• beta-Lactamase Inhibitors/pharmacokinetics
• beta-Lactamase Inhibitors/pharmacology
• beta-Lactamase Inhibitors/administration & dosage
• Humans
• Anti-Bacterial Agents/pharmacokinetics
• Anti-Bacterial Agents/pharmacology
• Anti-Bacterial Agents/administration & dosage
• Microbial Sensitivity Tests
• beta-Lactams/pharmacokinetics
• beta-Lactams/pharmacology
• beta-Lactams/administration & dosage
• beta-Lactams/therapeutic use
• beta-Lactamases/metabolism

• Erasmus+
• M.C. de Visser Fonds
• Leids Universiteits Fonds
• Hendrik Mullerfonds
• KNMP Stipendiafonds

• Enterococcus
• PK/PD index
• antibiotic combination
• antimicrobial combinations
• pharmacodynamics
• pharmacokinetics
• synergism

Respiratory tract infections in the elderly are difficult to cure and can easily recur, thereby posing a great threat to patient prognosis and quality of life.

To investigate the therapeutic effects of different antibiotics in elderly patients with respiratory tract infection.

Seventy-four elderly patients with respiratory tract infection were randomly allocated to a study (n = 37; treated with cefoperazone sodium/sulbactam sodium) or control (n = 37; treated with piperacillin sodium/tazobactam sodium on the basis of routine symptomatic support) group. Both groups were treated for 7 d. Time to symptom relief (leukocyte recovery; body temperature recovery; cough and sputum disappearance; and rale disappearance time), treatment effect, and laboratory indexes [procalcitonin (PCT), C-reactive protein (CRP), white blood cell count (WBC), and neutrophil percentage (NE)] before and 7 d after treatment and the incidence of adverse reactions were assessed.

In the study group, the time to WBC normalization (6.79 ± 2.09 d), time to body temperature normalization (4.15 ± 1.08 d), time to disappearance of cough and sputum (6.19 ± 1.56 d), and time to disappearance of rales (6.68 ± 1.43 d) were shorter than those of the control group (8.89 ± 2.32 d, 5.81 ± 1.33 d, 8.77 ± 2.11 d, and 8.69 ± 2.12 d, respectively; P = 0.000). Total effective rate was higher in the study group (94.59% vs 75.68%, P = 0.022). Serum PCT (12.89 ± 3.96 μg/L), CRP (19.62 ± 6.44 mg/L), WBC (20.61 ± 6.38 × 10⁹/L), and NE (86.14 ± 7.21%) levels of the study group before treatment were similar to those of the control group (14.05 ± 4.11 μg/L, 18.79 ± 5.96 mg/L, 21.21 ± 5.59 × 10⁹/L, and 84.39 ± 6.95%, respectively) with no significant differences (P = 0.220, 0.567, 0.668, and 0.291, respectively). After 7 d of treatment, serum PCT, CRP, WBC, and NE levels in the two groups were lower than those before treatment. Serum PCT (2.01 ± 0.56 μg/L), CRP (3.11 ± 1.02 mg/L), WBC (5.10 ± 1.83 × 10⁹/L), and NE (56.35 ± 7.17%) levels were lower in the study group than in the control group (3.29 ± 0.64 μg/L, 5.67 ± 1.23 mg/L, 8.13 ± 3.01 × 10⁹/L, and 64.22 ± 8.08%, respectively; P = 0.000). There was no significant difference in the incidence of adverse reactions between the groups (7.50% vs 12.50%, P = 0.708).

Piperacillin sodium/tazobactam sodium is superior to cefoperazone sodium/ sulbactam sodium in the treatment of elderly patients with respiratory tract infection with a similar safety profile.

• Cefoperazone sodium
• Sulbactam sodium
• Piperacillin sodium
• Tazobactam sodium
• Respiratory tract infection
• Elderly

Standard piperacillin–tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics and pharmacodynamics of standard- and high-dose P-T in obese adult inpatients.

Those receiving standard-dose P-T with BMI ≥ 30 kg/m² weighing 105–139 kg or ≥ 140 kg were given up to 6.75 g or 9 g every 6 h, respectively. Patients were monitored closely for safety. Elimination phase blood samples were drawn for 28 patients on standard and high doses to calculate the pharmacokinetic values using a one-compartment model. The likelihood of pharmacodynamic target attainment (100% fT > 16/4 mg/L) on various P-T regimens was calculated using each patient’s own pharmacokinetic values.

Piperacillin and tazobactam half-lives ranged from 0.5–10.6 to 0.9–15.0 h, while volumes of distribution ranged from 13.6–54.8 to 11.5–60.1 L, respectively. Predicted dose requirements for target attainment ranged from 2.25 g every 6 h in hemodialysis patients to a 27 g/24-h continuous infusion in a patient with a short P-T half-life. An amount of 4.5 g every 6 h would have met the target for only 1/12 (8%) patients with creatinine clearance ≥ 80 mL/min and 13/28 (46%) for all enrolled patients. One patient (3%) experienced an adverse event deemed probably related to high-dose P-T.

Some patients required high P-T doses for target attainment, but dosing requirements were highly variable. Doses up to 6.75 g or 9 g every 6 h may be tolerable; however, studies are needed to see if high dosing, prolonged infusions, or real-time therapeutic drug monitoring improves outcomes in obese patients.

NCT01923363.

The online version contains supplementary material available at 10.1007/s13318-021-00677-1.

The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enterococcus faecalis based on in vitro tests and the rabbit endocarditis model, however, in vitro assays 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 of E. faecalis and one of E. faecium in 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_max increase ≥2 log₁₀ CFU/g), antagonism (E_max reduction ≥1 log₁₀ CFU/g) and potentiation (ED₅₀ reduction ≥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 index fT_>MIC. CRO monotherapy showed no effect. The combination AMP+CRO against E. faecalis led to potentiation (59–81% ED₅₀ reduction) and not synergism (no changes in E_max). Against E. 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.

• Ampicillin/pharmacokinetics
• Ampicillin/pharmacology
• Animals
• Ceftriaxone/pharmacokinetics
• Ceftriaxone/pharmacology
• Disease Models, Animal
• Drug Therapy, Combination
• Endocarditis, Bacterial/drug therapy
• Endocarditis, Bacterial/metabolism
• Endocarditis, Bacterial/microbiology
• Enterococcus faecalis/metabolism
• Enterococcus faecium/metabolism
• Gram-Positive Bacterial Infections/drug therapy
• Gram-Positive Bacterial Infections/metabolism
• Gram-Positive Bacterial Infections/microbiology
• Mice
• Rabbits

• Anti-Bacterial Agents/administration & dosage
• Anti-Bacterial Agents/pharmacokinetics
• Humans
• Infusions, Intravenous
• Microbial Sensitivity Tests
• beta-Lactams/administration & dosage
• beta-Lactams/pharmacokinetics

• antimicrobial
• critical care
• critically ill
• intensive care
• pharmacokinetics
• sepsis
• therapeutic drug monitoring
• Β-lactam antibiotics

• Vancomycin
• efficacy
• generic
• innovator
• original

• Animals
• Anti-Bacterial Agents/pharmacokinetics
• Anti-Bacterial Agents/pharmacology
• Anti-Bacterial Agents/therapeutic use
• Disease Models, Animal
• Drugs, Generic/pharmacokinetics
• Drugs, Generic/pharmacology
• Drugs, Generic/therapeutic use
• Methicillin-Resistant Staphylococcus aureus/drug effects
• Mice
• Microbial Sensitivity Tests
• Republic of Korea
• Staphylococcal Infections/complications
• Staphylococcal Infections/drug therapy
• Staphylococcal Infections/microbiology
• Staphylococcus aureus/drug effects
• Thigh/microbiology
• Treatment Failure
• Vancomycin/pharmacokinetics
• Vancomycin/pharmacology
• Vancomycin/therapeutic use

• CRI13032-1 Chonnam National University Hospital

We demonstrated therapeutic nonequivalence of “bioequivalent” generics for meropenem, but there is no data with generics of other carbapenems.

One generic product of imipenem-cilastatin was compared with the innovator in terms of in vitro susceptibility testing, pharmaceutical equivalence, pharmacokinetic (PK) and pharmacodynamic (PD) equivalence in the neutropenic mouse thigh, lung and brain infection models. Both pharmaceutical forms were then subjected to analytical chemistry assays (LC/MS).

The generic product had 30% lower concentration of cilastatin compared with the innovator of imipenem-cilastatin. Regarding the active pharmaceutical ingredient (imipenem), we found no differences in MIC, MBC, concentration or potency or AUC, confirming equivalence in terms of in vitro activity. However, the generic failed therapeutic equivalence in all three animal models. Its E_max against S. aureus in the thigh model was consistently lower, killing from 0.1 to 7.3 million less microorganisms per gram in 24 hours than the innovator (P = 0.003). Against K. pneumoniae in the lung model, the generic exhibited a conspicuous Eagle effect fitting a Gaussian equation instead of the expected sigmoid curve of the Hill model. In the brain infection model with P. aeruginosa, the generic failed when bacterial growth was >4 log₁₀ CFU/g in 24 hours, but not if it was less than 2.5 log₁₀ CFU/g. These large differences in the PD profile cannot be explained by the lower concentration of cilastatin, and rather suggested a failure attributable to the imipenem constituent of the generic product. Analytical chemistry assays confirmed that, besides having 30% less cilastatin, the generic imipenem was more acidic, less stable, and exhibited four different degradation masses that were absent in the innovator.

• Animals
• Bacteria/drug effects
• Bacterial Infections/blood
• Bacterial Infections/drug therapy
• Bacterial Infections/microbiology
• Cilastatin/chemistry
• Cilastatin/pharmacokinetics
• Cilastatin/pharmacology
• Cilastatin, Imipenem Drug Combination/chemistry
• Cilastatin, Imipenem Drug Combination/pharmacokinetics
• Cilastatin, Imipenem Drug Combination/pharmacology
• Disease Models, Animal
• Drug Stability
• Drugs, Generic/chemistry
• Drugs, Generic/pharmacokinetics
• Drugs, Generic/pharmacology
• Humans
• Imipenem/chemistry
• Imipenem/pharmacokinetics
• Imipenem/pharmacology
• Klebsiella pneumoniae/drug effects
• Mice
• Microbial Sensitivity Tests
• Pseudomonas aeruginosa/drug effects
• Staphylococcus aureus/drug effects
• Therapeutic Equivalency

• Fundación Cientifica Rodrigo Vesga Meneses
• Universidad de Antioquia

• avibactam
• clavulanate
• clavulanic acid
• diazabicyclooctanone
• relebactam
• sulbactam
• tazobactam
• vaborbactam