibacterial agents in clinical development

“…All these resistance mechanism related factors explain the high variability of susceptibility rates to new β lactam based therapies against CRE. In addition, CRE are also often resistant to unrelated antibacterial classes, such as fluoroquinolones, aminoglycosides, fosfomycin and tigecycline, thus making them XDR and some times PDR 27 . Associated resistance to colistin and tigecycline is linked to worse clinical outcomes 28,29 .…”

“…Associated resistance to colistin and tigecycline is linked to worse clinical outcomes 28,29 . In Greece, prevalences of ~30% for XDR and ~5% for PDR have been reported 27 . The propensity for specific clones of K. pneumoniae to spread in hospital envi ronments has been shown to correlate with the degree of resistance; distressingly, carbapenemase producing isolates have the highest transmissibility 30,31 .…”

Plazomicin: A Next‐Generation Aminoglycoside

“…Although most data available are for Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria, in vitro data indicated that plazomicin had activity against some New Delhi metallo-b-lactamase (NDM)-producing organisms (80-92% susceptible), particularly when these isolates did not harbor the 16S rRNA methylase gene. [19][20][21] Plazomicin also has reduced or no activity against Enterococcus sp, Streptococcus sp, Acinetobacter sp, and Stenotrophomonas sp. 14 The drug has variable activity and higher minimum inhibitory concentrations (MICs) for 50% and 90% of isolates, respectively (MIC 50/90 ), to non-lactose-fermenting aerobic gram-negative pathogens including Morganella morganii, Proteus sp, and Pseudomonas sp.…”

“…Plazomicin (MIC 50/90 1/2 mg/L) inhibited 100% of the mcr-1 gene isolates at 2 mg/L or less and exhibited the most potent in vitro activity against colistinresistant Enterobacteriaceae, with an MIC 90 of 4 mg/L. 19,20,27,29,31,33,35 ≤ 0.5 1-2 ≤ 0.06 to > 128 CR-Enterobacteriaceae (n=1680) [19][20][21][28][29][30][31][32]34,35 0.25-1 1t o≥ 64 ≤ 0.06 to > 256 ESBL-producing Enterobacteriaceae (n=1261) 20,29,31,34,35 0.25-1 0.5-2 ≤ 0.06 to > 128 KPC-producing Enterobacteriaceae (n=267) 21,33,34 0.5 0.5 -AME producers (n=838) 20,27 0.5 2 16S RNA methylase producers (n=48) 20 > 128 > 128 E. coli (n=10,450) 19,20,23,25,29,31,[33][34][35] ≤ 0.5 to 2 1-2 ≤ 0.06 to > 128 Gent-R E. coli (n=288) 25 0.5 1 ≤ 0.12 to 2 Klebsiella pneumoniae (n=6680) 19,20,23,25,29,31,33,3...…”

“…In Vitro Susceptibility of Various Gram-Negative and Gram-Positive Bacteria to Plazomicin10,[19][20][21]23,[26][27][28][29][30][31][32][33][34][35][36][37] …”