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Penicillins
Published in Thomas T. Yoshikawa, Shobita Rajagopalan, Antibiotic Therapy for Geriatric Patients, 2005
Mezlocillin, azlocillin, and piperacillin belong to the ureidopenicillin group of antipseudomonal penicllins. Their antipseudomonal activity is superior to that of carboxypenicillins. The most important drug of this group is piperacillin. It is commonly used in combination with the P-lactamase inhibitor tazobactam (see also the chapter “P Lactam/p-lactamase Inhibitors”). Ureidopenicillins are dispensed as monosodium salts with lower sodium concentrations than carboxypenicillins; however, caution still needs to be exercised when treating elderly patients with cardiac or renal disease. These agents are minimally metabolized (< 10%) and mainly eliminated in active form by glomerular filtration and tubular secretion. They have considerable biliary excretion, which results in high levels in the biliary system. An important pharmacokinetic consideration is that increasing doses of these antibiotics result in nonlinear increased antibiotic levels and decreased clearance. Due to their structure, penetration of bacterial cell wall is enhanced and their affinity for PBP is also increased. An additional feature possessed by ueidopenicillins is inhibitory activity on the septum of the dividing bacteria (10).
An overview of ceftolozane sulfate + tazobactam for treating hospital acquired pneumonia
Published in Expert Opinion on Pharmacotherapy, 2020
Ibai Los-Arcos, Joaquin Burgos, Vicenç Falcó, Benito Almirante
In June 2019, the FDA approved Merck’s supplemental New Drug Application (sNDA) for the use of ceftolozane-tazobactam for the treatment of patients 18 years and older with HAP/VAP [65] caused by the following susceptible gram-negative microorganisms: E. cloacae, E. coli, H. influenzae, K. oxytoca, K. pneumoniae, Proteus mirabilis, P. aeruginosa, and Serratia marcescens. The sNDA for ceftolozane-tazobactam had previously been designated as priority review status by the FDA. To reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftolozane-tazobactam and other antibacterial drugs, ceftolozane-tazobactam should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. This expanded use is based on results of the pivotal phase III ASPECT-NP trial [55].
Laces out Dan! The role of tazobactam based combinations for invasive ESBL infections in a post-MERINO world
Published in Expert Opinion on Pharmacotherapy, 2019
The question arises however, given the PK/PD issues described with TZP, how does CT fare in this regard? VanScoy and colleagues assessed tazobactam pharmacodynamics in an in vitro PK/PD model similar to the previously described model for TZP [23]. Analogous to the findings for TZP, the authors demonstrated that time above a threshold tazobactam concentration was the PK/PD index that best correlated to restoration and that free tazobactam concentrations needed to be above the threshold concentration 66% and 77% of the time for bacteriostasis, and 1 log kill, respectively. The difference between CT and TZP was that whereas the threshold concentration for tazobactam when combined with piperacillin was the TZP MIC, the threshold concentration for tazobactam when combined with ceftolozane was 0.5 x the CT MIC [23]. Therefore, at the CT breakpoint of 2 mg/L, the threshold concentration needed would be 1 mg/L.
Pharmacokinetics-pharmacodynamics of β-lactamase inhibitors: are we missing the target?
Published in Expert Review of Anti-infective Therapy, 2019
Marguerite L Monogue, David P Nicolau
In humans, a simulated tazobactam 500mg dose q8h was estimated to achieve a PTA of >99% using a target exposure of fT > threshold = 44.4% >0.5 µg/ml, which previously resulted in a 1-log10 CFU kill in a murine thigh model (Table 2) [51]. In diabetic foot infections, 80–90% of patients should achieve a 1-log10 CFU bacterial reduction in tissue based on a fT > threshold of 50% >0.25 µg/ml [53]. These data support the use of tazobactam as formulated with ceftolozane; however, data regarding tazobactam exposures at doses lower than 500mg q8h are lacking. Notably, the population PK analyses should be interpreted with caution as these results are largely impacted by the target exposure used in the model, which is highly variable as demonstrated by the in vitro and animal work presented above. Furthermore, limited clinical data exists validating the clinical efficacy of tazobactam for the treatment of infections caused by β-lactamase producing organisms. In a randomized control trial, the 30-day mortality rate for patients with ceftriaxone-resistant E. coli or K. pneumoniae bacteremia was higher in the piperacillin-tazobactam arm compared with the meropenem arm (12.3% vs. 3.7%) [54]. Further clinical data are needed to elucidate piperacillin-tazobactam’s efficacy against β-lactamase producing organisms.