Tuberculosis (TB) is a leading cause of mortality worldwide, and resistance to anti-tuberculosis drugs is a challenge to effective treatment. Multi-drug resistant TB (MDR-TB) can be difficult to treat, requiring long durations of therapy and the use of second line drugs, increasing a patient’s risk for toxicities and treatment failure. Given the challenges treating MDR-TB, clinicians can improve the likelihood of successful outcomes by utilizing therapeutic drug monitoring (TDM). TDM is a clinical technique that utilizes measured drug concentrations from the patient to adjust therapy, increasing likelihood of therapeutic drug concentrations while minimizing the risk of toxic drug concentrations. This review paper provides an overview of the TDM process, pharmacokinetic parameters for MDR-TB drugs, and recommendations for dose adjustments following TDM.

Background: Antimicrobial resistance is a growing health concern worldwide. The objective of this study was to evaluate the effect of beta-lactam infusion on the emergence of bacterial resistance in patients with severe pneumonia in the intensive care unit. Methods: Adult intensive care patients receiving cefepime, meropenem, or piperacillin–tazobactam for severe pneumonia caused by Gram-negative bacteria were randomized to receive beta-lactams as an intermittent (30 minutes) or continuous (24 hours) infusion. Respiratory samples for culture and susceptibility testing, with minimum inhibitory concentrations (MIC), were collected once a week for up to 4 weeks. Beta-lactam plasma concentrations were measured and therapeutic drug monitoring was performed using Bayesian software as the standard of care. Results: The study was terminated early owing to slow enrollment. Thirty-five patients were enrolled in this study. Cefepime (n = 22) was the most commonly prescribed drug at randomization, followed by piperacillin (n = 8) and meropenem (n = 5). Nineteen patients were randomized into the continuous infusion arm and 16 into the intermittent infusion arm. Pseudomonas aeruginosa was the most common respiratory isolate (n = 19). Eighteen patients were included in the final analyses. No differences in bacterial resistance were observed between arms (P = 0.67). No significant differences in superinfection (P = 1), microbiological cure (P = 0.85), clinical cure at day 7 (P = 0.1), clinical cure at end of therapy (P = 0.56), mortality (P = 1), intensive care unit length of stay (P = 0.37), or hospital length of stay (P = 0.83) were observed. Achieving 100% ƒT > MIC (P = 0.04) and ƒT > 4 × MIC (P = 0.02) increased likelihood of clinical cure at day 7 of therapy. Conclusions: No differences in the emergence of bacterial resistance or clinical outcomes were observed between intermittent and continuous infusions. Pharmacokinetic/pharmacodynamic target attainment may be associated with a clinical cure on day 7.

Purpose: To assess the impact of beta-lactam therapeutic drug monitoring (TDM) timing and therapy adjustment on clinical cure and 30-day mortality. Methods: This was a prospective study of critically ill patients admitted to the University of Florida Health Shands Hospital intensive care unit (ICU) between 2021 and 2022, ≥18 years old, and requiring beta-lactam therapy for a suspected or confirmed infection. Beta-lactam concentrations were measured per standard of care, pharmacokinetic/dynamic (PK/PD) target attainment was calculated, and therapy was adjusted if needed. Multiple regression and time-to-event (TTE) analyses were performed. Results: A total of 297 infection episodes from 268 patients were included. The mean (SD) age was 56 years (17), weight was 82 kg (32), and 14% received renal replacement therapy. The most common infection source was the lung, and the most common beta-lactam was cefepime. The most common infusion duration was 30 min. The median (IQR) time to first TDM was 2.7 days (1.7–4.7). Fifty-seven percent of patients required therapy adjustment. Increases in beta-lactam dose, frequency, or infusion duration were associated with lower 30-day mortality compared to continuing the same regimen (aOR 0.30, p = 0.015). Delay in performing TDM was associated with lower probability of clinical cure (aOR 0.92, p = 0.0023). Patients who had the regimen increased had shorter hospital stay compared to those who had it decreased. Timing of beta-lactam TDM in ICU patients was a significant predictor of clinical cure, while adjusting beta-lactam therapy to achieve higher exposure was a significant predictor of 30-day mortality.

Beta‐lactam antibiotics (beta‐lactams) are first‐line treatments for most major infectious syndromes in acutely ill patients, with in vitro activity against common pathogens, demonstrated efficacy in trials, and a perceived low risk of adverse effects. The current dosing approach, informed by population‐level data, tends to be simplistically reduced to a “one size fits all” dosing method which only accounts for body weight (i.e., in pediatrics) and end organ function to estimate drug clearance (e.g., estimated glomerular filtration rate); this approach results in substantial variability in observed serum concentrations in acutely ill patients, which can compromise real‐world effectiveness and safety. Beta‐lactam dose individualization, therefore, defined as a dosing regimen for one patient informed by measured concentrations from that patient, has been recommended in international clinical guidelines. Comprehensive guidance on best practices for beta‐lactam dose individualization is lacking. To address this knowledge gap and develop guidance, a multidisciplinary panel of international experts was assembled from the disciplines of infectious diseases, critical care, pharmacometrics, and laboratory medicine, representing both adults and pediatrics. The panel systematically evaluated the literature, using the GRADE approach where feasible, to address broad thematic questions pertaining to whether beta‐lactam dose individualization should be pursued, for what indications beta‐lactam dose individualization is warranted, and the most critical considerations and best practices for implementation of beta‐lactam individualization. The resultant consensus recommendations will equip healthcare professionals caring for acutely ill patients treated with beta‐lactam therapy with the evidence and tools necessary to guide optimal use of beta‐lactam dose individualization.

Background: The objective was to identify associations between beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) targets and Gram-negative bacteria resistance emergence in patients. Methods: Retrospective data were collected between 2016 to 2019 at the University of Florida Health-Shands Hospital in Gainesville, FL. Adult patients with two Gram-negative isolates receiving cefepime, meropenem, or piperacillin-tazobactam and who had plasma beta-lactam concentrations were included. Beta-lactam exposures and time free drug concentrations that exceeded minimum inhibitory concentrations (ƒT > MIC), four multiples of MIC (ƒT > 4× MIC), and free area under the time concentration curve to MIC (ƒAUC/MIC) were generated. Resistance emergence was defined as any increase in MIC or two-fold increase in MIC. Multiple regression analysis assessed the PK/PD parameter impact on resistance emergence. Results: Two hundred fifty-six patients with 628 isolates were included. The median age was 58 years, and 59% were males. Cefepime was the most common beta-lactam (65%) and Pseudomonas aeruginosa the most common isolate (43%). The mean daily ƒAUC/MIC ≥ 494 was associated with any increase in MIC (p = 0.002) and two-fold increase in MIC (p = 0.004). The daily ƒAUC/MIC ≥ 494 was associated with decreased time on antibiotics (p = 0.008). P. aeruginosa was associated with any increase in MIC (OR: 6.41, 95% CI [3.34–12.28]) or 2× increase in MIC (7.08, 95% CI [3.56–14.07]). Conclusions: ƒAUC/MIC ≥ 494 may be associated with decreased Gram-negative resistance emergence.

Tuberculosis (TB) is a major cause of morbidity and mortality in children globally. This study developed models to describe population pharmacokinetics (PK) of pyrazinamide (PZA) and ethambutol (EMB) in children with TB with or without human immunodeficiency virus (HIV) coinfection. Ghanaian children with TB with or without HIV coinfection receiving first-line antituberculosis therapy for at least 4 weeks had blood samples collected at time 0 (pre-dose), 1-, 2-, 4-, 8-, and 12-h post-dose. PZA and EMB concentrations were quantified using liquid chromatography tandem mass spectrometry. Nonlinear mixed-effects models were applied to describe the population PK using Monolix2024R1. Maximum concentrations ( C _max ) and 24-h area under the time concentration curve (AUC _0–24 ) were compared to published values in adults. A total of 85 children (41 TB, 44 TB/HIV) were included. The median (range) age was 5 years (0.3–14.5), and 61.2% were male. Median (range) doses for PZA and EMB were 31.6 (21.4–49.7) and 21.4 mg/kg (14.3–34.2), respectively. PZA was best described using a one-compartment model and EMB by a two-compartment model. Allometric scaling improved both model fits. Children with TB/HIV coinfection had approximately 18.5% faster PZA clearance and 25% faster EMB clearance. Optimized dosing to achieve adult-equivalent exposures required higher-than-currently recommended doses, particularly among children in the lowest weight bands and those with HIV. The population PK of PZA and EMB was well described by the final models, but the higher-than-currently recommended doses needed to achieve adult-equivalent exposures raise concerns regarding risks for drug-associated toxicities and will require further evaluation.