Indy Sandaradura

Therapeutic drug monitoring (TDM) helps optimize pharmacotherapy, but research activity in low- and middle-income countries (LMICs) is poorly characterized. This scoping review systematically maps the volume, characteristics, and geographic distribution of TDM research in LMICs from 2015 to 2024. PubMed, Embase, and Web of Science were searched to identify peer-reviewed TDM studies conducted in World Bank-defined LMICs. Extracted data covered publication characteristics, study design, geographic distribution, drug classes, analytical methods, and descriptive quality indicators. A total of 385 publications from 38 LMICs were included; annual output steadily increased from 29 publications in 2015 to 53 in 2024. The Western Pacific Region accounted for 54.5% of all publications, with China contributing 197 (51.2%). Antimicrobials, immunosuppressants, antiseizure drugs, and antipsychotics accounted for 95.5% of drug-class attributions. Vancomycin (n = 84) and tacrolimus (n = 81) were the most studied drugs. Immunoassay was the predominant analytical method (35.1%), followed by liquid chromatography-mass spectrometry (18.7%). Pharmacy and clinical pharmacology departments were involved in 47.0% of studies. Only 6 low-income countries contributed publications (n = 7) through collaborations with high-income countries (10.4%). The analytical method did not align with the country's income. Pharmacogenetic studies (n = 45), guidelines (n = 2), and external quality assessment studies (n = 2) were rare. TDM research in LMICs has expanded substantially but remains geographically concentrated and focused on drugs with commercial assays. Key gaps remain in pharmacogenetics, implementation science, and guideline development. Strengthening laboratory infrastructure, equitable international collaboration, and locally adapted TDM strategies may help advance precision medicine in resource-limited settings.

Background and objectives: CYP2C19 phenotype is a known contributor to the interpatient variability in voriconazole response. Alternative therapy is recommended for ultrarapid/rapid and poor metabolizers due to increased probability of subtherapeutic exposure and side effects, respectively. We aimed to evaluate whether CYP2C19 phenotype is associated with switching from voriconazole to alternative antifungal therapy, in settings where genetic results were not available at the time prescribing decisions were made. Methods: A multicentre, retrospective observational study was conducted in three Australian hospitals. Patients who had previously taken voriconazole (from 1 May 2019 to 31 May 2024) were invited to undergo pharmacogenomic testing. Medical records were audited to compare switching decisions across patients with different CYP2C19 phenotypes. Differences in voriconazole exposure and voriconazole-related adverse effects were also explored. Results: Among 194 patients, most were normal or intermediate metabolizers (69%); 21% were rapid, 7% ultrarapid, and 3% poor metabolizers (underpowered). Switching to alternative antifungal therapy (32%; 62/194) mainly occurred due to adverse effect incidence and was not associated with CYP2C19 phenotype (P = 0.9041). C-reactive protein levels were significantly higher in patients who switched therapy (P < 0.001). All ultrarapid metabolizers on standard voriconazole 400 mg/day had subtherapeutic concentrations and only those on higher doses (500–1200 mg/day) achieved therapeutic concentrations. Conclusions: CYP2C19 phenotype was not predictive of switching, which is a multifactorial prescribing decision likely influenced by therapeutic drug monitoring, inflammation and clinical status. Our observations on voriconazole dosing and exposure support a complementary prescribing approach: pharmacogenomic testing to identify patients who require atypical voriconazole dosing regimens and subsequent therapeutic drug monitoring to guide dose adjustments.

Background: Approximately 10% of hospitalized patients globally report a penicillin allergy, leading to inappropriate antibiotic prescribing and inferior healthcare outcomes. Evidence supporting the effectiveness and widespread implementation of inpatient penicillin direct oral challenge (DOC) is limited. Methods: A prospective, multicenter, international type 2 hybrid effectiveness-implementation study was conducted in 40 hospitals across 8 countries between November 2022 and May 2025. Adult inpatients with a penicillin allergy underwent assessment using a digital penicillin allergy toolkit (National Antibiotic Allergy Network [NAAN] App). According to site clinical practice, participants received penicillin DOC (effectiveness intervention) or assessment only. Participating sites received bimonthly audit and feedback at least 3 months after site activation (implementation strategy). Observational data were used to emulate a target trial to examine secondary effectiveness outcomes, including antibiotic prescribing at 90 days in DOC versus non-DOC participants. The primary implementation outcome was adoption of the NAAN App within 6 months of site activation. Results: Among 5121 participants assessed, 1573 (30.7%) underwent DOC, of which 1502 (95.5%) were delabeled. Of 71 (4.5%) participants with a positive DOC, 6 (0.4%) had a serious adverse event. Of 1852 inpatients in the target trial analysis, 892 underwent DOC and 960 underwent assessment only. Participants who underwent DOC were more likely to be prescribed penicillin (risk ratio [RR], 13.25 [95% confidence interval {CI}, 7.82–22.46]), and less likely to be prescribed World Health Organization (WHO) “Watch” or “Reserve” antibiotics (RR, 0.73 [95% CI, .60–.89]) at 90 days post evaluation. Within 6 months of site activation, 77 clinicians adopted the NAAN App. Conclusions: Multidisciplinary adoption of inpatient penicillin DOC was safe and significantly improved penicillin prescribing and reduced use of WHO restricted antibiotics.

In this international, multicenter prospective study, implementing penicillin direct oral challenge (DOC) using a digital toolkit was acceptable, feasible, and sustainable. Audit and feedback increased activity, particularly among pharmacists. Safety was maintained across heterogeneous DOC protocols, validating a pragmatic, scalable approach that supports local adaptation.

Objectives: One of the biggest challenges for healthcare providers is the difficulty with screening for carbapenemase-producing, carbapenem-resistant Pseudomonas aeruginosa (CP-CRPa; P. aeruginosa), given the variety of mechanisms that can mediate carbapenem resistance in P. aeruginosa. We sought to develop an improved algorithm to screen for carbapenemase activity in P. aeruginosa using routine antimicrobial susceptibility testing readily available in most clinical microbiology laboratories. Methods: Antibiograms of a reference set of P. aeruginosa (n = 100) with diverse phenotypic and genotypic profiles were compared to determine which antibiotics optimally screen for and differentiate CP-CRPa from CRPa and non-CRPa. The developed algorithm was then applied to 1482 clinical P. aeruginosa isolates. Carbapenemase PCR and the modified carbapenem inactivation method were performed on all meropenem-resistant P. aeruginosa isolates. Results: The CP-CRPa screening algorithm developed here uses meropenem, ceftazidime and tobramycin. Carbapenem resistance was identified in 85 (5.7%) isolates, of which 26 (1.8%) were confirmed as CP-CRPa. blaGES (57.7%) was the predominant carbapenemase detected, whilst blaNDM, blaVIM, blaIMP and blaKPC carbapenemases were also detected. The CP-CRPa screening algorithm was 100% sensitive (CI95% 84.0%–100%) and 96.6% specific (CI95% 87.3%–99.4%). Conclusions: We present an antimicrobial susceptibility testing-based screening algorithm that uses meropenem, ceftazidime, and tobramycin to screen for CP-CRPa. When appropriate screening criteria are utilized, confirmatory testing can be significantly reduced, resulting in substantial time and resource savings, without compromising sensitivity, particularly in settings with varying carbapenemase epidemiology.

Objectives: Benzylpenicillin with ceftriaxone is used for outpatient antimicrobial therapy of Enterococcus faecalis infective endocarditis (EFIE) due to poor stability of aminopenicillins. The aim was to correlate the impact of benzylpenicillin-ceftriaxone synergy on EFIE treated with benzylpenicillin-ceftriaxone, and investigate whether simpler phenotypic methods can predict synergy. Methods: Clinical outcomes of a retrospective cohort of EFIE patients were correlated with treatment and synergy. Isolates were assessed for synergy using the checkerboard method, compared with double disc diffusion (DDD) and layered and crossed gradient diffusion strip (GDS) tests, with sensitivity and specificity of these methods calculated. Results: Thirty-eight episodes of EFIE in 34 patients were included; the majority received benzylpenicillin-ceftriaxone alone (n = 16) or in sequence (n = 12; any benzylpenicillin-ceftriaxone n = 28), and 10 received other regimens. There was no statistical difference between any benzylpenicillin-ceftriaxone versus other therapies on outcomes, nor between benzylpenicillin-ceftriaxone synergy and outcome. GDS was an unreliable predictor of checkerboard synergy; DDD was reasonable. Five isolates lacked benzylpenicillin-ceftriaxone synergy (one also lacking ampicillin-ceftriaxone synergy); these all had high-level ceftriaxone resistance [zone diameter 6 mm, or broth microdilution (BMD) MIC >512 mg/L]. Most isolates from relapse cases developed reduced zone diameters to ceftriaxone. Two isolates lacking synergy had the same mutation near the ceftriaxone response regulator (CroR) binding site in the pbp4 promoter region. Conclusions: Ceftriaxone susceptibility, either MIC 6 mm, is the best predictor of ampicillin-ceftriaxone and particularly benzylpenicillin-ceftriaxone synergy in E. faecalis. There was no clear relationship between the absence of benzylpenicillin-ceftriaxone synergy and outcome in this highly comorbid cohort.

Letter to the Editor regarding the Aminoglycosides: an update on indications, dosing and monitoring Article in June 2025 issue of Australian Prescriber

Purpose Fluconazole is the recommended step-down therapy from echinocandins for fluconazole-susceptible Candida spp in critically ill patients with invasive candidiasis. However, standard fluconazole dosing does not achieve adequate exposure in these patients. We aimed to identify factors impacting fluconazole pharmacokinetic–pharmacodynamic (PKPD) target attainment and provide a dosing regimen ensuring adequate target attainment in critically ill patients. Methods A population pharmacokinetics study (popPK) was conducted, combining fluconazole concentration data from eight studies. We used multiple imputation to handle missing covariate data, and Monte Carlo simulations to identify a dosing regimen with at least 90% probability of PKPD target attainment (PTA) in every patient. The PKPD target is the 24-hour area under the unbound concentration-time curve over the minimum inhibitory concentration of 100. Results Data from 177 critically ill patients were included. A two-compartment popPK model with linear elimination described the data best. Continuous renal replacement therapy (CRRT) status, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation, and total body weight were statistically significant covariates. However, with standard dosing, only CRRT status and total body weight were clinically relevant, as PTA dropped below 90% for all patients on CRRT, and for patients off-CRRT above 60 kg. A weight-based loading dose and flat maintenance doses of 400 mg (off-CRRT) and 800 mg (CRRT) predicted ≥ 90% PTA across the weight range. Conclusion We have developed a fluconazole dosing regimen, stratified by weight and CRRT status, that may achieve adequate PTA in critically ill patients. External validation is awaited.