BACKGROUND:Integrated genomic and phenotypic surveillance is essential to address the global spread of antimicrobial resistance. Conventional surveillance systems monitor resistance to established agents but often lack susceptibility data for newly developed antimicrobials, limiting evidence-based treatment selection. OBJECTIVES:To characterize the genomic epidemiology and antimicrobial susceptibility of Enterobacterales with reduced meropenem susceptibility in Japan using the upgraded Japan Antimicrobial Resistant Bacterial Surveillance system (JARBS 2.0). METHODS:In 2023, 873 Enterobacterales isolates with reduced meropenem susceptibility were collected from 82 hospitals and subjected to whole-genome sequencing. Standardized quantitative susceptibility testing, including seven recently developed antimicrobial agents (particularly nacubactam-based combinations under regulatory review), was performed for carbapenemase-producing Enterobacterales (CPE) and non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP CRE). RESULTS:Carbapenemase genes were detected in 101 isolates (11.6%), predominantly blaIMP (85%) and blaNDM (9%), demonstrating the predominance of metallo-β-lactamases (MBLs) in Japan. Among MBL producers, susceptibility rates were ≥96% for cefiderocol, cefepime/nacubactam, aztreonam/nacubactam, and aztreonam/avibactam. Among non-CP CRE isolates, only cefepime/nacubactam maintained similarly high activity. Notably, 13% of carbapenemase-producing isolates remained phenotypically susceptible to meropenem (MIC ≤1 mg/L), representing "stealth" MBL carriers. CONCLUSIONS:Nacubactam-based combinations, cefiderocol and aztreonam/avibactam show promise against MBL-producing Enterobacterales in Japan, whereas cefepime/nacubactam demonstrated the greatest activity against non-CP CRE. The upgraded JARBS 2.0 framework enables high-resolution genomic and phenotypic surveillance, bridging the gap between molecular resistance mechanisms and the clinical efficacy of emerging antimicrobial agents. These findings highlight the value of integrating genomic surveillance into routine monitoring to guide antimicrobial therapy and inform infection prevention and control strategies.
The British National Formulary and the NICE provide empirical treatment guidance for the management of various infections, including recommendations on antibiotic doses. In parallel, and for over 15 years, EUCAST has published details of the doses upon which their antimicrobial susceptibility breakpoints are predicated, termed here 'breakpoint-defining doses'. Recently, differences between these dosing recommendations have attracted attention, particularly since EUCAST introduced its 'susceptible, increased exposure' category of susceptibility. We discuss where and why these differences exist and how to reconcile them.
BACKGROUND:Dolutegravir (DTG)-based antiretroviral therapy has been widely adopted across sub-Saharan Africa, yet resistance pathways in non-B HIV-1 subtypes remain poorly defined. As lenacapavir (LEN), a long-acting capsid inhibitor, is introduced for prevention and treatment, characterizing baseline capsid variation alongside emerging integrase resistance is increasingly important. Whether DTG resistance pathways coexist with known capsid resistance mutations in West African epidemics remains poorly described. METHODS:We performed deep sequencing of 87 HIV-1 samples from adults (n = 47) and paediatric participants (n = 40) failing DTG-based antiretroviral therapy in Nigeria. Resistance mutations were interpreted using Stanford HIVdb and IAS-USA criteria, with resistance estimates based on gene- or drug-panel-specific denominators. Low-frequency variants were assessed at 2%, 5%, 10% and 20% read-frequency thresholds. Capsid mutations associated with LEN resistance were characterized, structurally mapped and compared to global sequence data. HIV-1 subtype and recombinant forms were assigned using COMET HIV-1 v2.4. RESULTS:At consensus, predicted resistance to ≥1 integrase strand transfer inhibitor (INSTI) was detected in 13/50 integrase-genotypable participants (26.0%; 95% CI 15.9%-39.6%), including 5/50 with a major INSTI resistance mutation. Reduced predicted susceptibility specifically to DTG was present in 6/50 (12.0%; 95% CI 5.6%-23.8%). G118R was detected in 4/50 participants at consensus, while Q148H/K/R and N155H were absent. In exploratory deep-sequencing analysis, G118R was detected in 8/47 participants with sufficient codon-level coverage at the ≥20% read-frequency threshold. No known primary LEN resistance mutation was detected among 33 participants with complete coverage of all six primary resistance positions (0/33; 95% CI 0%-10.4%); T107A, a polymorphic capsid substitution of uncertain effect on LEN susceptibility, was detected in in 3/33 individuals where sequence could be evaluated. CONCLUSIONS:These findings demonstrate DTG resistance in both adult and paediatric participants with virological failure with G118R emerging as a prominent resistance pathway. No known primary LEN resistance mutation was detected in the assessable capsid sequences, although phenotypic susceptibility and clinical outcomes were not evaluated. These findings support continued surveillance of integrase and capsid resistance as long-acting antiretroviral strategies expand.
OBJECTIVE:Fusidic acid with rifampicin is used for the treatment of severe staphylococcal infection, particularly prosthetic joint infections. Previous studies using twice daily fusidic acid showed rifampicin increases fusidic acid clearance, potentially causing sub-therapeutic concentrations. It is uncertain whether this occurs with three-times daily dosing. This study sought to re-evaluate this potential drug-drug interaction. METHODS:In this prospective, open-label drug-drug interaction population pharmacokinetic (PK) study, participants were randomized to receive fusidic acid or rifampicin for 24 hours, followed by combination therapy for the duration of treatment. Drug concentration assays used liquid-chromatography mass spectroscopy on dried blood spots. Population PK models were built for fusidic acid, rifampicin and 25-desacetyl rifampicin. RESULTS:Ten participants were recruited. Inter-individual variability for both absorption (98.1%) and clearance (77.8%) were high for fusidic acid. A population pharmacokinetic model for fusidic acid revealed that early autoinhibition dominated over later rifampicin-mediated induction, resulting in a net decrease in fusidic acid clearance. The mean fusidic acid area under the curve during each dosing interval (AUCτ) at steady state was 1.76-fold [0.049, 34.918] higher relative to Day 1, despite high uncertainty.Large inter-individual (110%) variability in absorption was observed for rifampicin. There was no apparent effect on rifampicin metabolism by fusidic acid co-administration, however, fusidic acid decreased clearance of 25-desacetyl rifampicin. CONCLUSION:In patients treated with fusidic acid three times daily in combination with rifampicin, autoinhibition potentially counteracted rifampicin induction such that fusidic acid concentrations were not reduced. Rifampicin clearance was not affected by fusidic acid, but 25-desacetyl rifampicin clearance was decreased. There was large inter-individual variability in the observed concentrations and final parameter estimates.
The global emergence and dissemination of epidemic Clostridioides difficile ribotype 027 (RT027) and related lineages illustrate the role of antimicrobial pressure in shaping the epidemiology of this pathogen. We propose a hierarchical model in which fluoroquinolones (FQs) served as the dominant selective force underlying the worldwide expansion of RT027-related strains, with rifampin and rifamycins acting as secondary modifiers that promoted persistence and regional dominance.
OBJECTIVES:The objective of this study is to evaluate the efficacy, resistance profile, pharmacokinetics (PK) and safety of switching from etravirine to doravirine in virologically suppressed, treatment-experienced individuals with prior non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations (NNRTI-RAMs). METHODS:DorSwitch is a prospective pilot study including 13 adults with sustained virological suppression and documented historical NNRTI-RAMs. Etravirine was replaced by doravirine while maintaining the remaining antiretroviral backbone. Drug-specific resistance penalty scores were generated using the Stanford HIV Drug Resistance Database (HIVdb) algorithm. PK analyses were performed in participants receiving darunavir/cobicistat plus doravirine. Virological, immunological, metabolic and safety outcomes were assessed over 48 weeks. RESULTS:Twelve participants completed 48 weeks of follow-up; one discontinued at Week 4 for personal reasons while virologically suppressed. All participants evaluable at Weeks 24 and 48 maintained HIV-1 RNA < 50 copies/mL, and no virological failures occurred. The median number of NNRTI-RAMs per individual was 2 (IQR 1-3). Doravirine showed lower or equal Stanford HIVdb penalty score (HIVdb-PS) than etravirine in 11/13 participants. In two cases, higher doravirine PS were driven by Y318F and G190E mutations detected in peripheral blood mononuclear cell HIV-1 DNA; both individuals remained virologically suppressed through Week 48. In seven participants receiving darunavir/cobicistat plus doravirine, trough concentrations (Cmin) were consistent with expected exposure concentrations. Total cholesterol and LDL cholesterol decreased significantly over follow-up, while body weight showed a modest, non-significant reduction. No doravirine-related serious adverse events were observed. CONCLUSIONS:In this small, highly selected pilot cohort, switching from etravirine to doravirine as part of an otherwise suppressive regimen was associated with maintenance of virological suppression through Week 48 and a more favourable predicted NNRTI resistance profile in most participants. The favourable resistance profile, safety, metabolic effects and PK findings consistent with expected exposure-particularly in combination with darunavir/cobicistat- support further evaluation of doravirine as a switch option in carefully selected individuals with prior NNRTI failure.
BACKGROUND AND OBJECTIVES:Staphylococcus aureus bacteraemia (SAB) is associated with high mortality and frequent complications, including acute kidney injury (AKI). Although flucloxacillin has been associated with higher AKI rates than cefazolin, the clinical characteristics of AKI, including severity, timing, recovery and the potential influence of dosing, remain unclear. METHODS:We conducted a retrospective multicentre cohort study across three hospitals in the Netherlands, including adults with SAB treated with cefazolin or flucloxacillin. AKI incidence and severity were compared using adjusted regression analyses. Time-to-event and cumulative incidence analyses were used to evaluate AKI timing and renal recovery. Among flucloxacillin-treated patients, the association between initial dose and AKI was evaluated. RESULTS:Among 1408 patients, 483 (34.3%) developed AKI. Most AKI episodes occurred early after index blood culture (median 1.3 days), and recovery within 30 days decreased with increasing AKI severity (81.7% in Stage 1 versus 50.5% in Stage 3). AKI occurred more frequently among patients treated with flucloxacillin than cefazolin (466/1324 [35.2%] versus 17/84 [20.2%], P = 0.004). After multivariable adjustment, flucloxacillin remained associated with higher AKI risk (adjusted OR 2.37, 95% CI 1.30-4.55). Among patients with AKI, severity distribution did not differ between treatments (P = 0.599). Initial flucloxacillin dose was not associated with AKI occurrence, timing or severity. CONCLUSIONS:Flucloxacillin was associated with increased AKI risk compared with cefazolin, with most AKI episodes occurring early after index blood culture and recovery decreasing with increasing AKI severity. Lower flucloxacillin doses were not associated with reduced AKI risk, suggesting that dose reduction alone may not mitigate flucloxacillin-associated nephrotoxicity.
BACKGROUND:Molecular surveillance is essential to detect emerging artemisinin partial resistance (ART-R) and partner drug resistance in Sub-Saharan Africa. OBJECTIVES:To describe the prevalence of Plasmodium falciparum resistance markers in two high-burden countries using artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL): the Democratic Republic of the Congo (DRC) and Tanzania. METHODS:A total of 1254 day-0 P. falciparum-positive samples were analysed: 837 from four sentinel sites of a therapeutic efficacy study (TES) in the DRC (2017) and 417 from an intermittent preventive treatment in schoolchildren (IPTsc) trial in Handeni and Kilindi districts, Tanga Region, Tanzania (2020-2021). Pfkelch13, Pfcrt and Pfmdr1 were analysed by Illumina MiSeq amplicon sequencing. RESULTS:Reliable sequences were obtained for 1193 isolates. The Pfkelch13 wild-type allele predominated (98.4%); none of the four non-synonymous mutations detected (N489Y, K568T, A578S, V589I) are classified as validated, candidate or potential ART-R markers, and the validated markers R561H, P441L and C469Y reported elsewhere in East Africa were absent. Pfcrt K76T was found in 23.3% of Tanzanian and 26.3% of DRC isolates, with substantial between-site variation in the DRC (4.3% to 93.6% at Rutshuru). Pfmdr1 haplotype profiles differed between countries: NFSND predominated in Tanzania (71.5%) while NYSND remained the most frequent in the DRC (60.9%); 86Y was twice as frequent in the DRC (11.1%) as in Tanzania (6.2%). CONCLUSIONS:No validated ART-R marker was detected, but partner-drug haplotype distributions reflected the first-line ACTs used in each country. Continued molecular surveillance is needed to track these signatures alongside the recent emergence of ART-R.
BACKGROUND:Clinical decision support systems (CDSS), computerized tools that assist clinicians in making guideline-based decisions, may support antimicrobial prescribing in primary care. METHODS:Studies on CDSS implementation, use and outcomes in primary care on PubMed/MEDLINE and Embase were included up to June 2025. RESULTS:Of the 64 full-text articles assessed, 40 were included. Most were multicentric (n = 33, 82.5%) and conducted in high-income countries (n = 33, 82.5%), and 19 were randomized controlled trials (47.5%). CDSS mainly targeted respiratory infections (n = 24, 60%) and were integrated into electronic health records in 24 studies (60%). Implementation strategies were assessed in 19 studies with almost all using a multimodal approach, most commonly involving modification of health record systems (n = 18, 45%) and audit and feedback (n = 17, 42.5%). Adoption was highly variable: among the 11 studies reporting use, CDSS were used in more than half of consultations in only five studies. Among the 32 studies assessing clinical outcomes, 17 reported reduced overall antibiotic prescribing. Barriers to CDSS use included perceptions of redundancy, time consumption, language limitations, alert fatigue, technical issues and concerns about negative impacts on patient-doctors trust. CONCLUSION:CDSS may improve guideline-concordant antibiotic prescribing in primary care, but wide variability in implementation and real-world adoption limits generalizability and scalability.
BACKGROUND:Resistance to ceftazidime/avibactam and meropenem/vaborbactam has been increasing among carbapenem-resistant Enterobacterales (CRE) in US hospitals recently. We evaluated the activity of aztreonam/avibactam and comparators against isolates that were not susceptible to ceftazidime/avibactam and/or meropenem/vaborbactam and against MBL-producing Enterobacterales. METHODS:A total of 80 927 Enterobacterales isolates were consecutively collected (one per patient) in 2016-2024 from 103 US medical centres and susceptibility tested by broth microdilution in a monitoring laboratory. Among those, 194 (0.24%) were not susceptible to ceftazidime/avibactam or meropenem/vaborbactam, 115 (0.14%) were not susceptible to both ceftazidime/avibactam and meropenem/vaborbactam, and 832 (1.0%) isolates were carbapenem resistant. These isolates were screened for carbapenemase (CBase) genes by WGS. RESULTS:Aztreonam/avibactam was active against 91.9% of ceftazidime/avibactam-non-susceptible isolates (n = 160), 94.0% of meropenem/vaborbactam-non-susceptible isolates (n = 149), 98.1% of CRE and 98.4% of MBL producers (n = 125). Cefiderocol retained activity against 78.8% of ceftazidime/avibactam-non-susceptible isolates, 83.2% of meropenem/vaborbactam-non-susceptible isolates, 94.7% of CRE and 82.1% of MBL producers. A CBase was identified in 159 (82.0%) of isolates not susceptible to ceftazidime/avibactam or meropenem/vaborbactam and in 683 (80.1%) of CREs. NDM (n = 114; 58.8% of isolates) was the most common CBase type among isolates not susceptible to ceftazidime/avibactam or meropenem/vaborbactam. Notably, an MBL was identified in 36.1% (73/202) of CRE collected in 2023-2024. CONCLUSIONS:Aztreonam/avibactam demonstrated potent activity against isolates not susceptible to ceftazidime/avibactam and/or meropenem/vaborbactam as well as against CRE isolates, including MBL producers. The activities of other β-lactamase inhibitor combinations and cefiderocol were adversely affected by the alarming increase of MBL producers in some US hospitals.
BACKGROUND:The waiting pens of slaughterhouses represent a critical control point in the 'farm-to-fork' continuum, yet their role in the emergence and dissemination of antimicrobial resistance remains understudied. This study investigated tigecycline-resistant Staphylococcus (TRS) in these high-risk zones to assess their prevalence, resistance mechanisms, and transmission dynamics. METHODS:400 samples were collected from the waiting pens of a pig slaughterhouse in Guangzhou, China. Antimicrobial susceptibility testing, whole-genome sequencing, phylogenetic analysis, and molecular cloning were employed to characterize resistance mechanisms and transmission patterns. RESULTS:78 TRS strains were isolated and classified into three species, including S. borealis, S. ureilyticus, and S. pasteuri. These isolates exhibited multidrug-resistant phenotypes and carried new mutations in rpsJ and tet(M), which were functionally confirmed to reduce tigecycline susceptibility. Phylogenetic evidence demonstrated clonal transmission between pig farms and the slaughterhouse. The tet(M) gene was located within Staphylococcal cassette chromosome mec elements mediated by IS257, while tet(L) was carried by plasmids formed through IS256/IS257-mediated recombination. CONCLUSIONS:Waiting pens serve as crucial reservoirs for the amplification and dissemination of antimicrobial resistance. Our findings underscore the urgent need for enhanced biosecurity measures, improved waste management, and routine molecular surveillance in these high-risk zones to mitigate the spread of resistance along the food production chain.
OBJECTIVES:To characterize pulmonary pharmacokinetics (PK), epithelial lining fluid (ELF) exposure, antibacterial activity and preliminary PK/pharmacodynamic (PK/PD) relationships of the pleuromutilin derivative APTM in neutropenic murine lung infection models. METHODS:Plasma PK and ELF exposure were assessed after a single oral dose in healthy mice. Minimum inhibitory concentrations (MICs) and in vitro time-kill activity were determined against methicillin-resistant Staphylococcus aureus USA300 and Streptococcus pneumoniae ATCC 49619. In vivo efficacy was assessed in neutropenic murine lung infection models. The ratio of the 24 h area under the plasma concentration-time curve to MIC (AUC0-24h/MIC) and the ratio of maximum plasma concentration to MIC (Cmax/MIC) were evaluated as candidate indices using Sigmoid Imax models. RESULTS:Plasma exposure increased approximately linearly over 10-150 mg/kg. Mean total ELF/plasma ratios were 1.21 for Cmax and 2.05 for the area under the concentration-time curve from time zero to infinity (AUC0-∞). MICs were 0.25 mg/L for USA300 and 0.5 mg/L for ATCC 49619. Relative to the 2 h baseline, maximal mean reductions in pulmonary bacterial burden at 150 mg/kg were 3.39 log10 cfu/mL for USA300 and 1.63 log10 cfu/mL for ATCC 49619. Under the single every-12-h (q12h) regimen, AUC0-24h/MIC showed a stronger association with antibacterial efficacy than Cmax/MIC. CONCLUSIONS:APTM achieved measurable pulmonary exposure and antibacterial activity in murine lung infection models. AUC0-24h/MIC was the best-performing exposure metric among those evaluated under the present conditions; it should not be interpreted as a definitive PK/PD driver. These exploratory, isolate-specific findings support further PK/PD studies of APTM for respiratory infections.
OBJECTIVES:To compare the effectiveness of dolutegravir/lamivudine (DTG/3TC) versus bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) at Week 48 in treatment-naive adults with high baseline viral loads (≥500 000 copies/mL) and CD4+ cell count ≥200/mm3 and to assess immune recovery and safety. METHODS:We conducted a single-centre retrospective cohort study including all ART-naive people with HIV-1 (PWH) and HIV-RNA ≥500 000 copies/mL and CD4+ ≥200 cells/mm3 who initiated DTG/3TC or BIC/FTC/TAF during 2019-2024. Effectiveness was assessed as the proportion of participants achieving HIV-1 RNA <50 copies/mL at Week 48 [intention-to-treat, missing = failure (ITT, M = F)]. Immune recovery, metabolic and renal safety were evaluated through changes in CD4+ count, weight, lipid profile and creatinine. Time-to-virologic suppression was analysed using Kaplan-Meier curves and log-rank testing. Safety profile and immune recovery were conducted using Mann-Whitney U test. RESULTS:A total of 40 patients (52.5% on DTG/3TC, 47.5% on BIC/FTC/TAF) were included, with a high prevalence of primary HIV infection (PHI) (76.2% and 84.2%, respectively). No baseline differences were observed between groups. At 48 weeks, virologic suppression rates were 90.5% (19/21) in the DTG/3TC group and 94.7% (18/19) in the BIC/FTC/TAF group (log-rank P = 0.73). Viral decay kinetics were similar between groups. No virologic failures with resistance or treatment discontinuations were observed. Median CD4+ gains were comparable between groups (385 vs 243 cells/mm3; P = 0.30). No significant differences in weight gain, lipid profile, or creatinine levels were observed. CONCLUSIONS:In ART-naive PWH with HIV-RNA ≥500 000 cp/mL and CD4+ ≥200/mm3, including those with PHI, DTG/3TC and BIC/FTC/TAF showed similar effectiveness and comparable safety profiles at Week 48.
BACKGROUND:Lamivudine and abacavir are key components of first-line paediatric antiretroviral therapy (ART). Rifampicin is part of drug-sensitive TB treatment in children. Rifampicin induces UDP-glucuronosyltransferases and renal transporters and inhibits gastrointestinal transporters involved in the pharmacokinetics of abacavir and lamivudine, but pharmacokinetic data on this potential interaction in infants are scarce. OBJECTIVE:To evaluate the effect of rifampicin on the pharmacokinetics of abacavir and lamivudine in infants aged 28-365 days and weighing >3 kg. METHODS:This pharmacokinetic sub-study was nested within the EMPIRICAL trial (NCT03915366). Eighteen infants from Mozambique, Uganda, Zambia and Zimbabwe received once-daily fixed-dose abacavir/lamivudine with dolutegravir according to WHO guidelines. Five infants received ART alone and 13 received ART plus rifampicin-based tuberculosis treatment. Abacavir/lamivudine dosing was unchanged during rifampicin co-treatment. Six plasma concentrations were measured over 24 h and analysed using non-compartmental pharmacokinetic analysis. RESULTS:Median (IQR) age and weight were 6.8 (5.2-10.2) months and 6.0 (5.3-6.8) kg, respectively, and were comparable between groups. Abacavir exposure was comparable with and without rifampicin (AUC0-24h: 21.9 versus 21.0 h mg/L; Cmax: 6.2 versus 6.3 mg/L, respectively). Lamivudine exposure was also comparable (AUC0-24h: 12.6 versus 12.4 h mg/LL, respectively). The slightly higher Cmax (2.4 versus 1.9 mg/L) in the rifampicin group is probably due to interindividual variability or increased absorption from rifampicin's inhibition of gastrointestinal drug transporters, and considered not clinically relevant. CONCLUSIONS:Rifampicin co-treatment had minimal impact on abacavir and lamivudine pharmacokinetics in infants. Dose adjustment of abacavir/lamivudine is not required during rifampicin-containing tuberculosis treatment.
Antimicrobial-loaded PMMA bone cement has been used since the 1970s as both a fixation material and a local antimicrobial reservoir. Its clinical roles differ between prophylaxis in primary arthroplasty and treatment of established infection, particularly during revision surgery and through the use of temporary spacers. Commercially manufactured products offer more predictable handling, but bespoke admixing may be considered when resistant or unusual organisms are encountered. This Viewpoint argues that such practice requires clearer governance. Cement formulation, antimicrobial choice, dose and mixing technique influence elution, bioactivity, mechanical strength and toxicity. Local delivery may support antimicrobial stewardship, but prolonged low-level elution could theoretically select for resistance if poorly planned. We propose a cautious, evidence-informed framework to support multidisciplinary decision-making and the development of PMMA-specific antimicrobial guidance.
BACKGROUND:HIV drug resistance (HIVDR) threatens the effectiveness of antiretroviral therapy (ART) programmes in low- and middle-income countries. The Cobas Plasma Separation Card (PSC) is a recently developed specimen collection tool with potential to expand access to HIVDR genotyping in remote settings. This study evaluates PSC performance for HIVDR genotyping compared with plasma. METHODS:Paired plasma and PSC specimens were selected from 250 people living with HIV (PLHIV) on ART ≥6 months with viral load (VL) ≥1000 copies/mL. HIVDR genotyping followed CDC Atlanta in-house protocol; resistance interpretation used the Stanford HIVdb algorithm. Paired sequences were compared for subtype, nucleotide similarity, mutation profile and drug-resistance classification. RESULTS:Twenty paired specimens met inclusion criteria. Amplification of the HIV-1 Pol gene succeeded in 19/20 (95%) PSC samples. Of 19 paired sequences, nucleotide similarity was 98.5% (IQR 98.0%-99.3%). Eleven plasma samples showed 37 major drug-resistance mutations (MDM); 35 (94.6%) concordant MDM were identified in PSC. Discordances in four pairs were limited to mixed versus single bases and did not alter drug-resistance classification. Only one pair showed a clinically significant discordance (K103N detected in plasma but not initially in PSC). CONCLUSIONS:PSC demonstrated good concordance with plasma for HIVDR genotyping and has potential as an alternative specimen type for clinical practice and surveillance in resource-limited settings.
OBJECTIVES:To evaluate the tolerability and safety of extended-dosing liposomal amphotericin B (LAmB) as primary antifungal prophylaxis against invasive fungal disease (IFD) in children receiving chemotherapy for newly diagnosed acute myeloid leukaemia (AML); breakthrough proven or probable IFD was assessed as an exploratory secondary endpoint. METHODS:This retrospective, multinational, multicentre observational study included children treated for newly diagnosed AML between January 2019 and December 2023. LAmB was administered according to local protocols at 1 mg/kg three times weekly, 2.5 mg/kg twice weekly or 5 mg/kg once weekly. Clinical and laboratory adverse events (AEs) were assessed to evaluate tolerability and safety. Breakthrough proven or probable IFD, defined according to EORTC/MSG criteria, was recorded as an exploratory secondary outcome. RESULTS:Eighty-six courses of extended-dosing LAmB were analysed. The median age at first LAmB administration was 91 months (IQR 26-156). The median treatment duration was 13 weeks (IQR 3-21) at a median dose of 2.7 mg/kg per infusion, with a median estimated cumulative dose of 77.6 mg/kg (IQR 21.3-110.1). Clinical AEs occurred in 21% of courses, predominantly skin rash and lumbosacral pain. Laboratory AEs were mainly hypokalaemia (48%) and hepatotoxicity (19%), both dose related. Treatment discontinuation due to toxicity occurred in 15% of courses. Breakthrough proven or probable IFD occurred in 3% of cases. CONCLUSIONS:Extended-dosing LAmB represents a reasonably well-tolerated mould-active option for primary antifungal prophylaxis in children with newly diagnosed AML, particularly when triazoles are contraindicated or daily intravenous echinocandin administration is impractical; the low observed rate of breakthrough IFD should be interpreted cautiously given the absence of a comparator group.
BACKGROUND:Meropenem is commonly used to treat serious bacterial infections, but its short half-life in mice impedes achieving human-like drug exposure profiles. This study aimed to create humanized meropenem dosage regimens in immunocompetent mice with bloodstream infections by Acinetobacter baumannii. METHODS:Cilastatin was administered to prolong the meropenem half-life in mice and match the concentration-time profiles of meropenem in patients. An integrated population pharmacokinetic model was developed to characterize the concentration-dependent inhibition of meropenem clearance by cilastatin. Murine dosage regimens were humanized based on a novel matching framework. Firstly, meropenem plasma concentrations in mice should remain within the 5th to 95th percentiles of plasma concentrations for meropenem monotherapy in critically ill patients. Secondly, the free-time-above-MIC versus MIC profiles of meropenem in mice should match those in patients. RESULTS:The meropenem half-life in mice increased from 22.2 min without cilastatin to 57.7 min at high cilastatin concentrations. Cilastatin inhibited the meropenem clearance half-maximally at 0.230 mg/L. Subcutaneous doses of 53/10 mg/kg meropenem/cilastatin at 0 h and 26/10 mg/kg at 3 h in mice, both repeated every 8 h, resulted in well-matched pharmacokinetic profiles to those of 2 g meropenem infusions over 30 min at the same dosing interval in patients. CONCLUSIONS:Co-administration of cilastatin substantially prolonged the meropenem half-life in mice and enabled humanized meropenem dosage regimens with six doses per day to stay within the 5th and 95th percentiles of plasma concentrations in patients. This novel framework to humanize murine dosage regimens is based on quantitative matching criteria and supports translational research by achieving clinically relevant exposure profiles in mice.
