Khoo SH, FitzGerald R, Edwards CJ
… +29 more, Ahmad S, Saunders G, Else LJ, Shaw V, Mozgunov P, Northey J, Dickinson L, Knox E, Buadi A, Hale C, Reynolds HE, Middleton C, Bullock K, Walker L, Tetlow M, Lyon R, Gibney J, Amara A, Greenhalf W, Burdon A, Dixon J, Jaki T, Chiong J, Lalloo DG, Owen A, Jacobs M, Fletcher T, Griffiths G, AGILE CST-8 study group
J Antimicrob Chemother
· 2026 Jun · PMID 42301199
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OBJECTIVES: The AGILE CST-8 (NCT04746183) Phase I de-escalation trial evaluated the safety and tolerability of combination molnupiravir and nirmatrelvir/ritonavir for mild-moderate COVID-19. METHODS: Adult outpatients wi...OBJECTIVES: The AGILE CST-8 (NCT04746183) Phase I de-escalation trial evaluated the safety and tolerability of combination molnupiravir and nirmatrelvir/ritonavir for mild-moderate COVID-19. METHODS: Adult outpatients with SARS-CoV-2 infection within 5 days of symptoms were randomly assigned 2:1 to receive molnupiravir [starting at 800 mg twice daily (BD) reducing to 600 and 400 mg if necessary] in combination with nirmatrelvir (300 mg)/ritonavir (100 mg) BD for 5 days versus standard of care. Using a dose de-escalation, open-label, Bayesian adaptive Phase I trial, a combination dose was considered unsafe if the probability of 30% or greater dose-limiting toxicity risk (DLT-the primary outcome) over standard of care was 25% or higher. Secondary endpoints included tolerability, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 49 participants screened, 24 were enrolled (16 combination, 8 standard of care) between January 2023 and September 2023. For the primary endpoint, to Day 11, no participant starting molnupiravir at 800 mg BD in combination with nirmatrelvir/ritonavir reported a DLT by Day 11 (primary endpoint) or by Day 29; dose de-escalation was not required. No participants reported severe adverse events (grade ≥3). Although proportions of swab PCR negativity at Day 5 and Day 11 were not statistically different, faster initial viral clearance was observed with treatment. Penetration of nirmatrelvir into saliva, nasal secretions and tears was 19%, 65% and 91% that of plasma. CONCLUSIONS: Molnupiravir in combination with nirmatrelvir/ritonavir was safe and well-tolerated; later phase trials should evaluate combination therapy at currently recommended doses for each drug.
Rodgers MP, Stemkens R, Dahl VN
… +5 more, van Laarhoven A, Hoefsloot W, Lemson A, van Ingen J, Aarnoutse RE
J Antimicrob Chemother
· 2026 Jun · PMID 42287072
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OBJECTIVES: Azithromycin is a key drug in the treatment of most non-tuberculous mycobacterial (NTM) diseases. Its exposure may be decreased by rifampicin co-administration, but to what extent is largely unknown. We measu...OBJECTIVES: Azithromycin is a key drug in the treatment of most non-tuberculous mycobacterial (NTM) diseases. Its exposure may be decreased by rifampicin co-administration, but to what extent is largely unknown. We measured azithromycin exposure in an NTM disease patient population and quantified the effect of rifampicin co-administration. METHODS: We retrospectively collected plasma azithromycin area-under-the-curve from 0 to 6 hours after administration in mg/L*hours (AUC0-6h), peak (Cmax), and trough (Cmin) concentrations from the TDM service at Radboudumc, The Netherlands. Azithromycin exposure measures were compared between patients with and without concurrent rifampicin use, and within patients who had rifampicin stopped during treatment. RESULTS: We analysed data of 130 patients, of whom 59% had NTM pulmonary disease. The azithromycin geometric mean of AUC0-6h in patients with (n = 48) and without (n = 82) rifampicin were 0.90 versus 1.83 mg/L*h, Cmax 0.22 versus 0.46 mg/L, and Cmin 0.043 versus 0.13 mg/L, respectively. A within-patient comparison in 14 subjects showed geometric means of AUC0-6h, Cmax, and Cmin (90%-CI) with rifampicin were 62% (45%-74%), 58% (38%-72%) and 66% (48%-77%) lower than without rifampicin. Interventions based on TDM enabled a strong increase in exposure to azithromycin. No association between azithromycin exposure and disease outcomes was shown, but the number of patients in these analyses was small. CONCLUSIONS: This study provides new population exposure data for TDM of azithromycin in NTM disease. Rifampicin co-administration reduces azithromycin exposure by at least half, underscoring the need for upfront azithromycin dose adjustment, application of TDM, or considering alternative drugs for rifampicin, also considering controversy around its effectiveness and adverse effects.
OBJECTIVES: The remote regions of Western Australia (WA) have high gonorrhoea notification rates but low Neisseria gonorrhoeae penicillin resistance permitting the use of empiric combination oral amoxicillin, azithromyci...OBJECTIVES: The remote regions of Western Australia (WA) have high gonorrhoea notification rates but low Neisseria gonorrhoeae penicillin resistance permitting the use of empiric combination oral amoxicillin, azithromycin and probenecid therapy. The predominance of molecular-based gonorrhoea diagnoses and consequent reduced phenotypic susceptibility data required PCR-based N. gonorrhoeae penicillin resistance surveillance to ensure the ongoing reliability of oral penicillin-based therapy for uncomplicated gonorrhoea in this setting. MATERIALS AND METHODS: N. gonorrhoeae PCR-positive genital and non-genital specimens were systematically assessed across remote regions of WA for penicillinase production from 2012 to 2025 by detection of the N. gonorrhoeae TEM-1 plasmid using a specific real-time PCR. RESULTS: In 2012 <5% of N. gonorrhoeae positive samples in all remote regions were penicillinase-producing. By 2024, penicillinase detection rates had increased to >5% across three of the four remote regions prompting a review of the penicillin-based oral therapy in these regions. CONCLUSIONS: The continued recommendation of oral penicillin-based therapy for locally acquired uncomplicated gonorrhoea in a highly endemic setting must be evidence-based to ensure its reliability. Molecular penicillin resistance surveillance was successfully used for this purpose in the remote regions of WA where most gonorrhoea diagnoses are by molecular tests.
Yang Q, Tuon FF, Shah S
… +5 more, Kamat S, Mohamed N, Stone GG, Perez KK, Cantón R
J Antimicrob Chemother
· 2026 Jun · PMID 42267542
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BACKGROUND: Hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP) and complicated intra-abdominal infections (cIAIs) caused by carbapenem-resistant Enterobacterales (CRE) are associated with high morta...BACKGROUND: Hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP) and complicated intra-abdominal infections (cIAIs) caused by carbapenem-resistant Enterobacterales (CRE) are associated with high mortality. Metallo-β-lactamase (MBL)-producing strains represent therapeutic challenge compromising β-lactams and limiting treatment options. Aztreonam/avibactam is a novel combination designed to overcome MBL-mediated resistance. OBJECTIVES: To evaluate in vitro activity of aztreonam/avibactam and comparators against Enterobacterales from patients with HAP, VAP or cIAI collected globally (Africa/Middle East, Asia-Pacific, Europe and Latin America) during 2021-22 ATLAS surveillance program focusing on MBL-positive strains. METHODS: 14 564 Enterobacterales isolates were tested by broth microdilution per CLSI guidelines. CRE isolates underwent molecular characterization and MBL-positive isolates underwent additional molecular and susceptibility analysis, including cefiderocol. MBL-positive Escherichia coli isolates were screened for PBP3 mutations by whole-genome sequencing. MICs were interpreted using EUCAST breakpoints as appropriate. RESULTS: Aztreonam/avibactam was 99.5% susceptible (MIC ≤4 mg/L) for all Enterobacterales (MIC90 0.25 mg/L) and maintained high susceptibility against MDR (98.9%), ESBL (99.0%) and CRE (96.4%). Among 577 MBL-positive isolates (88% NDM), aztreonam/avibactam was 95.1% susceptible, compared with cefiderocol (50.3%), colistin (73.8%) and tigecycline (95.0%). Activity was consistent across regions and carbapenemase genotypes, including co-producers of multiple β-lactamases. However, E. coli isolates harbouring PBP3 insertions (YRIK/YRIN) and plasmid-mediated AmpC β-lactamases (n = 35) were 31.4% susceptible (MIC ≤4 mg/L). CONCLUSIONS: Aztreonam/avibactam demonstrated potent and consistent in vitro activity against Enterobacterales causing serious hospital infections, including MBL-producing CRE. These findings underscore aztreonam/avibactam's therapeutic potential and the need for rapid diagnostics and global surveillance to guide regional stewardship and treatment strategies for MDR infections.
BACKGROUND: Pseudomonas aeruginosa is a major nosocomial pathogen, and its antibiotic tolerance under low-metabolism conditions severely compromises clinical efficacy, presenting a significant therapeutic challenge. OBJE...BACKGROUND: Pseudomonas aeruginosa is a major nosocomial pathogen, and its antibiotic tolerance under low-metabolism conditions severely compromises clinical efficacy, presenting a significant therapeutic challenge. OBJECTIVES: A quantitative assessment of the metabolic dependence of clinically relevant antibiotics against P. aeruginosa was conducted, and a novel combination strategy capable of eradicating its low-metabolic populations was developed. METHODS: We established a gradient nutrient model (0%-100% LB) to simulate a continuum of metabolic states. Through linear regression analysis correlating ATP levels with bactericidal efficiency, we developed a Metabolic Dependence Index classification system. Leveraging this system, we designed a Strongly Metabolism-Dependent (SMD) + Weakly Metabolism-Dependent (WMD) synchronous combination strategy, which was subsequently validated using five clinical isolates. RESULTS: Low-metabolism populations exhibited significantly reduced susceptibility to SMD agents but unaltered tolerance to WMD antibiotics. The SMD + WMD combination achieved enhanced killing of low-metabolism bacteria (>99.999% killing) with a marked dose reduction in vitro. This strategy also improved in vitro clearance efficacy compared to monotherapy. Collectively, our work provides a quantitative framework for targeting metabolic heterogeneity to overcome antibiotic tolerance.
J Antimicrob Chemother
· 2026 Jun · PMID 42262127
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Driveline infection, exemplifying medical device-associated infection, is a difficult-to-treat complication of ventricular assist device implantation in which biofilm formation underlies both infection onset and recurren...Driveline infection, exemplifying medical device-associated infection, is a difficult-to-treat complication of ventricular assist device implantation in which biofilm formation underlies both infection onset and recurrence. Although clinical experience remains limited, treatment success has been reported in cases where local antibiotics at high concentrations were used in combination with surgical debridement and/or device reimplantation. We recently identified the low metabolic state of biofilm cells as the central mechanism underlying the high antimicrobial resistance of staphylococcal biofilms and as a potential therapeutic target for driveline infections. We hypothesize that rationally combining weakly and strongly metabolism-dependent antibiotics at high concentrations for an extended period may eradicate staphylococcal biofilms, including the embedded tolerant and persister cells. If clinically validated, this strategy may hold the key to achieving long-term treatment success in many medical device-associated infections, including the driveline infection.
BACKGROUND: Klebsiella has recently been recognized as a potential host of mobile tigecycline-resistant gene tet(X4), posing a serious threat to public health. However, the occurrence of other tet(X) variants in Klebsiel...BACKGROUND: Klebsiella has recently been recognized as a potential host of mobile tigecycline-resistant gene tet(X4), posing a serious threat to public health. However, the occurrence of other tet(X) variants in Klebsiella remains uncommon. METHODS: We identified a novel tet(X5) variant in one Klebsiella pneumoniae and two Klebsiella quasipneumoniae isolates recovered from retail meat in Hainan, China and investigated its phenotypic resistance, genetic context and transferability. Antimicrobial susceptibility was determined by broth microdilution. Whole-genome sequencing, utilizing both Illumina and Nanopore platforms, facilitated the complete characterization of the genome sequence and plasmid structure. RESULTS: Resistance gene analysis revealed a novel tet(X5) variant encoding a 385-amino acid protein, designated Tet(X5.5), which exhibited 97.6% identity with the reference Tet(X5) protein. A total of 21 amino acid substitutions were identified, primarily located in the N- and C-terminal regions. Functional assays confirmed that expression of tet(X5.5) increased the tigecycline MIC in E. coli DH5α from 0.125 to 4 mg/L (32-fold). In K. pneumoniae 241CM75B, the tet(X5.5) gene was located on two conjugative plasmids: an ∼170 kb IncFIBK/IncFIIK8 hybrid plasmid and an ∼74 kb IncFIIpCRY plasmid. The other two isolates carried identical IncFIIpCRY plasmids. Conjugation assays confirmed that all tet(X5.5)-carrying plasmids were self-transmissible to E. coli C600, with transfer frequencies ranging from 10-6 to 10-5. Genetic analysis revealed that tet(X5.5) was embedded within an ISCR2-mediated transposon structure that was conserved across distinct plasmid backbones. CONCLUSIONS: This study reports a novel transferable tet(X5) variant in Klebsiella, underscoring the risk of foodborne transmission and the necessity for integrated surveillance across clinical and agricultural settings.
J Antimicrob Chemother
· 2026 Jun · PMID 42258601
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Companion animals are increasingly recognized as potential reservoirs of antimicrobial-resistant (AMR) bacteria, yet the frequency of sharing between pets and their owners remains unclear. We conducted a systematic revie...Companion animals are increasingly recognized as potential reservoirs of antimicrobial-resistant (AMR) bacteria, yet the frequency of sharing between pets and their owners remains unclear. We conducted a systematic review and meta-analysis to estimate household-level co-occurrence ('sharing') of AMR pathogens. We searched PubMed, Embase, and Web of Science for studies sampling pets and owners from the same household and assessing genetic or phenotypic relatedness of AMR bacteria. Random-effects generalized linear mixed models were used to estimate pooled prevalences, with subgroup and sensitivity analyses by host health status, pathogen group, typing method, and study design. Across 152 studies, the pooled prevalence of household-level sharing was 3.8% (95% CI: 2.7%-5.1%). Sharing was similarly low among households when pets and owners were healthy or when the pet or owner had an illness unrelated to the pathogen (3.0% in both cases), but higher when a pet or owner had a confirmed infection (9.0%, 95% CI: 5.0%-16.0%). Estimates were comparable for Staphylococci and Enterobacterales. Studies using phenotypic methods alone reported higher prevalences than those using molecular typing, consistent with lower discriminatory resolution. Substantial heterogeneity was observed, but findings were robust across study design, geography, and quality. Household sharing of AMR bacteria between pets and owners appears relatively uncommon under typical conditions and is more strongly associated with infection or active shedding than routine cohabitation.
Posaconazole delayed-release (DR) tablets are labelled as 'do not crush' medications. Despite this designation, emerging research demonstrates successful attainment of therapeutic serum concentrations, suggesting that th...Posaconazole delayed-release (DR) tablets are labelled as 'do not crush' medications. Despite this designation, emerging research demonstrates successful attainment of therapeutic serum concentrations, suggesting that they may be pharmacokinetically superior to the immediate-release (IR) suspension when given via enteric feeding tube (EFT). While crushed posaconazole DR tablets may be better suited than the IR suspension to attain therapeutic serum concentrations, several practical factors must be considered, including lack of dose equivalency between crushed DR tablets for EFT administration and DR tablets swallowed whole and the risk of EFT occlusion. This article summarizes the current evidence on posaconazole serum concentrations with crushed DR tablets administered via EFT, explores risks of this practice and provides mitigation strategies for application in the clinical setting, including proposed dosing and administration practices.
BACKGROUND: Chronic pulmonary aspergillosis (CPA) requires prolonged oral azole therapy, yet 30%-40% experience relapse after treatment discontinuation. The role of nebulized amphotericin B (NAB) in CPA as a maintenance...BACKGROUND: Chronic pulmonary aspergillosis (CPA) requires prolonged oral azole therapy, yet 30%-40% experience relapse after treatment discontinuation. The role of nebulized amphotericin B (NAB) in CPA as a maintenance therapy remains unexplored. METHODS: We retrospectively reviewed CPA patients treated with NAB deoxycholate (10 mg twice daily) preparation administered either on alternate days (three times weekly) or six times weekly (6/7-day). The primary objective was to compare the efficacy and safety of these two dosage schedules in maintaining CPA remission. RESULTS: We included 36 subjects (28 chronic cavitary pulmonary aspergillosis, 8 chronic fibrosing pulmonary aspergillosis ). Most received oral itraconazole (n = 34) for a median duration of 12 months before NAB initiation. Patients received NAB on alternate days (n = 16) or 6/7-day (n = 20) for a median duration of 11 months. Of 34 evaluable patients with a median follow-up of 27 months, remission was maintained in 23 (67.6%) during NAB therapy, with significantly higher rates with 6/7-day versus alternate-day therapy (16/19 [84.2%] versus 7/15 [46.7%]; P = 0.020). CPA relapse occurred in 11 patients (32.4%), more frequently with alternate-day treatment (8/15 [53.3%] versus 3/19 [15.8]; P = 0.020). Adverse events occurred in eight patients (22.2%), including bronchospasm (n = 5) and haemoptysis (n = 1); two discontinued NAB due to intolerance. CONCLUSION: Nebulized amphotericin B deoxycholate maintained CPA remission in two-thirds of patients, with 6/7-day administration achieving significantly better outcomes than alternate-day therapy. Prospective randomized controlled trials are needed to establish NAB as standard maintenance therapy in CPA.
Surveillance of antimalarial drug efficacy is essential for drug policy in the fight against malaria. This includes clinical trials of drug efficacy, molecular marker typing and ex vivo/in vitro drug susceptibility tests...Surveillance of antimalarial drug efficacy is essential for drug policy in the fight against malaria. This includes clinical trials of drug efficacy, molecular marker typing and ex vivo/in vitro drug susceptibility tests such as 50% inhibitory concentration (IC50) assay. The goal of this review was to elaborate on the variance in the IC50 assay across labs in sub-Saharan Africa (sSA) where malaria is endemic. We systematically reviewed 71 articles, published between 2015 and 2025, evaluating IC50 in sSA where only 56 were performed in labs in Western (WA), Central (CA), East (EA) and Southern Africa (SA). The IC50 values of the major antimalarial drugs, including dihydroartemisinin (DHA), lumefantrine (LUM), mefloquine (MFQ), amodiaquine (AMD), chloroquine (CQ), piperaquine (PPQ), artesunate (ATS), artemisinin (ART) and quinine (QN), were reported. An F-test performed on the IC50 values from WA and EA, where ex vivo assays were conducted, revealed a statistically significant variation (P value <0.05) in the IC50 values of some major antimalarials (DHA, CQ, LUM and AMD). The geometric means for DHA, CQ, LUM and AMD in WA versus EA were 2.46 versus 2.21, 83.15 versus 34.34, 10.06 versus 10.47, and 10.63 versus 17.61 nM, respectively. The overall ex vivo IC50 values of CQ were generally below the known resistance thresholds. Differences in drug reconstitution solvents, the range of drug concentrations, period of drug exposure (48 or 72 h), and curve-fitting tools and assay methods were observed. These differences together could account for the variance in IC50 values across sSA. We therefore recommend regional harmonization of the IC50 protocol for antimalarial drug efficacy surveillance and formation of a regional quality assessment network of malaria IC50 labs, as a step towards reliable data sharing and integration into strategic plans for malaria elimination.
Li G, El-Deeb IM, Whyte HG
… +4 more, Blaskovich MAT, Walker MJ, von Itzstein M, De Oliveira DMP
J Antimicrob Chemother
· 2026 Jun · PMID 42235930
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BACKGROUND AND OBJECTIVES: Enterococcus faecium and Staphylococcus aureus are opportunistic bacterial pathogens with a demonstrated capacity to develop antimicrobial resistance and cause serious life-threatening infectio...BACKGROUND AND OBJECTIVES: Enterococcus faecium and Staphylococcus aureus are opportunistic bacterial pathogens with a demonstrated capacity to develop antimicrobial resistance and cause serious life-threatening infections, underscoring the urgent need for new therapeutic options. METHODS: Here, we have synthesized and characterized the activities of an 8-hydroxyquinoline-based ionophore antibiotic (ionophoroantibiotic; IP antibiotic), designated 'IP-antibiotic 12.' RESULTS: Using multidrug-resistant strains of E. faecium and S. aureus, in vitro investigations revealed that IP-antibiotic 12 exhibits bactericidal activity, demonstrates a low propensity for resistance emergence, increases the susceptibility of particular strains to select antibiotics, possesses a favorable toxicity profile, and dysregulates bacterial metal homeostasis. IP-antibiotic 12 demonstrated therapeutic efficacy against multidrug-resistant S. aureus skin infection, as a direct-acting topical antimicrobial and antibiotic adjunct when co-administered with oral linezolid. Interestingly, it was not efficacious in murine models of systemic and pulmonary infection. CONCLUSIONS: These results highlight the potential of IP-antibiotic 12 as a novel therapeutic against multidrug-resistant gram-positive bacteria and provide a foundation for the development of next-generation IP-antibiotics with enhanced in vivo therapeutic efficacy.
Cree ML, Abdul-Aziz MH, Wallis SC
… +6 more, Won H, Sumi CD, Marjanovic D, Ordonez JL, Schlapbach LJ, Roberts JA
J Antimicrob Chemother
· 2026 Jun · PMID 42234487
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BACKGROUND: Critically ill children receiving continuous renal replacement therapy may experience sub-therapeutic concentrations for antimicrobials leading to treatment failure and antimicrobial resistant pathogens. The...BACKGROUND: Critically ill children receiving continuous renal replacement therapy may experience sub-therapeutic concentrations for antimicrobials leading to treatment failure and antimicrobial resistant pathogens. The objective of this study was to determine whether antimicrobial concentrations are reduced by a paediatric continuous renal replacement therapy (CRRT). METHOD: An ex vivo closed continuous veno-venous haemodiafiltration was simulated for a 3 kg infant to assess antimicrobial clearance across three ultrafiltration rates (zero, low and high flux). Slow continuous ultrafiltration was used to assess antimicrobial adsorption and recovery over 240 minutes. Controls were included to account for spontaneous drug degradation. This study was conducted in a university research laboratory with no participants. Antimicrobial concentrations were measured using a validated HPLC-MS/MS method. RESULTS: The antimicrobial filter clearance during high-flux filtration was significantly increased for fluconazole, piperacillin, tazobactam, vancomycin and voriconazole (P < 0.05). The antimicrobial recovery [mean (%)] at 240 minutes in the CRRT model was significantly different from baseline (time zero) for ampicillin 49%, fluconazole 76%, gentamicin (0%) meropenem 51%, piperacillin 54%, vancomycin 31% and voriconazole 47% (P < 0.05). A significant relationship was demonstrated between antimicrobial recovery and molecular charge (R2 = 0.58 P < 0.001) in the CRRT model; no relationships were reported for lipophilicity or protein binding. CONCLUSIONS: The concentrations were reduced in >70% of the study antimicrobials in the ex vivo paediatric CRRT model, as a result of an increase in filter clearance during high-flux filtration or from drug-circuit adsorption. These findings suggests that antimicrobial dosing in critically ill children receiving CRRT requires assessment to determine whether antimicrobial concentrations are therapeutic.
Cojutti PG, Toschi A, Pasquini Z
… +7 more, Paolini S, Maffini E, Bonifazi F, Zinzani PL, Giannella M, Viale P, Pea F
J Antimicrob Chemother
· 2026 Jun · PMID 42234486
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BACKGROUND: Onco-haematological patients with febrile neutropenia are at high risk of severe infections caused by multidrug-resistant pathogens. Continuous infusion (CI) of beta-lactams may improve pharmacokinetic/pharma...BACKGROUND: Onco-haematological patients with febrile neutropenia are at high risk of severe infections caused by multidrug-resistant pathogens. Continuous infusion (CI) of beta-lactams may improve pharmacokinetic/pharmacodynamic (PK/PD) target attainment, yet evidence in this population remains limited. OBJECTIVES: To evaluate the likelihood of achieving an aggressive PK/PD target with CI beta-lactams during the first week of therapy in onco-haematological patients and to identify predictors of target non-attainment. METHODS: This prospective observational study enrolled adult onco-haematological patients receiving CI beta-lactams for empirical or targeted treatment over a 1-year period. Steady-state plasma concentrations were measured between days 3 and 7. The aggressive PK/PD target was defined as a free steady-state concentration-to-MIC (or clinical breakpoint) ratio ≥4; for beta-lactam/beta-lactamase inhibitor combinations, a joint PK/PD target was applied. Multivariate logistic regression analysis identified factors associated with target attainment. RESULTS: A total of 256 patients were included, 82 of whom (32.1%) received targeted therapy. Aggressive PK/PD target attainment was achieved in 85.4% of patients undergoing targeted treatment, compared with 57.5% of those treated empirically. Target non-attainment occurred most frequently with piperacillin/tazobactam and ceftazidime/avibactam. Augmented renal clearance (OR 12.29, P < 0.001), male sex (OR 3.79, P < 0.001) and age <65 years (OR 2.40, P = 0.025) independently predicted target non-attainment, whereas targeted therapy and meropenem use were associated with a higher attainment. CONCLUSIONS: CI beta-lactams reliably achieve aggressive PK/PD targets during targeted therapy but not during empirical treatment in onco-haematological patients. Augmented renal clearance is a major determinant of underexposure, supporting the use of therapeutic drug monitoring to optimize dosing in this high-risk population.