Resistance to ceftazidime/avibactam in infections and colonisations by KPC-producing Enterobacterales: a systematic review of observational clinical studies.

OBJECTIVES: Ceftazidime/avibactam (CAZ-AVI), approved in 2015, is an important first-line option for Klebsiella pneumoniae carbapenemase-producing Enterobacterales (KPC-E). Although still uncommon, resistance to CAZ-AVI has emerged and may represent a serious cause of concern. METHODS: We performed a systematic literature review of clinical and microbiological features of infections and colonisations by CAZ-AVI-resistant KPC-E, focused on the in vivo emergence of CAZ-AVI resistance in different clinical scenarios. RESULTS: Twenty-three papers were retrieved accounting for 42 patients and 57 isolates, mostly belonging to K. pneumoniae ST258 harbouring D179Y substitution in the KPC enzyme. The USA, Greece and Italy accounted for 80% of cases. In one-third of isolates resistance was not associated with previous CAZ-AVI exposure. Moreover, 20% of the strains were colistin-resistant and 80% were extended-spectrum ß-lactamase (ESBL)-producers. The majority of infected patients had severe underlying diseases (39% cancer, 22% solid-organ transplantation) and 37% died. The abdomen, lung and blood were the most involved infection sites. Infections by CAZ-AVI-resistant strains were mainly treated with combination therapy (85% of cases), with meropenem being the most common (65%) followed by tigecycline (30%), gentamicin (25%), colistin (25%) and fosfomycin (10%). Despite the emergence of resistance, 35% of patients received CAZ-AVI. CONCLUSION: Taken together, these data highlight the need for prompt susceptibility testing including CAZ-AVI for Enterobacterales, at least in critical areas. Resistance to CAZ-AVI is an urgent issue to monitor in order to improve both empirical and targeted CAZ-AVI use as well as the management of patients with infections caused by CAZ-AVI-resistant strains.

Trends in the Incidence and Antibiotic Resistance of Enterococcal Bloodstream Isolates: A 7-Year Retrospective Multicenter Epidemiological Study in Italy.

The spread of resistance to vancomycin and other last-resort drugs in Enterococcus spp. remains of concern. In Italy, surveillance data for enterococcal bloodstream isolates in humans are scant. The aim of our study was to assess the incidence trends of bacteremias due to Enterococcus species and their prevalence trends of antimicrobial resistance. We retrospectively included all consecutive not-duplicate Enterococcus species isolated from blood cultures, in patients from 11 Italian hospitals (2011-2017). Incidence was defined as the number of isolates per 10,000 patient-days, while resistance prevalence was defined as the number of resistant strains divided by the number of tested strains. We included 4,858 isolates (59%, 36%, and 5% due to Enterococcus faecalis, E. faecium, and other Enterococcus spp., respectively). Over the study period, the incidence of bacteremias due to E. faecalis (incidence rate ratio [IRR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.008) and E. faecium increased (IRR: 1.03, 95% CI: 1.01-1.05, p < 0.001) alongside with the whole enterococcal bacteremias trend (IRR: 1.02, 95% CIs: 1.01-1.04, p = 0.002). A progressive increase in vancomycin-resistant E. faecium (VREfm) bacteremias was observed. Resistance to tigecycline and linezolid was rarely reported. The incidence of enterococcal bloodstream isolates is increasing in Italy, together with the prevalence of VREfm. Resistance to linezolid, a cornerstone drug used in the treatment of VRE bloodstream infection, remains negligible.

Polypyridine ligands as potential metallo-ß-lactamase inhibitors.

Bacteria have developed multiple resistance mechanisms against the most used antibiotics. In particular, zinc-dependent metallo-ß-lactamase producing bacteria are a growing threat, and therapeutic options are limited. Zinc chelators have recently been investigated as metallo-ß-lactamase inhibitors, as they are often able to restore carbapenem susceptibility. We synthesized polypyridyl ligands, N,N'-bis(2-pyridylmethyl)-ethylenediamine, N,N,N'-tris(2-pyridylmethyl)-ethylenediamine, N,N'-bis(2-pyridylmethyl)-ethylenediamine-N-acetic acid (N,N,N'-tris(2-pyridylmethyl)-ethylenediamine-N'-acetic acid, which can form zinc(II) complexes. We tested their ability to restore the antibiotic activity of meropenem against three clinical strains isolated from blood and metallo-ß-lactamase producers (Klebsiella pneumoniae, Enterobacter cloacae, and Stenotrophomonas maltophilia). We functionalized N,N,N'-tris(2-pyridylmethyl)-ethylenediamine with D-alanyl-D-alanyl-D-alanine methyl ester with the aim to increase bacterial uptake. We observed synergistic activity of four polypyridyl ligands with meropenem against all tested isolates, while the combination N,N'-bis(2-pyridylmethyl)-ethylenediamine and meropenem was synergistic only against New Delhi and Verona integron-encoded metallo-ß-lactamase-producing bacteria. All synergistic interactions restored the antimicrobial activity of meropenem, providing a significant decrease of minimal inhibitory concentration value (by 8- to 128-fold). We also studied toxicity of the ligands in two normal peripheral blood lymphocytes.

KPC-53, a KPC-3 Variant of Clinical Origin Associated with Reduced Susceptibility to Ceftazidime-Avibactam.

This study reports on the characterization of a Klebsiella pneumoniae clinical isolate showing high-level resistance to ceftazidime-avibactam associated with the production of KPC-53, a KPC-3 variant exhibiting a Leu167Glu168 duplication in the Ω-loop and a loss of carbapenemase activity. Whole-genome sequencing (WGS) revealed the presence of two copies of blaKPC-53, located on a pKpQIL-like plasmid and on a plasmid prophage of the Siphoviridae family, respectively. The present findings provide new insights into the mechanisms of resistance to ceftazidime-avibactam.

Fosfomycin as Partner Drug for Systemic Infection Management. A Systematic Review of Its Synergistic Properties from In Vitro and In Vivo Studies.

Fosfomycin is being increasingly prescribed for multidrug-resistant bacterial infections. In patients with systemic involvement, intravenous fosfomycin is usually administered as a partner drug, as part of an antibiotic regimen. Hence, the knowledge of fosfomycin pharmacodynamic interactions (synergistic, additive, indifferent and antagonistic effect) is fundamental for a proper clinical management of severe bacterial infections. We performed a systematic review to point out fosfomycin's synergistic properties, when administered with other antibiotics, in order to help clinicians to maximize drug efficacy optimizing its use in clinical practice. Interactions were more frequently additive or indifferent (65.4%). Synergism accounted for 33.7% of total interactions, while antagonism occurred sporadically (0.9%). Clinically significant synergistic interactions were mostly distributed in combination with penicillins (51%), carbapenems (43%), chloramphenicol (39%) and cephalosporins (33%) in Enterobactaerales; with linezolid (74%), tetracyclines (72%) and daptomycin (56%) in Staphylococcus aureus; with chloramphenicol (53%), aminoglycosides (43%) and cephalosporins (36%) against Pseudomonas aeruginosa; with daptomycin (97%) in Enterococcus spp. and with sulbactam (75%) and penicillins (60%) and in Acinetobacter spp. fosfomycin-based antibiotic associations benefit from increase in the bactericidal effect and prevention of antimicrobial resistances. Taken together, the presence of synergistic interactions and the nearly total absence of antagonisms, make fosfomycin a good partner drug in clinical practice.

Zinc Chelators as Carbapenem Adjuvants for Metallo-ß-Lactamase-Producing Bacteria: In Vitro and In Vivo Evaluation.

Infections caused by metallo-ß-lactamase (MBL)-producing bacteria are emerging and carry a significant impact on patients' outcome. MBL producers are spread worldwide, both in community and hospital setting, with increasingly reported epidemic clusters and the search for MBL inhibitors is an important topic for public health. MBLs are zinc-dependent enzymes whose functioning can be hampered by zinc chelators. We evaluated the potential of six zinc chelators (disulfiram, nitroxoline, 5-amino-8-hydroxyquinoline, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA], cyclam, and N,N,N',N'-tetrakis (2-pyridymethyl) ethylenediamine [TPEN]) in restoring carbapenem activity against MBL producers. Zinc chelators alone or in combination with meropenem against MBL-producing Klebsiella pneumoniae, Chryseobacterium indologenes, Elizabethkingia meningoseptica, and Stenotrophomonas maltophilia isolates were tested in vitro and in vivo (Galleria mellonella). In vitro experiments showed a synergistic activity between TPEN and meropenem toward all the strains. Nitroxoline alone retained activity against S. maltophilia, C. indologenes, and E. meningoseptica. In vivo experiments showed that TPEN or nitroxoline in combination with meropenem increased survival in larvae infected with E. meningoseptica, S. maltophilia, and K. pneumoniae. Based on our data, zinc chelators are potential carbapenem adjuvants molecules (restoring carbapenem activity) against MBL-sustained infections and could represent an interesting option for infections induced by these microorganisms.

In vitro activity of ceftazidime/avibactam against clinical isolates of ESBL-producing Enterobacteriaceae in Italy.

Resistance to carbapenems in Enterobacteriaceae is a serious concern for public health. Alternative treatment options involving carbapenem-sparing regimen for patients with serious infections caused by multidrug-resistant Enterobacteriaceae are urgently needed. Ceftazidime/avibactam (CZA) is a new combination of a third generation cephalosporin and a non-ß-lactam ß-lactamase inhibitor, in which avibactam is capable to expand the ceftazidime activity also against extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. To date, no data exist regarding the activity of CZA against strains isolated in the Italian context, which is known as endemic for ESBL producers. The aim of this study was to evaluate the in vitro activity of CZA, in comparison to ceftazidime (CAZ), against 90 ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates, collected from blood and urine samples at our Institute. Thus, avibactam has been able to restore the activity of CAZ in all cases, suggesting the potential use of CZA as a carbapenem-sparing model, especially when limited therapeutic options exist.