Early oral antibiotic switch in Staphylococcus aureus bacteraemia: The Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Early Oral Switch Protocol.

BACKGROUND: Staphylococcus aureus bloodstream infection (bacteraemia) is traditionally treated with at least two weeks of IV antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteraemia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients. PROTOCOL: The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 +/- 2 (uncomplicated SAB) and day 14 +/-2 (complicated SAB) to determine their eligibility for randomisation to EOS (intervention) or continued IV treatment (current standard of care). DISCUSSION: Recruitment is occurring to the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomised to the EOS domain, a total of 264 participants across 77 centres, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials.

Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand.

BACKGROUND: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete. METHODS: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included. RESULTS: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89). CONCLUSIONS: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV.

The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe.

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes.

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ß-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the ß-lactam was administered for 7 days. Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.

Implementation of a pharmacist-led penicillin allergy de-labelling service in a public hospital.

BACKGROUND: Inaccurate allergy labelling results in inappropriate antimicrobial management of the patient, which may affect clinical outcome, increase the risk of adverse events and increase costs. Inappropriate use of alternative antibiotics has implications for antimicrobial stewardship programmes and microbial resistance. METHODS: All adult inpatients labelled as penicillin allergic were identified and screened for eligibility by the study pharmacist. An accurate allergy and medication history was taken. Patients were 'de-labelled', underwent oral challenge or were referred to an immunology clinic, if study criteria were met. All patients included in the study were followed-up 1 year after intervention. RESULTS: Two hundred and fifty eligible patients with a label of 'penicillin allergy' were identified. The prevalence of reported penicillin allergy at Middlemore Hospital was 11%. We found that 80% of study patients could be 'de-labelled'. Of those, 80% were 'de-labelled' after an interview with the pharmacist alone, 16% had an uneventful oral challenge and 4% were deemed to be inappropriately labelled after referral to an immunology clinic. Appropriately labelled patients accounted for 20% of the study population. Changes to inpatient antibiotic therapy were recommended in 61% of 'de-labelled' patients, of which no patients had adverse events after commencing on penicillin antibiotics. At the 1 year follow-up, 98% of patients who were 'de-labelled' had no adverse events to repeated administration of penicillin antibiotics. CONCLUSIONS: This study showed that a pharmacist-led allergy management service is a safe option to promote antimicrobial stewardship and appropriate allergy labelling.

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial.

Importance: Extended-spectrum ß-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum ß-lactamase producers. Objectives: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. Design, Setting, and Participants: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Conclusions and relevance: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. Trial Registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

Prolonged Bacteroides pyogenes infection in a patient with multiple lung abscesses.

Bacteroides pyogenes is naturally found in the oral microbiome of cats and dogs and hence exposure, especially bites from these animals, is a major risk factor for human infections. B pyogenes is known to cause infections that persist despite antibiotic treatment and can have serious clinical outcomes. We present a novel case of complex lung abscesses associated with B pyogenes infection. A 55 year old man presents with a 3-month history of productive cough, night sweats, and 5 kg weight loss. An initial chest radiograph revealed mass-like opacities in the right upper lobe (RUL), right middle lobe (RML), and left lower lobe (LLL). Over the next 4 years the patient underwent multiple investigations and antimicrobial treatments until resolution of the abscesses. We believe that metronidazole in combination with moxifloxacin was a key component in the clinical cure of this patient.

Successful use of locally applied polyhexamethylene biguanide as an adjunct to the treatment of fungal osteomyelitis.

Fungal osteomyelitis is rare in immunocompetent patients and is often difficult to cure, even with optimal medical and surgical management. The authors present two cases of fungal osteomyelitis in which the common swimming pool cleaner, polyhexamethylene biguanide, was used successfully as an adjunct to standard surgical and medical treatment. Also presented is a literature review on the use of polyhexamethylene biguanide for this indication. The authors recommend that this safe and well-tolerated compound be considered as part of the treatment for fungal osteomyelitis.

L'ostéomyélite fongique, rare chez les patients immunocompétents, est souvent difficile à guérir, malgré une prise en charge médicale et chirurgicale optimale. Les auteurs présentent deux cas d'ostéomyélite fongique dans lesquels le polyhexaméthylène biguanide, un nettoyeur pour piscine courant, a été utilisé avec succès en plus du traitement chirurgical et médical. Ils présentent également une analyse bibliographique de l'utilisation de polyhexaméthylène biguanide pour cette indication. Les auteurs recommandent d'envisager d'utiliser ce composant sécuritaire et bien toléré dans le cadre du traitement de l'ostéomyélite fongique.

Drug-resistant tuberculosis in HIV-infected patients in a national referral hospital, Phnom Penh, Cambodia.

BACKGROUND AND OBJECTIVE: There are no recent data on the prevalence of drug-resistant tuberculosis (DR TB) in Cambodia. We aim to describe TB drug resistance amongst adults with pulmonary and extra-pulmonary TB and human immunodeficiency virus (HIV) co-infection in a national referral hospital in Phnom Penh, Cambodia. DESIGN: Between 22 November 2007 and 30 November 2009, clinical specimens from HIV-infected patients suspected of having TB underwent routine microscopy, Mycobacterium tuberculosis culture, and drug susceptibility testing. Laboratory and clinical data were collected for patients with positive M. tuberculosis cultures. RESULTS: M. tuberculosis was cultured from 236 HIV-infected patients. Resistance to any first-line TB drug occurred in 34.7% of patients; 8.1% had multidrug resistant tuberculosis (MDR TB). The proportion of MDR TB amongst new patients and previously treated patients was 3.7 and 28.9%, respectively (p<0.001). The diagnosis of MDR TB was made after death in 15.8% of patients; in total 26.3% of patients with MDR TB died. The diagnosis of TB was established by culture of extra-pulmonary specimens in 23.6% of cases. CONCLUSIONS: There is significant resistance to first-line TB drugs amongst new and previously treated TB-HIV co-infected patients in Phnom Penh. These data suggest that the prevalence of DR TB in Cambodia may be higher than previously recognised, particularly amongst HIV-infected patients. Additional prevalence studies are needed. This study also illustrates the feasibility and utility of analysis of non-respiratory specimens in the diagnosis of TB, even in low-resource settings, and suggests that extra-pulmonary specimens should be included in TB diagnostic algorithms.

Socioeconomic factors correlating with community antimicrobial prescribing.

BACKGROUND: Increasing antimicrobial resistance is a serious concern in New Zealand and worldwide. Antimicrobial resistance is tied to increased community antimicrobial consumption. Investigation of the drivers of antimicrobial prescribing in different locales is needed so that targeted interventions can be devised. Counties Manukau District Health Board (CMDHB) serves a diverse, relatively socio-economically deprived population that has the highest rate of community antimicrobial prescribing in New Zealand. We hypothesise that socio-economic factors are important in determining much of the prescribing of antimicrobials in the CMDHB population. METHODS: We collected data on the number of antibacterial prescriptions per person in each pre-defined geographical Area Unit in the CMDHB community in 2013, and compared these with demographic and socioeconomic parameters collected in the 2013 New Zealand census. Simple and multiple linear regression analyses were used to identify factors that correlated with antimicrobial prescribing. RESULTS: Multiple regression analysis showed that antimicrobial prescribing was strongly associated with a higher ratio of number of people to bedrooms in a dwelling (an index of crowding), with some added association with Maori ethnicity. When these factors were accounted for, there was no significant added influence from a range of other factors such as income, smoking or educational qualifications. CONCLUSIONS: Antimicrobial prescribing may be influenced by different factors within different communities. It is important to target the determinants of antimicrobial prescribing when addressing the issue of high community antimicrobial consumption. In the CMDHB community, crowding in homes is associated with higher rates of antimicrobial prescribing. This association may be because crowding directly increases infection rates, or that crowding serves as a proxy for other factors yet to be identified. Further investigation of the determinants of antimicrobial prescribing is needed.

Infective endocarditis in New Zealand: data from the International Collaboration on Endocarditis Prospective Cohort Study.

AIMS: The International Collaboration on Endocarditis Prospective Cohort Study (ICE-PCS) collected worldwide data on the presentation, management and outcome of infective endocarditis (IE). We present data from patients with endocarditis enrolled from New Zealand. METHODS: Patients who fulfilled the Duke criteria for definite or probable endocarditis were enrolled from five district health boards: Auckland, Counties Manukau, Waitemata, Capital and Coast, and Canterbury, between June 2000 and September 2005. RESULTS: There were 336 New Zealand patients enrolled in the ICE-PCS. Prosthetic valve endocarditis occurred in 31%. Underlying medical conditions were present in 28% of patients, but only 4% of patients had rheumatic heart disease. Forty patients (12%) had healthcare-associated endocarditis. Viridans streptococci were the most common cause of IE (32%), followed by Staphylococcus aureus (24%). Patients with S. aureus IE were more likely to present within a week of symptom onset than those with viridans streptococcus IE (OR 4.18, 95% CI 2.36-7.42). Surgery was performed in 33% of patients. In total, 20 patients (6%) died in hospital. Those with endocarditis caused by coagulase-negative staphylococci had an increased risk of death compared with those viridans streptococcus endocarditis (RR 4.7, 95% CI 1.2-17). The risk of stroke was higher in those with endocarditis caused by S. aureus and coagulase-negative staphylococci (RR 2.7, 95% CI 1.2-6.05, and 4.9, 95% CI 1.9-13, respectively). CONCLUSION: While viridans streptococci remain the predominant causative organisms of IE in New Zealand, many 'traditional' clinical and management aspects of this disease no longer apply. This paper provides a reference for local practitioners assessing and managing IE.