Pharmacokinetics and Pharmacodynamics of High-Dose Piperacillin-Tazobactam in Obese Patients.

BACKGROUND AND OBJECTIVE: Standard piperacillin-tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics and pharmacodynamics of standard- and high-dose P-T in obese adult inpatients. METHODS: Those receiving standard-dose P-T with BMI ≥ 30 kg/m2 weighing 105-139 kg or ≥ 140 kg were given up to 6.75 g or 9 g every 6 h, respectively. Patients were monitored closely for safety. Elimination phase blood samples were drawn for 28 patients on standard and high doses to calculate the pharmacokinetic values using a one-compartment model. The likelihood of pharmacodynamic target attainment (100% fT > 16/4 mg/L) on various P-T regimens was calculated using each patient's own pharmacokinetic values. RESULTS: Piperacillin and tazobactam half-lives ranged from 0.5-10.6 to 0.9-15.0 h, while volumes of distribution ranged from 13.6-54.8 to 11.5-60.1 L, respectively. Predicted dose requirements for target attainment ranged from 2.25 g every 6 h in hemodialysis patients to a 27 g/24-h continuous infusion in a patient with a short P-T half-life. An amount of 4.5 g every 6 h would have met the target for only 1/12 (8%) patients with creatinine clearance ≥ 80 mL/min and 13/28 (46%) for all enrolled patients. One patient (3%) experienced an adverse event deemed probably related to high-dose P-T. CONCLUSION: Some patients required high P-T doses for target attainment, but dosing requirements were highly variable. Doses up to 6.75 g or 9 g every 6 h may be tolerable; however, studies are needed to see if high dosing, prolonged infusions, or real-time therapeutic drug monitoring improves outcomes in obese patients. CLINICAL TRIAL REGISTRATION (CLINICALTRIALS.GOV): NCT01923363.

Old In Vitro Antimicrobial Breakpoints Are Misleading Stewardship Efforts, Delaying Adoption of Innovative Therapies, and Harming Patients.

The current antimicrobial market and old (pre-2000) in vitro antimicrobial susceptibility test interpretative criteria (STIC) are not working properly. Malfunctioning susceptibility breakpoints and antimicrobial markets have serious implications for both patients (ie, from a safety and efficacy perspective) and antibiotic-focused pharmaceutical and biotechnology company economic viability. Poorly functioning STIC fail both patients and clinicians since they do not discriminate between likely effective and ineffective antimicrobial regimens. Poor economic viability fails patients and clinicians as it decreases the industry's ability to develop antimicrobial agents that clinicians and patients urgently require now and in the future. Herein, we review how STIC for older antimicrobial agents were determined and how their correction can impact the perceived utility of old relative to new antimicrobial agents. Moreover, we describe the data and analysis needs to systematically reevaluate older STIC values. We call for professional infectious diseases societies, government agencies, and other consensus bodies interested in the appropriate use of antimicrobial agents to join an effort to systematically evaluate and, where warranted, correct STIC for all relevant antimicrobial agents. This effort will amplify the effects of other measures designed to increase appropriate antimicrobial use (ie, good antimicrobial stewardship), development, and regulation.

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.

Polymyxin Susceptibility Testing and Interpretive Breakpoints: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing (USCAST).

The polymyxins are important agents for carbapenem-resistant Gram-negative bacilli. The United States Committee on Antimicrobial Susceptibility Testing breakpoint recommendations for colistin and polymyxin B are that isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae are considered susceptible at MIC values of ≤2 mg/liter. These recommendations are contingent upon dosing and testing strategies that are described in this commentary. Importantly, these recommendations are not applicable to lower respiratory tract infections, for which we recommend no breakpoints. Furthermore, there is no breakpoint recommendation for polymyxin B for lower urinary tract infections.

The Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance Program.

Bloodstream infection (BSI) organisms were consecutively collected from >200 medical centers in 45 nations between 1997 and 2016. Species identification and susceptibility testing followed Clinical and Laboratory Standards Institute broth microdilution methods at a central laboratory. Clinical data and isolates from 264,901 BSI episodes were collected. The most common pathogen overall was Staphylococcus aureus (20.7%), followed by Escherichia coli (20.5%), Klebsiella pneumoniae (7.7%), Pseudomonas aeruginosa (5.3%), and Enterococcus faecalis (5.2%). S. aureus was the most frequently isolated pathogen overall in the 1997-to-2004 period, but E. coli was the most common after 2005. Pathogen frequency varied by geographic region, hospital-onset or community-onset status, and patient age. The prevalence of S. aureus isolates resistant to oxacillin (ORSA) increased until 2005 to 2008 and then declined among hospital-onset and community-acquired BSI in all regions. The prevalence of vancomycin-resistant enterococci (VRE) was stable after 2012 (16.4% overall). Daptomycin resistance among S. aureus and enterococci (DRE) remained rare (<0.1%). In contrast, the prevalence of multidrug-resistant (MDR) Enterobacteriaceae increased from 6.2% in 1997 to 2000 to 15.8% in 2013 to 2016. MDR rates were highest among nonfermentative Gram-negative bacilli (GNB), and colistin was the only agent with predictable activity against Acinetobacter baumannii-Acinetobacter calcoaceticus complex (97% susceptible). In conclusion, S. aureus and E. coli were the predominant causes of BSI worldwide during this 20-year surveillance period. Important resistant phenotypes among Gram-positive pathogens (MRSA, VRE, or DRE) were stable or declining, whereas the prevalence of MDR-GNB increased continuously during the monitored period. MDR-GNB represent the greatest therapeutic challenge among common bacterial BSI pathogens.

The Importance of Antimicrobial Resistance Monitoring Worldwide and the Origins of SENTRY Antimicrobial Surveillance Program.

The origins of how and why the SENTRY Antimicrobial Surveillance Program was created are briefly described, with additional details on how the isolates are collected and tested as well as the important uses of the data in monitoring antimicrobial resistance and drug development.

Antimicrobial Susceptibility of Streptococcus pneumoniae from North America, Europe, Latin America, and the Asia-Pacific Region: Results From 20 Years of the SENTRY Antimicrobial Surveillance Program (1997-2016).

BACKGROUND: The SENTRY Antimicrobial Surveillance Program monitors the frequency of occurrence and antimicrobial susceptibility of organisms from various infection types worldwide. In this investigation, we evaluated the antimicrobial susceptibility of Streptococcus pneumoniae isolates collected worldwide over 20 years (1997-2016). METHODS: A total of 65 993 isolates were consecutively collected (1 per infection episode) from North America (NA; n = 34 626; 2 nations), Europe (EUR; n = 19 123; 23 nations), the Asia-Pacific region (APAC; n = 7111; 10 nations), and Latin America (LATAM; n = 5133; 7 nations) and tested for susceptibility using reference broth microdilution methods. Resistant subgroups included multidrug-resistant (MDR; nonsusceptible to ≥3 classes of agents) and extensively drug-resistant (XDR; nonsusceptible to ≥5 classes). RESULTS: The isolates were collected primarily from respiratory tract infections (77.3%), and 25.4% were from pediatric patients. Penicillin susceptibility (≤0.06 mg/L) rates varied from 70.7% in EUR to 52.4% in APAC for all years combined. In NA, there was a slight improvement in susceptibility for the first few years of the program, from 66.5% in 1997-1998 to 69.4% in 1999-2000, followed by a decline until 2011-2012 (57.0%). Similar declines in penicillin susceptibility rates were observed in all regions, with the lowest rates of 67.3% in EUR (2011-2012), 41.6% in the APAC region (2007-2008), and 48.2% in LATAM (2013-2014). These declines were followed by improved susceptibility rates in all regions in later program years, with susceptibility rates of 55.6% to 71.8% in 2015-2016 (65.8% overall). Susceptibility rates to ceftriaxone, erythromycin, clindamycin, tetracycline, and trimethoprim-sulfamethoxazole followed a similar pattern, with a decrease in the first 12-14 years and a continued increase in the last 6-8 years of the program. MDR and XDR frequencies were highest in APAC (49.8% and 17.3% overall, respectively) and lowest in LATAM (10.8% and 1.9% overall, respectively). The most active agents for MDR/XDR isolates were ceftaroline (99.7%/99.1% susceptible), tigecycline (96.8%/95.9% susceptible), linezolid (100.0%/100.0% susceptible), and vancomycin (100.0%/100.0% susceptible). CONCLUSIONS: S. pneumoniae susceptibility to many antibiotics increased in all regions in the last few years, and these increases may be related to PCV13 immunization, which was introduced in 2010.

Antimicrobial Resistance Surveillance and New Drug Development.

Surveillance represents an important informational tool for planning actions to monitor emerging antimicrobial resistance. Antimicrobial resistance surveillance (ARS) programs may have many different designs and can be grouped in 2 major categories based on their main objectives: (1) public health ARS programs and (2) industry-sponsored/product-oriented ARS programs. In general, public health ARS programs predominantly focus on health care and infection control, whereas industry ARS programs focus on an investigational or recently approved molecule(s). We reviewed the main characteristics of industry ARS programs and how these programs contribute to new drug development. Industry ARS programs are generally performed to comply with requirements from regulatory agencies responsible for commercial approval of antimicrobial agents, such as the US Food and Drug Administration, European Medicines Agency, and others. In contrast to public health ARS programs, which typically collect health care and diverse clinical data, industry ARS programs frequently collect the pathogens and perform the testing in a central laboratory setting. Global ARS programs with centralized testing play an important role in new antibacterial and antifungal drug development by providing information on the emergence and dissemination of resistant organisms, clones, and resistance determinants. Organisms collected by large ARS programs are extremely valuable to evaluate the potential of new agents and to calibrate susceptibility tests once a drug is approved for clinical use. These programs also can provide early evaluations of spectrum of activity and postmarketing trends required by regulatory agencies, and the programs may help drug companies to select appropriate dosing regimens and the appropriate geographic regions in which to perform clinical trials. Furthermore, these surveillance programs provide useful information on the potency and spectrum of new antimicrobial agents against indications and organisms in which clinicians have little or no experience. In summary, large ARS programs, such as the SENTRY Antimicrobial Surveillance Program, contribute key data for new drug development.

Variations in the Occurrence of Resistance Phenotypes and Carbapenemase Genes Among Enterobacteriaceae Isolates in 20 Years of the SENTRY Antimicrobial Surveillance Program.

BACKGROUND: A total of 178 825 Enterobacteriaceae isolates collected in 199 hospitals from 42 countries worldwide over 20 years (1997 to 2016) of the SENTRY Program were susceptibility tested by reference broth microdilution methods. METHODS: Trends in percentages over time were analyzed by the χ2 test. Results were reported as the percentage difference between the first (1997-2000) and the last (2013-2016) time period. RESULTS: Enterobacteriaceae exhibiting resistance to cephalosporins (extended-spectrum ß-lactamase [ESBL] phenotype) and carbapenem resistance (CRE) significantly increased (P < 0.05; χ2 test) from 10.3% to 24.0% and 0.6% to 2.9%, respectively. Similar trends were noted for all regions and infection sources. Klebsiella pneumoniae mainly drove the CRE increase. Multidrug-resistance (MDR) rates significantly increased from 7.3% to 15.3% overall, with important trends in all regions and infection sources. Significant increases were noted for MDR K. pneumoniae and Escherichia coli, polymyxin-resistant K. pneumoniae (2.0% to 5.5% overall), and aminoglycoside-resistant E. coli (7.0% to 18.0%) and K. pneumoniae (18.1% to 26.9%) over time in North America and Latin America. Carbapenemase-encoding genes were screened after 2007, and the occurrence of these genes was compared for 2007-2009 and 2014-2016. Among 1298 CRE isolates from the 2 study periods, bla KPC was detected among 186 (49.7%) and 501 (54.2%) isolates in 2007-2009 and 2014-2016, respectively. Metallo-ß-lactamase genes were detected among 4.3% of the isolates from 2007 to 2009 and 12.7% of the isolates from 2014 to 2016, mainly due to the dissemination of isolates carrying bla NDM. Genes encoding IMP and VIM enzymes were observed in 1.9% and 2.4% (7 and 9 isolates) of the isolates from 2007 to 2009 and 0.4% and 1.9% of the isolates from 2014 to 2016. OXA-48 and variants increased from 4.3% in 2007-2009 to 12.6% in 2014-2016 (mainly in Europe). CONCLUSIONS: A change in the epidemiology of carbapenemases and important increases in ESBL, CRE, MDR, and other resistant phenotypes among virtually all geographic regions and infection sources were noted in the 20 years of surveillance, highlighting the impact of antimicrobial resistance and the importance of its continuous monitoring.

Twenty-Year Trends in Antimicrobial Susceptibilities Among Staphylococcus aureus From the SENTRY Antimicrobial Surveillance Program.

Background: Staphylococcus aureus is among the most common human pathogens, with therapy complicated by the epidemic spread of methicillin-resistant Staphylococcus aureus (MRSA). Methods: The SENTRY Antimicrobial Surveillance Program evaluated the in vitro activity of >20 antimicrobials against 191 460 clinical S. aureus isolates collected from 427 centers in 45 countries from 1997 to 2016. Each center contributed isolates and clinical data for consecutive episodes of bacteremia, pneumonia in hospitalized patients, urinary tract infection, and skin and skin structure infection. Results: Overall, 191 460 S. aureus isolates were collected, of which 77 146 (40.3%) were MRSA, varying geographically from 26.8% MRSA in Europe to 47.0% in North America. The highest percentage of MRSA was in nosocomial isolates from patients aged >80 years. Overall, MRSA occurrences increased from 33.1% in 1997-2000 to a high of 44.2% in 2005-2008, then declined to 42.3% and 39.0% in 2009-2012 and 2013-2016, respectively. S. aureus bacteremia had a similar trend, with nosocomial and community-onset MRSA rates peaking in 2005-2008 and then declining. Vancomycin activity against S. aureus remained stable (minimum inhibitory concentration [MIC]90 of 1 mg/L and 100% susceptibility in 2016; no increase over time in isolates with a vancomycin MIC >1 mg/L). Several agents introduced during the surveillance period exhibited in vitro potency against MRSA. Conclusions: In a large global surveillance program, the rise of MRSA as a proportion of all S. aureus peaked a decade ago and has declined since, consistent with some regional surveillance program reports. Vancomycin maintained high activity against S. aureus, and several newer agents exhibited excellent in vitro potencies.

Antimicrobial Susceptibility of Acinetobacter calcoaceticus-Acinetobacter baumannii Complex and Stenotrophomonas maltophilia Clinical Isolates: Results From the SENTRY Antimicrobial Surveillance Program (1997-2016).

BACKGROUND: Acinetobacter calcoaceticus-A. baumannii (Acb) complex and Stenotrophomonas maltophilia represent frequent causes of hospital-acquired infections. We evaluated the frequency and resistance rates of Acb complex and S. maltophilia isolates from medical centers enrolled in the SENTRY Program. METHODS: A total of 13 752 Acb complex and 6467 S. maltophilia isolates were forwarded to a monitoring laboratory by 259 participating sites from the Asia-Pacific region, Latin America, Europe, and North America between 1997 and 2016. Confirmation of species identification and antimicrobial susceptibility testing were performed using conventional methods and/or matrix-assisted laser desorption ionization-time of flight mass spectrometry and the broth microdilution method, respectively. Antimicrobial susceptibility results were interpreted by CLSI and EUCAST 2018 criteria. RESULTS: Acb complex and S. maltophilia were most frequently isolated from patients hospitalized with pneumonia (42.9% and 55.8%, respectively) and bloodstream infections (37.3% and 33.8%, respectively). Colistin and minocycline were the most active agents against Acb complex (colistin MIC50/90, ≤0.5/2 mg/L; 95.9% susceptible) and S. maltophilia (minocycline MIC50/90, ≤1/2 mg/L; 99.5% susceptible) isolates, respectively. Important temporal decreases in susceptibility rates among Acb complex isolates were observed for all antimicrobial agents in all regions. Rates of extensively drug-resistant Acb complex rates were highest in Europe (66.4%), followed by Latin America (61.5%), Asia-Pacific (56.9%), and North America (38.8%). Among S. maltophilia isolates, overall trimethoprim-sulfamethoxazole (TMP-SMX) susceptibility rates decreased from 97.2% in 2001-2004 to 95.7% in 2013-2016, but varied according to the geographic region. CONCLUSIONS: We observed important reductions of susceptibility rates to all antimicrobial agents among Acb complex isolates obtained from all geographic regions. In contrast, resistance rates to TMP-SMX among S. maltophilia isolates remained low and relatively stable during the study period.

Temporal and Geographic Variation in Antimicrobial Susceptibility and Resistance Patterns of Enterococci: Results From the SENTRY Antimicrobial Surveillance Program, 1997-2016.

BACKGROUND: The SENTRY Antimicrobial Surveillance Program was established in 1997 and presently encompasses more than 750 000 bacterial isolates from over 400 medical centers worldwide. Among these pathogens, enterococci represents a prominent cause of bloodstream (BSIs), intra-abdominal (IAIs), skin and skin structure, and urinary tract infections (UTIs). In the present study, we reviewed geographic and temporal trends in Enterococcus species and resistant phenotypes identified throughout the SENTRY Program. METHODS: From 1997 to 2016, a total of 49 491 clinically significant enterococci isolates (15 species) were submitted from 298 medical centers representing the Asia-Pacific (APAC), European, Latin American (LATAM), and North American (NA) regions. Bacteria were identified by standard algorithms and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Susceptibility (S) testing was performed by reference broth microdilution methods and interpreted using Clinical and Laboratory Standards Institute/US Food and Drug Administration and European Committee on Antimicrobial Susceptibility Testing criteria. RESULTS: The most common Enterococcus species in all 4 regions were Enterococcus faecalis (64.7%) and E. faecium (EFM; 29.0%). Enterococci accounted for 10.7% of BSIs in NA and was most prominent as a cause of IAIs (24.0%) in APAC and of UTIs (19.8%) in LATAM. A steady decrease in the susceptibility to ampicillin and vancomycin was observed in all regions over the 20-year interval. Vancomycin-resistant enterococci (VRE) accounted for more than 8% of enterococcal isolates in all regions and was most common in NA (21.6%). Among the 7615 VRE isolates detected, 89.1% were the VanA phenotype (91.0% EFM) and 10.9% were VanB. Several newer antimicrobial agents demonstrated promising activity against VRE, including daptomycin (99.6-100.0% S), linezolid (98.0%-99.6% S), oritavancin (92.2%-98.3% S), tedizolid (99.5%-100.0% S), and tigecycline (99.4%-100.0% S). CONCLUSIONS: Enterococci remained a prominent gram-positive pathogen in the SENTRY Program from 1997 through 2016. The overall frequency of VRE was 15.4% and increased over time in all monitored regions. Newly released agents with novel mechanisms of action show promising activity against VRE.

Geographic and Temporal Patterns of Antimicrobial Resistance in Pseudomonas aeruginosa Over 20 Years From the SENTRY Antimicrobial Surveillance Program, 1997-2016.

BACKGROUND: The SENTRY Antimicrobial Surveillance Program was established in 1997 and encompasses over 750 000 bacterial isolates from ≥400 medical centers worldwide. Among the pathogens tested, Pseudomonas aeruginosa remains a common cause of multidrug-resistant (MDR) bloodstream infections and pneumonia in hospitalized patients. In the present study, we reviewed geographic and temporal trends in resistant phenotypes of P. aeruginosa over 20 years of the SENTRY Program. METHODS: From 1997 to 2016, 52 022 clinically significant consecutive isolates were submitted from ≥200 medical centers representing the Asia-Pacific region, Europe, Latin America, and North America. Only 1 isolate per patient per infection episode was submitted. Isolates were identified by standard algorithms and/or matrix-assisted laser desorption ionization-time of flight mass spectrometry. Susceptibility testing was performed by Clinical and Laboratory Standards Institute (CLSI) methods and interpreted using CLSI and European Committee on Antimicrobial Susceptibility Testing 2018 criteria at JMI Laboratories. RESULTS: The most common infection from which P. aeruginosa was isolated was pneumonia in hospitalized patients (44.6%) followed by bloodstream infection (27.9%), with pneumonia having a slightly higher rate of MDR (27.7%) than bloodstream infections (23.7%). The region with the highest percentage of MDR phenotypes was Latin America (41.1%), followed by Europe (28.4%). The MDR rates were highest in 2005-2008 and have decreased in the most recent period. Colistin was the most active drug tested (99.4% susceptible), followed by amikacin (90.5% susceptible). CONCLUSIONS: Over the 20 years of SENTRY Program surveillance, the rate of MDR P. aeruginosa infections has decreased, particularly in Latin America. Whether the trend of decreasing resistance in P. aeruginosa is maintained will be documented in future SENTRY Program and other surveillance reports.

Application of Next-Generation Sequencing for Characterization of Surveillance and Clinical Trial Isolates: Analysis of the Distribution of ß-lactamase Resistance Genes and Lineage Background in the United States.

BACKGROUND: Sequencing technologies and techniques have seen remarkable transformation and innovation that have significantly affected sequencing capability. Data analyses have replaced sequencing as the main challenge. This paper provides an overview on applying next-generation sequencing (NGS) and analysis and discusses the benefits and challenges. In addition, this document shows results from using NGS and bioinformatics tools to screen for ß-lactamase genes and assess the epidemiological structure of Escherichia coli- and Klebsiella pneumoniae-causing bloodstream (BSIs) and urinary tract (UTIs) infections in patients hospitalized in the United States during the SENTRY Antimicrobial Surveillance Program for 2016. METHODS: A total of 3525 isolates (2751 E. coli and 774 K. pneumoniae) causing BSIs (n = 892) and UTIs (n = 2633) in hospitalized patients in the United States were included. Isolates were tested for susceptibility by broth microdilution, and those that met a minimum inhibitory concentration (MIC)-based screening criteria had their genomes sequenced and analyzed. RESULTS: A total of 11.6% and 16.1% of E. coli-causing UTIs and BSIs, respectively, met the MIC-based criteria, whereas 11.0% and 13.7% of K. pneumoniae isolates causing UTIs and BSIs, respectively, met the criteria. Among E. coli, bla CTX-M variants (87.6% overall) prevailed (60.5% of CTX-M group 1 and 26.9% of group 9). A total of 60.3% of K. pneumoniae isolates carried bla CTX-M variants (52.7% and 7.6% of groups 1 and 9, respectively). Two E. coli (0.6%) and 13 K. pneumoniae (12.9%) isolates harbored bla KPC. Among KPC-producing K. pneumoniae (2 from BSIs and 11 from UTIs), 84.6% (11/13) were ST258 (CC258). Seventeen and 38 unique clonal complexes (CCs) were noted in E. coli that caused BSIs and UTIs, respectively, and CC131 (or ST131) was the most common CC among BSI (53.6%) and UTI (58.2%) isolates. Twenty-three and 26 CCs were noted among K. pneumoniae-causing BSIs and UTIs, respectively. CC258 (28.3%) prevailed in UTI pathogens, whereas CC307 (15.0%) was the most common CC among BSI isolates. CONCLUSIONS: This study provides a benchmark for the distribution of ß-lactamase genes and the population structure information for the most common Enterobacteriaceae species responsible for BSIs and UTIs in US medical centers during the 2016 SENTRY Program.

Twenty Years of the SENTRY Antifungal Surveillance Program: Results for Candida Species From 1997-2016.

BACKGROUND: The emergence of antifungal resistance threatens effective treatment of invasive fungal infection (IFI). Invasive candidiasis is the most common health care-associated IFI. We evaluated the activity of fluconazole (FLU) against 20 788 invasive isolates of Candida (37 species) collected from 135 medical centers in 39 countries (1997-2016). The activity of anidulafungin, caspofungin, and micafungin (MCF) was evaluated against 15 308 isolates worldwide (2006-2016). METHODS: Species identification was accomplished using phenotypic (1997-2001), genotypic, and proteomic methods (2006-2016). All isolates were tested using reference methods and clinical breakpoints published in the Clinical and Laboratory Standards Institute documents. RESULTS: A decrease in the isolation of Candida albicans and an increase in the isolation of Candida glabrata and Candida parapsilosis were observed over time. Candida glabrata was the most common non-C. albicans species detected in all geographic regions except for Latin America, where C. parapsilosis and Candida tropicalis were more common. Six Candida auris isolates were detected: 1 each in 2009, 2013, 2014, and 2015 and 2 in 2016; all were from nosocomial bloodstream infections and were FLU-resistant (R). The highest rates of FLU-R isolates were seen in C. glabrata from North America (NA; 10.6%) and in C. tropicalis from the Asia-Pacific region (9.2%). A steady increase in isolation of C. glabrata and resistance to FLU was detected over 20 years in the United States. Echinocandin-R (EC-R) ranged from 3.5% for C. glabrata to 0.1% for C. albicans and C. parapsilosis. Resistance to MCF was highest among C. glabrata (2.8%) and C. tropicalis (1.3%) from NA. Mutations on FKS hot spot (HS) regions were detected among 70 EC-R isolates (51/70 were C. glabrata). Most isolates harboring FKS HS mutations were resistant to 2 or more ECs. CONCLUSIONS: EC-R and FLU-R remain uncommon among contemporary Candida isolates; however, a slow and steady emergence of resistance to both antifungal classes was observed in C. glabrata and C. tropicalis isolates.

The Infectious Diseases Society of America's 10 × '20 Initiative (10 New Systemic Antibacterial Agents US Food and Drug Administration Approved by 2020): Is 20 × '20 a Possibility?

BACKGROUND: Infections caused by antibiotic-resistant bacteria, including carbapenem-resistant Enterobacteriaceae, have increased in frequency, resulting in significant patient morbidity and mortality. The Infectious Diseases Society of America continues to propose legislative, regulatory, and funding solutions to address this escalating crisis. This report updates the status of development and approval of systemic antibiotics in the United States as of late 2018. METHODS: We performed a review of the published literature and on-line clinical trials registry at www.clinicaltrials.gov to identify new systemically acting orally and/or intravenously administered antibiotic drug candidates in the development pipeline, as well as agents approved by the US Food and Drug Administration since 2012. RESULTS: Since our 2013 pipeline status report, the number of new antibiotics annually approved for marketing in the United States has reversed its previous decline, likely influenced by new financial incentives and increased regulatory flexibility. Although our survey demonstrates progress in development of new antibacterial drugs that target infections caused by resistant bacterial pathogens, the majority of recently approved agents have been modifications of existing chemical classes of antibiotics, rather than new chemical classes. Furthermore, larger pharmaceutical companies continue to abandon the field, and smaller companies face financial difficulties as a consequence. CONCLUSIONS: Unfortunately, if 20 × '20 is achieved due to efforts embarked upon in decades past, it could mark the apex of antibiotic drug development for years to come. Without increased regulatory, governmental, industry, and scientific support and collaboration, durable solutions to the clinical, regulatory, and economic problems posed by bacterial multidrug resistance will not be found.

Pharmacokinetic and Pharmacodynamic Properties of Metronidazole in Pediatric Patients With Acute Appendicitis: A Prospective Study.

BACKGROUND: Metronidazole is traditionally dosed every 6-8 hours even though in adults it has a long half-life, concentration-dependent killing, and 3-hour postantibiotic effect. Based on this logic, some pediatric hospitals adopted once-daily dosing for appendicitis, despite limited pharmacokinetics-pharmacodynamics (PK/PD) in children. We studied pediatric patients with appendicitis given metronidazole once daily to determine whether this dosing would meet target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio of ≥70 for Bacteroides fragilis. METHODS: One hundred pediatric patients aged 4-17 years had an average of 3 blood draws per patient during the first 24 hours after a 30 mg/kg per dose of intravenous metronidazole. Concentrations of drug were determined using validated liquid chromatography and tandem mass spectrometry. A NONMEM model was constructed for determining PK, followed by Monte Carlo simulations to generate a population of plasma concentration-time AUC of metronidazole and hydroxy-metronidazole. RESULTS: Simulated AUC values met target attainment (AUC/MIC ratio of ≥70 to B fragilis MICs) for 96%-100% of all patients for an MIC of 2 mcg/mL. For MICs of 4 and 8 mcg/mL, target attainment ranged from 61% to 97% and 9% to 71%, respectively. Areas under the curve were similar to that of adults receiving 1000 mg and 1500 mg q24, or 500 mg q8 hours. CONCLUSIONS: Metronidazole, 30 mg/kg per dose, once daily achieved AUC target attainment for B fragilis with an MIC of 2 mcg/mL or less in pediatric appendicitis patients. Based on this and studies in adults, there does not seem to be any PK/PD advantage of more frequent dosing in this population.

Assessment of 30/20-Microgram Disk Content versus MIC Results for Ceftazidime-Avibactam Tested against Enterobacteriaceae and Pseudomonas aeruginosa.

We evaluated the correlation between MIC and disk diffusion inhibition zones when testing ceftazidime-avibactam, using the 30/20-µg disk and the disk diffusion and MIC breakpoints established by the U.S. FDA and the Clinical and Laboratory Standards Institute (CLSI). Organisms used included 2 groups of Enterobacteriaceae isolates and 2 groups of Pseudomonas aeruginosa isolates; 1 group of each consisted of randomly selected isolates and the second group consisted of a challenge group from thousands of surveillance isolates with an increased proportion of organisms displaying ceftazidime-avibactam MIC values close to the breakpoints. Broth microdilution, disk diffusion tests, and data analysis were performed according to reference standardized methods. Ceftazidime-avibactam breakpoints of ≤8/4 (susceptible) and ≥16/4 µg/ml (resistant) for MIC and ≥21/≤20 mm for disk diffusion, as established by the U.S. FDA and the CLSI, were applied for Enterobacteriaceae and P. aeruginosa Ceftazidime-avibactam MIC and disk zone (30/20-µg disk) correlation were acceptable when testing Enterobacteriaceae (overall, very major [VM] and major [Ma] error rates of 0.4% and 0.0%, respectively) and nearly so when testing P. aeruginosa (2.3% VM and 2.9% Ma errors). In summary, disk diffusion and broth microdilution testing results demonstrated good categorical agreement for ceftazidime-avibactam against Enterobacteriaceae and P. aeruginosa, using 30/20-µg disks.