Carlos Andrés Rodríguez

Antibiotic combination therapy is widely used in clinical practice; however, its application often lacks a clear understanding of the underlying pharmacological principles. This review critically examines the rationale, benefits, and limitations of combination therapy by integrating evidence from in vitro studies, animal models, and the relevant clinical literature. Elicit was used as a support tool to assist in the organization and analysis of the selected studies. While combinations may broaden antimicrobial coverage, enhance bactericidal activity, or prevent resistance, they can also result in additive or antagonistic interactions that limit their clinical effectiveness. This review emphasizes that antibiotic combinations should not be guided by empirical intuition but approached as a rational strategy supported by well-defined therapeutic goals and strong scientific evidence to optimize clinical outcomes and address antimicrobial resistance with greater precision.

Purpose Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (non-pCR) after neoadjuvant chemotherapy (NACT) have a high-risk of relapse. While adjuvant capecitabine (AdjCape) has demonstrated improved overall survival (OS) and disease-free survival (DFS) in Asian populations, its effectiveness in non-Asian settings remains uncertain. We aimed to evaluate the effect of AdjCape on survival outcomes using real-world data from a Latin American population. Methods We conducted a retrospective cohort study (2008–2024) including 360 women with non-metastatic TNBC and non-pCR treated at a single institution. Propensity score matching (PSM) was applied to adjust for baseline differences. Cox regression models assessed the association of AdjCape with OS and DFS, and stratified analyses identified subgroups with differential treatment effects. Results Among 360 patients, 106 (29.4%) received AdjCape. After PSM, 187 patients (72 AdjCape, 115 controls) were analyzed. AdjCape was not associated with improved OS (HR 0.79, 95% CI 0.51–1.23, p = 0.302) or DFS (HR 0.81, 95% CI 0.53–1.23, p = 0.321). However, significant benefit was observed in patients with high residual tumor burden (pT3–pT4: OS HR 0.29, p = 0.020; DFS HR 0.37, p = 0.044) and in those not receiving radiotherapy (DFS HR 0.47, p = 0.038). Conclusions AdjCape did not improve OS or DFS in the overall TNBC non-pCR cohort but may offer benefit in patients with extensive residual disease or those not treated with radiotherapy. These findings highlight the need for individualized treatment strategies and further evaluation of capecitabine in the context of modern therapies.

Purpose: Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous malignancy with poor prognosis. The optimal timing of chemotherapy—neoadjuvant (NACT) versus adjuvant (ACT)—remains controversial. This study assessed real-world outcomes in non-metastatic TNBC patients according to chemotherapy timing. Methods: This retrospective study (2008–2023) evaluated the impact of chemotherapy timing on overall survival (OS) and event-free survival (EFS) in a cohort of 711 patients. Propensity score (PS) matching with preoperative variables was used to adjust for baseline imbalances, and Cox regression models were applied to account for treatment-related variables. Results: NACT was administered to 525 patients (73.8%), with a 37.3% pathological complete response (pCR) rate. PS matching yielded 177 patient pairs; tumor stage, age and histologic grade remained unbalanced. In the unadjusted analysis, NACT was associated with worse OS (HR 1.56, 95% CI1.08–2.25, p = 0.018). However, multivariate analysis adjusting for unmatched and postoperative variables showed a potential benefit of NACT for OS (HR 0.53, 95% CI 0.07–4.13, p = 0.545) and EFS (HR 0.94, 95% CI 0.21–4.17, p = 0.932). Tumor stage acted as an effect modifier, and stratified analyses revealed that NACT was superior to ACT in patients with advanced-stage disease who achieved pCR (HR 0.22, 95% CI 0.07–0.7, p < 0.010). Conclusions: In our TNBC cohort, chemotherapy timing significantly influenced OS and EFS, particularly in relation to initial tumor stage and pCR status. NACT was more beneficial than ACT in patients with advanced disease who achieve pCR, underscoring its role in both prognostic stratification and therapeutic decision-making.

Los virus herpes simple (Herpes Simplex Virus, HSV) de tipo 1 y 2 producen la infección de transmisión sexual más común en mujeres, con mayor incidencia en los países en desarrollo. Además de generar secuelas principalmente neurológicas en el recién nacido, cuando la primoinfección ocurre durante el periodo perinatal, puede diseminarse y producir gran morbimortalidad de la madre y el neonato.A pesar de contarse con pruebas de laboratorio confiables, el diagnóstico de la infección por HSV durante el periodo perinatal es complejo, pues sus manifestaciones clínicas varían desde la forma diseminada hasta la asintomática o se pueden producir síntomas inespecíficos sin lesiones en piel o mucosas, por lo que es fundamental tener la sospecha clínica. Se presenta el caso de una madre con infección diseminada por HSV de tipo 2 que presentó hepatitis viral y cuyo neonato falleció, resaltándose la importancia de sospechar la infección por HSV en una mujer gestante febril con compromiso sistémico durante el periodo perinatal, aun en ausencia de brote.

Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for treating severe infections due to Enterococcus faecalis . However, the pharmacokinetic/pharmacodynamic (PK/PD) index linked to the in vivo efficacy of the combination is not yet defined, hindering dose optimization in the clinic.

The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic againstEnterococcus faecalisbased onin vitrotests and the rabbit endocarditis model, however,in vitroassays are limited by the use of fixed antibiotic concentrations and the rabbit model by poor bacterial growth, high variability, and the use of point dose-effect estimations, that may lead to inaccurate assessment of antibiotic combinations and hinder optimal translation. Here, we tested AMP+CRO against two strains ofE.faecalisand one ofE.faeciumin an optimized mouse thigh infection model that yields high bacterial growth and allows to define the complete dose-response relationship. By fitting Hill’s sigmoid model and estimating the parameters maximal effect (E_max) and effective dose 50 (ED₅₀), the following interactions were defined: synergism (E_maxincrease ≥2 log₁₀CFU/g), antagonism (E_maxreduction ≥1 log₁₀CFU/g) and potentiation (ED₅₀reduction ≥50% without changes in E_max). AMP monotherapy was effective against the three strains, yielding valid dose-response curves in terms of dose and the indexfT_>MIC. CRO monotherapy showed no effect. The combination AMP+CRO againstE.faecalisled to potentiation (59–81% ED₅₀reduction) and not synergism (no changes in E_max). AgainstE.faecium, the combination was indifferent. The optimized mouse infection model allowed to obtain the complete dose-response curve of AMP+CRO and to define its interaction based on pharmacodynamic parameter changes. Integrating these results with the pharmacokinetics will allow to derive the PK/PD index bound to the activity of the combination, essential for proper translation to the clinic.

Background: Tuberculosis (TB) remains one of the most important infectious diseases. Population pharmacokinetic (pop-PK) models are widely used to individualize dosing regimens of several antibiotics, but their application in anti-TB drug studies is scant. The aim of this study was to provide an insight regarding the status of pop-PK for these drugs and to compare results obtained through both parametric and nonparametric approaches to design precise dosage regimens. Methods: First, a systematic approach was implemented, searching in PubMed and Google Scholar. Articles that did not include human patients, that lacked an explicit structural model, that analyzed drugs inactive against M. tuberculosis, or were without full-text access, were excluded. Second, the PK parameters were summarized and categorized as parametric versus nonparametric results. Third, a Monte Carlo simulation was performed in Pmetrics using the results of both groups, and an error term was built to describe the imprecision of each PK modeling approach. Results: Thirty-three articles reporting at least 1 pop-PK model of 19 anti-TB drug were found; 46 different models including PK parameter estimates and their relevant covariates were also reported. Only 9 models were based on nonparametric approaches. Rifampin was the drug most studied, but only using parametric approaches. The simulations showed that nonparametric approaches improve the error term compared with parametric approaches. Conclusions: More and better models, ideally using nonparametric approaches linked with clear pharmacodynamic goals, are required to optimize anti-TB drug dosing, as recommended in the WHO End TB strategy.

Background: Isoniazid (INH) is a first-line antituberculosis (TB) agent with a pharmacokinetic profile characterized by high interindividual variation; however, population pharmacokinetic studies in patients with TB are scarce. The aim was to develop a population model for INH in Colombian patients with TB suitable for predicting drug exposure and assessing the probability of target attainment of pharmacodynamic goals. Methods: Ten hospitalized adult patients with TB undergoing INH treatment were recruited. After an 8-hour fasting, subjects took 300 mg of INH, and 10 samples were taken from 0 to 12 hours. INH was quantified by high-performance liquid chromatography–UV, and data were analyzed with the Pmetrics R package software. A Monte Carlo simulation with the model parameters was run to determine the probability of target attainment for optimal efficacy. Results: The best model included 2 compartments, first-order absorption (K_a), delayed absorption (T_lag), and linear clearance (CL). Median T_lag was 0.25 hours, 5.54 hour⁻¹ for K_a, JOURNAL/thdm/04.03/00007691-201912000-00005/inline-formula1/v/2023-08-14T203520Z/r/image-tiff for CL, JOURNAL/thdm/04.03/00007691-201912000-00005/inline-formula2/v/2023-08-14T203520Z/r/image-tiff for the volume of the central compartment (V_c), 1.04 L/h for intercompartmental clearance (Q), and 788 L for the volume of the peripheral compartment (V_p). CL and V_c were allometrically scaled on basis of the normalized body weight. Conclusions: The Monte Carlo simulation indicated that 300 mg of INH per day is appropriate for Mycobacterium tuberculosis strains with minimal inhibitory concentration (MIC) up to 0.03 mg/L (target: area under the concentration–time curve/MIC >597); however, to cover strains with MIC up to 0.125 mg/L (80% of clinical isolates), a dose of 900 mg per day would be required.

(2017). CIEMTO: the new drug and poison research and information center in Medellín, Colombia. Clinical Toxicology: Vol. 55, No. 7, pp. 684-685.