Antimicrobial activity of ceftazidime/avibactam, ceftolozane/tazobactam and comparator agents against Pseudomonas aeruginosa from cystic fibrosis patients.

OBJECTIVES: To evaluate the antimicrobial susceptibility patterns of Pseudomonas aeruginosa isolates collected from the lower respiratory tract of cystic fibrosis (CF) patients. METHODS: We susceptibility tested 273 contemporary P. aeruginosa isolates from 39 hospitals worldwide (17 countries) by the reference broth microdilution method. RESULTS: Ceftazidime/avibactam [MIC50/90, 2/8 mg/L; 96.0% susceptible (S)] was the most active agent, followed by ceftolozane/tazobactam (MIC50/90, 1/4 mg/L; 90.5% S), ceftazidime (MIC50/90, 2/>32 mg/L; 80.6% S), piperacillin/tazobactam (MIC50/90, 4/128 mg/L; 80.2% S) and tobramycin (MIC50/90, 2/>16 mg/L; 76.6% S). Ceftazidime/avibactam retained activity against P. aeruginosa isolates non-susceptible to meropenem (86.5% S to ceftazidime/avibactam), piperacillin/tazobactam (85.2% S to ceftazidime/avibactam) or ceftazidime (79.2% S to ceftazidime/avibactam). MDR phenotype was observed among 36.3% of isolates, and 88.9% and 73.7% of MDR isolates were susceptible to ceftazidime/avibactam and ceftolozane/tazobactam, respectively. Against isolates non-susceptible to meropenem, piperacillin/tazobactam and ceftazidime, susceptibility rates were 78.9% for ceftazidime/avibactam and 47.4% for ceftolozane/tazobactam. Ceftazidime/avibactam was active against 65.4% of ceftolozane/tazobactam-non-susceptible isolates and ceftolozane/tazobactam was active against 18.2% of ceftazidime/avibactam-non-susceptible isolates. CONCLUSIONS: Ceftazidime/avibactam and ceftolozane/tazobactam exhibited potent and broad-spectrum activity against P. aeruginosa isolated from CF patients worldwide, but higher susceptibility rates for ceftazidime/avibactam compared with ceftolozane/tazobactam were observed among the resistant subsets. Ceftazidime/avibactam and ceftolozane/tazobactam represent valuable options to treat CF pulmonary exacerbations caused by P. aeruginosa.

Multidrug-resistant Pseudomonas aeruginosa from sputum of patients with cystic fibrosis demonstrates a high rate of susceptibility to ceftazidime-avibactam.

PURPOSE: Ceftazidime-avibactam is a novel antimicrobial combining a third-generation cephalosporin with a non-ß-lactam ß-lactamase inhibitor that was recently approved to treat Gram-negative hospital- and ventilator-acquired pneumonia. The use of ceftazidime-avibactam to treat Pseudomonas aeruginosa respiratory infections in patients with cystic fibrosis (CF) has not been evaluated. In this study, we assessed the ceftazidime-avibactam susceptibility of multidrug-resistant (MDR) P. aeruginosa sputum isolates from adults with CF. METHODS: Sputum was collected from individuals with CF, aged ≥18 years, known to be colonized with MDR P. aeruginosa, and tested for susceptibility to 11 different antipseudomonal antimicrobial agents. Isolates were included in the analysis if they were resistant to both ceftazidime and at least one agent in ≥3 different antimicrobial categories routinely used to treat P. aeruginosa. Subject demographics and clinical characteristics were collected. Ceftazidime-avibactam-resistant isolates were screened for the presence of ß-lactam-resistant mechanisms. RESULTS: Thirty-two P. aeruginosa isolates were analyzed, of which 23 isolates were sensitive to ceftazidime-avibactam (71.9%). Ten of the isolates were mucoid and 22 isolates were nonmucoid, both demonstrating >70% susceptibility to ceftazidime-avibactam. The most notable difference in the subjects with resistant strains was an older age and lower body mass index (BMI). Ceftazidime-avibactam-resistant strains showed elevated AmpC expression in >60% of the strains and loss of OprD detection in >70% of the strains. CONCLUSION: Ceftazidime-avibactam demonstrated a significant in vitro activity against highly resistant P. aeruginosa sputum isolates from individuals with CF. Further evaluation of the cause of resistance and clinical impact of ceftazidime-avibactam in CF patients with MDR P. aeruginosa is warranted.

Antimicrobial activity of oritavancin and comparator agents when tested against Gram-positive bacterial isolates causing infections in cancer patients (2014-16).

Objectives: The in vitro activity of oritavancin was assessed against clinically relevant Gram-positive pathogens causing infections in cancer patients in European and US hospitals. Methods: A total of 1357 Gram-positive cocci (GPC) were included. Isolates were predominantly from bloodstream infections (54.6%). The most frequently isolated GPC were Staphylococcus aureus (43.6%), CoNS (14.4%) and Enterococcus spp. (22.0%). Results: Oritavancin (99.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.015, 0.015-0.03 and 0.06 mg/L, respectively, when tested against S. aureus, regardless of methicillin susceptibility or geographical region. CoNS isolates from the USA demonstrated an MIC90 of oritavancin (MIC90, 0.12 mg/L) that was slightly higher than that for isolates from European countries (MIC90 0.06 mg/L). Oritavancin inhibited all Enterococcus faecalis and Enterococcus faecium, including VRE, at ≤ 0.25 mg/L. Oritavancin exhibited MIC50 results of 0.03 and 0.008-0.015 mg/L when tested against isolates of ß-haemolytic streptococci and viridans group streptococci, respectively, regardless of geographical region. Conclusions: Oritavancin had potent activity in vitro against this contemporary collection of European and US GPC isolates from cancer patients.

Ceftolozane-tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in Latin America: report from an antimicrobial surveillance program (2013-2015)

ABSTRACT This study evaluated the in vitro activity of ceftolozane-tazobactam and comparator agents tested against Latin American isolates of Enterobacteriaceae and Pseudomonas aeruginosa from patients with health care-associated infections. Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor.A total of 2415 Gram-negative organisms (537 P. aeruginosa and 1878 Enterobacteriaceae) were consecutively collected in 12 medical centers located in four Latin American countries. The organisms were tested for susceptibility by broth microdilution methods as described by the CLSI M07-A10 document and the results interpreted according to EUCAST and CLSI breakpoint criteria. Results: Ceftolozane-tazobactam (MIC50/90, 0.25/32 µg/mL; 84.2% susceptible) and meropenem (MIC50/90, ≤0.06/0.12 µg/mL; 92.6% susceptible) were the most active compounds tested against Enterobacteriaceae. Among the Enterobacteriaceae isolates tested, 6.6% were carbapenem-resistant Enterobacteriaceae and 26.4% exhibited an extended-spectrum β-lactamase non-carbapenem-resistant phenotype. Whereas ceftolozane-tazobactam showed good activity against extended-spectrum beta-lactamase, non-carbapenem-resistant phenotype strains of Enterobacteriaceae (MIC50/90, 0.5/>32 µg/mL), it lacked useful activity against strains with a (MIC50/90, >32/>32 µg/mL; 1.6% S) carbapenem-resistant phenotype. Ceftolozane-tazobactam was the most potent (MIC50//90, 0.5/16 µg/mL) β-lactam agent tested against P. aeruginosa isolates, inhibiting 86.8% at an MIC of ≤4 µg/mL. P. aeruginosa exhibited high rates of resistance to cefepime (16.0%), ceftazidime (23.6%), meropenem (28.3%), and piperacillin-tazobactam (16.4%). Conclusions: Ceftolozane-tazobactam was the most active β-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than available cephalosporins and piperacillin-tazobactam when tested against Enterobacteriaceae.

Antimicrobial activity of ceftazidime-avibactam and comparator agents when tested against bacterial isolates causing infection in cancer patients (2013-2014).

We evaluated the antimicrobial susceptibility of 623 Gram-negative organisms causing infection in patients with cancer in 52 United States hospitals (2013-2014) as part of the International Network for Optimal Resistance Monitoring (INFORM) program. Isolates were tested for susceptibility by broth microdilution method. ß-lactamase encoding genes were evaluated for all Escherichia coli and Klebsiella spp. with an extended-spectrum ß-lactamase (ESBL) phenotype by microarray-based assay. ESBL-phenotype was observed among 17.3 and 9.9% of E. coli and Klebsiella pneumoniae, respectively; and 25.0% of Enterobacter cloacae were ceftazidime-non-susceptible. All Enterobacteriaceae (n=486) were susceptible to ceftazidime-avibactam (MIC50/90, 0.12/0.25µg/mL) with the highest MIC value at 1µg/mL. Meropenem was active against Enterobacteriaceae overall (MIC50/90, ≤0.06/≤0.06µg/mL; 99.6% susceptible); but showed more limited activity against Klebsiella spp. with an ESBL-phenotype (84.6% susceptible) and multidrug-resistant Enterobacteriaceae (93.3% susceptible). The most active agents tested against Pseudomonas aeruginosa were colistin (100.0% susceptible), amikacin (97.7% susceptible) and ceftazidime-avibactam (96.6% susceptible).

Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses.

BACKGROUND: Candida auris, a multidrug-resistant yeast that causes invasive infections, was first described in 2009 in Japan and has since been reported from several countries. METHODS: To understand the global emergence and epidemiology of C. auris, we obtained isolates from 54 patients with C. auris infection from Pakistan, India, South Africa, and Venezuela during 2012-2015 and the type specimen from Japan. Patient information was available for 41 of the isolates. We conducted antifungal susceptibility testing and whole-genome sequencing (WGS). RESULTS: Available clinical information revealed that 41% of patients had diabetes mellitus, 51% had undergone recent surgery, 73% had a central venous catheter, and 41% were receiving systemic antifungal therapy when C. auris was isolated. The median time from admission to infection was 19 days (interquartile range, 9-36 days), 61% of patients had bloodstream infection, and 59% died. Using stringent break points, 93% of isolates were resistant to fluconazole, 35% to amphotericin B, and 7% to echinocandins; 41% were resistant to 2 antifungal classes and 4% were resistant to 3 classes. WGS demonstrated that isolates were grouped into unique clades by geographic region. Clades were separated by thousands of single-nucleotide polymorphisms, but within each clade isolates were clonal. Different mutations in ERG11 were associated with azole resistance in each geographic clade. CONCLUSIONS: C. auris is an emerging healthcare-associated pathogen associated with high mortality. Treatment options are limited, due to antifungal resistance. WGS analysis suggests nearly simultaneous, and recent, independent emergence of different clonal populations on 3 continents. Risk factors and transmission mechanisms need to be elucidated to guide control measures.

High Rates of Nonsusceptibility to Ceftazidime-avibactam and Identification of New Delhi Metallo-ß-lactamase Production in Enterobacteriaceae Bloodstream Infections at a Major Cancer Center.

Resistance to the novel ß-lactam/ß-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) among carbapenem-resistant Enterobacteriaceae (CRE) has infrequently been reported in the United States. We report unexpectedly high rates of resistance to CAZ-AVI in CRE bloodstream isolates at our institution associated with the nonoutbreak spread of New Delhi metallo-ß-lactamase in diverse Enterobacteriaceae species.

Susceptibility rates in Latin American nations: report from a regional resistance surveillance program (2011)

OBJECTIVE: To establish a resistance (R) surveillance program monitoring antimicrobial susceptibility patterns in Latin America (LATAM; Argentina [ARG], Brazil [BRA], Chile, Colombia [CBA], Costa Rica, Ecuador [ECU], Guatemala [GUA], Mexico [MEX], Panama [PAN], Peru, and Venezuela [VEN]). METHODS: In 2011, 4979 organisms were collected from 11 nations (20 laboratories) for susceptibility testing in a central laboratory design. Antimicrobials were tested by CLSI methods and results interpreted by CLSI and EUCAST breakpoints. Most common Gram-positive (Staphylococcus aureus [SA, 921], other staphylococci [CoNS; 299], enterococci [218], Streptococcus pneumoniae [SPN; 182], β-haemolytic streptococci [115]) and Gram-negative (E. coli [EC; 644], Klebsiella spp. [KSP; 517], Enterobacters [272], Pseudomonas aeruginosa [PSA; 586], Acinetobacters [ACB; 494]) pathogens were analyzed against linezolid (LZD), vancomycin (VAN), tigecycline (TIG), colistin (COL), cefoperazone/sulbactam (C/S), and amikacin (AMK). RESULTS: MRSA rates varied from 29% (CBA, BRA) to 79% (Peru); but LZD (MIC90, 2 mg/L), TIG (MIC90, 0.12mg/L) and VAN (MIC90, 1mg/L) covered all strains. Enterococci showed a 14% VRE rate, highest in BRA and MEX; all inhibited by TIG and daptomycin, but not LZD (three non-susceptible with G2576T mutations or cfr). Penicillin-R among SPN and viridans streptococci was 51.6 and 41.1%, respectively. LZD overall R against Gram-positives was 0.3%. High ESBL rates were observed in EC (54-71%) and KSP (>50%) from GUA, MEX and Peru, and six nations, respectively. Carbapenem-R in KSP was 9%, highest rates associated with KPC in BRA, CBA, ECU, PAN and VEN; also a NDM-1 in KSP from CBA. AMK, TIG, C/S and carbapenems were the broadest-spectrum agents tested against Enterobacteriaceae. Only COL inhibited >90% of PSA; COL and TIG (<2 mg/L) covered >85% of ACB. CONCLUSIONS: LATAM nations demonstrated variable levels of antimicrobial R especially among Enterobacteriaceae (β-lactamase-mediated), PSA and ACB. MRSA (48%), VRE (14%) and multidrug-R SPN were also regional therapeutic challenges.

Susceptibility rates in Latin American nations: report from a regional resistance surveillance program (2011).

OBJECTIVE: To establish a resistance (R) surveillance program monitoring antimicrobial susceptibility patterns in Latin America (LATAM; Argentina [ARG], Brazil [BRA], Chile, Colombia [CBA], Costa Rica, Ecuador [ECU], Guatemala [GUA], Mexico [MEX], Panama [PAN], Peru, and Venezuela [VEN]). METHODS: In 2011, 4979 organisms were collected from 11 nations (20 laboratories) for susceptibility testing in a central laboratory design. Antimicrobials were tested by CLSI methods and results interpreted by CLSI and EUCAST breakpoints. Most common Gram-positive (Staphylococcus aureus [SA, 921], other staphylococci [CoNS; 299], enterococci [218], Streptococcus pneumoniae [SPN; 182], ß-haemolytic streptococci [115]) and Gram-negative (E. coli [EC; 644], Klebsiella spp. [KSP; 517], Enterobacters [272], Pseudomonas aeruginosa [PSA; 586], Acinetobacters [ACB; 494]) pathogens were analyzed against linezolid (LZD), vancomycin (VAN), tigecycline (TIG), colistin (COL), cefoperazone/sulbactam (C/S), and amikacin (AMK). RESULTS: MRSA rates varied from 29% (CBA, BRA) to 79% (Peru); but LZD (MIC90, 2mg/L), TIG (MIC90, 0.12mg/L) and VAN (MIC90, 1mg/L) covered all strains. Enterococci showed a 14% VRE rate, highest in BRA and MEX; all inhibited by TIG and daptomycin, but not LZD (three non-susceptible with G2576T mutations or cfr). Penicillin-R among SPN and viridans streptococci was 51.6 and 41.1%, respectively. LZD overall R against Gram-positives was 0.3%. High ESBL rates were observed in EC (54-71%) and KSP (≥50%) from GUA, MEX and Peru, and six nations, respectively. Carbapenem-R in KSP was 9%, highest rates associated with KPC in BRA, CBA, ECU, PAN and VEN; also a NDM-1 in KSP from CBA. AMK, TIG, C/S and carbapenems were the broadest-spectrum agents tested against Enterobacteriaceae. Only COL inhibited >90% of PSA; COL and TIG (≤2mg/L) covered ≥85% of ACB. CONCLUSIONS: LATAM nations demonstrated variable levels of antimicrobial R especially among Enterobacteriaceae (ß-lactamase-mediated), PSA and ACB. MRSA (48%), VRE (14%) and multidrug-R SPN were also regional therapeutic challenges.

Update of contemporary antimicrobial resistance rates across China: reference testing results for 12 medical centers (2011).

Antimicrobial resistance (R) surveillance across Asia and especially in China has documented unique patterns and mechanisms. This 2011 study reports results for 2278 isolates from 12 hospitals in China (94-216 strains/site); most from bacteremia (20.4%), pneumonias (29.1%), or skin and skin structure infections (20.9%). Samples were tested by reference broth microdilution methods, interpreted by published susceptibility (S) breakpoints. The most common species were Staphylococcus aureus (343, 45.8% MRSA), Escherichia coli (EC; 288), Pseudomonas aeruginosa (PSA; 221), Klebsiella spp. (KSP; 208), acinetobacters (ACB; 178), enterobacters (155), Streptococcus pneumoniae (SPN; 154, 46.8% penicillin-S), and enterococci (ENT; 137). Among 849 Gram-positive (GP) cocci, linezolid, tigecycline (TIG), daptomycin, and vancomycin provided best antimicrobial coverage (≥99.7% S). Resistance patterns of concern were 0.3% VISA, 15.4% teicoplanin non-S coagulase-negative staphylococci, 1.5% vancomycin-R ENT (all Enterococcus faecium), 1.9% levofloxacin-R ß-haemolytic streptococci, and 35.1 and 12.7% ceftriaxone-non-S rates for SPN and viridans group streptococci, respectively. For Gram-negative bacilli, R among Enterobacteriaceae was highest against ß-lactams (extended spectrum ß-lactamase-phenotype strains at 73.6 and 42.8% in EC and KSP, respectively; carbapenem-R was only 2.1-4.3% with KPC and IMP type enzymes detected in KSP). The widest spectrum agents were cefoperazone/sulbactam (79.5-86.1%), piperacillin/tazobactam (88.9-92.0%), TIG (98.6-100%), amikacin (AMK; 91.8-93.7%), and meropenem (95.7-97.1% S). PSA was most inhibited by AMK (90.5% S) and colistin (COL; 99.5%), with cefepime (67.9%) best among the tested ß-lactams. Only COL (100% S) and TIG (MIC90, 2 µg/mL) showed significant potencies against ACB. In conclusion, R among pathogens from 12 Chinese hospitals illustrates several agents active against GP pathogens, but more serious R problems were noted among Enterobacteriaceae, PSA, and ACB. Combination treatment for the latter multidrug-R strains appears necessary, guided by local antibiograms and national surveillance results applying reference methods.

Trends in Klebsiella pneumoniae carbapenemase-positive K. pneumoniae in US hospitals: report from the 2007-2009 SENTRY Antimicrobial Surveillance Program.

We report the prevalence of carbapenemase-positive Klebsiella pneumoniae among clinical isolates collected from US medical centers (n = 42) from 2007-2009 through the SENTRY Antimicrobial Surveillance Program. Isolates with imipenem or meropenem MIC ≥ 2 µg/mL were screened by PCR for various carbapenemase genes. Of 2049 K. pneumoniae isolates, 126 (6.1%) were non-susceptible to imipenem or meropenem. blaKPC was identified in 113 isolates (5.5%). No other carbapenemase genes were identified. For US regions combined, prevalence of K. pneumoniae carbapenemase (KPC)-positive isolates were 5.9% in 2007, 4.9% in 2008, and 5.7% in 2009. Rates were highest in the Mid-Atlantic region (28.6% overall), with fluctuation over time (29%, 23%, and 33% from 2007-2009), followed by the East North Central region (2.4% overall), with a slightly increasing trend (nil, 3.1%, 3.8% from 2007-2009). All KPC-positive organisms were carbapenem non-susceptible according to updated CLSI breakpoints, although all but one was similarly classified according to previous breakpoints.

Metalo-beta-lactamases / Metallo-beta-lactamases

Nos últimos anos tem sido observada maior incidência de bacilos Gram-negativos resistentes a cefalosporinas de espectro ampliado no ambiente hospitalar, ocasionando, assim, maior uso de betalactâmicos mais potentes, como os carbapenens. A utilização de carbapenens exerce maior pressão seletiva sobre a microbiota hospitalar, o que pode ocasionar aumento da resistência a esses agentes. Entre os mecanismos de resistência a carbapenens mais comumente identificados estão a produção de betalactamases, como, por exemplo, as pertencentes à classe D de Ambler e as que pertencem à classe B de Ambler, ou metalo-beta-lactamases (MbetaL). Essas últimas hidrolisam todos betalactâmicos comercialmente disponíveis, sendo a única exceção o monobactam aztreonam. Desde o início da década de 1990, novos genes que codificam MbetaLs têm sido descritos em microrganismos clinicamente importantes, como Pseudomonas spp., Acinetobacter spp. e membros da família Enterobacteriaceae. O encontro desses microrganismos não-sensíveis a carbapenens pode ser submetido a metodologias fenotípicas para detecção da produção de MbetaL com o intuito de auxiliar a Comissão de Controle de Infecção Hospitalar (CCIH) e prevenir a disseminação desses determinantes de resistência, uma vez que genes que codificam MbetaLs estão contidos em estruturas genéticas que propiciam sua mobilidade de forma muito efetiva, sendo então facilmente disseminados.