Infections due to Candida haemulonii: species identification,antifungal susceptibility and outcomes

Here we report the clinical features and treatment outcomes of three patients with Candida haemulonii infection. Candida haemulonii was confirmed by sequence analysis of the internal transcribed spacer (ITS) regions of the rRNA genes and the 18S rRNA genes. Two of the three isolates were associated with fungaemia and reduced susceptibility to fluconazole [minimum inhibitory concentrations (MICs) of 16 mg/L] and amphotericin B (MICs of 2 mg/L). However, one of these two patients responded to fluconazole therapy. Echinocandins, voriconazole and posaconazole demonstrated excellent in vitro potency against the isolates.     

Outbreak of Candida auris in Spain: A comparison of antifungal activity by three methods with published data

Candida auris is an emerging pathogen causing candidaemia outbreaks in several countries for which azole, amphotericin B (AmB) and echinocandin resistance has been reported. In this study, the antifungal susceptibilities of 73 Spanish C. auris isolates (56 bloodstream and 17 urine) to eight antifungal agents were determined using three methods. Isolates were identified by internal transcribed spacer (ITS) sequencing, and minimum inhibitory concentrations (MICs) of fluconazole, isavuconazole, itraconazole, posaconazole, voriconazole, anidulafungin, micafungin and AmB were determined by EUCAST methodology and Sensititre^® YeastOne^® (SYO) (bloodstream isolates) and Liofilchem^® MIC Test Strip (all isolates). Agreement between the methods was analysed and the MICs (ours and published data) were categorised using recently proposed epidemiological cut-off values (ECVs). Fluconazole MICs were >64 mg/L, whilst >60% of voriconazole MICs were >1 mg/L by the three methods. Posaconazole was the most active azole (EUCAST geometric mean MIC, 0.053 mg/L), followed by isavuconazole (0.066 mg/L) and itraconazole (0.157 mg/L). Echinocandins MICs were ≤0.5 mg/L by SYO and EUCAST. The overall lowest AmB MICs (≤0.25 mg/L) were obtained by EUCAST. Essential agreement (±2 dilutions) between EUCAST and SYO was >93% for the eight antifungals. For this new C. auris clade, all isolates were resistant to fluconazole, and MICs for anidulafungin, micafungin and AmB were ≤1 mg/L using dilution methods. Voriconazole MICs were method-dependent. The number of non-wild-type (non-WT) isolates depended on the ECV applied; by the 97.5% ECV all isolates were WT except for isavuconazole (1.8% non-WT). Good essential agreement (>93%) was observed between EUCAST and SYO.     

Antimicrobial susceptibility of non-fermenting Gram-negative pathogens isolated from cystic fibrosis patients

Non-fermenting Gram-negative bacteria (NFGNB) are increasingly cultured in respiratory samples from cystic fibrosis (CF) patients. This study determined the antimicrobial susceptibility of clinical CF respiratory isolates from distinct geographical regions. A total of 286 isolates (106 Stenotrophomonas maltophilia, 100 Burkholderia spp., 59 Achromobacter spp., 12 Pandoraea spp., 9 Ralstonia spp.) from the Netherlands, Northern Ireland, Spain, USA and Australia were tested. MIC_50/90 values and susceptibility categorisation were determined. Trimethoprim/sulfamethoxazole (SXT) was the most active compound for all micro-organisms (MIC₅₀, 0.12–4 mg/L; MIC₉₀, 1–16 mg/L). For S. maltophilia, 47% and 62% of isolates were susceptible to SXT according to CLSI and EUCAST breakpoints, respectively. Ceftazidime presented lower susceptibility (35%; MIC₅₀, 32 mg/L; MIC₉₀, 256 mg/L). MIC₉₀ values for tobramycin and colistin were >128 mg/L and >16 mg/L, respectively. Regarding Burkholderia, 72%, 56% and 44% were susceptible to SXT, ceftazidime and meropenem, respectively. For both ceftazidime and meropenem, MIC₅₀ and MIC₉₀ values were within the intermediate or resistant category. The most active antibiotics for Achromobacter spp. were SXT (MIC₅₀, 0.5 mg/L; MIC₉₀, 8 mg/L) and imipenem (MIC₅₀, 2 mg/L; MIC₉₀, 8 mg/L). SXT, imipenem and ciprofloxacin were active against 12 Pandoraea spp. (MIC₅₀, 0.12–4 mg/L; MIC₉₀, 1–8 mg/L). Ciprofloxacin (MIC₅₀, 4 mg/L) and SXT (MIC₅₀, 1 mg/L) were the only active antibiotics for Ralstonia spp. There were no statistically significant differences in susceptibility rates between countries. NFGNB other than Pseudomonas aeruginosa are potential pathogens in CF. SXT was demonstrated to be the most active compound against these isolates.     

Activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacterales isolates recovered from intensive care unit patients in Spain: The SUPERIOR multicentre study

Patients in intensive care units (ICUs) present a high risk of developing an infection caused by multidrug-resistant bacteria. Consequently, new antimicrobials and combinations are required. In this study, the activity of ceftolozane/tazobactam (C/T) was evaluated against Enterobacterales (n?=?400) and Pseudomonas aeruginosa (n?=?80) clinical isolates collected from patients in Spanish ICUs with complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). Overall susceptibility to C/T in P. aeruginosa isolates by infection type was 95.7% in cUTI (MIC_50/90, 1/4 mg/L) and 85.3% in cIAI (MIC_50/90, 1/64 mg/L). Activity against P. aeruginosa was maintained regardless of its resistance pattern, confirming that C/T is one of the best antipseudomonal agents along with colistin and amikacin. Susceptibility to C/T in Enterobacterales by infection type was 79.5/81.9% and 89.3/92.3% (EUCAST/CLSI) in cIAI and cUTI isolates, respectively. Activity was excellent against wild-type organisms, with 100% susceptible and inhibited at MIC ≤1 mg/L. Nevertheless, C/T susceptibility decreased against extended-spectrum β-lactamase (ESBL)-producing isolates: Escherichia coli (80.4/84.8% susceptible by EUCAST/CLSI) and Klebsiella pneumoniae (59.1/77.3% susceptible by EUCAST/CLSI). No activity of C/T was observed in carbapenemase-producing isolates. The in vitro activity of C/T observed in this surveillance study suggests that this agent can be considered as a therapeutic option for cUTI and cIAI due to Enterobacterales and P. aeruginosa in ICU patients, particularly when carbapenemase-producing isolates are not involved.     

Surveillance of tigecycline activity tested against clinical isolates from a global (North America,Europe, Latin America and Asia-Pacific) collection (2016)

Tigecycline and comparators were tested by the reference broth microdilution method against 33 348 non-duplicate bacterial isolates collected prospectively in 2016 from medical centres in the Asia-Pacific (3443 isolates), Europe (13 530 isolates), Latin America (3327 isolates) and the USA (13 048 isolates). Among 7098 Staphylococcus aureus isolates tested, >99.9% were inhibited by ≤0.5?mg/L tigecycline (MIC_50/90, 0.06/0.12?mg/L), including >99.9% of methicillin-resistant S. aureus and 100.0% of methicillin-susceptible S. aureus. Tigecycline was slightly more active against Enterococcus faecium (MIC_50/90, 0.03/0.06?mg/L) compared with Enterococcus faecalis (MIC_50/90, 0.06/0.12?mg/L) and its activity was not adversely affected by vancomycin resistance when tested against these organisms. Tigecycline potency was comparable for Streptococcus pneumoniae (MIC_50/90, 0.03/0.06?mg/L), viridans group streptococci (MIC_50/90, 0.03/0.06?mg/L) and β-haemolytic streptococci (MIC_50/90, 0.06/0.06?mg/L) regardless of species and penicillin susceptibility. Tigecycline was active against Enterobacteriaceae (MIC_50/90, 0.25/1?mg/L; 97.8% inhibited at ≤2?mg/L) but was slightly less active against Enterobacteriaceae isolates expressing resistant phenotypes: carbapenem-resistant Enterobacteriaceae (MIC_50/90, 0.5/2?mg/L; 98.0% susceptible); multidrug-resistant (MIC_50/90, 0.5/2?mg/L; 93.1% susceptible); and extensively drug-resistant (MIC_50/90, 0.5/4?mg/L; 87.8% susceptible). Tigecycline inhibited 74.4% of 888 Acinetobacter baumannii isolates at ≤2?mg/L (MIC_50/90, 2/4?mg/L) and demonstrated good in vitro activity against Stenotrophomonas maltophilia (MIC_50/90, 1/2?mg/L; 90.6% inhibited at ≤2?mg/L) Tigecycline was active against Haemophilus influenzae (MIC_50/90, 0.12/0.25?mg/L) regardless of β-lactamase status. Tigecycline represents an important treatment option for resistant Gram-negative and Gram-positive bacterial infections.     

Activity of ceftolozane-tazobactam against Gram-negative pathogens isolated from lower respiratory tract infections in the Asia-Pacific region: SMART 2015-2016

The aim of this study was to investigate the susceptibility of respiratory Gram-negative bacteria to ceftolozane/tazobactam and other antibiotics in the Asia-Pacific region during 2015-2016. MICs were determined using the CLSI standard broth microdilution method and interpreted accordingly. Pseudomonas aeruginosa (1574 isolates), Klebsiella pneumoniae (1226), Acinetobacter baumannii (627) and Escherichia coli (476) accounted for 73.1% of 5342 Gram-negative respiratory pathogens. Susceptibility to ceftolozane/tazobactam of individual Enterobacteriaceae was >80%, except for Enterobacter cloacae (76.6%). Ceftolozane/tazobactam inhibited 81.9% of K. pneumoniae and 91.9% of E. coli, with respective MIC₅₀/MIC₉₀ values of 0.5/>32 and 0.25/2 mg/L. For carbapenem-susceptible, ESBL-producing K. pneumoniae and E. coli, susceptibility was 65.5% and 93.3%, respectively, and respective MIC₅₀/MIC₉₀ values were 2/>32 and 0.5/2 mg/L. Bla_{CTX-M-1 group} was most prevalent in selected ESBL-producing K. pneumoniae (40 of 54 isolates) and E. coli (15 of 22 isolates), with ceftolozane/tazobactam susceptibility rates of 50% and 80%, respectively. Bla_SHV-ESBL was the second most prevalent, and ceftolozane/tazobactam inhibited 20% of 20 K. pneumoniae isolates with bla_SHV-ESBL. The only effective antibiotics for carbapenem-non-susceptible K. pneumoniae (111 isolates) and E. coli (24 isolates) were amikacin and colistin. Ceftolozane/tazobactam was effective against almost all tested P. aeruginosa and carbapenem-non-susceptible strains, with susceptibility of 92.3% and 72.8%, respectively; the respective MIC₅₀/MIC₉₀ values were 1/4 and 2/>32 mg/L. The high susceptibility of ceftolozane/tazobactam remained in different age groups, patient locations, recovery times and countries, except Vietnam. In conclusion, ceftolozane/tazobactam was effective against most respiratory Gram-negative pathogens in the Asia-Pacific region; however, the emergence of carbapenem resistance mandates ongoing surveillance.     

Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012)

During 2012, a total of 2968 isolates were consecutively collected from 59 medical centres in the USA and 15 European countries from hospitalised patients with pneumonia. Ceftolozane/tazobactam (tazobactam at a fixed concentration of 4 mg/L) and comparator agents were tested by reference methods, and MIC endpoints were interpreted by CLSI (2013) and EUCAST (2013) breakpoint criteria. Pseudomonas aeruginosa was the most common isolated pathogen (1019 strains; 34.3%), and ceftolozane/tazobactam was the most active β-lactam tested against P. aeruginosa (MIC_50/90, 0.5/4 mg/L; 94.1% inhibited at ≤8 mg/L). P. aeruginosa exhibited moderate susceptibility to meropenem (MIC_50/90, 0.5/>8 mg/L; 73.7% susceptible), ceftazidime (MIC_50/90, 2/>32 mg/L; 73.6% susceptible), cefepime (MIC_50/90, 4/>16 mg/L; 76.5% susceptible), piperacillin/tazobactam (MIC_50/90, 8/>64 mg/L; 69.5% susceptible), levofloxacin [MIC_50/90, 0.5/>4 mg/L; 69.9/61.0% susceptible (CLSI/EUCAST criteria)] and gentamicin (MIC_50/90, 2/>8 mg/L; 80.7% susceptible). Ceftolozane/tazobactam exhibited activity against many ceftazidime-non-susceptible, meropenem-non-susceptible and piperacillin/tazobactam-non-susceptible, multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa isolates. Ceftolozane/tazobactam was active (MIC_50/90, 0.25/4 mg/L; 94.6% inhibited at ≤8 mg/L) against 1530 Enterobacteriaceae, including activity against many MDR and XDR strains. MDR and XDR prevalence varied widely between countries both for P. aeruginosa (24.1% MDR and 17.1% XDR overall) and Enterobacteriaceae (15.4% MDR and 2.7% XDR overall). All β-lactams had limited activity against Acinetobacter spp. and Stenotrophomonas maltophilia. Ceftolozane/tazobactam demonstrated greater in vitro activity than currently available cephalosporins, carbapenems and piperacillin/tazobactam when tested against P. aeruginosa. In addition, ceftolozane/tazobactam demonstrated greater activity than contemporary cephalosporins and piperacillin/tazobactam when tested against most Enterobacteriaceae.     

Nosocomial bloodstream infections due to Candida spp. in the USA: species distribution,clinical features and antifungal susceptibilities

Candida spp. are among the most frequent nosocomial pathogens, contributing significantly to morbidity and mortality. Longitudinal data on the epidemiology of Candida bloodstream infections (BSIs) are still limited. Isolates and clinical data from 1218 episodes of Candida BSI were prospectively collected from patients in 52 hospitals in the USA between 1998 and 2006. Susceptibilities to amphotericin B, flucytosine, fluconazole, posaconazole, voriconazole, anidulafungin, caspofungin and micafungin were determined for 1077 Candida isolates by the CLSI reference broth microdilution method using the recently published species-specific clinical breakpoints. Candida albicans was the most prevalent species (50.7%), followed by Candida parapsilosis (17.4%), Candida glabrata (16.7%) and Candida tropicalis (10.2%). The prevalence of non-albicans Candida spp. increased over time. Patients had a mean age of 51 years and a mean length of hospital stay prior to BSI of 22 days. The main underlying conditions were gastrointestinal (20.1%) and pulmonary (13.0%) diseases. Intravenous catheters (19.1%) and the urinary tract (8.0%) were the most frequently determined likely sources, whilst in the majority of patients (61.1%) no source could be identified. Overall mortality was 38.1%. Of the isolates studied, 0.8% of C. albicans, 100.0% of C. glabrata, 2.9% of C. parapsilosis and 4.9% of C. tropicalis were non-susceptible to fluconazole, and 0.6% of C. albicans, 5.0% of Candida krusei, 7.6% of C. parapsilosis and 9.8% of C. tropicalis were non-susceptible to voriconazole. All echinocandins showed good activity against most Candida spp., including the majority of C. parapsilosis isolates, but only 38.1% of C. glabrata tested susceptible to caspofungin.     

Analysis of global antifungal surveillance results reveals predominance of Erg11 Y132F alteration among azole-resistant Candida parapsilosis and Candida tropicalis and country-specific isolate dissemination

This study evaluated the activity of echinocandins, azoles and amphotericin B against Candida spp. isolates and other yeasts and characterised azole resistance mechanisms in Candida parapsilosis and Candida tropicalis. Invasive Candida spp. isolates (n = 2936) collected in 60 hospitals worldwide during 2016–2017 underwent antifungal susceptibility testing by broth microdilution. Azole-resistant C. parapsilosis and C. tropicalis were submitted to qPCR for ERG11, CDR1 and MDR1, and the whole genome sequence was analysed. Results of non-susceptibility to echinocandins ranged from 0.0–2.3%, being highest in Candida glabrata. More than 99.0% of the Candida albicans isolates were susceptible to both fluconazole and voriconazole. Fluconazole resistance in C. glabrata was 6.5% overall, being highest in the USA (13.0%). Resistance to voriconazole in Candida krusei was only noted in the USA (5.0%). Azoles inhibited 89.1–91.6% of C. parapsilosis isolates, with most resistant isolates noted in Europe (15.1%), including 36 isolates from Italy (three hospitals), of which 34 harboured Erg11 Y132F mutations and overexpressed MDR1. Azole non-wild-type C. tropicalis (7/227) were found in five countries: 3 isolates from Thailand had the same Erg11 Y132F alteration. Fluconazole non-wild-type isolates were noted among 3/77 (3.9%) Candida dubliniensis, 4/17 (23.5%) Candida guilliermondii, 4/47 (8.5%) Candida lusitaniae and other less common yeast species. Echinocandin use has been recommended over fluconazole for invasive Candida infections. However, azoles are still active against the most common Candida spp. and resistance appears to be restricted to certain geographic regions and associated with Erg11 Y132 alterations in C. parapsilosis and C. tropicalis.     

In vitro activity of cefiderocol,a siderophore cephalosporin,against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli,including serine carbapenemase- and metallo-β-lactamase-producing isolates (SIDERO-WT-2014 Study)

Cefiderocol is a siderophore cephalosporin in development for treatment of infections caused by Gram-negative bacilli, including carbapenem-resistant and multidrug-resistant isolates. β-Lactamase carriage and in vitro activity of cefiderocol were determined against 1272 meropenem-non-susceptible isolates of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii collected as part of the SIDERO-WT-2014 surveillance study. Minimum inhibitory concentration (MIC) values for cefiderocol were ≤4 µg/mL against 97.7% of tested isolates, including 100% of IMP-positive (range, 1-2 µg/mL), OXA-58-positive (MIC₉₀, 1 µg/mL), KPC-positive (MIC₉₀, 2 µg/mL), VIM-positive (MIC₉₀, 2 µg/mL), and OXA-48-like-positive (MIC₉₀, 4 µg/mL) isolates; 99.3% of carbapenemase-negative isolates (MIC₉₀, 1 µg/mL); 97.2% of OXA-23-positive isolates (MIC₉₀, 1 µg/mL); 95.2% of OXA-24-positive isolates (MIC₉₀, 1 µg/mL); 91.7% of GES-positive isolates (MIC₉₀, 4 µg/mL); and 64.3% of NDM-positive isolates (MIC₉₀, 8 µg/mL). A total of 29 isolates (2.3%; 15 OXA-23-producers, 6 OXA-24-producers, 5 NDM-producers, and 3 carbapenemase-negative isolates) exhibited cefiderocol MIC ≥8 µg/mL, confirming there was no clear correlation between carriage of β-lactamases included in the molecular testing algorithm and elevated cefiderocol MICs. Similarly, no correlation was observed between cefiderocol MICs and truncation or loss of porin proteins in meropenem-non-susceptible isolates of E. coli and K. pneumoniae. Cefiderocol MICs were also ≤4 µg/mL against 99.3% of 136 colistin-resistant Enterobacteriaceae collected as part of the SIDERO-WT-2014 study, including isolates carrying mcr-1 (MIC₉₀, 2 µg/mL). Cefiderocol demonstrated potent in vitro activity against a collection of carbapenemase-producing and carbapenemase-negative meropenem-non-susceptible Gram-negative bacilli for which few treatment options are available, including the majority of metallo-β-lactamase producing isolates identified.     

High efficacy of clofazimine and its synergistic effect with amikacin against rapidly growing mycobacteria

The aim of this study was to determine whether clofazimine, dapsone and cycloserine may be suitable antimicrobial agents for the treatment of infections due to rapidly growing mycobacteria (RGM). The antimicrobial activity of the three drugs against 117 Mycobacterium abscessus isolates, 48 Mycobacterium fortuitum isolates and 20 Mycobacterium chelonae isolates was evaluated based on their broth microdilution minimal inhibitory concentrations (MICs) against the isolates. Clofazimine was highly efficacious against these RGM. The vast majority of M. abscessus, M. fortuitum and M. chelonae isolates (99.1%, 91.7% and 100%, respectively) had clofazimine MICs of ≤1 mg/L. MIC₅₀ values (MIC for 50% of the organisms) of clofazimine against the isolates ranged from 0.25 mg/L to 0.5 mg/L and MIC₉₀ values (MIC for 90% of the organisms) ranged from 0.5 mg/L to 1.0 mg/L. Cycloserine and dapsone had little or no activity against the isolates. The effects of combined application of clofazimine and amikacin on 40 M. abscessus isolates, 48 M. fortuitum isolates and 20 M. chelonae isolates were evaluated. Addition of 0.25× MIC of amikacin for the isolates to clofazimine reduced clofazimine MICs in all of the M. abscessus and M. chelonae isolates and in 48% of the M. fortuitum isolates tested. Clofazimine, either alone or combined with amikacin, may serve as a promising drug for the treatment of RGM infections.     

Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: Time for harmonization of CLSI and EUCAST broth microdilution methods

BackgroundBoth the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) have MIC clinical breakpoints (CBPs) for fluconazole (FLU) and Candida. EUCAST CBPs are species-specific, and apply only to C. albicans, C. tropicalis and C. parapsilosis, while CLSI CBPs apply to all species. We reassessed the CLSI CBPs for FLU and Candida in light of recent data.MethodsWe examined (1) molecular mechanisms of resistance and cross-resistance profiles, (2) wild-type (WT) MICs and epidemiological cutoff values (ECVs) for FLU and major Candida species by both CLSI and EUCAST methods, (3) determination of essential (EA) and categorical agreement (CA) between CLSI and EUCAST methods, (4) correlation of MICs with outcomes from previously published data using CLSI and EUCAST methods, and (5) pharmacokinetic and pharmacodynamic considerations. We applied these findings to propose new species-specific CLSI CBPs for FLU and Candida.ResultsWT distributions from large collections of Candida revealed similar ECVs by both CLSI and EUCAST methods (0.5–1 mcg/ml for C. albicans, 2 mcg/ml for C. parapsilosis and C. tropicalis, 32 mcg/ml for C. glabrata, and 64–128 for C. krusei). Comparison of CLSI and EUCAST MICs reveal EA and CA of 95% and 96%, respectively. Datasets correlating CLSI and EUCAST FLU MICs with outcomes revealed decreased response rates when MICs were >4 mcg/ml for C. albicans, C. tropicalis and C. parapsilosis, and >16 mcg/ml for C. glabrata.ConclusionsAdjusted CLSI CBPs for FLU and C. albicans, C. parapsilosis, C. tropicalis (S, ≤2 mcg/ml; SDD, 4 mcg/ml; R, ≥8 mcg/ml), and C. glabrata (SDD, ≤32 mcg/ml; R, ≥64 mcg/ml) should be more sensitive for detecting emerging resistance among common Candida species and provide consistency with EUCAST CBPs.     

Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in the Asia-Pacific region (minus China,Australia and New Zealand): report from an Antimicrobial Surveillance Programme (2013–2015)

The aim of this study was to evaluate the in vitro activity of ceftolozane/tazobactam and comparator agents tested against Enterobacteriaceae and Pseudomonas aeruginosa isolates from patients in the Asia-Pacific (APAC) region with healthcare-associated infections. Ceftolozane/tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. A total of 1963 Gram-negative organisms (489 P. aeruginosa and 1474 Enterobacteriaceae) were consecutively collected using a prevalence-based approach from 14 medical centres in the APAC region. Antimicrobial susceptibility testing was performed by broth microdilution method as described by the CLSI and the results were interpreted according to EUCAST and CLSI breakpoint criteria. Ceftolozane/tazobactam [MIC_50/90, 0.25/4?µg/mL; 89.2/85.8% susceptible (CLSI/EUCAST)] and meropenem [MIC_50/90, ≤0.06/≤0.06?µg/mL; 96.3/96.5% susceptible (CLSI/EUCAST)] were the most active compounds tested against Enterobacteriaceae. Isolates displayed susceptibility rates to other β-lactam agents ranging from 85.8/81.0% for piperacillin/tazobactam to 74.4/72.7% for cefepime and 72.8/68.1% for ceftazidime using CLSI/EUCAST breakpoints. Among the Enterobacteriaceae isolates, 3.6% were carbapenem-resistant Enterobacteriaceae (CRE) and 25.6% exhibited an extended-spectrum β-lactamase (ESBL) non-CRE phenotype. Ceftolozane/tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacteriaceae (MIC_50/90, 0.5/16?µg/mL), but not against isolates with a CRE phenotype (MIC_50/90, >32/>32?µg/mL). Ceftolozane/tazobactam was the most potent (MIC_50/90, 0.5/4?µg/mL) β-lactam agent tested against P. aeruginosa isolates, inhibiting 90.8% at an MIC of ≤4?µg/mL. Pseudomonas aeruginosa exhibited high rates of susceptibility to amikacin [91.2/89.4% (CLSI/EUCAST)] and colistin [98.4/100.0% (CLSI/EUCAST)]. Ceftolozane/tazobactam was the most active β-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than available cephalosporins when tested against Enterobacteriaceae.     

Daptomycin activity tested against 164 457 bacterial isolates from hospitalised patients: Summary of 8 years of a Worldwide Surveillance Programme (2005–2012)

We report the results of 8 years (2005–2012) of the Daptomycin Surveillance Programme Worldwide. Consecutive non-duplicate bacterial isolates (prevalence design) were collected from patients with documented infections in 410 medical centres and were susceptibility tested by reference broth microdilution methods. A total of 164 457 Gram-positive isolates were evaluated, including 97 542 Staphylococcus aureus, 21 413 coagulase-negative staphylococci (CoNS), 29 619 enterococci and 15 883 β-haemolytic streptococci. The prevalence of daptomycin-non-susceptible isolates was extremely low for all species in all geographic regions. Overall, the highest occurrence of non-susceptible isolates was observed among CoNS (0.19%), followed by Enterococcus faecium (0.18%), S. aureus (0.05%), Enterococcus faecalis (0.02%) and β-haemolytic streptococci (0.00%). Moreover, no trend towards increased daptomycin resistance (non-susceptibility) was observed for any species in any geographic region during the study interval. Against S. aureus, the daptomycin MIC_50/90 was 0.25/0.5 mg/L in all geographic regions (99.95% susceptible overall). Only 53 daptomycin-non-susceptible S. aureus isolates were observed and the vast majority (49; 92.5%) had a daptomycin MIC value only 1 log₂ dilution above the published susceptible breakpoint. Daptomycin was also active against CoNS (MIC_50/90, 0.25/0.5 mg/L; 99.81% susceptible), E. faecalis (MIC_50/90, 1/2 mg/L; 99.98% susceptible), E. faecium (MIC_50/90, 2/4 mg/L; 99.82% susceptible) including vancomycin-non-susceptible isolates (4521 isolates; MIC_50/90, 2/2 mg/L; 99.76% susceptible), and β-haemolytic streptococci (MIC_50/90, ≤0.06/0.25 mg/L; 100.0% susceptible). In conclusion, daptomycin has remained very active against indicated species worldwide, and no significant year-to-year or regional variation in daptomycin activity has been detected.     

In vitro activity of avibactam (NXL104) in combination with β-lactams against Gram-negative bacteria, including OXA-48 β-lactamase-producing Klebsiella pneumoniae

The objective of this study was to investigate the in vitro antibacterial activity of avibactam (formerly NXL104) in combination with imipenem, cefepime or ceftazidime against Gram-negative bacteria. Bacterial isolates included: Pseudomonas aeruginosa harbouring PER-1 β-lactamase (n = 14); Acinetobacter baumannii harbouring PER-1, OXA-51 and OXA-58 (n = 20); carbapenem-non-susceptible Klebsiella pneumoniae (n = 25) and Escherichia coli (n = 1) harbouring OXA-48; carbapenem-non-susceptible E. coli (n = 1) harbouring both IMP-1 metallo-β-lactamase and extended-spectrum β-lactamase (ESBL); carbapenem-non-susceptible Serratia marcescens (n = 1); and carbapenem-susceptible E. coli (n = 20) and K. pneumoniae isolates (n = 12) with CTX-M-15 ESBL. Minimum inhibitory concentrations (MICs) of imipenem, cefepime and ceftazidime were determined in combination with 4 mg/L avibactam by the Clinical and Laboratory Standards Institute (CLSI) method on Mueller-Hinton agar. Imipenem/avibactam and ceftazidime/avibactam displayed limited potency against A. baumannii isolates, whereas cefepime/avibactam and ceftazidime/avibactam were active against P. aeruginosa. Klebsiella pneumoniae isolates with OXA-48 β-lactamase were resistant to imipenem [MIC for 90% of the organisms (MIC₉₀) ≥4 mg/L]. MIC₉₀ values for the combination of avibactam 4 mg/L with imipenem, cefepime and ceftazidime were in the susceptible range for all strains (MIC₉₀ ≤ 0.5 mg/L). All E. coli and K. pneumoniae isolates with CTX-M-15 β-lactamase were inhibited at ≤1 mg/L for combinations with avibactam and 100% were susceptible by CLSI breakpoint criteria to imipenem, cefepime and ceftazidime. In conclusion, combinations of imipenem, cefepime and ceftazidime with avibactam may present a promising therapeutic strategy to treat infections due to K. pneumoniae with OXA-48 enzyme as well as K. pneumoniae and E. coli with CTX-M-15 enzyme.     

In-vitro pharmacokinetic/pharmacodynamic model data suggest a potential role of new formulations of posaconazole against Candida krusei but not Candida glabrata infections

Posaconazole exhibits in-vitro activity against Candida glabrata and Candida krusei. Epidemiological cut-off values set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI) are 1/1 and 0.5/0.5 mg/L, respectively, but clinical breakpoints have not been established to date. This study explored the pharmacodynamics (PD) of posaconazole in a validated one-compartment in-vitro pharmacokinetic (PK)/PD model, and determined the probability of PK/PD target attainment (PTA) for the available formulations. Five C. glabrata and three C. krusei isolates with posaconazole minimum inhibitory concentrations (MICs) of 0.06–2 and 0.03–0.25 mg/L, respectively, were tested in the PK/PD model simulating different time–concentration profiles of posaconazole. The exposure–effect relationship fAUC_0–24/MIC was described for EUCAST/CLSI methods, and PTA was calculated in order to determine PK/PD susceptibility breakpoints for oral solution (400 mg q12h), and intravenous (i.v.)/tablet formulations (300 mg q24h). Fungicidal activity (~2log kill) was found against the most susceptible C. glabrata isolate alone, and against all three C. krusei isolates. The corresponding EUCAST/CLSI PK/PD targets (fAUC_0–24/MIC) were 102/79 for C. glabrata and 12/8 for C. krusei. Mean PTA was high (>95%) for C. glabrata isolates with EUCAST/CLSI MICs ≤0.03/≤0.03 mg/L for oral solution and ≤0.125/≤0.125 mg/L for i.v. and tablet formulations for the wild-type population. For C. krusei isolates, mean PTA was high (>95%) for EUCAST/CLSI MICs ≤0.25/≤0.5 mg/L for oral solution and ≤1/≤2 mg/L for i.v. and tablet formulations for the wild-type population. The use of posaconazole to treat C. glabrata infections is questionable. Intravenous and tablet formulations may be therapeutic options for the treatment of C. krusei infections, and oral exposure can be optimized with therapeutic drug monitoring (trough levels >0.6–0.9 mg/L).     

依维莫司单独与联合唑类药物对耐药念珠菌体外敏感研究

目的探讨依维莫司单独及联合伊曲康唑、伏立康唑、泊沙康唑和氟康唑对耐药念珠菌及耳念珠菌的体外作用。方法于 2022年 3—6月,采用美国临床实验室标准研究所 M27-A3微量稀释法和微量肉汤稀释棋盘技术研究依维莫司联合伊曲康唑、伏立康唑、泊沙康唑及氟康唑对耐药念珠菌及耳念珠菌的体外治疗作用。通过测定最低抑菌浓度( MIC)和部分抑菌浓度指数来确定协同效应。结果依维莫司单药治疗 22株耐药念珠菌及 10株耳念珠菌的 MIC为 0.250~4.000 mg/L、1.000 mg/L,伊曲康唑、伏立康唑、泊沙康唑、氟康唑单独使用对 22株耐药念珠菌 MIC范围分别为 0.125~4.000 mg/L、<0.125~2.000 mg/L、0.063~2.000 mg/L、1.000~64.000 mg/L,伊曲康唑、伏立康唑、泊沙康唑单独使用对 10株耳念珠菌 MIC范围分别为 0.500~2.000 mg/L、0.125~8.000 mg/L、0.125~1.000 mg/L。当依维莫司与伊曲康唑、伏立康唑、泊沙康唑、氟康唑联合使用时,对耐药念珠菌的协同作用分别是 9株( 40.90%)、 4株( 18.18%)、 8株( 36.36%)、 9株( 40.90%)。当依维莫司联合唑类作用于耳念珠菌,未发现任何拮抗作用。结论依维莫司单独使用对耐药念珠菌及耳念珠菌菌株具有明显抗真菌作用,同时依维莫司联合唑类作用于耐药念珠菌时,表现出良好的协同作用,且没有拮抗作用,其进一步提升其抗耐药念珠及耳念珠菌的作用。     

Activity of ceftobiprole against methicillin-resistant Staphylococcus aureus strains with reduced susceptibility to daptomycin,linezolid or vancomycin,and strains with defined SCCmec types

Ceftobiprole is a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative pathogens including Pseudomonas aeruginosa. The aim of this study was to evaluate the activity of ceftobiprole against MRSA isolates with decreased susceptibility to daptomycin, linezolid or vancomycin as well as isolates from staphylococcal chromosome cassette mec (SCCmec) types I, II, III and IV. Overall, ceftobiprole demonstrated high potency against the 216 isolates tested, with MIC₅₀ and MIC₉₀ values (minimum inhibitory concentrations required to inhibit 50% and 90% of the isolates, respectively) of 1 mg/L and 2 mg/L (97.2% susceptible). The MIC₉₀ for ceftobiprole was 2 mg/L against the linezolid-non-susceptible, daptomycin-non-susceptible and vancomycin-intermediate (VISA and hVISA) subsets and was 1 mg/L against the vancomycin-resistant (VRSA) strains. The MIC_50/90 values for ceftobiprole were 2/4, 1/2, 2/2 and 1/1 mg/L against SCCmec types I, II, III and IV, respectively. SCCmec type I strains had the highest MICs, with six strains exhibiting a ceftobiprole MIC of 4 mg/L and 15 strains at 2 mg/L. Ceftobiprole demonstrated potent activity against MRSA, including subsets of isolates with reduced susceptibility to daptomycin, linezolid and vancomycin. The activity of ceftobiprole against these resistant phenotypes indicates that it may have clinical utility in the treatment of infections caused by multidrug-resistant S. aureus and across strains from prevalent SCCmec types.     

Potent inhibitory activity of taniborbactam towards NDM-1 and NDM-1Q119X mutants,and in vitro activity of cefepime/taniborbactam against MBLs producing Enterobacterales

Objective: This study aimed to investigate the in vitro activity of taniborbactam (VNRX-5133), a novel broad-spectrum bicyclic boronate, against NDM-1 and Q119E, Q119K, Q119C, Q119F, Q119V, and Q119Y NDM-1 variants, which showed an increased activity towards some β-lactams, including cefepime.Methods: Inhibition kinetic assays were spectrophotometrically performed using cefepime (50 μM) as the reporter substrate and 80 nM of each enzyme. Taniborbactam behaves as a competitive inhibitor towards NDM-1 and NDM-1 Q119 variants with lower Ki values (range 3–16 nM). The phenotypic profile was assessed in both Enterobacterales clinical isolates and engineered Escherichia coli BL21(DE3) strains by conventional broth microdilution procedures according to the Clinical and Laboratory Standards Institute (CLSI).Results: Taniborbactam at a fixed concentration of 4 mg/L was able to restore activity of cefepime in 24 of 26 Enterobacterales clinical isolates harbouring metallo-β-lactamases with MIC₅₀/MIC₉₀ values of 14 mg/L. Cefepime MICs were drastically reduced in all clinical isolates and in NDM-1 and Q119X producing Escherichia coli BL21(DE3). Taniborbactam was unable to restore susceptibility to cefepime in two IMP variants producing clinical isolates.Conclusion: The inhibition level of NDM enzymes provided by taniborbactam protects the antibacterial activity of cefepime from this important metallo-β-lactamase.     

In Vitro Activity of Cefiderocol,a Siderophore Cephalosporin,Against Gram-Negative Bacilli Isolated by Clinical Laboratories in North America and Europe in 2015-2016: SIDERO-WT-2015

Cefiderocol (S-649266) is a parenteral siderophore cephalosporin in phase III of clinical development. In this study, we determined the in vitro susceptibility to cefiderocol and comparators of a 2015-2016 collection of 8954 clinical isolates of Gram-negative bacilli (GNB), provided by 100 clinical laboratories in North America and Europe, using the Clinical and Laboratory Standards Institute broth microdilution method. Iron-depleted cation-adjusted Mueller-Hinton broth was used to test cefiderocol. The concentration of cefiderocol inhibiting 90% of isolates (MIC₉₀) was 0.5 mg/L (North America; n=2470) and 1 mg/L (Europe; n=3,543) for Enterobacteriaceae, 0.5 mg/L (North America; n=619) and 0.5 mg/L (Europe; n=921) for Pseudomonas aeruginosa, 1 mg/L (North America; n=308) and 2 mg/L (Europe; n=664) for Acinetobacter spp., 0.5 mg/L (North America; n=165) and 0.25 mg/L (Europe; n=175) for Stenotrophomonas maltophilia, and 0.12 mg/L (North America; n=40) and 0.5 mg/L (Europe; n=49) for Burkholderia cepacia complex spp. Cefiderocol MICs were ≤4 mg/L for 99.9% (6005/6013) of Enterobacteriaceae, 99.9% (1539/1540) of P. aeruginosa, 96.4% (937/972) of Acinetobacter spp., 99.4% (338/340) of S. maltophilia, and 94.4% (84/89) of Burkholderia cepacia complex spp. isolates tested. Against meropenem-non-susceptible isolates, MICs to cefiderocol were ≤4 mg/L for 99.6% (245/246) of Enterobacteriaceae, 99.7% (394/395) of P. aeruginosa, 96.1% (540/562) of Acinetobacter spp., and 87.1% (27/31) of B. cepacia complex spp. We conclude that cefiderocol demonstrated potent in vitro activity (MIC ≤4 mg/L) against the majority (99.4%, 8903/8954) of clinical isolates of GNB in a recent (2015-2016), multi-continent collection, including carbapenem-non-susceptible isolates.