Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Prevalence of healthcare-associated infections and antimicrobial use among inpatients in a tertiary hospital in Fiji: a point prevalence survey.

BACKGROUND: Healthcare-associated infections (HAIs) and antimicrobial use (AMU) are important drivers of antimicrobial resistance, yet there is minimal data from the Pacific region. We sought to determine the point prevalence of HAIs and AMU at Fiji's largest hospital, the Colonial War Memorial Hospital (CWMH) in Suva. A secondary aim was to evaluate the performance of European Centre for Diseases Prevention and Control (ECDC) HAI criteria in a resource-limited setting. METHODS: We conducted a point prevalence survey of HAIs and AMU at CWMH in October 2019. Survey methodology was adapted from the ECDC protocol. To evaluate the suitability of ECDC HAI criteria in our setting, we augmented the survey to identify patients with a clinician diagnosis of a HAI where diagnostic testing criteria were not met. We also assessed infection prevention and control (IPC) infrastructure on each ward. RESULTS: We surveyed 343 patients, with median (interquartile range) age 30 years (16-53), predominantly admitted under obstetrics/gynaecology (94, 27.4%) or paediatrics (83, 24.2%). Thirty patients had one or more HAIs, a point prevalence of 8.7% (95% CI 6.0% to 12.3%). The most common HAIs were surgical site infections (n = 13), skin and soft tissue infections (7) and neonatal clinical sepsis (6). Two additional patients were identified with physician-diagnosed HAIs that failed to meet ECDC criteria due to insufficient investigations. 206 (60.1%) patients were receiving at least one antimicrobial. Of the 325 antimicrobial prescriptions, the most common agents were ampicillin (58/325, 17.8%), cloxacillin (55/325, 16.9%) and metronidazole (53/325, 16.3%). Use of broad-spectrum agents such as piperacillin/tazobactam (n = 6) and meropenem (1) was low. The majority of prescriptions for surgical prophylaxis were for more than 1 day (45/76, 59.2%). Although the number of handwashing basins throughout the hospital exceeded World Health Organization recommendations, availability of alcohol-based handrub was limited and most concentrated within high-risk wards. CONCLUSIONS: The prevalence of HAIs in Fiji was similar to neighbouring high-income countries, but may have been reduced by the high proportion of paediatric and obstetrics patients, or by lower rates of inpatient investigations. AMU was very high, with duration of surgical prophylaxis an important target for future antimicrobial stewardship initiatives.

Mobile phones and computer keyboards: unlikely reservoirs of multidrug-resistant organisms in the tertiary intensive care unit.

Few studies have used molecular epidemiological methods to study transmission links to clinical isolates in intensive care units. Ninety-four multidrug-resistant organisms (MDROs) cultured from routine specimens from intensive care unit (ICU) patients over 13 weeks were stored (11 meticillin-resistant Staphylococcus aureus (MRSA), two vancomycin-resistant enterococci and 81 Gram-negative bacteria). Medical staff personal mobile phones, departmental phones, and ICU keyboards were swabbed and cultured for MDROs; MRSA was isolated from two phones. Environmental and patient isolates of the same genus were selected for whole genome sequencing. On whole genome sequencing, the mobile phone isolates had a pairwise single nucleotide polymorphism (SNP) distance of 183. However, >15,000 core genome SNPs separated the mobile phone and clinical isolates. In a low-endemic setting, mobile phones and keyboards appear unlikely to contribute to hospital-acquired MDROs.

Vancomycin-intermediate Staphylococcus aureus isolates are attenuated for virulence when compared with susceptible progenitors.

OBJECTIVES: Vancomycin-intermediate Staphylococcus aureus (VISA) is associated with genetic changes that may also impact upon pathogenicity. In the current study, we compared the virulence of clinical VISA strains with their isogenic vancomycin-susceptible progenitors (VSSA). METHODS: Production of the critical virulence protein, α toxin, was assessed using Western blot analysis and was correlated to agr activity using a bioluminescent agr-reporter. Cytotoxicity and intracellular persistence were compared ex vivo for VSSA and VISA within non-professional phagocytes (NPP). Virulence and host immune responses were further explored in vivo using a murine model of bacteraemia. RESULTS: VISA isolates produced up to 20-fold less α toxin compared with VSSA, and this was corroborated by either loss of agr activity due to agr mutation, or altered agr activity in the absence of mutation. VISA were less cytotoxic towards NPP and were associated with enhanced intracellular persistence, suggesting that NPP may act as a reservoir for VISA. Infection with VSSA strains produced higher mortality in a murine bacteraemia model (≥90% 7-day mortality) compared with infection with VISA isolates (20% to 50%, p <0.001). Mice infected with VISA produced a dampened immune response (4.6-fold reduction in interleukin-6, p <0.001) and persistent organ bacterial growth was observed for VISA strains out to 7 days. CONCLUSIONS: These findings highlight the remarkable adaptability of S. aureus, whereby, in addition to having reduced antibiotic susceptibility, VISA alter the expression of pathogenic factors to circumvent the host immune response to favour persistent infection over acute virulence.

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.

OBJECTIVES: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). METHODS: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. RESULTS: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. CONCLUSIONS: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.

Changing microbial epidemiology in hematopoietic stem cell transplant recipients: increasing resistance over a 9-year period.

UNLABELLED: Infections remain important contributors to mortality in hematopoietic stem cell transplantation (HSCT). METHOD: We studied the evolving epidemiology and trends in susceptibility of bacterial and Candida isolates at an Australian HSCT center. A total of 528 HSCTs in 508 patients were performed from April 2001 to May 2010. A total of 605 isolates were eligible for study inclusion; 318 (53%) were gram-positive, 268 (44%) were gram-negative, and 19 (3%) were Candida species. RESULTS: The most common site for isolates was blood (380 isolates, 63%). Staphylococcus aureus was the most common gram-positive organism (n = 107, 34%), but trends to increasing coagulase-negative staphylococci (P = 0.002) and vancomycin-resistant Enterococcus (P < 0.001) were observed. Escherichia coli was the most common gram-negative isolate (n = 74, 28%). Fluoroquinolone resistance increased with widespread use of protocol fluoroquinolone prophylaxis (P = 0.001). Carbapenem resistance was found in 44% of Pseudomonas or Acinetobacter isolates. Bloodstream infection with a multidrug-resistant organism (odds ratio 3.61, 95% confidence interval: 1.40-9.32, P = 0.008) was an independent predictor of mortality at 7 days after a positive blood culture. CONCLUSIONS: Antimicrobial resistance is an increasing problem in this vulnerable patient population, and not only has an impact on choice of empiric therapy for febrile neutropenia but also on mortality.

OXA- and GES-type ß-lactamases predominate in extensively drug-resistant Acinetobacter baumannii isolates from a Turkish University Hospital.

We determined the antibiotic susceptibility and genetic mechanisms of resistance in clinical strains of Acinetobacter baumannii from Istanbul, Turkey. A total of 101 clinical strains were collected between November 2011 and July 2012. Antimicrobial susceptibility was performed using the Vitek 2 Compact system and E-test. Multiplex PCR was used for detecting bla(OXA -51-like), bla(OXA -23-like), bla(OXA -40-like) and bla(OXA -58-like) genes. ISAba1, bla(IMP -like), bla(VIM -like), bla(GES), bla(VEB), bla(PER -2), aac-3-Ia and aac-6'-Ib and NDM-1 genes were detected by PCR and sequencing. By multiplex PCR, all strains were positive for bla(OXA -51), 79 strains carried bla(OXA -23) and one strain carried bla(OXA -40). bla(OXA -51) and bla(OXA -23) were found together in 79 strains. ISAba1 element was detected in 81 strains, and in all cases it was found upstream of blaOXA -51 . GES-type carbapenemases were found in 24 strains (GES-11 in 16 strains and GES-22 in 8 strains) while bla(PER -2), bla(VEB -1), bla(NDM -1), blaIMP - and blaVIM -type carbapenemases were not observed. Aminoglycoside modifying enzyme (aac-3-Ia and aac-6'Ib) genes were detected in 13 and 15 strains, respectively. Ninety-seven (96%) A. baumannii strains were defined as MDR and of these, 98% were extensively drug resistant (sensitive only to colistin). Colistin remains the only active compound against all clinical strains. As seen in other regions, OXA-type carbapenemases, with or without an upstream ISAba1, predominate but GES-type carbapenemases also appear to have a significant presence. REP-PCR analysis was performed for molecular typing and all strains were collected into 12 different groups. To our knowledge, this is the first report of GES-11 and OXA-40 in A. baumannii from Turkey.

Clinical characteristics of bacteraemia caused by extended-spectrum ß-lactamase-producing Enterobacteriaceae in the era of CTX-M-type and KPC-type ß-lactamases.

Clin Microbiol Infect 2012; 18: 887-893 ABSTRACT: A multicentre, case-control study was conducted to assess risk factors and patient outcomes of bacteraemia caused by Enterobacteriaceae producing extended-spectrum ß-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs). One hundred and five and 20 patients with bacteraemia caused by ESBL-producing and KPC-producing organisms were matched to controls who had bacteraemia caused by non-ESBL/KPC-producing organisms, respectively. Independent risk factors for ESBL production included admission from a nursing home (OR 4.64; 95% CI 2.64-8.16), chronic renal failure (OR 2.09; 95% CI 1.11-3.92), the presence of a gastrostomy tube (OR 3.36; 95% CI 1.38-8.18), length of hospital stay before infection (OR 1.02; 95% CI 1.01-1.03), transplant receipt (OR 2.48; 95% CI 1.24-4.95), and receipt of antibiotics with Gram-negative activity in the preceding 30 days (OR 1.76; 95% CI 1.00-3.08). Twenty-eight-day crude mortality rates for patients infected with ESBL-producing or KPC-producing organisms and controls were 29.1% (34/117) and 19.5% (53/272), respectively (OR 1.70; 95% CI 1.04-2.80). On multivariate analysis, inadequate empirical therapy (OR 2.26; 95% CI 1.18-4.34), onset of bacteraemia while in the intensive-care unit (OR 2.74; 95% CI 1.47-5.11), Apache II score (OR 1.17; 95% CI 1.12-1.23) and malignancy (OR 2.66; 95% CI 1.31-5.41) were independent risk factors for mortality. CTX-M was the most common ESBL type in Escherichia coli, whereas SHV predominated in Klebsiella spp. and Enterobacter spp.

Pseudomonas aeruginosa bacteremia over a 10-year period: multidrug resistance and outcomes in transplant recipients.

AIM: Transplant recipients are at risk for hospital-acquired infections (HAIs), including those caused by Pseudomonas aeruginosa. Of all HAIs, bloodstream infection (BSI) remains one of the most life-threatening. METHODS: Over a 10-year period, we studied 503 patients, including 149 transplant recipients, with pseudomonal BSI from the University of Pittsburgh Medical Center. Trends in antimicrobial susceptibility, risk factors for multidrug resistance (MDR), and outcomes were compared between transplant and non-transplant patients. RESULTS: Resistance to all antibiotic classes was significantly greater in pseudomonal blood culture isolates from transplant compared with non-transplant patients (P<0.001). Of isolates from transplant recipients (n=207), 43% were MDR, compared with 18% of isolates from non-transplant patients (n=391) (odds ratio [OR] 3.47; 95% confidence interval [CI] 2.34-5.14, P<0.001). Among all patients, independent risk factors for MDR P. aeruginosa BSI included previous transplantation (OR 2.38; 95% CI 1.51-3.76, P<0.001), hospital-acquired BSI (OR 2.41; 95% CI 1.39-4.18, P=0.002), and prior intensive care unit (ICU) admission (OR 2.04; 95% CI 1.15-3.63, P=0.015). Mortality among transplant recipients was 42%, compared with 32% in non-transplant patients (OR 1.55; 95% CI 0.87-2.76, P=0.108). For transplant recipients, onset of BSI in the ICU was the only independent predictor of mortality (OR 8.00; 95% CI 1.71-37.42, P=0.008). CONCLUSIONS: Transplant recipients are at greater risk of MDR P. aeruginosa BSI, with an appreciable mortality. Future management must concentrate on the implementation of effective preventative strategies.

Utility of peptide nucleic acid fluorescence in situ hybridization for rapid detection of Acinetobacter spp. and Pseudomonas aeruginosa.

The utility of peptide nucleic acid fluorescence in situ hybridization (PNA FISH) for the detection of Acinetobacter spp. and Pseudomonas aeruginosa was evaluated on broth suspensions and spiked blood cultures of ATCC strains and clinical isolates with select gram-negative rods. After testing 60 clinical isolates, PNA FISH had a sensitivity and specificity of 100% and 100%, respectively, for Acinetobacter spp. and 100% and 95%, respectively, for P. aeruginosa. PNA FISH was able to detect both pathogens simultaneously and directly from spiked blood cultures.

Comparison of quantiferon-TB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation.

Screening for latent tuberculosis infection (LTBI) is recommended prior to organ transplantation. The Quantiferon-TB Gold assay (QFT-G) may be more accurate than the tuberculin skin test (TST) in the detection of LTBI. We prospectively compared the results of QFT-G to TST in patients with chronic liver disease awaiting transplantation. Patients were screened for LTBI with both the QFT-G test and a TST. Concordance between test results and predictors of a discordant result were determined. Of the 153 evaluable patients, 37 (24.2%) had a positive TST and 34 (22.2%) had a positive QFT-G. Overall agreement between tests was 85.1% (kappa= 0.60, p < 0.0001). Discordant test results were seen in 12 TST positive/QFT-G negative patients and in 9 TST negative/QFT-G positive patients. Prior BCG vaccination was not associated with discordant test results. Twelve patients (7.8%), all with a negative TST, had an indeterminate result of the QFT-G and this was more likely in patients with a low lymphocyte count (p = 0.01) and a high MELD score (p = 0.001). In patients awaiting liver transplantation, both the TST and QFT-G were comparable for the diagnosis of LTBI with reasonable concordance between tests. Indeterminate QFT-G result was more likely in those with more advanced liver disease.

Breakthrough Scedosporium prolificans infection while receiving voriconazole prophylaxis in an allogeneic stem cell transplant recipient.

Breakthrough invasive fungal infections among patients with hematologic malignancies receiving voriconazole are being reported with increasing frequency, with zygomycete infections predominating. We report a case of disseminated Scedosporium prolificans infection in a patient receiving voriconazole prophylaxis. Despite poor in vitro activity of voriconazole for this organism, synergy studies using the checkerboard method demonstrated synergy with the combination of voriconazole and terbinafine. This regimen, in conjunction with central venous line removal and intravitreal voriconazole, contributed to the recovery of the patient. S. prolificans is a life-threatening mold that should be considered in patients with breakthrough invasive fungal infections while on voriconazole prophylaxis.

Life-threatening community-acquired methicillin-resistant Staphylococcus aureus infection in Australia.

Eight patients with invasive bacteremic community-acquired methicillin-resistant Staphylococcus aureus infection in southeast Queensland, Australia, are reported. One patient died of septic shock. Haematogenous seeding to lungs, bone, and other sites was common. All isolates carried the virulence factor Panton-Valentine leukocidin and were either the southwest Pacific clone or the newly described Queensland clone. Clinicians should consider community-acquired methicillin-resistant Staphylococcus aureus infection in any patient presenting to hospital with severe staphylococcal sepsis or pneumonia.

Continuous and 4 h infusion of amphotericin B: a comparative study involving high-risk haematology patients.

OBJECTIVES: To assess whether a continuous infusion of amphotericin B (CI-AmB) is less nephrotoxic than a 4 h infusion in haematology patients with fever and neutropenia, including bone-marrow transplant recipients. Efficacy was assessed as a secondary end-point. PATIENTS AND METHODS: We conducted a retrospective cohort study over a 2 year period. A total of 1073 haematology admissions were reviewed (98.3% complete) and 81 admissions were eligible for study entry; 39 received CI-AmB and 42 a 4 h infusion of AmB. RESULTS: Renal impairment occurred significantly less frequently with CI-AmB compared with a 4 h infusion of AmB [10% versus 45%, respectively, odds ratio (OR) 0.14; 95% confidence interval (CI) 0.04-0.5, P < 0.001]. The difference was maintained among allogeneic transplant recipients (P = 0.007) and patients receiving concurrent nephrotoxic drugs (P < 0.001). An AmB infusion rate of <0.08 mg/kg/h was associated with a significant reduction in renal impairment (P < 0.001). A difference in survival was observed between the continuous and 4 h infusion of AmB (95% versus 79%, respectively, OR 5.1; 95% CI 1.02-25.1, P = 0.03). CONCLUSIONS: CI-AmB appears to be significantly less nephrotoxic than 4 h infusion AmB in haematology patients with fever and neutropenia--including high-risk bone-marrow transplant recipients--without increasing mortality. An AmB infusion rate of <0.08 mg/kg/h appears to be a safe threshold, associated with reduced renal impairment.