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Vancomycin-resistant enterococci (VRE) are common causes of bloodstream infections (BSIs) with high morbidity and mortality rates. They are pathogens of global concern with a limited treatment pipeline. Significant challenges exist in the management of VRE BSI, including drug dosing, the emergence of resistance, and the optimal treatment for persistent bacteremia and infective endocarditis. Therapeutic drug monitoring (TDM) for antimicrobial therapy is evolving for VRE-active agents; however, there are significant gaps in the literature for predicting antimicrobial efficacy for VRE BSIs. To date, TDM has the greatest evidence for predicting drug toxicity for the three main VRE-active antimicrobial agents daptomycin, linezolid, and teicoplanin. This article presents an overview of the treatment options for VRE BSIs, the role of antimicrobial dose optimization through TDM in supporting clinical infection management, and challenges and perspectives for the future.
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Antiinfecciosos , Bacteriemia , Infecciones por Bacterias Grampositivas , Sepsis , Enterococos Resistentes a la Vancomicina , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Vancomicina/farmacología , Vancomicina/uso terapéutico , Linezolid/uso terapéutico , Bacteriemia/tratamiento farmacológico , Antiinfecciosos/uso terapéutico , Infecciones por Bacterias Grampositivas/tratamiento farmacológicoRESUMEN
BACKGROUND: Nocardia is a ubiquitous saprophyte capable of causing human disease. Disease is primarily respiratory or cutaneous, usually acquired via inhalation or inoculation. Under the influence of environmental and host factors, Nocardia incidence and species distribution demonstrate geographical variation. AIMS: To examine for differences in Nocardia incidence within Western Australia (WA) and analyse species distribution in the context of prior published studies. To analyse antibiogram data from a nationwide passive antimicrobial resistance surveillance program. METHODS: Retrospective extraction of laboratory data for Western Australian Nocardia isolates over a 21-year period. Analysis of Nocardia antimicrobial susceptibility testing data submitted to the Australian Passive Antimicrobial Resistance Surveillance (APAS) program between 2005 and 2022. RESULTS: Nine hundred sixty WA isolates were identified, giving an annual incidence of 3.03 per 100 000 population with apparent latitudinal variation. The four most common species identified within WA and amongst APAS isolates were N. nova, N. cyriacigeorgica, N. brasiliensis and N. farcinica. APAS data demonstrated that all species exhibited high rates of susceptibility to linezolid (100%) and trimethoprim-sulfamethoxazole (98%). Amikacin (>90% susceptibility for all species except N. transvalensis) was the next most active parenteral agent, superior to both carbapenems and third-generation cephalosporins. Susceptibility to oral antimicrobials (other than linezolid) demonstrated significant interspecies variation. CONCLUSIONS: We demonstrate geographical variation in the distribution of Nocardia incidence. Four species predominate in the Australian setting, and nationwide data confirm a high in vitro susceptibility to trimethoprim-sulphamethoxazole and linezolid, justifying their ongoing role as part of first-line empiric therapy.
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OBJECTIVES: Pharmacodynamic profiling of oral ciprofloxacin dosing for urinary tract infections caused by ceftriaxone-resistant Escherichia coli isolates with ciprofloxacin MICâ≥â0.25 mg/L. BACKGROUND: Urine-specific breakpoints for ciprofloxacin do not exist. However, high urinary concentrations may promote efficacy in isolates with low-level resistance. METHODS: Ceftriaxone-resistant E. coli urinary isolates were screened for ciprofloxacin susceptibility. Fifteen representative strains were selected and tested using a dynamic bladder infection model. Oral ciprofloxacin dosing was simulated over 3 days (250 mg daily, 500 mg daily, 250 mg 12 hourly, 500 mg 12 hourly and 750 mg 12 hourly). The model was run for 96 h. Primary endpoint was change in bacterial density at 72 h. Secondary endpoints were follow-up change in bacterial density at 96 h and area-under-bacterial-kill-curve. Bacterial response was related to exposure (AUC0-24/MIC; Cmax/MIC). PTA was determined using Monte-Carlo simulation. RESULTS: Ninety-three clinical isolates demonstrated a trimodal ciprofloxacin MIC distribution (modal MICs at 0.016, 0.25 and 32 mg/L). Fifteen selected clinical isolates (ciprofloxacin MIC 0.25-512 mg/L) had a broad range of quinolone-resistance genes. Following ciprofloxacin exposure, E. coli ATCC 25922 (MIC 0.008 mg/L) was killed in all dosing experiments. Six isolates (MICâ≥â16 mg/L) regrew in all experiments. Remaining isolates (MIC 0.25-8 mg/L) regrew variably after an initial period of killing, depending on simulated ciprofloxacin dose. A >95% PTA, using AUC0-24/MIC targets, supported 250 mg 12 hourly for susceptible isolates (MICâ≤â0.25 mg/L). For isolates with MICâ≤â1 mg/L, 750 mg 12 hourly promoted 3 log10 kill at the end of treatment (72 h), 1 log10 kill at follow-up (96 h) and 90% maximal activity (AUBKC0-96). CONCLUSIONS: Bladder infection modelling supports oral ciprofloxacin activity against E. coli with low-level resistance (ciprofloxacin MICâ≤â1 mg/L) when using high dose therapy (750 mg 12 hourly).
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Cistitis , Infecciones Urinarias , Humanos , Ciprofloxacina/farmacología , Ceftriaxona/uso terapéutico , Escherichia coli , Vejiga Urinaria/microbiología , Infecciones Urinarias/microbiología , Bacterias , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacologíaRESUMEN
INTRODUCTION: The use of oral fosfomycin for urinary tract infections (UTIs) caused by non-Escherichia coli uropathogens is uncertain, including Klebsiella pneumoniae, the second most common uropathogen. METHODS: A multicompartment bladder infection in vitro model was used with standard media and synthetic human urine (SHU) to simulate urinary fosfomycin exposure after a single 3â g oral dose (fAUC0-72 16884â mg·h/L, t½ 5.5â h) against 15 K. pneumoniae isolates including ATCC 13883 (MIC 2 to >1024â mg/L) with a constant media inflow (20â mL/h) and 4-hourly voiding of each bladder. The impact of the media (CAMHB + G6P versus SHU) on fosfomycin MIC measurements, drug-free growth kinetics and regrowth after fosfomycin administration was assessed. A low and high starting inoculum (5.5 versus 7.5 log10 cfu/mL) was assessed in the bladder infection model. RESULTS: Compared with CAMHB, isolates in SHU had a slower growth rate doubling time (37.7 versus 24.1â min) and reduced growth capacity (9.0 ± 0.3 versus 9.4 ± 0.3â log10 cfu/mL), which was further restricted with increased inflow rate (40â mL/h) and more frequent voids (2-hourly). Regrowth was commonly observed in both media with emergence of fosfomycin resistance promoted by a high starting inoculum in CAMHB (MIC rise to ≥1024â mg/L in 13/14 isolates). Resistance was rarely detected in SHU, even with a high starting inoculum (MIC rise to ≥1024â mg/L in 2/14 isolates). CONCLUSIONS: Simulated in an in vitro UTI model, the regrowth of K. pneumoniae urinary isolates was inadequately suppressed following oral fosfomycin therapy. Efficacy was further reduced by a high starting inoculum.
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Cistitis , Fosfomicina , Infecciones por Klebsiella , Infecciones Urinarias , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Medios de Cultivo , Cistitis/tratamiento farmacológico , Escherichia coli , Femenino , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae , Masculino , Pruebas de Sensibilidad Microbiana , Vejiga Urinaria , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
OBJECTIVES: Fosfomycin is an established treatment for uncomplicated urinary tract infections (UTIs), yet evidence supporting susceptibility breakpoints is limited. We examine the UTI susceptibility criteria. METHODS: Fosfomycin susceptibility, heteroresistance and in vitro growth in a bladder infection model, after a single 3 g dose of oral fosfomycin, were bridged to human pharmacokinetics with pharmacokinetic/pharmacodynamic and Monte Carlo analyses. Data from common uropathogens (24 Escherichia coli, 20 Klebsiella pneumoniae, 4 Enterobacter cloacae, 14 Pseudomonas aeruginosa, 8 Enterococcus faecalis and 8 Enterococcus faecium) were compared and analysed to ascertain species-specific PTA. RESULTS: Glucose-6-phosphate (G6P) increased MICs of E. coli, K. pneumoniae and E. cloacae (median 2-fold dilutions 3-5), but not of P. aeruginosa and Enterococcus. Atypical E. coli lacking G6P potentiation were killed in the bladder infection model despite high MICs (32-128 mg/L). Fosfomycin heteroresistance was uncommon in E. coli (MICâ>â2 mg/L) but was detected in the majority of K. pneumoniae (MICâ>â1 mg/L) and P. aeruginosa (MICâ>8 mg/L). For these species, baseline heteroresistance was a strong predictor for treatment failure in the model. No heteroresistance was found in Enterococcus. The fAUC/MIC targets for stasis were 1935, 3393, 9968, 2738 and 283 for typical E. coli, K. pneumoniae, E. cloacae, P. aeruginosa and E. faecalis, respectively (synthetic human urine medium alone promoted a 1 log10 kill in E. faecium). A >95% PTA for stasis was only found at MICâ≤âepidemiological cut-off (ECOFF) for E. coli (4 mg/L). For other species, PTAs were low for WT populations. CONCLUSIONS: With the exception of E. coli, fosfomycin is a poor target for other uropathogen species. A reduction in oral fosfomycin UTI breakpoints is supported.
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Fosfomicina , Infecciones Urinarias , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Enterococcus , Escherichia coli , Fosfomicina/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa , Vejiga Urinaria , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
BACKGROUND: Third-generation cephalosporin-resistant Gram-negatives (3GCR-GN) and vancomycin-resistant enterococci (VRE) are common causes of multi-drug resistant healthcare-associated infections, for which gut colonisation is considered a prerequisite. However, there remains a key knowledge gap about colonisation and infection dynamics in high-risk settings such as the intensive care unit (ICU), thus hampering infection prevention efforts. METHODS: We performed a three-month prospective genomic survey of infecting and gut-colonising 3GCR-GN and VRE among patients admitted to an Australian ICU. Bacteria were isolated from rectal swabs (n = 287 and n = 103 patients ≤2 and > 2 days from admission, respectively) and diagnostic clinical specimens between Dec 2013 and March 2014. Isolates were subjected to Illumina whole-genome sequencing (n = 127 3GCR-GN, n = 41 VRE). Multi-locus sequence types (STs) and antimicrobial resistance determinants were identified from de novo assemblies. Twenty-three isolates were selected for sequencing on the Oxford Nanopore MinION device to generate completed reference genomes (one for each ST isolated from ≥2 patients). Single nucleotide variants (SNVs) were identified by read mapping and variant calling against these references. RESULTS: Among 287 patients screened on admission, 17.4 and 8.4% were colonised by 3GCR-GN and VRE, respectively. Escherichia coli was the most common species (n = 36 episodes, 58.1%) and the most common cause of 3GCR-GN infection. Only two VRE infections were identified. The rate of infection among patients colonised with E. coli was low, but higher than those who were not colonised on admission (n = 2/33, 6% vs n = 4/254, 2%, respectively, p = 0.3). While few patients were colonised with 3GCR- Klebsiella pneumoniae or Pseudomonas aeruginosa on admission (n = 4), all such patients developed infections with the colonising strain. Genomic analyses revealed 10 putative nosocomial transmission clusters (≤20 SNVs for 3GCR-GN, ≤3 SNVs for VRE): four VRE, six 3GCR-GN, with epidemiologically linked clusters accounting for 21 and 6% of episodes, respectively (OR 4.3, p = 0.02). CONCLUSIONS: 3GCR-E. coli and VRE were the most common gut colonisers. E. coli was the most common cause of 3GCR-GN infection, but other 3GCR-GN species showed greater risk for infection in colonised patients. Larger studies are warranted to elucidate the relative risks of different colonisers and guide the use of screening in ICU infection control.
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Infección Hospitalaria , Farmacorresistencia Bacteriana Múltiple/genética , Escherichia coli , Tracto Gastrointestinal/microbiología , Control de Infecciones , Unidades de Cuidados Intensivos , Enterococos Resistentes a la Vancomicina , Antibacterianos/farmacología , Australia/epidemiología , Resistencia a las Cefalosporinas/genética , Infección Hospitalaria/epidemiología , Infección Hospitalaria/microbiología , Infección Hospitalaria/prevención & control , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Escherichia coli/patogenicidad , Humanos , Control de Infecciones/métodos , Control de Infecciones/normas , Unidades de Cuidados Intensivos/normas , Unidades de Cuidados Intensivos/estadística & datos numéricos , Estudios Prospectivos , Enterococos Resistentes a la Vancomicina/genética , Enterococos Resistentes a la Vancomicina/aislamiento & purificaciónRESUMEN
Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat in both solid organ and stem cell transplant recipients. Invasive CPE infections in transplant recipients are associated with a high mortality, often due to limited therapeutic options and antibacterial toxicities. One of the most therapeutically challenging group of CPE are the metallo-ß-lactamase (MBL)-producing Gram-negative bacteria, which are now found worldwide, and often need treatment with older, highly toxic antimicrobial regimens. Newer ß-lactamase inhibitors such as avibactam have well-established activity against certain carbapenemases such as Klebsiella pneumoniae carbapenemases (KPC), but have no activity against MBL-producing organisms. Conversely, aztreonam has activity against MBL-producing organisms but is often inactivated by other co-existing ß-lactamases. Here, we report four cases of invasive MBL-CPE infections in transplant recipients caused by IMP-4-producing Enterobacter cloacae who were successfully treated with a new, mechanism-driven antimicrobial combination of ceftazidime/avibactam with aztreonam. This novel antimicrobial combination offers a useful treatment option for high-risk patients with CPE infection, with reduced drug interactions and toxicity.
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Compuestos de Azabiciclo , Aztreonam , Ceftazidima , Infecciones por Enterobacteriaceae , Humanos , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Aztreonam/uso terapéutico , Proteínas Bacterianas , beta-Lactamasas , Ceftazidima/uso terapéutico , Combinación de Medicamentos , Enterobacter cloacae , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , Receptores de TrasplantesRESUMEN
Oral fosfomycin trometamol is licensed as a single oral dose for the treatment of uncomplicated urinary tract infections, with activity against multidrug-resistant uropathogens. The impact of interindividual variability in urinary concentrations on antimicrobial efficacy, and any benefit of giving multiple doses, is uncertain. We therefore performed pharmacodynamic profiling of oral fosfomycin, using a dynamic bladder infection in vitro model, to assess high and low urinary exposures following a single oral dose and three repeat doses given every 72 h, 48 h, and 24 h against 16 clinical isolates with various MICs of fosfomycin (8 Escherichia coli, 4 Enterobacter cloacae, and 4 Klebsiella pneumoniae isolates). Baseline fosfomycin high-level-resistant (HLR) subpopulations were detected prior to drug exposure in half of the isolates (2 E. coli, 2 E. cloacae, and 4 K. pneumoniae isolates; proportion, 1 × 10-5 to 5 × 10-4% of the total population). Fosfomycin exposures were accurately reproduced compared to mathematical modeling (linear regression slope, 1.1; R2, 0.99), with a bias of 3.8% ± 5.7%. All 5/5 isolates with MICs of ≤1 µg/ml had no HLR and were killed, whereas 8/11 isolates with higher MICs regrew regardless of exposure to high or low urinary concentrations. A disk diffusion zone of <24 mm was a better predictor for baseline HLR and regrowth. Administering 3 doses with average exposures provided very limited additional kill. These results suggest that baseline heteroresistance is important for treatment response, while increased drug exposure and administering multiple doses may not be better than standard single-dose fosfomycin therapy.
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Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Fosfomicina/administración & dosificación , Fosfomicina/uso terapéutico , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/virología , Escherichia coli/patogenicidad , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/virología , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/virología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/metabolismo , Klebsiella pneumoniae/patogenicidad , Pruebas de Sensibilidad MicrobianaRESUMEN
There are limited treatment options for enterococcal urinary tract infections, especially vancomycin-resistant Enterococcus (VRE). Oral fosfomycin is a potential option, although limited data are available guiding dosing and susceptibility. We undertook pharmacodynamic profiling of fosfomycin against E. faecalis and E. faecium isolates using a dynamic in vitro bladder infection model. Eighty-four isolates underwent fosfomycin agar dilution susceptibility testing (E. faecalis MIC50/90 32/64 µg/ml; E. faecium MIC50/90 64/128 µg/ml). Sixteen isolates (including E. faecalis ATCC 29212 and E. faecium ATCC 35667) were chosen to reflect the MIC range and tested in the bladder infection model with synthetic human urine (SHU). Under drug-free conditions, E. faecium demonstrated greater growth restriction in SHU compared to E. faecalis (E. faecium maximal growth 5.8 ± 0.6 log10 CFU/ml; E. faecalis 8.0 ± 1.0 log10 CFU/ml). Isolates were exposed to high and low fosfomycin urinary concentrations after a single dose, and after two doses given over two days with low urinary concentration exposure. Simulated concentrations closely matched the target (bias 2.3%). E. faecalis isolates required greater fosfomycin exposure for 3 log10 kill from the starting inoculum compared with E. faecium The ƒAUC0-72/MIC and ƒ%T > MIC0-72 for E. faecalis were 672 and 70%, compared to 216 and 51% for E. faecium, respectively. There was no rise in fosfomycin MIC postexposure. Two doses of fosfomycin with low urinary concentrations resulted in equivalent growth inhibition to a single dose with high urinary concentrations. With this urinary exposure, fosfomycin was effective in promoting suppression of regrowth (>3 log10 kill) in the majority of isolates.
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Enterococcus faecium , Fosfomicina , Infecciones por Bacterias Grampositivas , Infecciones Urinarias , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Enterococcus , Enterococcus faecalis , Fosfomicina/farmacología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Humanos , Pruebas de Sensibilidad Microbiana , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
OBJECTIVES: We used a dynamic bladder infection in vitro model with synthetic human urine (SHU) to examine fosfomycin exposures to effectively kill, or prevent emergence of resistance, among Pseudomonas aeruginosa isolates. METHODS: Dynamic urinary fosfomycin concentrations after 3 g oral fosfomycin were simulated, comparing single and multiple (daily for 7 days) doses. Pharmacodynamic response of 16 P. aeruginosa (MIC range 1 to >1024 mg/L) were examined. Baseline disc diffusion susceptibility, broth microdilution MIC and detection of heteroresistance were assessed. Pathogen kill and emergence of resistance over 72 h following a single dose, and over 216 h following daily dosing for 7 days, were investigated. The fAUC0-24/MIC associated with stasis and 1, 2 and 3â log10 kill were determined. RESULTS: Pre-exposure high-level resistant (HLR) subpopulations were detected in 11/16 isolates after drug-free incubation in the bladder infection model. Five of 16 isolates had >2â log10 kill after single dose, reducing to 2/16 after seven doses. Post-exposure HLR amplification occurred in 8/16 isolates following a single dose and in 11/16 isolates after seven doses. Baseline MIC ≥8â mg/L with an HLR subpopulation predicted post-exposure emergence of resistance following the multiple doses. A PK/PD target of fAUC0-24/MIC >5000 was associated with 3â log10 kill at 72 h and 7 day-stasis. CONCLUSIONS: Simulated treatment of P. aeruginosa urinary tract infections with oral fosfomycin was ineffective, despite exposure to high urinary concentrations and repeated daily doses for 7 days. Emergence of resistance was observed in the majority of isolates and worsened following prolonged therapy. Detection of a baseline resistant subpopulation predicted treatment failure.
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Fosfomicina , Infecciones por Pseudomonas , Infecciones Urinarias , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Fosfomicina/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa , Vejiga Urinaria , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
OBJECTIVES: To assess the antibacterial effects of a single 3 g oral fosfomycin dose on Escherichia coli and Klebsiella pneumoniae clinical isolates within a dynamic bladder infection model. METHODS: An in vitro model simulating dynamic urinary fosfomycin concentrations was used. Target fosfomycin exposure (Cmax = 1984 mg/L and Tmax = 7.5 h) was validated by LC-MS/MS. Pharmacodynamic responses of 24 E. coli and 20 K. pneumoniae clinical isolates were examined (fosfomycin MIC ≤0.25-128 mg/L). Mutant prevention concentration (MPC), fosfomycin heteroresistance, fosfomycin resistance genes and fosA expression were examined. Pathogen kill and emergence of high-level resistance (HLR; MIC >1024 mg/L) were quantified. RESULTS: Following fosfomycin exposure, 20 of 24 E. coli exhibited reductions in bacterial counts below the lower limit of quantification without regrowth, despite baseline fosfomycin MICs up to 128 mg/L. Four E. coli regrew (MIC = 4-32 mg/L) with HLR population replacement. At baseline, these isolates had detectable HLR subpopulations and MPC >1024 mg/L. All E. coli isolates were fosA negative. In contrast, 17 of 20 K. pneumoniae regrew post exposure, 6 with emergence of HLR (proportion = 0.01%-100%). The three isolates without regrowth did not have a detectable HLR subpopulation after dynamic drug-free incubation. All K. pneumoniae had MPC >1024 mg/L and were fosA positive. WGS analysis and fosA expression failed to predict fosfomycin efficacy. CONCLUSIONS: E. coli and K. pneumoniae isolates demonstrate discrepant responses to a single fosfomycin dose in a dynamic bladder infection in vitro model. Treatment failure against E. coli was related to an HLR subpopulation, not identified by standard MIC testing. Activity against K. pneumoniae appeared limited, regardless of MIC testing, due to universal baseline heteroresistance.
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Fosfomicina , Infecciones por Klebsiella , Infecciones Urinarias , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Cromatografía Liquida , Escherichia coli/genética , Fosfomicina/farmacología , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/genética , Pruebas de Sensibilidad Microbiana , Espectrometría de Masas en Tándem , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
Coagulase-negative staphylococci (CoNS) represent one of the major causes of health care- and medical device-associated infections. Emerging antimicrobial resistance has complicated the treatment of systemic infections caused by CoNS. Here, we describe the prevalence of antimicrobial resistance in clinical CoNS strains from a tertiary care hospital over a 4-year period, and we observed a significant increase in resistance to daptomycin. Notably, Staphylococcus capitis accounted for the majority of these daptomycin-resistant (DAP-R) CoNS. To further investigate the mechanisms of daptomycin resistance in CoNS, daptomycin-susceptible clinical strains of S. capitis and Staphylococcus epidermidis underwent in vitro daptomycin exposure to generate DAP-R CoNS mutants. Unlike that seen with Staphylococcus aureus, alteration of cell surface charge was not observed in the DAP-R CoNS strains, but biofilm formation was compromised. Whole-genome sequencing analysis of the DAP-R CoNS strains identified single nucleotide polymorphisms (SNPs) in walKR, the essential two-component regulatory system controlling cell wall biogenesis. PCR and sequencing of walK and walR from 17 DAP-R CoNS clinical isolates identified seven nonsynonymous mutations. The results were confirmed by the recreation of the walK SNP in S. epidermidis, which resulted in reduced susceptibility to daptomycin and vancomycin. This study highlights the significance of CoNS in evolving daptomycin resistance and showed that walKR is shared among the staphylococcal species and is involved in antibiotic resistance development. Notably, we did not observe mutations in genes responsible for phospholipid biosynthesis or an altered cell surface charge, suggesting that reduced daptomycin susceptibility in CoNS may emerge in a fashion distinct from that in S. aureus.
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Antibacterianos/farmacología , Daptomicina/farmacología , Farmacorresistencia Bacteriana/genética , Staphylococcus capitis/genética , Staphylococcus epidermidis/genética , Sustitución de Aminoácidos/genética , Proteínas Bacterianas/genética , Biopelículas/crecimiento & desarrollo , Infección Hospitalaria/microbiología , Histidina Quinasa/genética , Humanos , Pruebas de Sensibilidad Microbiana , Polimorfismo de Nucleótido Simple/genética , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus capitis/efectos de los fármacos , Staphylococcus capitis/aislamiento & purificación , Staphylococcus epidermidis/efectos de los fármacos , Staphylococcus epidermidis/aislamiento & purificación , Centros de Atención Terciaria , Vancomicina/farmacologíaRESUMEN
Background: Urinary tract infections (UTIs) are among the most common bacterial infections and a frequent indication for antibiotic use. Fosfomycin, an important oral antibiotic for outpatient UTIs, remains a viable option for MDR uropathogens. We aimed to perform pharmacodynamic profiling simulating urinary concentrations to assess the adequacy of the current dosing regimen. Methods: A dynamic in vitro bladder infection model was developed, replicating urinary fosfomycin concentrations after gastrointestinal absorption, systemic distribution and urinary elimination. Concentrations were measured by LC-MS/MS. Twenty-four Enterobacteriaceae strains (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae; MIC range 0.25-64 mg/L) were examined. Pathogen kill and emergence of resistance was assessed over 72 h. Results: Observed in vitro fosfomycin concentrations accurately simulated urinary fosfomycin exposures (Tmax 3.8â±â0.5 h; Cmax 2630.1â±â245.7 mg/L; AUC0-24 33â¯932.5â±â1964.2 mg·h/L). Fifteen of 24 isolates regrew, with significant rises in fosfomycin MIC (total population MIC50 4 to 64 mg/L, MIC90 64 to >â1024 mg/L, P = 0.0039; resistant subpopulation MIC50 128 to >â1024 mg/L, MIC90 >1024 mg/L, P = 0.0020). E. coli and E. cloacae isolates were killed with pharmacokinetic/pharmacodynamic EI50 of fAUC0-24/MIC = 1922, fCmax/MIC = 149 and fTime>4×MIC = 44 h. In contrast, K. pneumoniae isolates were not reliably killed. Conclusions: Using dynamic in vitro simulations of urinary fosfomycin exposures, E. coli and E. cloacae isolates with MIC >16 mg/L, and all K. pneumoniae isolates, were not reliably killed. Emergence of resistance was significant. This challenges fosfomycin dosing and clinical breakpoints, and questions the utility of fosfomycin against K. pneumoniae. Further work on in vitro dose optimization is required.
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Antibacterianos/farmacología , Enterobacteriaceae/efectos de los fármacos , Fosfomicina/farmacología , Pruebas de Sensibilidad Microbiana , Infecciones Urinarias/microbiología , Farmacorresistencia Bacteriana Múltiple , Escherichia coli/efectos de los fármacos , Humanos , Klebsiella pneumoniae/efectos de los fármacos , Vejiga Urinaria/microbiología , Infecciones Urinarias/tratamiento farmacológico , Orina/químicaRESUMEN
BACKGROUND: Owing to limited availability of donor organs, previous solid organ transplant (SOT) recipients are increasingly considered as potential organ donors. We report donor-derived transmission of herpes simplex virus type-2 (HSV-2) to two clusters of SOT recipients with transmission from the original donor and an HSV-2-infected recipient who subsequently became a donor. METHODS: We reviewed medical records of the donors and recipients in both clusters. Pre-transplant serology and virological features of HSV-2 were characterized. Genotyping of HSV-2 isolates to determine potential for donor transmission of HSV-2 through transplantation of organs from prior organ recipients was performed. RESULTS: A kidney-pancreas recipient died day 9 post transplant. Following confirmation of brain death, the lungs and recently transplanted kidney were donated to two further recipients. The liver was not retrieved, but biopsy confirmed HSV-2 infection. Testing on the original donor showed negative HSV-2 polymerase chain reaction and HSV immunoglobulin (Ig)M, but positive HSV-2 IgG. The liver recipient from the original donor developed HSV-2 hepatitis and cutaneous infection that responded to treatment with intravenous acyclovir. In the second cluster, lung and kidney recipients both developed HSV-2 viremia that was successfully treated with antiviral therapy. Genotyping of all HSV-2-positive samples showed 100% sequence homology for three recipients. CONCLUSIONS: Donor-derived HSV infection affected two clusters of recipients because of transplantation of organs from a prior organ recipient. HSV should be considered as a possible cause of illness in febrile SOT recipients in the immediate post-transplant period and may cause disseminated disease and re-infection in HSV-2-seropositive recipients. Testing of HSV serology and prophylaxis may be considered in SOT recipients not receiving cytomegalovirus prophylaxis.
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Herpes Simple/transmisión , Herpesvirus Humano 2 , Trasplante de Órganos/efectos adversos , Donantes de Tejidos , Adulto , Antivirales/uso terapéutico , Femenino , Herpes Simple/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and nonmelioid Burkholderia species, namely, Burkholderia cepacia complex, collectively are a group of troublesome nonfermenters. Although not inherently virulent organisms, these environmental Gram negatives can complicate treatment in those who are immunocompromised, critically ill in the intensive care unit and those patients with suppurative lung disease, such as cystic fibrosis. Through a range of intrinsic antimicrobial resistance mechanisms, virulence factors, and the ability to survive in biofilms, these opportunistic pathogens are well suited to persist, both in the environment and the host. Treatment recommendations are hindered by the difficulties in laboratory identification, the lack of reproducibility of antimicrobial susceptibility testing, the lack of clinical breakpoints, and the absence of clinical outcome data. Despite trimethoprim-sulfamethoxazole often being the mainstay of treatment, resistance is widely encountered, and alternative regimens, including combination therapy, are often used. This review will highlight the important aspects and unique challenges that these three nonfermenters pose, and, in the absence of clinical outcome data, our therapeutic recommendations will be based on reported antimicrobial susceptibility and pharmacokinetic/pharmacodynamic profiles.
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Achromobacter/efectos de los fármacos , Burkholderia/efectos de los fármacos , Farmacorresistencia Bacteriana , Stenotrophomonas/efectos de los fármacos , Achromobacter/patogenicidad , Antibacterianos/uso terapéutico , Burkholderia/patogenicidad , Infecciones por Burkholderia/tratamiento farmacológico , Infecciones por Burkholderia/microbiología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Stenotrophomonas/patogenicidadAsunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Proteínas de Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Fosfomicina/farmacología , Transferencia de Gen Horizontal , Simbiosis , Anciano , Bacteriemia/tratamiento farmacológico , Escherichia coli/genética , Infecciones por Escherichia coli/tratamiento farmacológico , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
OBJECTIVES: Antimicrobial stewardship programs are recommended to reduce antimicrobial resistance by reducing inappropriate use of antimicrobials. We implemented an antimicrobial stewardship program and aimed to evaluate its effect on broad-spectrum antimicrobial use. DESIGN, SETTING AND PARTICIPANTS: Observational study with historical control using interrupted time series analysis conducted in a tertiary referral hospital. Hospital inpatients prescribed restricted antimicrobials for non-standard indications, where approval had expired or without approval. INTERVENTION: Baseline period of 30 months immediately followed by an 18-03 intervention period commencing January 2011. MAIN OUTCOME MEASURES: Number and type of interventions made by antimicrobial stewardship team; monthly rate of use of broad-spectrum antimicrobial agents (in defined daily doses/1000 occupied bed-18s). RESULTS: The antimicrobial stewardship team made 1104 recommendations in 779 patients during the 18-03 intervention period. In 64% of cases, the recommendation was made to cease or de-escalate the antimicrobial therapy, or to change from intravenous to oral therapy. The introduction of the intervention resulted in an immediate 17% (95% CI, 13%-20%) reduction in broad-spectrum antimicrobial use in the intensive care unit and a 10% (95% CI, 4%-16%) reduction in broad-spectrum antimicrobial use outside the intensive care unit. Reductions were particularly seen in cephalosporin and glycopeptide use, although these were partially offset by increases in the use of ß-lactam-ß-lactamase inhibitors. CONCLUSIONS: The introduction of an antimicrobial stewardship program, including postprescription review, resulted in an immediate reduction in broad-spectrum antimicrobial use in a tertiary referral centre. However, the effect of this intervention reduced over time.
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Antiinfecciosos/uso terapéutico , Prescripciones de Medicamentos/estadística & datos numéricos , Revisión de la Utilización de Medicamentos/organización & administración , Utilización de Medicamentos/tendencias , Australia , Estudios de Casos y Controles , Farmacorresistencia Microbiana , Femenino , Hospitales de Enseñanza , Humanos , Masculino , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Mejoramiento de la CalidadRESUMEN
BACKGROUND: As one of the most common indications for antimicrobial prescription in the community, the management of urinary tract infections (UTIs) is both complicated by, and a driver of, antimicrobial resistance. OBJECTIVES: To highlight the key clinical decisions involved in the diagnosis and treatment of UTIs in adult women, focusing on clinical effectiveness and both diagnostic and antimicrobial stewardship as we approach the post-antimicrobial era. SOURCES: Literature reviewed via directed PubMed searches and manual searching of the reference list for included studies to identify key references to respond to the objectives. A strict time limit was not applied. We prioritised recent publications, randomised trials, and systematic reviews (with or without meta-analyses) where available. Searches were limited to English language articles. A formal quality assessment was not performed; however, the strengths and limitations of each paper were reviewed by the authors throughout the preparation of this manuscript. CONTENT: We discuss the management of UTIs in ambulatory adult women, with particular focus on uncomplicated infections. We address the diagnosis of UTIs, including the following: definition and categorisation; bedside assessments and point-of-care tests; and the indications for, and use of, laboratory tests. We then discuss the treatment of UTIs, including the following: indications for treatment, antimicrobial sparing approaches, key considerations when selecting a specific antimicrobial agent, specific treatment scenarios, and duration of treatment. We finally outline emerging areas of interest in this field. IMPLICATIONS: The steady increase in antimicrobial resistance among common uropathogens has had a substantial affect on the management of UTIs. Regarding both diagnosis and treatment, the clinician must consider both the patient (clinical effectiveness and adverse effects, including collateral damage) and the community more broadly (population-level antimicrobial selection pressure).
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Antiinfecciosos , Programas de Optimización del Uso de los Antimicrobianos , Infecciones Urinarias , Adulto , Femenino , Humanos , Antibacterianos/uso terapéutico , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , Antiinfecciosos/uso terapéutico , Resultado del TratamientoRESUMEN
AIM: Daptomycin therapeutic drug monitoring (TDM) is a potentially valuable intervention for a relatively new drug. The aim of this study was to determine whether daptomycin TDM, including dose adjustment where necessary, improves the clinical outcomes of adult patients with Gram-positive infections. METHODS: A systematic review of English-language studies in MEDLINE (Ovid MEDLINE and Epub Ahead of Print, In-process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions), EMBASE via OVID, Cochrane Central Register of Controlled Trials via the OVID platform, Scopus and Web of Science online databases was performed and conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. There was no discrimination on study type or time of publication. STUDY SELECTION: Adults (age ≥18 years) with a Gram-positive infection requiring treatment with daptomycin who received TDM, with subsequent reporting of serum concentrations and dose adjustment where necessary, were included. RESULTS: In total, 2869 studies were identified, of which nine met the inclusion criteria. No studies of daptomycin TDM including a relevant control arm have been published to date. All of the included studies were single-arm observational cohort studies. Broad heterogeneity was observed between the studies in terms of included pathogens, infection types, daptomycin TDM practices, reported clinical outcomes, and reporting of potential confounders. CONCLUSIONS: No studies exploring the efficacy of routine daptomycin TDM on patient-centred outcomes in comparison with fixed dosing regimens have been published to date. This represents a key knowledge gap as opposed to an inherent lack of efficacy. Further well-designed, comparative studies are required to determine the role of daptomycin TDM in patients with Gram-positive infections.