Pharmacokinetics of cefotaxime in healthy volunteers and patients

Patel, Kalpana B.; Nicolau, David P.; Nightingale, Charles H.; Quintiliani, Richard

doi:10.1016/0732-8893(95)00072-i

Cited by 30 publications

(19 citation statements)

References 29 publications

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“…The mean log ratio of AUIC to predicted AUC/MIC was 1.03, showing excellent agreement. Cefotaxime exhibits protein binding ranging from 27 to 38% (22). This binding would tend to reduce the measured AUIC, since only free drug is active.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers

Nix

Wilton

Hyatt

et al. 1997

Antimicrob Agents Chemother

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The pharmacokinetics (PK) and pharmacodynamics (PD) of cefotaxime and ofloxacin and of their combination were examined in a three-period randomized crossover study involving 12 healthy adults. The PK of cefotaxime and ofloxacin were modeled. PD was assessed from the predicted concentrations in serum and serum untrafiltrate inhibitory titers for 10 test organisms. An inhibitory sigmoid Emax model based on the probability of bacterial growth was used, where Emax = 1 and EC50 is the concentration resulting in a 50% probability of growth. The total body clearance (CL(T)) and volume of distribution at steady state (V(SS)) for cefotaxime were 0.236 liters/kg/h and 0.207 liters/kg, respectively, for the monotherapy and 0.231 liters/kg/h and 0.208 liters/kg for the combination therapy. Ofloxacin exhibited PK parameters of 0.143 liters/kg/h for CL(T) and 1.20 liters/kg for V(SS) following the monotherapy and of 0.141 liters/kg/h for CL(T) and 1.16 liters/kg for V(SS) following combination therapy. For the combination therapy, an interaction term, theta, defined the type and relative extent of interaction. The range of observed theta values (-0.033 to 0.067) is consistent with an additive PD interaction according to standards similar to those used for the in vitro fractional inhibitory concentration index.

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Section: Discussionmentioning

confidence: 99%

Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers

Nix

Wilton

Hyatt

et al. 1997

Antimicrob Agents Chemother

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“…Reported MIC values (MIC distributions of wild-type microorganisms [www.Eucast.org]) are at or below 4 g/ml (S. aureus). Assuming a worst-case scenario of up to 40% protein binding (29), the maximal MIC value in plasma is around 8 g/ml. Using the individual parameter estimates derived from the final PK model, concentration-time curves were constructed for each individual by simulating the predicted concentration over intervals of 0.2 h. We calculated t ϾMIC over 24 h for each individual patient and compared the median values for each dose regimen; we considered the antimicrobial effect to be optimal at a t ϾMIC of at least 50% (24).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Cefotaxime and Desacetylcefotaxime in Infants during Extracorporeal Membrane Oxygenation

Ahsman

Wildschut

Tibboel

et al. 2010

Antimicrob Agents Chemother

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Extracorporeal membrane oxygenation (ECMO) is used to temporarily sustain cardiac and respiratory function in critically ill infants but can cause pharmacokinetic changes necessitating dose modifications. Cefotaxime (CTX) is used to prevent and treat infections during ECMO, but the current dose regimen is based on pharmacokinetic data obtained for non-ECMO patients. The objective of this study was to validate the standard dose regimen of 50 mg/kg of body weight twice a day (postnatal age [PNA], <1 week), 50 mg/kg three times a day (PNA, 1 to 4 weeks), or 37.5 mg/kg four times a day (PNA, >4 weeks). We included 37 neonates on ECMO, with a median (range) PNA of 3.3 (0.67 to 199) days and a median (range) body weight of 3.5 (2.0 to 6.2) kg at the onset of ECMO. Median (range) ECMO duration was 108 (16 to 374) h. Plasma samples were taken during routine care, and pharmacokinetic analysis of CTX and its active metabolite, desacetylcefotaxime (DACT), was done using nonlinear mixed-effects modeling (NONMEM). A one-compartment pharmacokinetic model for CTX and DACT adequately described the data. During ECMO, CTX clearance (CL CTX ) was 0. Extracorporeal membrane oxygenation (ECMO) is used as a standardized last resort to support critically ill infants who can no longer maintain sufficient cardiac and respiratory function with conventional life support techniques (5,8). Over a period of up to a maximum of 3 weeks, blood flow is continuously diverted via a venous cannula into an extracorporeal circuit, oxygenated via a membrane, and returned to the general circulation via a venous or arterial cannula. A hemofiltration unit can be added to the circuit to supplement insufficient renal function. Standard pharmacological treatment includes high doses of antibiotics for the treatment of preexisting or nosocomial infections, which are facilitated by the direct microbial access to the patient's general circulation via cannulae and circuit components (15). One of the antibiotics commonly used in neonates on ECMO is cefotaxime (CTX), which possesses antimicrobial activity against many of the pathogens commonly involved in neonatal and ECMO-related infections, such as Escherichia coli, Klebsiella pneumoniae, Enterobacter, and Staphylococcus spp. (27). In adults, cefotaxime can be excreted unchanged via the renal system, but also after hepatic conversion into its active metabolite, desacetylcefotaxime (DACT) (for 15 to 25% of a dose) (33). There appears to be an inverse correlation between renal function and elimination half-life, particularly for DACT (32).In the absence of specific pharmacokinetic (PK) data, our current cefotaxime dose regimen is the same for both ECMO and non-ECMO patients. In general, however, ECMO is associated with altered pharmacokinetics for a variety of drugs, probably due to an increase in circulatory volume, a diseaserelated clearance reduction, or adsorption of drugs to membranes and other circuit components (7). We designed this study to evaluate the pharmacokinetics of cefotaxime and desacetylcefotaxim...

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“…The pharmacokinetic parameters after single injection have been presented in several species such as rats (3), sheep (4), goats (5), calves (6), cats (7), dogs (8), and humans (9). An approximate serum half-life of 1.1-1.3 h after injection was confirmed in different studies (10)(11)(12)(13). The drug is primarily eliminated by the kidney, but also converted into the less active metabolite desacetyl-cefotaxime in the liver to a significant level (14)(15).…”

Section: Introductionmentioning

confidence: 87%

Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug

et al. 2017

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-PURPOSE: Liposomes have been studied as a colloidal carrier in drug delivery systems, especially for oral administration. However, their low structural integrity in the gut is still a major shortcoming. Membrane disruptive effects of physiological bile salts in the small intestine result in premature drug release prior to intestinal absorption. Thus, we analyzed the stabilizing effect of sodium deoxycholate when incorporated into nano-sized liposomes. METHOD: Cefotaxime-loaded liposomes were prepared with different sodium deoxycholate concentrations (3.75-30 mM) by rotary film evaporation followed by nanosize reduction. The physical integrity of liposomes was evaluated by monitoring cefotaxime leakage, particle sizes in different simulated physiological media. The oral bioavailability and pharmacokinetics of cefotaxime was assessed in rats (n = 6 per group) after single dose of drug-encapsulated in liposomes containing bile salt, drug in conventional liposomes, and cefotaxime solution (oral and intravenous). RESULTS: Simulated gastric fluid with low pH showed less effect on the stability of liposomes in comparison to media containing physiological bile salts. Liposomes containing 15 mM sodium deoxycholate were most stable in size and retained the majority of encapsulated cefotaxime even in fed state of simulated intestinal fluid being the most destructive media. Pharmacokinetics data showed an increase in Cmax and AUC0-inf in the following order: cefotaxime solution < conventional liposomes < liposomes made with bile salts. The total oral bioavailability of cefotaxime in liposomes containing bile salt was found to be 5-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. CONCLUSION: Incorporation of bile salts, initially used as membrane permeation enhancer, also acted as a stabilizer against physiological bile salts. The nanosized liposomes containing sodium deoxycholate were able to reduce the leakage of encapsulated cefotaxime in the gut due to the improved vesicle stability and to enhance the oral bioavailability of acid-labile drugs up to 5-fold.

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Pharmacokinetics of cefotaxime in healthy volunteers and patients

Cited by 30 publications

References 29 publications

Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers

Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers

Pharmacokinetics of Cefotaxime and Desacetylcefotaxime in Infants during Extracorporeal Membrane Oxygenation

Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug

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