Retrospective study of outcomes of short versus long duration of antibiotic therapy for residual osteomyelitis in surgically resected diabetic foot infection.

INTRODUCTION: Optimal treatment duration for residual osteomyelitis (OM) post-amputation in diabetic foot infection (DFI) remains unclear, with resultant heterogeneity in prescribing noted in clinical practice. We aimed to identify a difference in outcomes of long duration of antibiotics (LD) with short duration (SD) in patients with culture-positive proximal bone specimen post-amputation. METHODS: In this single-centre retrospective cohort study (Melbourne, Australia), we analysed antibiotic duration of DFI patients requiring amputation with culture-positive proximal bone specimen over a 31 month period (January 2019-September 2021). Primary outcome was reamputation or debridement at the same and/or contiguous site of amputation at 6 months. Secondary outcomes were readmission to hospital and/or recommencement of antibiotics for DFI at the same and/or contiguous site at 6 months. RESULTS: Among 92 patients (83% male, median age 67 years), 26 received <4 weeks (SD) and 66 received ≥4 weeks (LD) antibiotic therapy. In the SD group, primary outcome occurred in 9 patients (35%) compared with 15 patients (23%) in the LD group (P = 0.246). Both secondary outcomes occurred in 12 patients (46%) in the SD group compared with 18 patients (27%) in the LD group (P = 0.086). Adjusted logistic regression analysis showed SD was not significantly associated with primary outcome [OR 1.12 (95% CI 0.38-3.31)] or secondary outcomes [OR 1.67 (95% CI 0.60-4.66)]. CONCLUSIONS: This single-centre experience did not demonstrate significant difference in outcomes between antibiotic duration of <4 weeks and ≥4 weeks in DFI patients with culture-positive proximal bone specimen post-amputation. These data provide background for larger international randomized control trials to establish optimal treatment duration.

Evaluation of a pharmacist-led penicillin allergy de-labelling ward round: a novel antimicrobial stewardship intervention.

BACKGROUND: Antibiotic allergy labels (AALs), reported by up to 25% of hospitalized patients, are a significant barrier to appropriate prescribing and a focus of antimicrobial stewardship (AMS) programmes. METHODS: A prospective audit of a pharmacist-led AMS penicillin allergy de-labelling ward round at Austin Health (Melbourne, Australia) was evaluated. Eligible inpatients with a documented penicillin allergy receiving an antibiotic were identified via an electronic medical report and then reviewed by a pharmacist-led AMS team. The audit outcomes evaluated were: (i) AMS post-prescription review recommendations; (ii) direct de-labelling; (iii) inpatient oral rechallenge referral; (iv) skin prick testing/intradermal testing referral; and (v) outpatient antibiotic allergy clinic assessment. RESULTS: Across a 5 month period, 106 patients were identified from a real-time electronic prescribing antibiotic allergy report. The highest rate of penicillin allergy de-labelling was demonstrated in patients who were referred for an inpatient oral rechallenge with 95.2% (n = 21) successfully having their penicillin AAL removed. From the 22 patients with Type A reactions, 63.6% had their penicillin AAL removed. We demonstrated a significant decrease in the prescribing of restricted antibiotics (defined as third- or fourth-generation cephalosporins, fluoroquinolones, glycopeptides, carbapenems, piperacillin/tazobactam, lincosamides, linezolid or daptomycin) in patients reviewed (pre 42.5% versus post 17.9%, P = 0.0002). CONCLUSIONS: A pharmacist-led AMS penicillin allergy de-labelling ward round reduced penicillin AALs and the prescribing of restricted antibiotics. This model could be implemented at other hospitals with existing AMS programmes.

Taking the challenge: A protocolized approach to optimize Pneumocystis pneumonia prophylaxis in renal transplant recipients.

While trimethoprim-sulfamethoxazole is considered first-line therapy for Pneumocystis pneumonia prevention in renal transplant recipients, reported adverse drug reactions may limit use and increase reliance on costly and less effective alternatives, often aerosolized pentamidine. We report our experience implementing a protocolized approach to trimethoprim-sulfamethoxazole adverse drug reaction assessment and rechallenge to optimize prophylaxis in this patient cohort. We retrospectively reviewed 119 patients receiving Pneumocystis pneumonia prophylaxis prior to and after protocol implementation. Forty-two patients (35%) had 48 trimethoprim-sulfamethoxazole adverse drug reactions documented either at baseline or during the prophylaxis period, of which 83% were non-immune-mediated and 17% were immune-mediated. Significantly more patients underwent trimethoprim-sulfamethoxazole rechallenge after protocol implementation (4/22 vs 23/27; P = .0001), with no recurrence of adverse drug reactions in 74%. In those who experienced a new or recurrent reaction (26%), all were mild and self-limiting with only 1 recurrence of an immune-mediated reaction. After protocol implementation, aerosolized pentamidine-associated costs were reduced. The introduction of a standard approach to trimethoprim-sulfamethoxazole rechallenge in the context of both prior immune and non-immune-mediated reactions was safe and successful in improving the uptake of first-line Pneumocystis pneumonia prophylaxis in renal transplant recipients.

Beyond Penicillin: Rapid Desensitization for Specific Flucloxacillin Hypersensitivity.

Beta-lactam therapy for severe staphylococcal infections is associated with superior outcomes, compared to non-beta-lactam therapy. For patients with immediate hypersensitivity to beta-lactams, desensitization has been widely employed to allow beta-lactam therapy, but published protocols for antistaphylococcal beta-lactams such as flucloxacillin are lacking. Here, we report a case and describe the desensitization protocol successfully used for a patient with isolated flucloxacillin immediate hypersensitivity, for whom a penicillin desensitization protocol would likely have resulted in an adverse drug reaction.

Antimicrobial allergy 'labels' drive inappropriate antimicrobial prescribing: lessons for stewardship.

BACKGROUND: The presence of antimicrobial allergy designations ('labels') often substantially reduces prescribing options for affected patients, but the frequency, accuracy and impacts of such labels are unknown. METHODS: The National Antimicrobial Prescribing Survey (NAPS) is an annual de-identified point prevalence audit of Australian inpatient antimicrobial prescribing using standardized definitions of guideline compliance, appropriateness and indications. Data were extracted for 2 years (2013-14) and compared for patients with an antimicrobial allergy label (AAL) and with no AAL (NAAL). RESULTS: Among 21 031 patients receiving antimicrobials (33 421 prescriptions), an AAL was recorded in 18%, with inappropriate antimicrobial use significantly higher in the AAL group versus the NAAL group (OR 1.12, 95% CI 1.05-1.22, P < 0.002). Patterns of antimicrobial use were significantly influenced by AAL, with lower ß-lactam use (AAL versus NAAL; OR 0.47, 95% CI 0.43-0.50, P < 0.001) and higher quinolone (OR 2.07, 95% CI 1.83-2.34, P < 0.0001), glycopeptide (OR 1.59, 95% CI 1.38-1.83, P < 0.0001) and carbapenem (OR 1.74, 95% CI 1.43-2.13, P < 0.0001) use. In particular, among immunocompromised patients, AAL was associated with increased rates of inappropriate antimicrobial use (OR 1.68, 95% CI 1.21-2.30, P = 0.003), as well as increased use of quinolones (OR 1.88, 95% CI 1.16-3.03, P = 0.02) and glycopeptides (OR 1.82, 95% CI 1.17-2.84, P = 0.01). CONCLUSIONS: AALs are common and appear to be associated with higher rates of inappropriate prescribing and increased use of broad-spectrum antimicrobials. Improved accuracy in defining AALs is likely to be important for effective antimicrobial stewardship (AMS), with efforts to 'de-label' inappropriate AAL patients a worthwhile feature of future AMS initiatives.

Clinical utility of panfungal polymerase chain reaction for the diagnosis of invasive fungal disease: a single center experience.

The role of panfungal polymerase chain reaction (PCR) assays for diagnosis of invasive fungal disease (IFD) is inadequately defined. We describe the use of an internal transcribed spacer 1 (ITS-1) region-directed panfungal PCR in this context at a tertiary referral transplant center. A retrospective review of patients at Alfred Health, Melbourne, Australia (2009-2014) who had clinical samples referred for panfungal PCR testing was conducted. Baseline patient characteristics, antifungal drug history, fungal culture/histopathology, and radiology results were recorded. For bronchoalveolar lavage (BAL) fluid samples, identification of a fungus other than a Candida spp. was defined as a potential pathogen.Of 138 panfungal PCR tests (108 patients), 41 (30%) were positive for a fungal product. Ninety-seven percent (134/138) of specimens were from immunocompromised hosts. Thirteen percent (19/138) of panfungal PCR positive results were for potential pathogens and potential pathogens were detected more frequently in tissue as compared with BAL (12/13 vs. 6/26; P = .0001). No positive panfungal PCR results were obtained from CSF specimens. If histopathology examination was negative, panfungal PCR identified a potential pathogen in only 12% (11/94) of specimens. For the 20 culture negative/histopathology positive specimens, diagnosis of IFD to causative species level by panfungal PCR occurred in 35% (6/20).Sterile site specimens, in particular tissue, were more frequently panfungal PCR positive for potential pathogens than BAL. The utility of panfungal PCR appears greatest in tissue specimens, as an adjunct to histopathology to improve diagnostic sensitivity and specificity. Based on the results of this study we are now only testing tissue specimens by panfungal PCR.

Return to sender: the need to re-address patient antibiotic allergy labels in Australia and New Zealand.

BACKGROUND/AIM: Antibiotic allergies are frequently reported and have significant impacts upon appropriate prescribing and clinical outcomes. We surveyed infectious diseases physicians, allergists, clinical immunologists and hospital pharmacists to evaluate antibiotic allergy knowledge and service delivery in Australia and New Zealand. METHODS: An online multi-choice questionnaire was developed and endorsed by representatives of the Australasian Society of Clinical Immunology and Allergy (ASCIA) and the Australasian Society of Infectious Diseases (ASID). The 37-item survey was distributed in April 2015 to members of ASCIA, ASID, the Society of Hospital Pharmacists of Australia and the Royal Australasian College of Physicians. RESULTS: Of 277 respondents, 94% currently use or would utilise antibiotic allergy testing (AAT) and reported seeing up to 10 patients/week labelled as antibiotic-allergic. Forty-two per cent were not aware of or did not have AAT available. Most felt that AAT would aid antibiotic selection, antibiotic appropriateness and antimicrobial stewardship (79, 69 and 61% respectively). Patients with the histories of immediate hypersensitivity were more likely to be referred than those with delayed hypersensitivities (76 vs 41%, P = 0.0001). Lack of specialist physicians (20%) and personal experience (17%) were barriers to service delivery. A multidisciplinary approach was a preferred AAT model (53%). Knowledge gaps were identified, with the majority overestimating rates of penicillin/cephalosporin (78%), penicillin/carbapenem (57%) and penicillin/monobactam (39%) cross-reactivity. CONCLUSIONS: A high burden of antibiotic allergy labelling and demand for AAT is complicated by a relative lack availability or awareness of AAT services in Australia and New Zealand. Antibiotic allergy education and deployment of AAT, accessible to community and hospital-based clinicians, may improve clinical decisions and reduce antibiotic allergy impacts. A collaborative approach involving infectious diseases physicians, pharmacists and allergists/immunologists is required.

Australasian Society of Infectious Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand.

The incidence of Clostridium difficile infection (CDI) continues to rise, whilst treatment remains problematic due to recurrent, refractory and potentially severe nature of disease. The treatment of C. difficile is a challenge for community and hospital-based clinicians. With the advent of an expanding therapeutic arsenal against C. difficile since the last published Australasian guidelines, an update on CDI treatment recommendations for Australasian clinicians was required. On behalf of the Australasian Society of Infectious Diseases, we present the updated guidelines for the management of CDI in adults and children.

Mucormycete infection or colonisation: experience of an Australian tertiary referral centre.

Mucormycosis is associated with significant morbidity and mortality. We reviewed patients with mucormycete isolated at Alfred Health, Australia. A retrospective review of 66 patients with mucormycete(s) identified, between 1 April 2008 and 30 June 2014. Baseline demographic, microbiological, radiological, treatment/outcome data were recorded. Site of isolation was sinopulmonary in 77% and skin/soft tissue in 21%. A total of 32% of cases were proven-IFD, 12% probable-IFD and 56% were defined as no-IFD (or colonisation). Rhizopus spp. was identified in 48%. Comparing probable/proven-IFD with no-IFD/colonisation, more patients were postallogeneic stem cell transplantation (28% vs. 0%, P < 0.01) and were receiving immunosuppressive therapy (59% vs. 24%, P < 0.01) including prednisolone >20 mg daily (24% vs. 5%, P = 0.04). A total of 93% of patients with proven/probable IFD received treatment while 30% of no-IFD/colonisation were treated. A total of 72% of patients with proven/probable IFD and 92% of those with colonisation had no further mucormycete isolated. Thirty day mortality was higher in the proven/probable-IFD cohort (24%) compared with no-IFD/colonisation (3%) (P = 0.02). Mucormycosis remains uncommon, with 56% of cases not associated with clinical infection. Immunosuppressive therapy remains strongly associated with mucormycosis. Mortality remains high in those with proven/probable IFD.

Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort.

OBJECTIVES: The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD. METHODS: As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured. RESULTS: The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%). CONCLUSIONS: Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required.

Non-O1, non-O139 Vibrio cholerae bacteraemia in an Australian population.

This retrospective case series identifies the largest cohort of non-O1, non-O139 Vibrio cholerae bacteraemia in an Australian population from 2000 to 2013. We examine the risk factors, epidemiology, clinical presentations and mortality of non-O1, non-O139 V. cholerae bacteraemia in Victoria and compare them with published cases in the literature. This case series highlights the pathogenic potential of non-O1, non-O139 V. cholerae and identifies possible associations with host (underlying chronic liver disease and malignancy) and environmental factors (contaminated water supply and raw seafood). Clinicians should be aware of the morbidity and mortality associated with invasive non-O1, non-O139 V. cholerae infections, particularly in immunocompromised patients.

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014.

Antifungal agents may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy. These risks may be minimised by clinical assessment, laboratory monitoring, avoidance of particular drug combinations and dose modification. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. Therapeutic drug monitoring (TDM) of antifungal agents is warranted, especially where non-compliance, non-linear pharmacokinetics, inadequate absorption, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Recommended indications for voriconazole and posaconazole TDM in the clinical management of haematology patients are provided. With emerging knowledge regarding the impact of pharmacogenomics upon metabolism of azole agents (particularly voriconazole), potential applications of pharmacogenomic evaluation to clinical practice are proposed.

Disseminated Scedosporium prolificans infection in an 'extensive metaboliser': navigating the minefield of drug interactions and pharmacogenomics.

We report a case of non-fatal disseminated Scedosporium prolificans infection, including central nervous system disease and endophthalmitis, in a relapsed acute myeloid leukaemia patient with extensive CYP2C19 metabolism. Successful treatment required aggressive surgical debridement, three times daily voriconazole dosing and cimetidine CYP2C19 inhibition. In addition, the unique use of miltefosine was employed due to azole-chemotherapeutic drug interactions. Prolonged survival following disseminated S. prolificans, adjunctive miltefosine and augmentation of voriconazole exposure with cimetidine CYP2C19 inhibition has not been reported.

Impact of a sustained, collaborative antimicrobial stewardship programme in spinal cord injury patients.

Background: In patients with spinal cord injuries (SCIs), infections continue to be a leading cause of morbidity, mortality and hospital admission. Objectives: This study evaluated the long-term impact of a weekly, multidisciplinary Spinal/Antimicrobial Stewardship (AMS) meeting for acute-care SCI inpatients, on antimicrobial prescribing over 3 years. Methods: A retrospective, longitudinal, pre-post comparison of antimicrobial prescribing was conducted at our tertiary hospital in Melbourne. Antimicrobial prescribing was audited in 6 month blocks pre- (25 April 2017 to 24 October 2017), immediately post- (27 March 2018 to 25 September 2018) and 3 years post-implementation (2 March 2021 to 31 August 2021). Antimicrobial orders for patients admitted under the spinal unit at the meeting time were included. Results: The number of SCI patients prescribed an antimicrobial at the time of the weekly meeting decreased by 40% at 3 years post-implementation [incidence rate ratio (IRR) 0.63; 95% CI 0.51-0.79; P ≤ 0.001]. The overall number of antimicrobial orders decreased by over 22% at 3 years post-implementation (IRR 0.78; 95% CI 0.61-1.00; P = 0.052). A shorter antimicrobial order duration in the 3 year post-implementation period was observed (-28%; 95% CI -39% to -15%; P ≤ 0.001). This was most noticeable in IV orders at 3 years (-36%; 95% CI -51% to -16%; P = 0.001), and was also observed for oral orders at 3 years (-25%; 95% CI -38% to -10%; P = 0.003). Antimicrobial course duration (days) decreased for multiple indications: skin and soft tissue infections (-43%; 95% CI -67% to -1%; P = 0.045), pulmonary infections (-45%; 95% CI -67% to -9%; P = 0.022) and urinary infections (-31%; 95% CI -47% to -9%; P = 0.009). Ninety-day mortality rates were not impacted. Conclusions: This study showed that consistent, collaborative meetings between the Spinal and AMS teams can reduce antimicrobial exposure for acute-care SCI patients without adversely impacting 90 day mortality.

Long-term impacts of antibiotic allergy testing on patient perceptions and antibiotic utilization.

OBJECTIVES: To define the long-term impacts of antibiotic allergy testing (AAT) on patient allergy perception and antibiotic utilization. METHODS: Patients were identified from a prospective AAT database as having completed testing during a 15 month period beginning January 2017. Patients were contacted for a follow-up survey at least 12 months post-AAT. For those contacted, baseline demographics, antibiotic allergy label (AAL) history, age-adjusted Charlson comorbidity index, infection history, antibiotic de-labelling (≥1 AAL removed following AAT) and antibiotic usage for 12 months prior to testing (pre-AAT) and 12 months following testing (post-AAT) were recorded for each patient. RESULTS: From the follow-up survey of 112 patients post-AAT, 95.2% (59/62) of patients with complete AAL removal expressed willingness to use 'de-labelled' antibiotics and 91.9% (57/62) were adherent to allergy label modification. Comparing antibiotic utilization 12 months pre-AAT versus 12 months post-AAT, AAT was associated with a significant increase in preferred antibiotic therapy [adjusted odds ratio (aOR) 3.29, 95% CI 1.56-6.92] and reduction in restricted antibiotic utilization (aOR 0.42, 95% CI 0.19-0.93). CONCLUSIONS: An antimicrobial stewardship (AMS)-led AAT programme was safe and effective in the long term in the promotion of preferred and narrow-spectrum antibiotic usage, and favourable patient perception towards the AAT testing results was identified. This study further supports the routine incorporation of AAT into AMS programmes, confirming safety and durability of testing impacts on patients as well as increasing preferred antibiotic utilization.

Oral pristinamycin for the treatment of resistant Gram-positive infections in patients with cancer: Evaluation of clinical outcomes.

Pristinamycin has been used to treat a range of Gram-positive infections, but reported experience in patients with malignancy is limited. This study aimed to evaluate the use of pristinamycin in patients with cancer at an Australian centre. All patients commenced on oral pristinamycin therapy at the Peter MacCallum Cancer Centre between January 2005 and December 2014 were identified using the hospital pharmacy dispensing system. Information on demographics, co-morbidities, cancer diagnosis, infection characteristics, pristinamycin regimen, pristinamycin tolerability and outcomes was collected. The median duration of follow-up was 398 days. In total, 26 patients received pristinamycin, with median age of 61 years and a male predominance (65%). Underlying diagnoses were haematological malignancies (50%) and solid tumours (50%). Pathogens included 13 meticillin-resistant Staphylococcus aureus, 6 vancomycin-resistant Enterococcus faecium, 4 meticillin-resistant Staphylococcus epidermidis, 2 meticillin-susceptible S. aureus and 1 vancomycin-susceptible E. faecium. Infection sites were osteomyelitis (6), skin and soft-tissue (4), intra-abdominal/pelvic abscess (4), bloodstream (3), empyema (3), endocarditis/endovascular (3), prosthesis-related infection (2) and epididymo-orchitis (1). One patient ceased pristinamycin due to nausea. Regarding outcome, 13 patients (50%) were cured of infection, 8 (31%) had suppression and 5 (19%) had relapse. Relapses included 1 endovascular infection, 2 episodes of osteomyelitis, 1 pelvic abscess and 1 skin and soft-tissue infection. Overall, 81% of patients achieved cure or suppression of antibiotic-resistant or complex Gram-positive infections, consistent with published experience in non-cancer populations. A favourable tolerability profile makes oral pristinamycin a viable treatment option, particularly in settings where outpatient management of cancer is the objective.

Travel risk assessment, advice and vaccinations in immunocompromised travellers (HIV, solid organ transplant and haematopoeitic stem cell transplant recipients): A review.

International travellers with immunocompromising conditions such as human immunodeficiency virus (HIV) infection, solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT) are at a significant risk of travel-related illnesses from both communicable and non-communicable diseases, depending on the intensity of underlying immune dysfunction, travel destinations and activities. In addition, the choice of travel vaccinations, timing and protective antibody responses are also highly dependent on the underlying conditions and thus pose significant challenges to the health-care providers who are involved in pre-travel risk assessment. This review article provides a framework of understanding and approach to aforementioned groups of immunocompromised travellers regarding pre-travel risk assessment and management; in particular travel vaccinations, infectious and non-infectious disease risks and provision of condition-specific advice; to reduce travel-related mortality and morbidity.