MIC Distributions Research Articles

1244. Assessment of the In Vivo Activity of Human-Simulated Exposure of WCK 4282 (High Dose Cefepime [FEP]-Tazobactam [TZB]) against Enterobacterales (EB) and Pseudomonas aeruginosa (PA) in the Neutropenic Murine Thigh Infection Model

BackgroundCarbapenems are often used for infections due to extended-spectrum-β-lactamase (ESBL) and cephalosporinase (CSase)-producers. As increased carbapenem utilization is associated with the development of carbapenem resistance, antimicrobial stewardship has targeted non-carbapenem options. WCK 4282 (FEP 2 g-TZB 2 g) offers pharmacodynamically optimized TZB exposure and demonstrated potent activity in vitro against ESBL-phenotype isolates. We describe the pharmacodynamics of a WCK 4282 human-simulated regimen (HSR) in the neutropenic murine thigh model.Methods19 clinical strains harboring ESBLs or CSase (EB; n=8 and PA; n=4) or serine-carbapenemases (EB; KPC n=4 or OXA-48-like n=3) were tested in vivo. Per CLSI, 19, 18, and 17 isolates were cefepime, ceftolozane/tazobactam, and piperacillin/tazobactam (TZP) non-susceptible, respectively. Thighs of neutropenic, female, CD-1 mice (3 per group) were inoculated with ~107 CFU/mL of bacterial suspension 2 h prior to dosing. Mice received WCK 4282 HSR, FEP HSR, or saline (controls) for 24 h. WCK 4282 HSR and FEP HSR provided plasma exposures in mice that were similar in f%T > MIC and fAUC to FEP-TZB 2 g-2 g and FEP 2 g, respectively, as IV infusions over 1.5 h q8h in humans. Bacterial densities and their changes at 24 h relative to 0 h controls were determined to assess efficacy and reported as mean±SD log10 CFU/thigh.ResultsBacterial burdens were 5.81±0.36 at 0 h and 9.29±0.88 at 24 h in untreated controls. WCK 4282 produced potent activity against ESBL/CSase producing EB and PA with WCK 4282 MIC ≤ 16 mg/L; mean change in log10 CFU from 0 h was -1.70±0.77, while growth was observed with FEP alone. WCK 4282 produced variable activity against OXA-48-like harboring EB. Against KPC-harboring EB, WCK 4282 produced stasis to growth. Mean Log10 CFU changes are reported in Table 1 and Figure 1.Table 1. Comparative efficacy of FEP HSR and WCK 4282 HSR by genotypic β-lactamase Figure 1. Mean Change in log10CFU/thigh for 24 h controls, FEP HSR, and WCK 4282 HSR across the tested MIC distribution. ConclusionWCK 4282, a novel TZB containing regimen, resulted in enhance in vitro potency against ESBL/CSase and OXA-48-like producers. Humanized exposures of WCK 4282 produced substantial kill in vivo against ESBL/CSase producers with MICs ≤ 16 mg/L including FEP resistant/TZP non-susceptible PA. These data support further evaluations of WCK 4282 as a carbapenem-sparing regimen for ESBL/cephalosporinase harboring strains.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

1317. Pharmacokinetics (PK) of Ampicillin-Sulbactam (SAM) during Orthotopic Liver Transplantation (OLT)

BackgroundSAM is used as surgical prophylaxis during OLT due to its broad spectrum activity against Gram-positive,-negative and anaerobic pathogens. SAM resistance among Gram-negatives is rising, making dosage selection paramount to preventing surgical site infections. Current guidelines recommend a 3g dose, consisting of 2g ampicillin (AMP) and 1g sulbactam (SUL), every 2h. There are no data; however, describing SAM PK during OLT to support an optimized dosing regimen.MethodsThis was a single-center PK study of OLT patients receiving SAM for surgical prophylaxis at a dose selected by the anesthesiologist. Patients were excluded if they were undergoing simultaneous liver and kidney transplantation and had a CrCL < 30 mL/min at start of surgery. Up to 24 blood samples, along with times of pertinent events, were collected throughout the OLT. AMP and SUL plasma concentrations were determined. Population PK analyses were conducted in Pmetrics using R. Akaike information criterion (AIC) and visual inspection determined best model fit. Individual PK parameters were simulated to describe free AMP time above the MIC90 (fT >MIC90) of 32 mg/L.ResultsFive patients were enrolled. Participants had a mean ± SD age of 64 ± 7 years, body weight 82 ± 8 kg, CrCL of 75 ± 35 mL/min, and received various SAM doses (1.5-3g q2-3h). A 2 compartment model fitted the data better than a 1 compartment model for both AMP (AIC: 396 vs. 423) and SUL (AIC: 334 vs. 347). Final models included fractional clearance (CLf) terms on typical total body clearance (CLθ) to account for the placement of the portal vein clamp. AMP PK parameters (AIC: 372) were: CLθ, 9.7 ± 2.6 L/h; CLf, 0.73 ± 0.49; volume of central compartment (Vc), 7.2 ± 1.4 L; intercompartment constants (k12 and k21), 4.08 ± 3.28 and 2.63 ± 2.9 h-1, respectively. Final SUL PK parameters (AIC: 314) were: CLθ, 8.3 ± 2.5 L/h; CLf, 0.92 ± 0.55; Vc, 7.3 ± 1.6 L; k12, 4.60 ± 4.41 h-1, and k21, 4.07 ± 3.31 h-1. Exposures ranged from 58-96% with only 3g q2h providing nearly 100% fT >MIC90.ConclusionThis is the first study to describe intra-operative SAM PK in OLT recipients and the effect of portal vein clamp on AMP and SUL clearance. These data will help guide optimized SAM dosing regimens for OLT surgery based on local MIC distributions for targeted pathogens.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))

305. Prevalence of Ceftriaxone Susceptible, Piperacillin-tazobactam Non-susceptible Escherichia coli Bacteremia in Patients with Hematologic Malignancy

BackgroundPiperacillin-tazobactam (TZP) is common empiric and targeted therapy for gram-negative bacteremia in patients with hematologic malignancy. Resistance to TZP tends to occur concurrently with ceftriaxone (CRO) resistance; however, the prevalence of TZP nonsusceptibility in CRO susceptible Escherichia coli (E. coli) in patients with hematologic malignancy is unknown. Therefore, we sought to determine the prevalence of TZP nonsusceptible, CRO susceptible E. coli bacteremia at a cancer center.MethodsThis is a retrospective cohort study of adult (age > 18) patients with E. coli bacteremia admitted to the Leukemia or Stem Cell Transplant (SCT) services at The University of Texas MD Anderson Cancer Center (MDACC) between 8/2016 and 7/2019. Isolates were categorized according to current CLSI resistance breakpoints. A first isolate was defined as the first positive blood culture and subsequent episodes of bacteremia were defined as any E. coli isolate obtained at least 24 hours after the first negative blood culture.ResultsThe overall prevalence of TZP resistant CRO susceptible E. coli from 404 isolates was 7.7% and varied by service. There was a higher prevalence in the Leukemia service compared to SCT, 9.8% vs 2.5%, respectively (p < 0.01). 46% of isolates were CRO nonsusceptible, of which 91% were extended-spectrum beta-lactamase (ESBL) producers, identified by Vitek 2 or Accelerate Pheno. The TZP MIC50 was 4ug/ml, MIC90 was 128ug/ml, with an MIC range of 3ug/ml to ≥ 256ug/ml. The TZP MIC distribution varied based upon CRO phenotype. In CRO susceptible isolates the MIC50 and MIC90 were 4ug/ml and 64ug/ml, respectively, compared to 8ug/ml and 128ug/ml in CRO nonsusceptible isolates (p < 0.01). TZP resistance was more common in CRO nonsusceptible isolates (31.6% vs 12.0%, p < 0.01) and was more frequent with subsequent episodes of bacteremia compared to the first (39.5% vs 20.1%, p < 0.01).ConclusionIn patients with hematologic malignancy and E. coli bacteremia, TZP resistance is common with significant variations by CRO phenotype. TZP resistance becomes more common with subsequent episodes of bacteremia compared to the first. The clinical implications and genetic cause of this phenotype is currently unknown and warrants further investigation.Disclosures All Authors: No reported disclosures

Serotype Is Associated With High Rate of Colistin Resistance Among Clinical Isolates of Salmonella.

To investigate the prevalence, probable mechanisms and serotype correlation of colistin resistance in clinical isolates of Salmonella from patients in China, Salmonella isolates were collected from fecal and blood samples of patients. In this study, 42.8% (136/318) clinical isolated Salmonella were resistant to colistin. MIC distribution for colistin at serotype level among the two most prevalent serotypes originating from humans in China indicated that Salmonella Enteritidis (83.9% resistance, 125/149) were significantly less susceptible than Salmonella Typhimurium (15.3% resistance, 9/59, P < 0.01). mcr genes and mutations in PmrAB confer little for rate of colistin resistant Salmonella isolated from human patients. Phylogenetic tree based on core-genome single nucleotide polymorphisms (SNPs) was separately by the serotypes and implied a diffused distribution of MICs in the same serotype isolates. Relatvie expression levels of colistin resistant related pmr genes were significantly higher in non-mcr colistin resistant S. Typhimurium than in colistin sensitive S. Typhimurium, but no discernable differences between colistin resistant and sensitive S. Enteritidis, indicating a different mechanism between colistin resistant S. Typhimurium and S. Enteritidis. In conclusion, colistin susceptibility and colistin resistant mechanism of clinical isolated Salmonella were closely associated with specific serotypes, at least in the two most prevalent serotype Enteritidis and Typhimurium. We suggest clinical microbiology laboratory interpreting Salmonella colistin MIC results in the serotype level.

Do high MICs predict the outcome in invasive fusariosis?

Invasive fusariosis (IF) affects mostly severely immunocompromised hosts and is associated with poor outcome. Since Fusarium species exhibit high MICs for most antifungal agents, this could explain the poor prognosis. However, a clear-cut correlation between MIC and outcome has not been established. To evaluate the correlation between MIC and outcome (6 week death rate) in patients with IF. We performed a multicentre retrospective study of patients with IF who received treatment and had MIC levels determined by EUCAST or CLSI for the drug(s) used during treatment. We compared the MIC50 and MIC distribution among survivors and patients who died within 6 weeks from the diagnosis of IF. Among 88 patients with IF, 74 had haematological diseases. Primary treatment was monotherapy in 52 patients (voriconazole in 27) and combination therapy in 36 patients (liposomal amphotericin B + voriconazole in 23). The MIC50 and range for the five most frequent agents tested were: voriconazole 8 mg/L (range 0.5-64), amphotericin B 2 mg/L (range 0.25-64), posaconazole 16 mg/L (range 0.5-64), itraconazole 32 mg/L (range 4-64), and isavuconazole 32 mg/L (range 8-64). There was no difference in MIC50 and MIC distribution among survivors and patients who died. By contrast, persistent neutropenia and receipt of corticosteroids were strong predictors of 6 week mortality. Our study did not show any correlation between MIC and mortality at 6 weeks in patients with IF.

Prevalence and mechanisms of fosfomycin resistance among KPC-producing Klebsiella pneumoniae clinical isolates in China

The threat of antibiotic resistance has increased dramatically in recent years. Fosfomycin, an old antibiotic agent, has been re-introduced to fight infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP). However, the trend of fosfomycin resistance among KPC-KP strains is increasing. In this study, 80 KPC-KP clinical isolates were collected from three teaching hospitals during 2014-2017 in China and were subjected to whole-genome sequencing (WGS). The fosfomycin resistance phenotype and resistance mechanisms were investigated by antimicrobial susceptibility testing and carbon source growth test, respectively. Among all KPC-KP strains, 80.0% (64/80) were resistant to fosfomycin and 36.3% (29/80) were positive for the mobile fosfomycin resistance gene fosA3. Among the 63 strains that were unable to grow in M9 basic medium with glycerol-3-phosphate (G3P) as the sole carbon source (mediated by mutation of the target gene glpT), there was no significant difference regarding the MIC distribution of fosfomycin between fosA3-positive and fosA3-negative strains (P=0.577). Among the 50 strains that were negative for fosA3 but positive for fosA, the fosfomycin MICs of strains unable to grow in M9 basic medium with G3P as the sole carbon source were significantly higher (P < 0.001) than in strains that were able to grow in M9 basic medium with G3P as the sole carbon source. Our findings indicate that fosfomycin resistance among KPC-KP in China is an emerging problem and the two major mechanisms of resistance identified were plasmid-mediated fosfomycin resistance gene fosA3 and mutation of the target gene glpT.

Employing MIC Data for Mink Pathogens to Propose Tentative Epidemiological Cut-Off Values: A Step Toward Rationalizing Antimicrobial Use in Mink.

Optimizing antimicrobial dosage regimens and development of breakpoints for antimicrobial susceptibility testing are important prerequisites for rational antimicrobial use. The objectives of the study were (1) to produce MIC data for four mink pathogens and (2) to employ these MIC data to support the development of tentative epidemiological cut-off values (TECOFFs), which may be used for future development of mink-specific antimicrobial dosages and breakpoints. Broth microdilution was used to establish MIC distributions for 322 mink bacterial isolates of clinical origin from six European mink-producing countries. The included species were E. coli (n = 162), S. delphini (n = 63), S. canis (n = 42), and P. aeruginosa (n = 55). Sixty-four E. coli isolates and 34 S. delphini isolates were whole-genome sequenced and analyzed for antimicrobial resistance genes. No EUCAST MIC data are available on S. delphini and S. canis, hence tentative ECOFFs were suggested for the majority of the tested antimicrobials. For E. coli and P. aeruginosa, the wildtype distributions were in accordance with EUCAST data. Overall, the genotypes of the sequenced isolates were in concordance with the phenotypes. These data constitute an important piece in the puzzle of developing antimicrobial dosages and clinical breakpoints for mink. Until pharmacokinetic and clinical data become available, the (tentative) ECOFFs can be used for monitoring resistance development and as surrogates for clinical breakpoints.

Optimal regimens based on PK/PD cutoff evaluation of ceftiofur against Actinobacillus pleuropneumoniae in swine

BackgroundActinobacillus pleuropneumoniae formerly known as Haemophilus pleuropneumoniae, can cause pleuropneumoniae in pigs, which lead to significant mortality. Ceftiofur was the first cephalosporin antibiotic used in animals, which was effective against gram-negative and gram-positive bacterium. This study aimed to formulate a rational dosage strategy and review the preceding recommended dosage based on PK/PD modeling and Establish Clinical breakpoint of ceftiofur against Actinobacillus pleuropneumoniae based on the pharmacodynamic-pharmacokinetic cutoff.ResultsThe epidemiologic cutoff value was 0.125 μg/mL. The results of the pharmacodynamic study showed that the MICs of BW39 were 0.5 μg/mL and 1 μg/mL in vitro and ex-vivo, respectively. The minimal bactericidal concentrations (MBCs) under in vitro and ex vivo conditions were both 1 μg/mL. The time-killing profiles of ceftiofur against BW39 were time-dependent with a partly concentration-dependent pattern. Based on the inhibitory sigmoid Emax model, the AUC24 h/MIC values for the bacteriostatic, bactericidal, and elimination effects in serum were 45.73, 63.83, and 69.04 h for healthy pigs separately. According to the Monte Carlo simulation, the COPD was calculated as 2 μg/mL, and the optimized dosage regimen of ceftiofur against Actinobacillus pleuropneumoniae to achieve bacteriostatic, bactericidal, and elimination effects over 24 h was 2.13, 2.97, and 3.42 mg/kg for the 50% target attainment rate (TAR) and 2.47, 3.21, and 3.70 mg/kg for the 90% TAR respectively.ConclusionsIn conclusion, we reveal the EOFF and PK/PD cutoff values of ceftiofur against A. pleuropneumoniae in piglets. However, with the paucity of clinical data for ceftiofur to establish a clinical cutoff against A. pleuropneumoniae, the PK/PD cutoff value of 2 μg/mL will be recommended as surrogate. According to the PK/PD data and the MIC distribution in China, the single bactericidal dose was 3.21 mg/kg for the 90% target, which would be more able to cure Actinobacillus pleuropneumoniae and avoid the emergence of resistance for clinical ceftiofur use in piglet.

Antimicrobial susceptibility of Corynebacterium diphtheriae and Corynebacterium ulcerans in Germany 2011-17.

Diphtheria is mainly caused by diphtheria-toxin-producing strains of Corynebacterium diphtheriae and Corynebacterium ulcerans. The recommended first-line antibiotic is penicillin or erythromycin, but reliable susceptibility data are scarce. To define WT MIC distributions of 12 antimicrobial agents and provide data for the determination of tentative epidemiological cut-off values (TECOFFs) for potentially toxigenic corynebacteria and to evaluate the potential usefulness of a gradient test (Etest) for susceptibility testing of penicillin, erythromycin and clindamycin. For the 421 human or veterinary isolates from the period 2011-17, MICs of 12 antimicrobial agents were determined. Etest performance was evaluated for penicillin, erythromycin and clindamycin. MIC distributions were characterized and TECOFFs could be set for 11 out of 24 antibiotic/species combinations. The current EUCAST clinical breakpoints, predominantly determined for Corynebacterium species other than C. diphtheriae and C. ulcerans, divide the WT MIC distributions of penicillin and clindamycin, thereby making reproducible susceptibility testing of C. diphtheriae and C. ulcerans difficult. For erythromycin, 4% of C. diphtheriae and 2% of C. ulcerans had MICs higher than those for WT isolates. Phenotypically detectable resistance to other antibiotics was rare. Etest underestimated MICs of penicillin and lower concentrations needed to be included for erythromycin, while for clindamycin the Etest was not a good surrogate method. MIC distributions based on reference broth microdilution for potentially toxigenic Corynebacterium spp. were developed. For five and six agents, TECOFFs were suggested for C. diphtheriae and C. ulcerans, respectively, but for Corynebacterium pseudotuberculosis the number of isolates was too low.

&lt;p&gt;&lt;em&gt;Acinetobacter baumannii&lt;/em&gt; Sequence Types Harboring Genes Encoding Aminoglycoside Modifying Enzymes and 16SrRNA Methylase; a Multicenter Study from Pakistan&lt;/p&gt;

IntroductionThe aminoglycosides are widely used for the therapeutic management of infections caused by gram-negative bacteria, including the Acinetobacter baumannii strains. However, the resistance to the members of the aminoglycoside family, such as amikacin, gentamicin, and tobramycin, is increasingly being common among the clinical isolates.PurposeThis study aimed to investigate the presence of 16SrRNA methylases and aminoglycoside modifying enzymes (AMEs) genes among aminoglycoside resistant A. baumannii isolates and to study the genetic diversity of the clinical population of A. baumannii in local hospitals.Material and MethodsThe 143 A. baumannii clinical strains were analyzed for antimicrobial susceptibility, genetic screening for enzymes conferring aminoglycosides resistance followed by the multilocus sequence typing.ResultsThe 133/143 (93%) isolates were non-susceptible to at least one of the tested aminoglycosides, including amikacin, gentamicin, and tobramycin. The MIC distribution has shown that 87.486.7% strains were resistant to amikacin and gentamicin, respectively. The aphA6, aadB, aacC1, and aphA1 were found in 74.1%, 59.4%, 16.1%, and 11.2% isolates, respectively, whereas the armA was found in 28% of the strains having a higher MIC value (MIC; ≥256µg/mL). The MLST data have shown that the ST589 and ST2 were the most common STs and corresponded to 51 (35.7%) and 38 (26.6%) isolates, respectively, and few of the isolates corresponding to these STs were found to harbor the armA gene with a variable genotypic profile for AMEs.DiscussionThe study has reported the incidence of various enzymes conferring aminoglycoside resistance among the A. baumannii clones for the first time from Pakistan. The findings suggest the possibility of transmission of aminoglycoside resistance determinants through the lateral gene transfer as well as clonal dissemination.

Burkholderia pseudomallei multi-centre study to establish EUCAST MIC and zone diameter distributions and epidemiological cut-off values

ObjectivesMelioidosis, caused by Burkholderia pseudomallei, requires intensive antimicrobial treatment. However, standardized antimicrobial susceptibility testing (AST) methodology based on modern principles for determining breakpoints and ascertaining performance of methods are lacking for B. pseudomallei. This study aimed to establish MIC and zone diameter distributions on which to set epidemiological cut-off (ECOFF) values for B. pseudomallei using standard EUCAST methodology for non-fastidious organisms. MethodsNon-consecutive, non-duplicate clinical B. pseudomallei isolates (9–70 per centre) were tested at eight study centres against eight antimicrobials by broth microdilution (BMD) and the EUCAST disc diffusion method. Isolates without and with suspected resistance mechanisms were deliberately selected. The EUCAST Development Laboratory ensured the quality of study materials, and provided guidance on performance of the tests and interpretation of results. Aggregated results were analysed according to EUCAST recommendations to determine ECOFFs. ResultsMIC and zone diameter distributions were generated using BMD and disc diffusion results obtained for 361 B. pseudomallei isolates. MIC and zone diameter ECOFFs (mg/L; mm) were determined for amoxicillin-clavulanic acid (8; 22), ceftazidime (8; 22), imipenem (2; 29), meropenem (2; 26), doxycycline (2; none), tetracycline (8; 23), chloramphenicol (8; 22) and trimethoprim-sulfamethoxazole (4; 28). ConclusionsWe have validated the use of standard BMD and disc diffusion methodology for AST of B. pseudomallei. The MIC and zone diameter distributions generated in this study allowed us to establish MIC and zone diameter ECOFFs for the antimicrobials studied. These ECOFFs served as background data for EUCAST to set clinical MIC and zone diameter breakpoints for B. pseudomallei.

Antimicrobial Susceptibility Pattern of Helicobacter heilmannii and Helicobacter ailurogastricus Isolates.

A combined agar and broth dilution method followed by qPCR was used to determine the antimicrobial susceptibility of feline H. heilmannii and H. ailurogastricus isolates. All H. ailurogastricus isolates showed a monomodal distribution of MICs for all the antimicrobial agents tested. For H. heilmannii, a bimodal distribution was observed for azithromycin, enrofloxacin, spectinomycin, and lincomycin. Single nucleotide polymorphisms (SNPs) were found in 50S ribosomal proteins L2 and L3 of the H. heilmannii isolate not belonging to the WT population for azithromycin, and in 30S ribosomal proteins S1, S7, and S12 of the isolate not belonging to the WT population for spectinomycin. The antimicrobial resistance mechanism to enrofloxacin and lincomycin remains unknown (2 and 1 H. heilmannii isolate(s), resp.). Furthermore, H. heilmannii isolates showed higher MICs for neomycin compared to H. ailurogastricus isolates which may be related to the presence of SNPs in several 30S and 50S ribosomal protein encoding genes and ribosomal RNA methyltransferase genes. This study shows that acquired resistance to azithromycin, spectinomycin, enrofloxacin, and lincomycin occasionally occurs in feline H. heilmannii isolates. As pets may constitute a source of infection for humans, this should be kept in mind when dealing with a human patient infected with H. heilmannii.

Prevalence and antimicrobial susceptibility of Arcobacter species in human stool samples derived from out- and inpatients: the prospective German Arcobacter prevalence study Arcopath

BackgroundArcobacter species, particularly A. butzleri, but also A. cryaerophilus constitute emerging pathogens causing gastroenteritis in humans. However, isolation of Arcobacter may often fail during routine diagnostic procedures due to the lack of standard protocols. Furthermore, defined breakpoints for the interpretation of antimicrobial susceptibilities of Arcobacter are missing. Hence, reliable epidemiological data of human Arcobacter infections are scarce and lacking for Germany. We therefore performed a 13-month prospective Arcobacter prevalence study in German patients.ResultsA total of 4636 human stool samples was included and Arcobacter spp. were identified from 0.85% of specimens in 3884 outpatients and from 0.40% of specimens in 752 hospitalized patients. Overall, A. butzleri was the most prevalent species (n = 24; 67%), followed by A. cryaerophilus (n = 10; 28%) and A. lanthieri (n = 2; 6%). Whereas A. butzleri, A. cryaerophilus and A. lanthieri were identified in outpatients, only A. butzleri could be isolated from samples of hospitalized patients. Antimicrobial susceptibility testing of Arcobacter isolates revealed high susceptibilities to ciprofloxacin, whereas bimodal distributions of MICs were observed for azithromycin and ampicillin.ConclusionsIn summary, Arcobacter including A. butzleri, A. cryaerophilus and A. lanthieri could be isolated in 0.85% of German outpatients and ciprofloxacin rather than other antibiotics might be appropriate for antibiotic treatment of infections. Further epidemiological studies are needed, however, to provide a sufficient risk assessment of Arcobacter infections in humans.

Prevalence of the carbapenem-heteroresistant phenotype among ESBL-producing Escherichia coli and Klebsiella pneumoniae clinical isolates.

Carbapenem-heteroresistant (cHR) Enterobacteriaceae strains have been reported worldwide; however, the prevalence among clinical ESBL-producing Enterobacteriaceae isolates obtained from patients with repeated hospital admissions remains largely unknown. Heteroresistance was screened by disc diffusion and confirmed by a modified population analysis profiling (PAP) method against ertapenem, imipenem, meropenem and ceftolozane/tazobactam. MIC testing was performed by broth microdilution against carbapenems and a panel of agents with potential activity against ESBL-producing strains. One hundred and seventy-three ESBL-producing meropenem-susceptible Escherichia coli and Klebsiella pneumoniae isolates were selected for testing. A total of 519 bacteria/carbapenem combinations were screened by disc diffusion; 84 combinations were identified as cHR. Modified PAP confirmed 70 bacteria/carbapenem combinations as heteroresistant; most (63%, 44/70) confirmed cHR colonies grew within the ertapenem zone of inhibition, followed by imipenem (30%, 21/70), then meropenem (7%, 5/70). In total, one-third of the unique patient isolates (32%, 55/173) were identified as being heteroresistant to at least one carbapenem; of those patients, 16% (9/55) had a carbapenem-non-susceptible isolate on subsequent visits. Only two cHR isolates screened positive for ceftolozane/tazobactam heteroresistance (1%, 2/173), of which one was confirmed heteroresistant by modified PAP. cHR isolates were more likely to be collected from a non-urinary source (e.g. respiratory) compared with non-cHR isolates (31% versus 19%, P = 0.02). MIC distributions of all tested antibiotic agents did not differ between non-cHR and cHR isolates. Our findings raise concerns for the continued use of carbapenems as first-line therapy for ESBL infections and for the potential selection for strains with full carbapenem resistance.

In Vitro Activity of Ibrexafungerp (SCY-078) against Candida auris Isolates as Determined by EUCAST Methodology and Comparison with Activity against C. albicans and C. glabrata and with the Activities of Six Comparator Agents.

Ibrexafungerp (SCY-078) is a novel first-in-class antifungal agent targeting glucan synthase. Candida auris is an emerging multidrug-resistant species that has caused outbreaks on five continents. We investigated the in vitro activity of ibrexafungerp against C. auris by applying EUCAST E.Def 7.3.1 methodology. C. albicans and C. glabrata, as well as anidulafungin, micafungin, amphotericin B, fluconazole, voriconazole, and isavuconazole, were included as comparators. Three C. auris reference strains (CBS12372, CBS12373, and CBS10913) and 122 C. auris, 16 C. albicans, and 16 C. glabrata isolates were evaluated. C. albicans ATCC 64548, C. parapsilosis ATCC 22019, and C. krusei ATCC 6258 served as quality control strains. Echinocandin-resistant isolates were fks sequenced. MIC ranges and modal MIC and MIC50 values were determined. Wild-type upper limits (the upper MIC value where the wild-type distribution ends) were determined according to EUCAST principles for setting ECOFFs. Nine repetitions of three QC strains and MICs for C. albicans and C. glabrata yielded narrow MIC ranges with modal MICs in agreement with established EUCAST modal MICs, confirming a robust test performance. The ibrexafungerp MICs against C. auris isolates displayed a Gaussian distribution with a modal MIC (range) of 0.5 mg/liter (0.06 to 2 mg/liter), suggesting uniform susceptibility. Of 122 isolates, 8 were echinocandin resistant and harbored the S639F Fks1 alteration. All but one were fluconazole resistant, and the MIC distributions for voriconazole and isavuconazole were multimodal confirming variable susceptibility. Ibrexafungerp demonstrated promising activity against C. auris, including isolates resistant to echinocandins and/or other agents. The MICs were similar to those reported for the Clinical and Laboratory Standards Institute method, suggesting that a common clinical breakpoint may be appropriate.

Pharmacokinetic/Pharmacodynamic Analysis of Daptomycin Against Staphylococcus aureus and Enterococcus faecium in Pediatric Patients by Monte Carlo Simulation

The objective of this study was to evaluate the efficacy of various daptomycin dosing regimens against Staphylococcus aureus and Enterococcus faecium in pediatric patients with proven/suspected gram-positive infection. Monte Carlo simulations (MCSs) were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (MIC) targets of daptomycin. According to the results of the MCSs, currently approved pediatric dosage regimens were sufficient against Staphylococcus aureus with MIC ≤ 0.5 μg/mL for all pediatric patients, but poor when MIC ≥ 1 μg/mL except for adolescents (12-17 years) who need a dosage of ≥10 mg/kg/day at MIC = 1 μg/mL. For Enterococcus faecium with MIC ≤ 4 μg/mL, the recommended dosage of 8-12 mg/kg/day in adults was enough for adolescents, but not subjected to younger pediatric patients. Furthermore, based on MIC distributions obtained from the European Committee on Antimicrobial Susceptibility Testing, the approved high-dose regimen should be recommended for infants aged 3-12 months, children (2-11 years), and adolescents to achieve better clinical efficacy against methicillin-resistant Staphylococcus aureus. In addition, the dosage of 8-12 mg/kg/day was powerful against Enterococcus faecium for adolescents; however, only the highest dosage of 12 mg/kg/day was effective for infants aged 3-12 months and children. All the simulated regimens were not optimal for infants aged 13-24months. These PK/PD-based simulations rationalize and optimize the dosage regimens of daptomycin against Staphylococcus aureus and Enterococcus faecium in pediatric patients.

MIC distributions for amphotericin B, fluconazole, itraconazole, voriconazole, flucytosine and anidulafungin and 35 uncommon pathogenic yeast species from the UK determined using the CLSI broth microdilution method.

Epidemiological cut-off values and clinical interpretive breakpoints have been developed for a number of antifungal agents with the most common Candida species that account for the majority of infections due to pathogenic yeasts species. However, less-common species, for which susceptibility data are limited, are increasingly reported in high-risk patients and breakthrough infections. The UK National Mycology Reference Laboratory performs routine antifungal susceptibility testing of clinical yeast isolates submitted from across the UK. Between 2002 and 2016, >32 000 isolates representing 94 different yeast species were referred to the laboratory. Here we present antifungal susceptibility profiles generated over this period for amphotericin B, fluconazole, voriconazole, itraconazole, anidulafungin and flucytosine against 35 species of uncommon yeast using CLSI methodologies. MIC data were interpreted against epidemiological cut-off values and clinical breakpoints developed with Candida albicans, in order to identify species with unusually skewed MIC distributions that potentially indicate resistance. Potential resistance to at least one antifungal agent (>10% of isolates with MICs greater than the epidemiological cut-off or clinical breakpoint) was evidenced for 29/35 species examined here. Four species exhibited elevated MICs with all of the triazole antifungal drugs against which they were tested, and 21 species exhibited antifungal resistance to agents from at least two different classes of antifungal agent. This study highlights a number of yeast species with unusual MIC distributions and provides data to aid clinicians in deciding which antifungal regimens may be appropriate when confronted with infections with rarer yeasts.

Optimization of Dosage Regimen of Rezafungin against &amp;lt;i&amp;gt;Candida spp. &amp;lt;/i&amp;gt;Based on Pharmacokinetic/Pharmacodynamic Analysis

Invasive candidiasis was the most common nosocomial fungal infection with high morbidity and mortality, which is mainly occurring in immunodeficiency and critical patients. Echinocandins were recommended as first-line drugs for the treatment and prevention of invasive candidiasis. In our study, we aimed to optimize the dosage of Rezafungin against Candida spp. based on pharmacokinetic/pharmacodynamics (PK/PD) analysis. We collected the published data about pharmacokinetic parameters of rezafungin and the MIC distribution of Candida spp. on rezafungin. Monte Carlo simulation was used to calculate probability of target attainment and a cumulative fraction of response to assess the best dosing regimen. The optimal dosage regimen for C. albicans and C. glabrata was 50 mg IV, and the optimal dosage regimen for C. parapsilosis was 100 mg IV. Lastly, rezafungin has an excellent antifungal effect on C. albicans, C. glabrata and C. parapsilosis.

Where have all the susceptible gonococci gone? A historical review of changes in MIC distribution over the past 75\u2009years

BackgroundDoes the emergence of antimicrobial resistance in Neisseria gonorrhoeae include the erasure of highly susceptible strains or does it merely involve a stretching of the MIC distribution? If it was the former this would be important to know as it would increase the probability that the loss of susceptibility is irreversible.MethodsWe conducted a historical analysis based on a literature review of changes of N. gonorrhoeae MIC distribution over the past 75 years for 3 antimicrobials (benzylpenicillin, ceftriaxone and azithromycin) in five countries (Denmark, Japan, South Africa, the United Kingdom and the United States).ResultsChanges in MIC distribution were most marked for benzylpenicillin and showed evidence of a right shifting of MIC distribution that was associated with a reduction/elimination of susceptible strains in all countries. In the case of ceftriaxone and azithromycin, where only more recent data was available, right shifting was also found in all countries but the extent of right shifting varied and the evidence for the elimination of susceptible strains was more mixed.ConclusionsThe finding of right shifting of MIC distribution combined with reduction/elimination of susceptible strains is of concern since it suggests that this shifting may not be reversible. Since excess antimicrobial consumption is likely to be responsible for this right shifting, this insight provides additional impetus to promote antimicrobial stewardship.

2253. Comparison of Outcomes Between Patients with and without Cystic Fibrosis Treated with Ceftolozane–Tazobactam for Pseudomonas aeruginosa Infections

BackgroundCeftolozane–tazobactam (C/T) was designed to have enhanced activity against P. aeruginosa and has been shown to retain activity against many isolates that are resistant to other antipseudomonal β-lactams. However, there are no data comparing outcomes in patients with and without cystic fibrosis (CF).MethodsRetrospective, multicenter cohort study conducted at 5 hospitals that included all patients with P. aeruginosa infections who received C/T as definitive therapy between November 2016 and December 2018. The primary outcome at 90 days was a composite of mortality, recurrence, readmission, and inappropriate response at end of therapy (EOT). The secondary outcome was to describe baseline C/T susceptibility and emergence of resistance. All outcomes were adjudicated by 2 infectious diseases specialists.ResultsThirty-five, 27 non-CF and 8 CF, patients were included. CF patients were younger, had greater baseline C/T resistance (50.0% vs. 8.3%, P = 0.02) and were more likely to receive combination therapy. The most common site of infection was pulmonary (71.4%) followed by intra-abdominal (14.3%) and osteomyelitis (5.7%). Overall, 54.3% of patients had an unsuccessful outcome with no difference between CF and non-CF patients (62.5% vs. 51.9%, P = 0.70). There was also no difference between each component of the primary outcome. All 4 CF patients with a baseline-resistant isolate had an appropriate response at EOT, while neither of the 2 non-CF patients did. The C/T MIC distribution in CF and non-CF patients was ≤ 2 μg/mL (0.0%, 64.2%), 4 μg/mL (50.0%, 25%) ≥ 8 μg/mL (50.0%, 8.4%). The median duration of C/T in CF and non-CF patients was 18.5 days (interquartile range [IQR], 14–37.5 days) and 15 days (IQR, 10–25 days). Ten, 7 non-CF and 3 CF, patients had a P. aeruginosa isolate cultured and tested for C/T susceptibility within 90 days of index culture with 80% having an MIC increase. Non-CF patients treated for > 14 days were more likely to have an MIC increase (P = 0.047). All CF patients had an MIC increase.ConclusionWe did not observe a difference in the rate of unsuccessful outcome between CF and non-CF patients; however, our sample size was small. CF patients were more likely to be resistant to C/T at baseline. Resistance emerged frequently in both groups following exposure to C/T.Disclosures All authors: No reported disclosures.