Reanalysis of cefazolin surrogate susceptibility breakpoints utilized as guidances for oral cephalosporin treatments of uncomplicated urinary tract infections: caution concerning application to cefadroxil.

Based on antimicrobial susceptibility test interpretive breakpoint criteria from Clinical and Laboratory Standards Institute and United States Committee on Antimicrobial Susceptibility Testing, cefazolin uncomplicated urinary tract infection (uUTI) surrogate breakpoints do not accurately predict cefadroxil or cephradine susceptibility when testing indicated Enterobacteriaceae species isolates. Hence, these two orally-administered cephalosporins (OC) are not equivalent spectrum substitutes for cephalexin or six other related OC agents for contemporary uUTI therapy.

Activity of Plazomicin Tested against Enterobacterales Isolates Collected from U.S. Hospitals in 2016-2017: Effect of Different Breakpoint Criteria on Susceptibility Rates among Aminoglycosides.

Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.

Changes in the Frequencies of ß-Lactamase Genes among Enterobacteriaceae Isolates in U.S. Hospitals, 2012 to 2014: Activity of Ceftazidime-Avibactam Tested against ß-Lactamase-Producing Isolates.

Among 15,588 Enterobacteriaceae isolates collected in 63 U.S. hospitals from 2012 to 2014, 2,129 (13.7%) displayed an extended-spectrum ß-lactamase (ESBL) phenotype. These rates were similar over time (13.2 to 13.9%); however, differences among Escherichia coli (12.7 and 15.1% in 2012 and 2014; P = 0.007) and Klebsiella pneumoniae (18.9 and 15.5% in 2012 and 2014; P = 0.006) were noted when comparing 2014 and 2012. Carbapenem-resistant Enterobacteriaceae (CRE) (2.3 and 1.8%) and carbapenem-resistant K. pneumoniae (6.8 and 5.1%; P = 0.003) rates were lower in 2014 than in 2012. Isolates carrying blaCTX-M-15-like genes were stable (42.1 to 42.4%), but a decrease among E. coli isolates (59.1 and 49.7%; P = 0.008) and an increase among K. pneumoniae isolates (32.7 and 41.2%; P = 0.022) in 2014 were observed. Isolates carrying blaKPC (304) decreased over the years (16.5 and 10.9%; P = 0.008), mainly due to the decrease in K. pneumoniae isolates harboring blaKPC (n = 285; 35.6 and 28.4%; P = 0.041) in hospitals in the Mid-Atlantic and South Atlantic regions, where these isolates were highly prevalent during 2012 and 2013. Isolates carrying blaCMY-2-like and blaCTX-M-14-like genes increased (8.2 and 11.9% and 9.1 and 12.9%, respectively; P = 0.04 for both), and those producing blaSHV ESBL decreased (24.9 and 12.7%; P < 0.001) over the studied years, due to a decreased occurrence of the enzymes among K. pneumoniae isolates. Other enzymes were detected in smaller numbers of isolates, including four K. pneumoniae isolates carrying blaNDM-1 metallo-ß-lactamase (two in 2012 and two in 2014). Ceftazidime-avibactam, a recently approved ß-lactamase inhibitor combination, was very active against the ESBL phenotype isolates (MIC50/90, 0.12 and 1 µg/ml; 99.7% susceptible) and CRE strains (MIC50/90, 0.5 and 2 µg/ml; 98.5% susceptible) that displayed elevated MIC values for many comparator agents. In conclusion, significant changes were noted in the frequencies of isolates harboring various ß-lactamases among U.S. hospitals between 2012 and 2014 that will require continued monitoring.

Antimicrobial Activities of Ceftazidime-Avibactam and Comparator Agents against Gram-Negative Organisms Isolated from Patients with Urinary Tract Infections in U.S. Medical Centers, 2012 to 2014.

A total of 7,272 unique patient clinical isolates were collected from 71 U.S. medical centers from patients with urinary tract infections in 2012 to 2014 and tested for susceptibility to ceftazidime-avibactam and comparators by broth microdilution methods. Ceftazidime-avibactam inhibited >99.9% of all Enterobacteriaceae at the susceptible breakpoint of ≤8 µg/ml (there were only three nonsusceptible strains). Ceftazidime-avibactam was also active against Pseudomonas aeruginosa isolates (MIC50, 2 µg/ml; MIC90, 4 µg/ml; 97.7% susceptible), including many isolates not susceptible to meropenem, ceftazidime, and/or piperacillin-tazobactam.

Ceftazidime-Avibactam Activity against Aerobic Gram Negative Organisms Isolated from Intra-Abdominal Infections in United States Hospitals, 2012-2014.

BACKGROUND: Ceftazidime-avibactam is ceftazidime combined with the novel non-ß-lactam ß-lactamase inhibitor avibactam, which inhibits Ambler class A (e.g., extended-spectrum ß-lactamase [ESBL] and KPC), class C, and some class D enzymes. We evaluated the activity of ceftazidime-avibactam against aerobic gram negative bacteria causing intra-abdominal infections (IAI). METHODS: A total of 1,540 isolates were collected, one each from patient, with IAI in 57 United States hospitals in 2012-2014. Susceptibility testing was performed by reference broth microdilution methods, and Enterobacteriaceae isolates with an ESBL phenotype were evaluated by a microarray-based assay for the presence of genes encoding the CTX-M, TEM, SHV, KPC, NDM, and transferable AmpC enzymes. RESULTS: All Escherichia coli isolates were susceptible to ceftazidime-avibactam, whereas the susceptibility rates for meropenem, piperacillin-tazobactam, and gentamicin were 99.8%, 93.6%, and 85.5%, respectively. Among Klebsiella pneumoniae isolates, the highest ceftazidime-avibactam minimum inhibitory concentration (MIC) value was only 2 mcg/mL (MIC50/90 0.12/0.25 mcg/mL; 100% susceptible), whereas susceptibility rates to meropenem and gentamicin were 94.5% and 91.9%, respectively. The ESBL-phenotype rates among E. coli and K. pneumoniae were 15.8% and 13.3%, respectively. Overall, only one Enterobacteriaceae isolate (Enterobacter cloacae) was not susceptible to ceftazidime-avibactam and had negative results for all ß-lactamases tested. Against Pseudomonas aeruginosa, ceftazidime-avibactam (MIC50/90 2/4 mcg/mL; 97.1% susceptible) and amikacin (MIC50/90 2/8 mcg/mL; 99.0% susceptible) were the most active compounds, and ceftazidime-avibactam retained activity against many meropenem-non-susceptible (88.6% susceptible) and piperacillin-tazobactam-non-susceptible (82.9% susceptible) strains. CONCLUSION: Ceftazidime-avibactam coverage (98.7% inhibited at ≤8 mcg/mL) of intra-abdominal infection pathogens was greater than that observed for meropenem (95.7% susceptible) and piperacillin-tazobactam (88.4% susceptible).

In vitro activity of ceftazidime/avibactam against Gram-negative pathogens isolated from pneumonia in hospitalised patients, including ventilated patients.

The activities of the novel ß-lactam/non-ß-lactam ß-lactamase inhibitor combination ceftazidime/avibactam and comparators were evaluated against isolates from pneumonia in hospitalised patients including ventilated patients (PHP, pneumonia not designated as VABP; VABP, pneumonia in ventilated patients). Isolates were from the European-Mediterranean region (EuM), China and the USA collected in the SENTRY Antimicrobial Surveillance Program between 2009 and 2011 inclusive. A total of 2393 organisms from PHP were from the EuM, 888 from China and 3213 from the USA; from VABP patients there were 918, 97 and 692 organisms collected, respectively. Among Enterobacteriaceae from PHP, ceftazidime/avibactam MIC90 values against Escherichia coli ranged from 0.25-0.5mg/L and Klebsiella spp. MIC90 values were 0.5mg/L in each region. Among VABP isolates, MIC90 values for ceftazidime/avibactam against E. coli were 0.25mg/L; for Klebsiella spp. from VABP patients, MIC90 values were similar to those obtained against PHP isolates. The MIC of ceftazidime/avibactam was ≤8mg/L against 92-96% of Pseudomonas aeruginosa isolated from PHP patients. Isolates of P. aeruginosa from VABP patients were of lower susceptibility to all antibacterial agents (e.g. depending on region, meropenem susceptibilities were 51.2-69.4% in contrast to 68.3-76.7% among PHP patients). However, ceftazidime/avibactam inhibited 79.2-95.4% of VABP isolates at an MIC of ≤8mg/L. Acinetobacter spp. were resistant to many agents and only rates of susceptibility to colistin were >90% across all regions both for PHP and VABP isolates. Ceftazidime/avibactam was generally active against a high proportion of isolates resistant to ceftazidime from PHP and VAPB patients.

Linezolid Surveillance Results for the United States (LEADER Surveillance Program 2014).

Thelinezolidexperience andaccuratedetermination ofresistance (LEADER) surveillance program has monitored linezolid activity, spectrum, and resistance since 2004. In 2014, a total of 6,865 Gram-positive pathogens from 60 medical centers from 36 states were submitted. The organism groups evaluated wereStaphylococcus aureus(3,106), coagulase-negative staphylococci (CoNS; 797), enterococci (855),Streptococcus pneumoniae(874), viridans group streptococci (359), and beta-hemolytic streptococci (874). Susceptibility testing was performed by reference broth microdilution at the monitoring laboratory. Linezolid-resistant isolates were confirmed by repeat testing. PCR and sequencing were performed to detect mutations in 23S rRNA, L3, L4, and L22 proteins and acquired genes (cfrandoptrA). The MIC50/90forStaphylococcus aureuswas 1/1 µg/ml, with 47.2% of isolates being methicillin-resistantStaphylococcus aureus Linezolid was active against allStreptococcus pneumoniaestrains and beta-hemolytic streptococci with a MIC50/90of 1/1 µg/ml and against viridans group streptococci with a MIC50/90of 0.5/1 µg/ml. Among the linezolid-nonsusceptible MRSA strains, one strain harboredcfronly (MIC, 4 µg/ml), one harbored G2576T (MIC, 8 µg/ml), and one containedcfrand G2576T with L3 changes (MIC, ≥8 µg/ml). Among CoNS, 0.75% (six isolates) of all strains demonstrated linezolid MIC results of ≥4 µg/ml. Five of these were identified asStaphylococcus epidermidis, four of which containedcfrin addition to the presence of mutations in the ribosomal proteins L3 and L4, alone or in combination with 23S rRNA (G2576T) mutations. Six enterococci (0.7%) were linezolid nonsusceptible (≥4 µg/ml; five with G2576T mutations, including one with an additionalcfrgene, and one strain withoptrAonly). Linezolid demonstrated excellent activity and a sustained susceptibility rate of 99.78% overall.

Klebsiella pneumoniae Isolate from a New York City Hospital Belonging to Sequence Type 258 and Carrying blaKPC-2 and blaVIM-4.

Among 69 of 139 (49.6%) carbapenem-nonsusceptible Enterobacteriaceae carrying blaKPC, 1 Klebsiella pneumoniae was also positive for blaVIM. The isolate belonged to sequence type 258 (ST258) and carried blaKPC-2 on a copy of Tn4401a and blaVIM-4 on a class 1 integron. Genes were located on distinct plasmids belonging to Inc types A/C and FII. Elevated expression of the efflux pump AcrAB-TolC (acrA, 15.3 times) and reduced expression of outer membrane protein genes ompK35 and ompK37 (0.16 and 0.081 times, respectively) associated with various amino acid alterations on OmpK37 were observed. The presence of two carbapenemases in ST258 K. pneumoniae is of great concern due to the ability of this organism to widely disseminate.

Genotypic Characterization of Methicillin-Resistant Staphylococcus aureus Recovered at Baseline from Phase 3 Pneumonia Clinical Trials for Ceftobiprole.

Baseline methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with nosocomial and community-acquired pneumonia collected during Phase 3 trials for ceftobiprole were characterized. Eighty-four unique isolates from patients enrolled in Europe (50.0%), Asia-Western Pacific region (APAC; 20.2%), North America (19.0%), Latin America (8.3%), and South Africa (2.4%) were included. Antimicrobial susceptibility testing was performed by broth microdilution and isolates screened for Panton-Valentine leukocidin. SCCmec and agr types were determined. Strains were subjected to pulsed-field gel electrophoresis and spa typing. Clonal complexes (CCs) were assigned based on spa and/or multilocus sequence typing. Most isolates were CC5-MRSA-I/II/IV (44.0%; 37/84), followed by CC8-MRSA-IV (22.6%; 19/84) and CC239-MRSA-III (21.4%; 18/84). Other MRSA formed seven clonal clusters. Isolates from North America were associated with USA100, while those from South America belonged to the Cordobes/Chilean CC. A greater clonal diversity was observed in Europe; however, each country had CC5, CC8, or CC239 as prevalent lineages. Isolates from APAC were CC5-MRSA-II (47.1%; 8/17) or CC239-MRSA-III (47.1%; 8/17). Isolates carrying SCCmec I and III had ceftobiprole MIC50 values of 2 µg/ml, while those isolates with SCCmec II and IV had MIC50 values of 1 µg/ml. Ceftobiprole inhibited 96% and 100.0% of the isolates at ≤ 2 and ≤ 4 µg/ml, respectively. These isolates represented common circulating MRSA clones. Ceftobiprole demonstrated in vitro activity with a slight variation of minimum inhibitory concentrations (MICs) according to SCCmec or clonal type.

ß-Lactamase Characterization of Gram-Negative Pathogens Recovered from Patients Enrolled in the Phase 2 Trials for Ceftazidime-Avibactam: Clinical Efficacies Analyzed against Subsets of Molecularly Characterized Isolates.

The correlation of the clinical efficacies of ceftazidime-avibactam and comparators (carbapenems) was evaluated against baseline Gram-negative isolates having characterized ß-lactam resistance mechanisms from complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) phase 2 trials. Enterobacteriaceae displaying ceftriaxone and/or ceftazidime MICs of ≥ 2 µg/ml (69 isolates) and nonfermentative Gram-negative bacilli (NF-GNB [three isolates]) with ceftazidime MICs of ≥ 16 µg/ml were characterized for their narrow- and extended-spectrum ß-lactamase (ESBL) content. Enterobacteriaceae (one isolate) and NF-GNB (three isolates) with imipenem/meropenem MICs of ≥ 2 and ≥ 16 µg/ml, respectively, were tested for carbapenemases. All cUTI E. coli had the lineage background investigated (ST131-like versus non-ST131-like). The primary efficacy endpoint was microbiological response (eradication) at test of cure (TOC) for cUTI and clinical response (inferred microbiological eradication) at TOC for cIAI. A total of 34.1% of baseline cUTI (36.4%) and cIAI (33.1%) pathogens met the MIC-based screening criteria (screen positive). All screen-positive cUTI pathogens were CTX-M-producing E. coli, except for one E. cloacae isolate with AmpC overexpression. The majority (66.7%) of screen-positive cIAI isolates produced CTX-M-type coupled with a diverse array of other ß-lactamases. Similar favorable responses were observed with ceftazidime-avibactam (93.3%) and carbapenems (90.9%), when a non-ESBL Enterobacteriaceae isolate was recovered at the baseline visit. When an ESBL Enterobacteriaceae isolate was present, the favorable responses were 85.7% and 80.0% with ceftazidime-avibactam and carbapenems, respectively. Higher favorable responses were observed with ceftazidime-avibactam (75.0%) than with carbapenems (66.7%) when an ST131-like E. coli isolate was recovered at baseline, as when a non-ST131-like isolate was present (93.8% versus 86.7%, respectively). The efficacy of ceftazidime-avibactam was similar to that of carbapenems for treatment of cUTI and cIAI caused by ESBL organisms.

Ceftaroline: clinical and microbiology experience with focus on methicillin-resistant Staphylococcus aureus after regulatory approval in the USA.

Ceftaroline fosamil was approved in 2010 by the United States Food and Drug Administration (USA-FDA) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). After approval, several studies and case reports have described the postmarketing clinical experience with ceftaroline in ABSSSIs and CABP and in patients with invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, many of whom had failed prior antibiotics. Successful clinical outcomes observed among the majority of these patients were supported by preapproval and postapproval in vitro surveillance of ceftaroline activity using breakpoint criteria that have been harmonized between the USA-FDA and CLSI. MIC90 values/percentage of strains susceptible to ceftaroline has remained stable over the period 2009-2012. Taken together, these postapproval studies support the use of ceftaroline for ABSSSI as well as CABP. Importantly, these data also suggest that ceftaroline can be effective in patients with serious invasive MRSA infections who have failed other therapies.

Baseline activity of telavancin against Gram-positive clinical isolates responsible for documented infections in U.S. hospitals (2011-2012) as determined by the revised susceptibility testing method.

Telavancin had MIC50 and MIC90 values of 0.03 and 0.06 µg/ml (100.0% susceptible), respectively, against methicillin-resistant and -susceptible Staphylococcus aureus. Telavancin was active against vancomycin-susceptible Enterococcus faecalis (MIC50/90, 0.12/0.12 µg/ml; 100% susceptible) and Enterococcus faecium (MIC50/90, 0.03/0.06 µg/ml), while higher MIC values were obtained against vancomycin-resistant E. faecium (MIC50/90, 1/2 µg/ml) and E. faecalis (MIC50/90, >2/>2 µg/ml). Streptococci showed telavancin modal MIC results of ≤ 0.015 µg/ml, except against Streptococcus agalactiae (i.e., 0.03 µg/ml). This study reestablishes the telavancin spectrum of activity against isolates recovered from the United States (2011-2012) using the revised broth microdilution method.

Update on Acinetobacter species: mechanisms of antimicrobial resistance and contemporary in vitro activity of minocycline and other treatment options.

Among Acinetobacter species, A. baumannii and other closely related species are commonly implicated in nosocomial infections. These organisms are usually multidrug resistant (MDR), and therapeutic options to treat A. baumannii infections are very limited. Clinicians have been resorting to older antimicrobial agents to treat infections caused by MDR A. baumannii, and some of these agents have documented toxicity and/or are not optimized for the infection type to be treated. Recent clinical experience supported by antimicrobial susceptibility data suggests that minocycline has greater activity than other tetracyclines and glycylcyclines against various MDR pathogens that have limited therapeutic options available, including Acinetobacter species. An intravenous formulation of minocycline has recently become available for clinical use, and in contrast to most older tetracyclines, minocycline has high activity against Acinetobacter species. In this report, we summarized some of the characteristics of the tetracycline class, and quantified the minocycline activity against contemporary (2007-2011) isolates and its potential therapeutic role against a collection of 5477 A. baumannii and other relevant gram-negative organisms when compared directly with tetracycline, doxycycline, and other broad-spectrum antimicrobial agents. Acinetobacter baumannii strains were highly resistant to all agents tested, with the exception of minocycline (79.1% susceptible) and colistin (98.8% susceptible). Minocycline (minimum inhibitory concentration that inhibits 50% and 90% of the isolates [MIC(50/90)]: 1/8 µg/mL) displayed greater activity than doxycycline (MIC(50/90): 2/>8 µg/mL) and tetracycline hydrochloride (HCL) (only 30.2% susceptible) against A. baumannii isolates, and was significantly more active than other tetracyclines against Burkholderia cepacia, Escherichia coli, Serratia marcescens, and Stenotrophomonas maltophilia isolates. In vitro susceptibility testing using tetracycline HCL as a surrogate for the susceptibility other tetracyclines fails to detect minocycline-susceptible isolates and the potential utility of minocycline for the treatment of many MDR A. baumannii infections and other difficult-to-treat species, where there are often limited choices of antimicrobials.

Linezolid update: stable in vitro activity following more than a decade of clinical use and summary of associated resistance mechanisms.

Linezolid, approved for clinical use since 2000, has become an important addition to the anti-Gram-positive infection armamentarium. This oxazolidinone drug has in vitro and in vivo activity against essentially all Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The in vitro activity of linezolid was well documented prior to its clinical application, and several ongoing surveillance studies demonstrated consistent and potent results during the subsequent years of clinical use. Emergence of resistance has been limited and associated with invasive procedures, deep organ involvement, presence of foreign material and mainly prolonged therapy. Non-susceptible organisms usually demonstrate alterations in the 23S rRNA target, which remain the main resistance mechanism observed in enterococci; although a few reports have described the detection of cfr-mediated resistance in Enterococcus faecalis. S. aureus isolates non-susceptible to linezolid remain rare in large surveillance studies. Most isolates harbour 23S rRNA mutations; however, cfr-carrying MRSA isolates have been observed in the United States and elsewhere. It is still uncertain whether the occurrences of such isolates are becoming more prevalent. Coagulase-negative isolates (CoNS) resistant to linezolid were uncommon following clinical approval. Surveillance data have indicated that CoNS isolates, mainly Staphylococcus epidermidis, currently account for the majority of Gram-positive organisms displaying elevated MIC results to linezolid. In addition, these isolates frequently demonstrate complex and numerous resistance mechanisms, such as alterations in the ribosomal proteins L3 and/or L4 and/or presence of cfr and/or modifications in 23S rRNA. The knowledge acquired during the past decades on this initially used oxazolidinone has been utilized for developing new candidate agents, such as tedizolid and radezolid, and as linezolid patents soon begin to expire, generic brands will certainly become available. These events will likely establish a new chapter for this successful class of antimicrobial agents.

Antimicrobial susceptibility of Gram-negative organisms isolated from patients hospitalised with pneumonia in US and European hospitals: results from the SENTRY Antimicrobial Surveillance Program, 2009-2012.

Here we evaluated the frequency of occurrence and antimicrobial susceptibility patterns of Gram-negative bacteria isolated from patients hospitalised with pneumonia in medical centres in the USA (n=28) and Europe and the Mediterranean region (EMR) (n=25) in 2009-2012. Susceptibility testing was performed by reference broth microdilution methods. Overall, 12851 isolates were collected (6873/5978 in USA/EMR). The same top 11 organisms were observed in both geographic regions, but in different rank orders, and Gram-negative organisms represented 61.5/76.1% of strains in USA/EMR. Pseudomonas aeruginosa was the most frequently isolated Gram-negative organism in both regions (20.9/20.9% of cases in USA/EMR) and showed reduced susceptibility to most antimicrobials tested, including ceftazidime (79.6/68.7% susceptibility in USA/EMR), meropenem (76.3/65.8%) and piperacillin/tazobactam (72.9/63.9%). Klebsiella spp. was isolated from 9.7/11.6% of cases and showed extended-spectrum ß-lactamase (ESBL) phenotype rates of 19.5/35.1% in USA/EMR. Meropenem and amikacin were active against 62.3/78.7% and 60.8/85.2% of ESBL phenotype Klebsiella spp. from USA/EMR, respectively. Enterobacter spp. ranked fourth in the USA (5.9%) and sixth in EMR (5.5%), whereas Escherichia coli ranked fifth in the USA (5.5%) and third in EMR (11.8%). Acinetobacter spp. and Stenotrophomonas maltophilia combined were isolated from 8.0/10.7% of cases in USA/EMR. A significant increase in P. aeruginosa susceptibility to meropenem and a significant decrease in gentamicin susceptibility among Klebsiella spp. were noted in EMR. These results confirm that very few agents remain broadly active against the most frequently isolated Gram-negative organisms from patients with pneumonia in US and EMR medical centres.

Variation in potency and spectrum of tigecycline activity against bacterial strains from U.S. medical centers since its approval for clinical use (2006 to 2012).

Tigecycline was initially approved by the U.S. Food and Drug Administration (FDA) in June 2005. We assessed the evolution of tigecycline in vitro activities since the initial approval of tigecycline for clinical use by analyzing the results of 7 years (2006 to 2012) of data from the SENTRY Antimicrobial Surveillance Program in the United States. We also analyzed trends over time for key resistance phenotypes. The analyses included 68,608 unique clinical isolates collected from 29 medical centers and tested for susceptibility using reference broth microdilution methods. Tigecycline was highly active against Gram-positive organisms, with MIC50 and MIC90 values of 0.12 and 0.25 µg/ml for Staphylococcus aureus (28,278 strains; >99.9% susceptible), 0.06 to 0.12 and 0.12 to 0.25 µg/ml for enterococci (99.3 to 99.6% susceptible), and ≤0.03 and ≤0.03 to 0.06 µg/ml for streptococci (99.9 to 100.0% susceptible), respectively. When tested against 20,457 Enterobacteriaceae strains, tigecycline MIC50 and MIC90 values were 0.25 and 1 µg/ml, respectively (98.3% susceptible using U.S. FDA breakpoints). No trend toward increasing tigecycline resistance (nonsusceptibility) was observed for any species or group during the study period. The prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae increased from 4.4 and 0.5%, in 2006 to 8.5 and 1.5% in 2012, respectively. During the same period, the prevalence of Escherichia coli and Klebsiella spp. with an extended-spectrum ß-lactamase (ESBL) phenotype increased from 5.8 and 9.1% to 11.1 and 20.4%, respectively, whereas rates of meropenem-nonsusceptible Klebsiella pneumoniae escalated from 2.2% in 2006 to 10.8% in 2012. The results of this investigation show that tigecycline generally retained potent activities against clinically important organisms isolated in U.S. institutions, including MDR organism subsets of Gram-positive and Gram-negative pathogens.

Contemporary diversity of ß-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent ß-lactamase groups.

Escherichia coli (328 isolates), Klebsiella pneumoniae (296), Klebsiella oxytoca (44), and Proteus mirabilis (33) isolates collected during 2012 from the nine U.S. census regions and displaying extended-spectrum-ß-lactamase (ESBL) phenotypes were evaluated for the presence of ß-lactamase genes, and antimicrobial susceptibility profiles were analyzed. The highest ESBL rates were noted for K. pneumoniae (16.0%, versus 4.8 to 11.9% for the other species) and in the Mid-Atlantic and West South Central census regions. CTX-M group 1 (including CTX-M-15) was detected in 303 strains and was widespread throughout the United States but was more prevalent in the West South Central, Mid-Atlantic, and East North Central regions. KPC producers (118 strains [112 K. pneumoniae strains]) were detected in all regions and were most frequent in the Mid-Atlantic region (58 strains). Thirteen KPC producers also carried blaCTX-M. SHV genes encoding ESBL activity were detected among 176 isolates. Other ß-lactamase genes observed were CTX-M group 9 (72 isolates), FOX (10), TEM ESBL (9), DHA (7), CTX-M group 2 (3), NDM-1 (2 [Colorado]), and CTX-M groups 8 and 25 (1). Additionally, 62.9% of isolates carried ≥2 ß-lactamase genes. KPC producers were highly resistant to multiple agents, but ceftazidime-avibactam (MIC50/90, 0.5/2 µg/ml) and tigecycline (MIC50/90, 0.5/1 µg/ml) were the most active agents tested. Overall, meropenem (MIC50, ≤0.06 µg/ml), ceftazidime-avibactam (MIC50, 0.12 to 0.5 µg/ml), and tigecycline (MIC50, 0.12 to 2 µg/ml) were the most active antimicrobials when tested against this collection. NDM-1 producers were resistant to all ß-lactams tested. The diversity and increasing prevalence of ß-lactamase-producing Enterobacteriaceae have been documented, and ceftazidime-avibactam was very active against the vast majority of ß-lactamase-producing strains isolated from U.S. hospitals.

Pharmacological basis of ß-lactamase inhibitor therapeutics: tazobactam in combination with Ceftolozane.

We recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of blaCTX-M-15. The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single ß-lactamase enzyme and that clinical isolates typically produce multiple ß-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in an in vitro PK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized ß-lactamase-producing E. coli strains with variable enzyme expression and other resistance determinants. As evidenced by r(2) values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log10 CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolate's ceftolozane-tazobactam MIC value and 0.5. As evidenced by an r(2) value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log10 CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized ß-lactamase-producing Klebsiella pneumoniae strains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the four E. coli isolates performed well for the expanded data set (seven isolates in total; four E. coli and three K. pneumoniae), as evidenced by an r(2) value of 0.84. This simple translational relationship is especially useful as it is directly linked to in vitro susceptibility test results, which are used to guide the clinician's choice of drug and dosing regimen.

Regional resistance surveillance program results for 12 Asia-Pacific nations (2011).

The Regional Resistance Surveillance program monitored susceptibility rates and developing resistance by geographic region, including 12 Asia-Pacific (APAC) countries. Reference broth microdilution methods for susceptibility/interpretations were applied, processing 5,053 strains. Among Staphylococcus aureus isolates (37% methicillin-resistant S. aureus [MRSA], highest in South Korea [73%]), linezolid (LZD), tigecycline (TIG), and vancomycin were 100% active, but 33 and 34% of strains were levofloxacin (LEV) or macrolide resistant, respectively. Streptococcus pneumoniae was most resistant to ß-lactams and macrolides (45%) but was LZD, LEV, and TIG susceptible (>98%). Extended-spectrum ß-lactamase (ESBL) phenotype rates in Escherichia coli and Klebsiella spp. were 48 and 47%, respectively, and were highest in Taiwan, at 75 to 91%. The best anti-ESBL-phenotype agents were amikacin (81 to 96% susceptible), colistin (COL; >98%), TIG (>98%), and carbapenems (81 to 97%). Pseudomonas aeruginosa showed ≥20% resistance to all drugs except COL (99% susceptible). In conclusion, endemic evolving antimicrobial resistances in APAC nations show compromised roles for many commonly used antimicrobials.

Characterization of methicillin-resistant Staphylococcus aureus strains recovered from a phase IV clinical trial for linezolid versus vancomycin for treatment of nosocomial pneumonia.

A total of 434 methicillin-resistant Staphylococcus aureus (MRSA) baseline isolates were collected from subjects enrolled in a prospective, double-blind randomized trial comparing linezolid versus vancomycin for the treatment of nosocomial pneumonia. Isolates were susceptibility tested by broth microdilution, examined for inducible clindamycin resistance by D-test, and screened for heterogeneous resistance to vancomycin (hVISA) by the Etest macromethod. All strains were subjected to Panton-Valentine leukocidin (PVL) screening, and SCCmec, pulsed-field gel electrophoresis (PFGE), and spa typing. Selected strains were evaluated by multilocus sequence typing (MLST). Clonal complexes (CCs) were assigned based on the spa and/or MLST results. Most strains were CC5 (56.0%), which originated from North America (United States) (CC5-MRSA-SCCmec II/IV; 70.0%), Asia (CC5-MRSA-II; 14.0%) and Latin America (CC5-MRSA-I/II; 12.3%). The second- and third-most-prevalent clones were CC8-MRSA-IV (23.3%) and CC239-MRSA-III (11.3%), respectively. Furthermore, the CC5-MRSA-I/II clone predominated in Asia (50.7% within this region) and Latin America (66.7%), followed by CC239-MRSA-III (32.8% and 28.9%, respectively). The European strains were CC8-MRSA-IV (34.5%), CC22-MRSA-IV (18.2%), or CC5-MRSA-I/II/IV (16.4%), while the U.S. MRSA isolates were CC5-MRSA-II/IV (64.4%) or CC8-MRSA-IV (28.8%). Among the U.S. CC8-MRSA-II/IV strains, 73.7% (56/76 [21.2% of all U.S. MRSA strains]) clustered within USA300. One strain from the United States (USA800) was intermediate to vancomycin (MIC, 4 µg/ml). All remaining strains were susceptible to linezolid, daptomycin, vancomycin, and teicoplanin. hVISA strains (14.5%) were predominantly CC5-MRSA-II, from South Korea, and belonged to a single PFGE type. Overall, each region had two predominant clones. The USA300 rate corroborates previous reports describing increased prevalence of USA300 strains causing invasive infections. The prevalence of hVISA was elevated in Asia, and these strains were associated with CC5.