Free Antibiotic Concentrations Research Articles

Cefadroxil and cephalexin pharmacokinetics and pharmacodynamics in children with musculoskeletal infections.

Cephalexin, a first-generation cephalosporin, is the first-line oral therapy for children with musculoskeletal infections due to methicillin-susceptible Staphylococcus aureus (MSSA). Cefadroxil, a similar first-generation cephalosporin, is an attractive alternative to cephalexin given its longer half-life. In this study, we describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of cephalexin and cefadroxil in children with musculoskeletal infections. Children aged 6 months to 18 years with a musculoskeletal infection were enrolled in a prospective, open-label, crossover PK study and given single oral doses of cefadroxil (50-75 mg/kg up to 2,000 mg) and cephalexin (50 mg/kg up to 1,375 mg). Population PK models were developed and used for dosing simulations. Our primary PD target was the achievement of free antibiotic concentrations above the minimum inhibitory concentration (fT >MIC) for 40% of the day for MICs ≤ 4 mg/L. PK of cephalexin (n = 15) and cefadroxil (n = 14) were best described using a one-compartment, first-order absorption model, with a lag time component for cefadroxil. PK parameters were notable for cefadroxil's longer half-life (1.61 h) than cephalexin's (1.10 h). For pediatric weight bands, our primary PD target was achieved by cephalexin 25 mg/kg/dose, maximum 750 mg/dose, administered three times daily and cefadroxil 40 mg/kg/dose, maximum 1,500 mg/dose, administered twice daily. More aggressive dosing was required to achieve higher PD targets. Among children with musculoskeletal infections, oral cephalexin and cefadroxil achieved PD targets for efficacy against MSSA. Given less frequent dosing, twice-daily cefadroxil should be further considered as an alternative to cephalexin for oral step-down therapy for serious infections due to MSSA.

Liquid chromatography–tandem mass spectrometry methods for quantification of total and free antibiotic concentrations in serum and exudate from patients with post-sternotomy deep sternal wound infection receiving negative pressure wound therapy

BackgroundSystemically administered antibiotics are thought to penetrate the wounds more effectively during negative pressure wound therapy (NPWT).To test this hypothesis total and free antibiotic concentrations were quantified in serum and wound exudate. MethodsUHPLC-MS/MS methods were developed and validated for the determination of ceftazidime, cefepime, cefotaxime, cefuroxime, cefazolin, meropenem, oxacillin, piperacillin with tazobactam, clindamycin, ciprofloxacin, sulfamethoxazole/trimethoprim (cotrimoxazole), gentamicin, vancomycin, and linezolid. The unbound antibiotic fraction was obtained by ultrafiltration using a Millipore Microcon-30kda Centrifugal Filter Unit. Analysis was performed on a 1.7-µm Acquity UPLC BEH C18 2.1 × 100-mm column with a gradient elution. ResultsThe validation was performed for serum, exudates and free fractions. For all matrices, requirements were met regarding linearity, precision, accuracy, limit of quantitation, and matrix effect. The coefficient of variation was in the range of 1.2–13.6%.and the recovery 87.6–115.6%, respectively. Among the 29 applications of antibiotics thus far, including vancomycin, clindamycin, ciprofloxacin, oxacillin, cefepime, cefotaxime, cotrimoxazole, and gentamicin, total and free antibiotic concentrations in serum and exudate were correlated. ConclusionThis method can accurately quantify the total and free concentrations of 16 antibiotics. Comparison of concentration ratios between serum and exudates allows for monitoring individual antibiotics' penetration capacity in patients receiving NPWT.

1094. Determination of Plasma Protein Binding of Dalbavancin

Abstract Background Dalbavancin is a semi-synthetic glycopeptide with a long half-life, making it a promising alternative for infections requiring prolonged therapy such as complicated Staphylococcus aureus bacteremia. A critical pharmacokinetic consideration with prolonged treatment is the unbound or “free” concentration-time profile, as free antibiotic concentrations may correlate with tissue penetration and therapeutic effects better than total drug. Dalbavancin’s plasma protein binding (PB) remains poorly studied and has been reported to range between 93-99%. A reliable and validated free drug assay is needed to link dalbavancin concentrations with patient outcomes. Methods The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 µg/mL) in duplicate. Centrifuge tubes and pipette tips were treated for 24 hours before use with Tween 80 to assess adsorption. PB centrifugation conditions: 400,000 g (106,000 RPM in TLA-120.1 rotor) for 4 hours at 37°C. Dalbavancin concentrations were analyzed from the plasma samples (total) and middle layer samples (free) by liquid chromatography – tandem mass spectrometry (LC/MS/MS) with isotopically labeled internal standard. Warfarin served as a positive control with known high protein binding. Results Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during PB experiments (Figure 1). Addition of 2% Tween 80 did not affect PB results of warfarin. In PB experiments with 2% Tween 80 coated tubes, the free fraction of dalbavancin was 0.96% (95% CI: 0.94-0.98) at 50 µg/mL and 1.11% (95% CI: 1.08-1.13) at 200 µg/mL. Figure 1. Percent Free Dalbavancin vs Varying Concentrations of Tween 80 for Pretreatment of Tubes Conclusion By the ultracentrifugation method, dalbavancin’s PB was estimated to be approximately 99%. Given dalbavancin’s high PB, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should also determine if the active fraction is best predicted by the free or total fraction, as this remains a subject of debate. Supported by NIAID/NIH grant UM1AI104681. Content is solely the authors’ responsibility and does not represent official NIH views. Disclosures Thomas L. Holland, MD, Aridis (Consultant)Basilea Pharmaceutica (Consultant)Lysovant (Consultant) Thomas L. Holland, MD, Aridis (Individual(s) Involved: Self): Consultant; Basilea Pharmaceutica (Individual(s) Involved: Self): blinded adjudication, Consultant, Other Financial or Material Support; Genentech (Individual(s) Involved: Self): Consultant; Lysovant (Individual(s) Involved: Self): Consultant; Motif Bio (Individual(s) Involved: Self): Consultant Thomas Lodise, Jr., PharmD, PhD, Astra-Zeneca (Consultant)Bayer (Consultant)DoseMe (Consultant, Advisor or Review Panel member)ferring (Consultant)genentech (Consultant)GSK (Consultant)Melinta (Consultant)merck (Consultant, Independent Contractor)nabriva (Consultant)paratek (Consultant, Advisor or Review Panel member, Speaker’s Bureau)shionogi (Consultant, Advisor or Review Panel member, Speaker’s Bureau)Spero (Consultant)tetraphase (Consultant)Venatrox (Consultant) Thomas Lodise, Jr., PharmD, PhD, Melinta Therapeutics (Individual(s) Involved: Self): Consultant; Merck (Individual(s) Involved: Self): Consultant, Scientific Research Study Investigator; Paratek (Individual(s) Involved: Self): Consultant; Shionogi (Individual(s) Involved: Self): Consultant, Speakers’ bureau; Spero (Individual(s) Involved: Self): Consultant; Tetraphase Pharmaceuticals Inc. (Individual(s) Involved: Self): Consultant

Continuous Infusion of Piperacillin/Tazobactam and Meropenem in ICU Patients Without Renal Dysfunction: Are Patients at Risk of Underexposure?

Morbidity and mortality from serious infections are common in intensive care units(ICUs). The appropriateness of the antibiotic treatment is essential to combat sepsis. We aimed to evaluate pharmacokinetic/pharmacodynamic target attainment of meropenem and piperacillin/tazobactam administered at standard total daily dose as continuous infusion in critically ill patients without renal dysfunction and to identify risk factors of non-pharmacokinetic/pharmacodynamic target attainment. We included 118 patients (149 concentrations), 47% had microorganism isolation. Minimum inhibitory concentration (MIC)[median (interquartile range, IQR) values in isolated pathogens were: meropenem: 0.05 (0.02-0.12) mg/l; piperacillin: 3 (1-4) mg/l]. Pharmacokinetic/pharmacodynamic target attainments (100%fCss≥1xMIC, 100%fCss≥4xMIC and 100%fCss ≥ 8xMIC, respectively) were: 100%, 96.15%, 96.15% (meropenem) and 95.56%, 91.11%, 62.22% (piperacillin) for actual MIC; 98.11%, 71.70%, 47.17% (meropenem, MIC 2 mg/l), 95.83%, 44.79%, 6.25% (piperacillin, MIC 8 mg/l), 83.33%, 6.25%, 1.04% (piperacillin, MIC 16 mg/l) for EUCAST breakpoint of Enterobacteriaceae spp. and Pseudomonas spp. Multivariable linear analysis identified creatinine clearance (CrCL) as a predictive factor of free antibiotic concentrations (fCss) of both therapies (meropenem [β = - 0.01 (95% CI - 0.02 to - 0.0; p = 0.043)] and piperacillin [β = - 0.01 (95% CI - 0.02 to 0.01, p < 0.001)]). Neurocritical status was associated with lower piperacillin fCss [β = - 0.36 (95% CI - 0.61 to - 0.11; p = 0.005)]. Standard total daily dose of meropenem allowed achieving pharmacokinetic/pharmacodynamic target attainmentsin ICU patients without renal dysfunction. Higher doses of piperacillin/tazobactam would be needed to cover microorganisms with MIC > 8 mg/l. CrCL was the most powerful factor predictive of fCss in both therapies.

Analysis of Paradoxical Efficacy of Carbapenems against Carbapenemase-Producing Escherichia coli in a Murine Model of Lethal Peritonitis.

The clinical benefit of carbapenems against carbapenemase-producing Enterobacteriaceae (CPE) remains in question. MICs of imipenem (IMP) and ertapenem (ERT) against isogenic derivatives of the wild-type strain Escherichia coli CFT073 producing KPC-3, OXA-48, or NDM-1 were 0.25, 2, 16, and 64 mg/liter for IMP and 0.008, 0.5, 8, and 64 mg/liter for ERT, respectively. Swiss ICR-strain mice with peritonitis were treated for 24 h with IMP or ERT. Despite a limited duration of time during which free antibiotic concentrations were above the MIC (down to 0% for the NDM-1-producing strain), IMP and ERT significantly reduced bacterial counts in spleen and peritoneal fluid at 24 h (P < 0.005) and prevented mortality. Several possible explanations were investigated. Addition of 4% albumin or 50% normal human serum did not modify IMP activity. Bacterial fitness of resistant strains was not altered and virulence did not decrease with resistance. In the presence of subinhibitory concentrations of ERT, growth rates of OXA-48, KPC-3, and NDM-1 strains were significantly decreased and filamentation of the NDM-1 strain was observed. The expression of blaNDM-1 was not decreased in vivo compared to in vitro No zinc depletion was observed in infected mice compared with Mueller-Hinton broth. In conclusion, a paradoxical in vivo efficacy of IMP and ERT against highly resistant carbapenemase-producing E. coli was confirmed. Alternative mechanisms of antibacterial effects of subinhibitory concentrations of carbapenems may be involved to explain in vivo activity. These results are in agreement with a potential clinical benefit of carbapenems to treat CPE infections, despite high carbapenem MICs.

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients.

Critically ill patients undergoing aggressive fluid resuscitation and treated empirically with hydrosoluble time-dependent beta-lactam antibiotics are at risk for sub-therapeutic plasma concentrations. The aim of this study was to assess the impact of two covariates - creatinine clearance (Clcr) and cumulative fluid balance (CFB) on pharmacokinetics/pharmacodynamics (PK/PD) target attainment within a week of treatment with meropenem (ME) or piperacillin/tazobactam (PIP/TZB). In this prospective observational pharmacokinetic (PK) study, 18 critically ill patients admitted to a surgical Intensive Care Unit (ICU) were enrolled. The primary PK/PD target was free antibiotic concentrations above MIC at 100% of the dosing interval (100%fT>MIC) to obtain maximum bactericidal activity. Drug concentration was measured using liquid chromatography-tandem mass spectrometry. The treatment of both 8 septic patients with IV extended ME dosing 2 g/3 h q8 h and 10 polytraumatized patients with IV intermittent PIP/TZB dosing 4.0/0.5 g q8 h was monitored. 8/18 patients (44%) manifested augmented renal clearence (ARC) where Clcr ≥130 mL/min/1.73 m2. Maximum changes were reported on days 2-3: the median positive CFB followed by the large median volume of distribution: Vdme=70.3 L (41.9-101.5), Vdpip = 46.8 L (39.7-60.0). 100%fTme>MIC was achieved in all patients on ME (aged ≥60 years), and only in two patients (non-ARC, aged ≥65 years) out of 10 on PIP/TZB. A mixed model analysis revealed positive relationship of CFBpip with Vdpip (P=0.021). Assuming that the positive correlation between CFB and Vd exists for piperacillin in the setting of the pathological state, then CFB should predict Vdpip across subjects at each and every time point.

Albumin concentration significantly impacts on free teicoplanin plasma concentrations in non-critically ill patients with chronic bone sepsis

The impact of decreased serum albumin concentrations on free antibiotic concentrations in non-critically ill patients is poorly described. This study aimed to describe the pharmacokinetics of a high-dose regimen of teicoplanin, a highly protein-bound antibiotic, in non-critically ill patients with hypoalbuminaemia. Ten patients with chronic bone sepsis and decreased serum albumin concentrations (<35g/L) receiving teicoplanin 12mg/kg 12-hourly intravenously for 48h followed by 12mg/kg once daily were enrolled. Surgical debridement was performed on Day 3. Samples of venous blood were collected pre-infusion and post-infusion during the first 4 days of therapy. Total and free teicoplanin concentrations were assayed using validated chromatographic methods. The median serum albumin concentration for the cohort was 18 (IQR 15–24) g/L. After 48h, the median (IQR) free trough (fCmin) and total trough (tCmin) concentrations were 2.90 (2.67–3.47) mg/L and 15.54 (10.28–19.12) mg/L, respectively, although trough concentrations declined thereafter. Clearance of the free concentrations was significantly high relative to the total fraction at 38.6 (IQR 29.9–47.8) L/h and 7.0 (IQR 6.8–9.8) L/h, respectively (P<0.001). Multiple linear regression analysis demonstrated that whereas total teicoplanin concentration did not impact on free concentrations (P=0.174), albumin concentration did (P<0.001). This study confirms the significant impact of hypoalbuminaemia on free concentrations of teicoplanin in non-critically ill patients, similar to that in critically ill patients. Furthermore, the poor correlation with total teicoplanin concentration suggests that therapeutic drug monitoring of free concentrations should be used in these patients.

Measurement of meropenem concentration in different human biological fluids by ultra-performance liquid chromatography-tandem mass spectrometry.

Meropenem is a broad-spectrum antibiotic, often used for the empirical treatment of infections in critically ill patients with acute kidney injury. Meropenem has clinically insignificant protein binding and, as a carbapenem antibiotic, shows time-dependent bacterial killing, meaning that the unbound or free antibiotic concentration in blood should be maintained above the minimal inhibitory concentration of the pathogen for at least 40 % of the dosing interval. We developed and validated simple chromatographic methods by ultra-performance liquid chromatography-tandem mass spectrometry to measure plasma, filtrate-dialysate, and urine concentrations of meropenem. Chromatographic separation was achieved using an Acquity(®) UPLC(®) BEH(TM) (2.1 × 100 mm id, 1.7 μm) reverse-phase C(18) column, with a water/acetonitrile linear gradient containing 0.1 % formic acid at a 0.4-mL/min flow rate. Meropenem and its internal standard (ertapenem) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode. The limits of quantification were 0.27, 0.24, and 1.22 mg/L, and linearity was observed between 0.27-150, 0.24-150, and 1.22-2,000 mg/L for plasma, filtrate-dialysate, and urine samples, respectively. Coefficients of variation and relative biases were less than 13.5 and 8.0 % for all biological fluids. Recovery values were greater than 68.3 %. Evaluation of the matrix effect showed ion suppression for meropenem and ertapenem. No carry-over was observed. The validated methods are useful for both therapeutic drug monitoring and pharmacokinetic studies. It could be applied to daily clinical laboratory practice to measure the concentration of meropenem in plasma, filtrate-dialysate, and urine.

Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: Lessons from the DALI Study

The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20mg/L and the higher range as 10–30mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2–26.0) and free 1.5 (0.7–2.5); trough, total 11.9 (10.2–22.7) and free 1.8 (0.6–2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5–15.6%) and 8.2% (5.5–16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ=0.79, P=0.0021) and trough (ρ=0.63, P=0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients.

DALI: Defining Antibiotic Levels in Intensive Care Unit Patients: Are Current -Lactam Antibiotic Doses Sufficient for Critically Ill Patients?

Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.

Therapeutic Drug Monitoring of Beta-Lactam Antibiotics in Burns Patients—A One-Year Prospective Study

Beta-lactams are first-line antibiotics for the management of superficial infections due to burn injury. There is sparse data available on therapeutic drug monitoring (TDM) in patients with burns in a ward setting. This study was conducted to evaluate the utility of a beta-lactam TDM program in a cohort of burn injury patients in a ward environment. Steady-state blood samples were collected immediately before a scheduled dose. The therapeutic concentration targets assessed were (1) free antibiotic concentrations exceeding the minimum inhibitory concentration (MIC; fT > MIC) and (2) free concentrations ≥4× MIC of the known or suspected pathogen (fT > 4× MIC). The duration of therapy was also assessed. A total of 50 patients were included for TDM over a 12-month period. The mean (±SD) age was 49 ± 16 years. The mean percent total body surface area burn was 17 ± 13%. The mean serum creatinine concentration was 86 ± 20 μmole/L. Sixty percent of the patients did not achieve fT > MIC, and only 18% achieved the higher target of fT > 4× MIC. Although all the patients achieved a positive clinical outcome, the duration of antibiotic treatment was shorter in patients who achieved fT > MIC compared with those who did not (4.2 ± 1.1 versus 5.3 ± 2.3 days; P = 0.03). We found TDM to be a reliable intervention for burn injury patients in a ward environment. This study supports pharmacokinetic data that burns patients may be at risk of subtherapeutic dosing, which may prolong the duration of antibiotic therapy.

Influence of different resistance traits on the competitive growth of Haemophilus influenzae in antibiotic-free medium and selection of resistant populations by different -lactams: an in vitro pharmacodynamic approach

The aim was to study the pharmacodynamics of cefditoren, amoxicillin/clavulanic acid and cefuroxime against mixed Haemophilus influenzae strains. Isolates [MICs (mg/L) of cefditoren, cefuroxime and amoxicillin/clavulanic acid] used were: one beta-lactamase-negative (beta(-); 0.015, 1 and 1), one beta-lactamase-positive (beta(+); 0.03, 4 and 8) and two strains exhibiting ftsI gene mutations [one beta(-) ampicillin-resistant (BLNAR; 0.015, 8 and 4) and one beta(+) amoxicillin/clavulanic acid-resistant (BLPACR; 0.03, 8 and 4)]. A computerized pharmacodynamic model simulating free antibiotic concentrations (calculated considering reported percentages of protein binding) of 400 mg twice-daily cefditoren, 500 mg twice-daily cefuroxime and 875/125 mg three times daily amoxicillin/clavulanic acid was used to explore antibacterial activity against initial mixed inocula with 25% of each strain. Areas under bacterial curves (AUBCs) from 0 to 24 h (log cfu.h/mL) were calculated and differences between values in antibiotic-free (AUBC(K)) and in antibiotic simulations determined (ABBC(0-24) = AUBC(K0-24)-AUBC(0-24)). In antibiotic-free medium, total population increased by 1.7 log(10) cfu/mL from 0 to 24 h: final composition approximately 90% beta(-), approximately 6.5% beta(+), approximately 2.5% BLNAR and approximately 1% BLPACR. At the end of antibiotic simulations, the predominant population was BLPACR followed by beta(+) after amoxicillin/clavulanic acid or BLNAR after cefuroxime exposures. ABBC(0-24) was higher (P < 0.01) for cefditoren compared with cefuroxime or amoxicillin/clavulanic acid whether considering total population (70.4 versus approximately 33), beta(+) (77.8 versus approximately 52), BLNAR (66.1 versus 18.6-30.4) or BLPACR (40.8 versus approximately 0). Cefditoren offered higher antibacterial effect than cefuroxime and amoxicillin/clavulanic acid against a mixed population of H. influenzae strains due to its higher activity against beta-lactamase-producing strains and those carrying ftsI gene mutations.

Tissue Penetration of Cefpodoxime and Cefixime in Healthy Subjects

Microdialysis is a technique that allows the measurement of free antibiotic concentrations in different tissues, which are responsible for the antibacterial activity at the infection site. In an open, randomized, 2-way crossover study in healthy volunteers, the muscle penetration of orally administered cefpodoxime (400 mg) and cefixime (400 mg) was compared using microdialysis. The results show that the total plasma concentration-time profiles of each antibiotic were similar; the area under the curve for cefpodoxime was 22.4 +/- 8.7 versus 25.6 +/- 8.5 mg/L*h for cefixime. However, tissue penetration was twice as high for cefpodoxime (area under the curve 15.4 +/- 5.1 mg/L*h) as for cefixime (area under the curve 7.3 mg/L*h). This degree of tissue distribution is consistent with their protein binding of 21% for cefpodoxime and 65% for cefixime. After equilibration, the unbound tissue concentrations of both antibiotics were similar to their unbound plasma concentrations. Pharmacokinetic modeling was applied to describe the pharmacokinetic profiles in plasma and muscle. The study demonstrates that cefpodoxime shows greater tissue penetration than cefixime.

Ceftriaxone pharmacokinetics during iatrogenic hydroxyethyl starch-induced hypoalbuminemia: a model to explore the effects of decreased protein binding capacity on highly bound drugs.

Although various drugs used by anesthesiologists highly bind to plasma proteins, the impact of iatrogenically induced hypoproteinemia on their pharmacologic effects has never been investigated. The authors determined the pharmacokinetics of ceftriaxone, a cephalosporin that binds strongly to albumin in postsurgical patients with hydroxyethyl starch-induced hypoalbuminemia. Eleven hypoalbuminemic (serum albumin < 25 g/l) patients and age (+/- 5 yr)-, sex-, and body surface area (+/- 10%)-matched healthy volunteers received a 2-g ceftriaxone dose infused over a 15-min period. Fourteen venous blood samples were collected during the 24-h study period. Free ceftriaxone concentrations were determined by ultrafiltration. Antibiotic concentrations in plasma and ultrafiltrate were measured by ion-paired reversed-phase chromatography. The pharmacokinetic parameters derived from total and free antibiotic concentrations were determined using a noncompartmental method. Data are expressed as median and range. The pharmacokinetic parameters derived from total ceftriaxone concentrations were similar for the two groups, except for the median corrected volume of distribution at steady state, which was increased (P = 0.05) to 0.18 l/kg (range, 0. 11-0.29 l/kg) in patients, compared with 0.15 l/kg (range, 0.13-0.22 l/kg) in volunteers. The area under the free ceftriaxone concentration-time curve was twice as high in patients as in volunteers (median 192, range 114-301 vs. median 122, range 84-169 h. mg-1. l-1;P = 0.03). Moreover, the free ceftriaxone concentration remained more than 4 mg/l during more time in patients (median, 16. 7; range, 12.6-21.4 vs. median, 11.1; range, 6.0-19.0 h; P = 0.03). Compared with healthy volunteers, patients with iatrogenic hypoalbuminemia have higher free ceftriaxone concentrations during the 24 h after antibiotic administration. This modification increases drug distribution into extravascular space and may enhance effectiveness.

Effect of antibiotic protein binding on the killing rate of Staphylococcus aureus and on the paradoxical phenomenon.

The killing kinetics of Staphylococcus aureus, exposed to various concentrations of dicloxacillin in broth and in broth with 40 g/l human albumin was studied. When the free concentrations of dicloxacillin were identical in the two media, no difference in killing capacity could be demonstrated at concentrations above MIC, indicating that only the free antibiotic fraction is antibacterially active. However, at concentrations identical to the MIC, a better bactericidal effect in the medium containing albumin was found. In experiments where equal total concentrations were compared in the two media, an increasing bactericidal effect in the medium containing albumin could be demonstrated at concentrations between 10-100 X MIC. The most probable explanation for this was a prominent paradoxical effect with increasing antibiotic concentrations on the killing rate of S. aureus in broth. This effect was neutralized in the presence of albumin due to the lower free antibiotic concentration in this medium.

Antibiotic concentration in ocular tissues. Penicillin G and dihydrostreptomycin.

The total antibiotic concentration of penicillin G potassium (benzylpenicillin) and dihydrostreptomycin sulfate were determined in the ocular tissues of rabbits by radioactive tracer methods following systemic and subconjunctival administration. Free, unbound active antibiotic concentrations were determined by a modified disk diffusion assay. Both methods correlated well at concentrations greater than 200μg/gm wet tissue, but below this level the free antibiotic concentrations averaged 30% of the total for penicillin G and 75% for dihydrostreptomycin. After both systemic and subconjunctival administration, the free antibiotic levels in all tissues except lens and vitreous exceeded that in aqueous humor. Thus, the use of aqueous humor assays to determine the intraocular penetration of penicillin G and dihydrostreptomycin is not a valid indication of ocular tissue concentration.