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Carbapenemase-producing Klebsiella pneumoniae infections are an increasing global threat with scarce and uncertain treatment options. In this context, combination therapies are often used for these infections. The bactericidal and synergistic activity of fosfomycin plus amikacin and gentamicin was studied trough time–kill assays against four clonally unrelated clinical isolates of carbapenemase-producing K. pneumoniae, VIM-1, VIM-1 plus DHA-1, OXA-48 plus CTXM-15, and KPC-3, respectively. The efficacy of antimicrobials that showed synergistic activity in vitro against all the carbapenemase-producing K. pneumoniae were tested in monotherapy and in combination, in a murine peritoneal sepsis model. In vitro, fosfomycin plus amikacin showed synergistic and bactericidal effect against strains producing VIM-1, VIM-1 plus DHA-1, and OXA-48 plus CTX-M-15. Fosfomycin plus gentamicin had in vitro synergistic activity against the strain producing KPC-3. In vivo, fosfomycin and amikacin and its combination reduced the spleen bacterial concentration compared with controls groups in animals infected by K. pneumoniae producing VIM-1 and OXA-48 plus CTX-M-15. Moreover, amikacin alone and its combination with fosfomycin reduced the bacteremia rate against the VIM-1 producer strain. Contrary to the in vitro results, no in vivo efficacy was found with fosfomycin plus amikacin against the VIM-1 plus DHA-1 producer strain. Finally, fosfomycin plus gentamicin reduced the bacterial concentration in spleen against the KPC-3 producer strain. In conclusion, our results suggest that fosfomycin plus aminoglycosides has a dissimilar efficacy in the treatment of this severe experimental infection, when caused by different carbapenemase-producing K. pneumoniae strains. Fosfomycin plus amikacin or plus gentamycin may be useful to treat infections by OXA-48 plus CTX-M-15 or KPC-3 producer strains, respectively., This study was supported by the Consejería de Salud of the Junta de Andalucía (PI-0622-2012) and supported by Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI, RD16/0016/0001, RD16/0016/0009)—co-financed by European Development Regional Fund A way to achieve Europe, Operative program Intelligent Growth 2014-2020. MP-I is a researcher belonging to the program Nicolás Monardes (C1-0038-2019), Servicio Andaluz de Salud, Junta de Andalucía, Spain. TC-C was supported by the V Plan Propio of the University of Seville with a postdoctoral contract as research personnel in training. GL-H has a grant from the Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund (A Way to Achieve Europe) and by the Spanish Network for Research in Infectious Diseases (Grant REIPI RD16/0016/0009).

The activity of ceftazidime-avibactam was compared with that of ceftazidime alone and meropenem against a collection of 190 Pseudomonas aeruginosa clinical isolates recovered from a multicenter study of bloodstream infections. The addition of avibactam increased ceftazidime susceptibility in the complete collection of strains (64.7% to 91.1%) and particularly among subsets of isolates showing AmpC hyperproduction (10.9% to 76.1%) or multidrug resistance (MDR) profiles (27% to 77.8%). The MICs of ceftazidime-avibactam, in contrast with those of ceftazidime or meropenem, remained at ≤4 μg/ml for a panel of 16 P. aeruginosa PAO1 isogenic mutants expressing multiple combinations of the most relevant β-lactam resistance mechanisms.

OBJECTIVES To evaluate the proficiency of Spanish laboratories regarding accurate susceptibility testing, detection and interpretation of Pseudomonas aeruginosa β-lactam resistance phenotypes. METHODS Thirteen characterized strains were sent to 54 participating centres: clinical strains producing horizontally acquired β-lactamases [extended-spectrum β-lactamases (ESBLs; PER-1 and OXA-161) and class A (GES-5) and B (VIM-2) carbapenemases] and mutants with combinations of chromosomal mechanisms (AmpC, OprD and/or efflux). The centres were requested to evaluate six antipseudomonal β-lactams, provide raw/interpreted clinical categories and detect/infer the resistance mechanisms. Consensus results from reference centres were used to assign minor, major or very major errors (mEs, MEs or VMEs). RESULTS Vitek2, MicroScan WalkAway and Wider were the most used devices (25%-30% each). CLSI/EUCAST breakpoints were used in 86%/14% of the determinations. Discrepancies exclusively due to the differential application of breakpoints were highest for aztreonam, followed by piperacillin/tazobactam. The lowest percentage of VMEs was for Vitek2, followed by Wider. The highest percentages of VMEs (6%) were for the AmpC-hyperproducing OprD(-) strain and for the GES-5 producer, while among antibiotics the highest percentage of VMEs (22%) involved piperacillin/tazobactam. Appropriate inference of resistance mechanisms was high for the VIM-2-producing strain (83%), but low (

Transparency declarations M. J. R. has received speaking honoraria from Cubist, Forest, Novartis and Sunovion, consulting fees from Durata, Cubist, Forest, Cepheid and Theravance, and research grant support from Cubist, Forest and Cerexa Pharmaceuticals. G. S. has received speaking honoraria from Cubist, Forest and Novartis Pharmaceuticals, consulting fees from Cubist and Forest Pharmaceuticals, and research grant support from Forest Pharmaceuticals. K. E. B.: none to declare.

The activities of carbapenems against Pseudomonas aeruginosa decreased in the presence of siliconized latex urinary catheters (SLUCs). This effect was associated with the loss of OprD. The zinc that eluted from SLUCs is responsible for this phenomenon. We have found that zinc exerts a negative effect on the expression of OprD, the porin responsible for carbapenem entry into P. aeruginosa .

Tigecycline showed excellent in vitro activity against 50 clinical isolates of Klebsiella pneumoniae producing extended-spectrum beta-lactamases, plasmid-mediated AmpC-type beta-lactamases, or both. This activity was not affected by porin loss. Porin loss, however, did affect the activity of imipenem against strains that expressed both types of enzymes.

Bacteria exhibiting elevated mutation frequencies may present an enhanced risk for the emergence of antibiotic resistance during chemotherapy ([1][1]). Galan et al. ([2][2]) described a simple method for detecting hypermutable strains in which commercial disks of fosfomycin (50 μg) and rifampin (

Introduction: Antimicrobial resistance in Enterobacteriaceae is increasing worldwide and is making treating infections caused by multidrug-resistant Enterobacteriaceae a challenge. The use of beta-lactam agents is compromised by microorganisms harboring extended-spectrum beta-lactamases (ESBLs) and other mechanisms of resistance. Avibactam is a non beta-lactam agent that inhibits clinically relevant beta-lactamases, such as ESBL and AmpC. The ceftazidime-avibactam combination (CAZ-AVI) was recently approved for use in certain complicated infections, and may provide a therapeutic alternative for infections caused by these microorganisms. Methods: The in vitro activity of CAZ and CAZ-AVI (AVI at a fixed concentration of 4 mg/L) was tested against 250 clinical isolates of Enterobacteriaceae using broth microdilution. EUCAST breakpoint criteria were used for CAZ, and FDA criteria for CAZ-AVI. Clinical isolates included bacteria producing extended spectrum beta-lactamases (ESBLs) and acquired AmpC beta-lactamases (AACBLs). Porin loss in IClebsiella pneumoniae was also evaluated. Results: The combination of AVI with CAZ displayed excellent activity against clinical isolates of ESBL-producing Escherichia coli and Klebsiella pneumoniae, rendering all the ceftazidime-resistant isolates susceptible to ceftazidime. CAZ-AVI retained activity against porin-deficient isolates of K. pneumoniae producing ESBLs, AACBLs, or both, although MIC values were higher compared to porin-expressing isolates. CAZ-AVI rendered all the ceftazidime-resistant AACBL-producing Enterobacteriaceae tested susceptible to ceftazidime. Conclusion: CAZ-AVI showed potent in vitro activity against clinical isolates of Enterobacteriaceae producing ESBLs and/or AACBLs, including K. pneumoniae with loss of porins. (C) 2016 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.