Pharmacokinetics and Inflammatory Fluid Penetration of Intravenous Daptomycin in Volunteers

The lipopeptide antimicrobial daptomycin was administered intravenously at a dose of 4 mg/kg of body weight to seven healthy male volunteers. The concentrations of daptomycin in plasma, cantharidin-induced inflammatory fluid, and urine were measured by a microbiological assay. The mean +/- standard deviation peak concentrations in plasma and inflammatory fluid were 77.5 +/- 8.3 and 27.6 +/- 9.5 microg/ml, respectively; the mean terminal elimination half-lives were 7.74 and 13.2 h, respectively. The overall penetration of total drug into the inflammatory fluid (measured by ratio of the area under the concentration-time curve from 0 to 24 h for inflammatory fluid compared with that for plasma) was 68.4%. The mean urinary recovery over 24 h was 59.7%.     

Single-Dose Pharmacokinetics and Penetration of BMS 284756 into an Inflammatory Exudate

The pharmacokinetics of a single dose of BMS 284756 were determined following oral administration of a 600-mg dose to eight healthy male volunteers. Concentrations of the drug were measured in plasma and a cantharidine-induced inflammatory exudate by a microbiological assay. The mean peak concentration in plasma of 10.4 microg/ml (standard deviation [SD], 1.3 microg/ml) was attained at a mean time of 1.2 h (SD, 0.5 h) after the dose. The penetration into the inflammatory exudate was 82% (SD, 15.7%). A mean peak concentration of 7.2 microg/ml (SD, 2.4 microg/ml) was attained in the inflammatory exudate at 5.3 h (SD, 1.5 h). The elimination half-lives from plasma and inflammatory fluid were 9.8 h (SD, 1.1 h) and 8.5 h (SD, 1.9 h), respectively. The areas under the concentration-time curves for plasma and inflammatory fluid were 96.7 microg x h/ml (SD, 10.3 microg x h/ml) and 77.9 microg x h/ml (SD, 19.2 microg x h/ml), respectively.     

Moxifloxacin Pharmacokinetics and Pleural Fluid Penetration in Patients with Pleural Effusion

The aim of this study was to evaluate the pharmacokinetics and penetration of moxifloxacin (MXF) in patients with various types of pleural effusion. Twelve patients with empyema/parapneumonic effusion (PPE) and 12 patients with malignant pleural effusion were enrolled in the study. A single-dose pharmacokinetic study was performed after intravenous administration of 400 mg MXF. Serial plasma (PL) and pleural fluid (PF) samples were collected during a 24-h time interval after drug administration. The MXF concentration in PL and PF was determined by high-performance liquid chromatography, and main pharmacokinetic parameters were estimated. Penetration of MXF in PF was determined by the ratio of the area under the concentration-time curve from time zero to 24 h (AUC₂₄) in PF (AUC_24PF) to the AUC₂₄ in PL. No statistically significant differences in the pharmacokinetics in PL were observed between the two groups, despite the large interindividual variability in the volume of distribution, clearance, and elimination half-life. The maximum concentration in PF (Cmax_PF) in patients with empyema/PPE was 2.23 ± 1.31 mg/liter, and it was detected 7.50 ± 2.39 h after the initiation of the infusion. In patients with malignant effusion, Cmax_PF was 2.96 ± 1.45 mg/liter, but it was observed significantly earlier, at 3.58 ± 1.38 h (P < 0.001). Both groups revealed similar values of AUC_24PF (31.83 ± 23.52 versus 32.81 ± 12.66 mg · h/liter). Penetration of MXF into PF was similarly good in both patient groups (1.11 ± 0.74 versus 1.17 ± 0.39). Despite similar plasma pharmacokinetics, patients with empyema/parapneumonic effusion showed a significant delay in achievement of PF maximum MXF levels compared to those with malignant effusion. However, in both groups, the degree of MXF PF penetration and the on-site drug exposure, expressed by AUC_24PF, did not differ according to the type of pleural effusion.     

Pharmacokinetics and Penetration of Ceftazidime and Avibactam into Epithelial Lining Fluid in Thigh- and Lung-Infected Mice

Ceftazidime and the β-lactamase inhibitor avibactam constitute a new, potentially highly active combination in the battle against extended-spectrum-β-lactamase (ESBL)-producing bacteria. To determine possible clinical use, it is important to know the pharmacokinetic profiles of the compounds related to each other in plasma and the different compartments of infection in experimentally infected animals and in humans. We used a neutropenic murine thigh infection model and lung infection model to study pharmacokinetics in plasma and epithelial lining fluid (ELF). Mice were infected with ca. 10⁶ CFU of Pseudomonas aeruginosa intramuscularly into the thigh or intranasally to cause pneumonia and were given 8 different (single) subcutaneous doses of ceftazidime and avibactam in various combined concentrations, ranging from 1 to 128 mg/kg of body weight in 2-fold increases. Concomitant samples of serum and bronchoalveolar lavage fluid were taken at up to 12 time points until 6 h after administration. Pharmacokinetics of both compounds were linear and dose proportional in plasma and ELF and were independent of the infection type, with estimated half-lives (standard deviations [SD]) in plasma of ceftazidime of 0.28 (0.02) h and of avibactam of 0.24 (0.04) h and volumes of distribution of 0.80 (0.14) and 1.18 (0.34) liters/kg. The ELF-plasma (area under the concentration-time curve [AUC]) ratios (standard errors [SE]) were 0.24 (0.03) for total ceftazidime and 0.27 (0.03) for unbound ceftazidime; for avibactam, the ratios were 0.20 (0.02) and 0.22 (0.02), respectively. No pharmacokinetic interaction between ceftazidime and avibactam was observed. Ceftazidime and avibactam showed linear plasma pharmacokinetics that were independent of the dose combinations used or the infection site in mice. Assuming pharmacokinetic similarity in humans, this indicates that similar dose ratios of ceftazidime and avibactam could be used for different types and sites of infection.     

Cerebrospinal Fluid Penetration of Amikacin

Adult volunteers underwent a single lumbar puncture 1 to 8.5 h after one 7.5-mg/kg intramuscular amikacin injection. Eighteen showed no detectable drug in cerebrospinal fluid; six had concentrations <0.5 μg/ml.     

Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

The pharmacokinetics and bone concentrations of oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of oritavancin for the treatment of infections in bone tissues is warranted.     

Penetration of Cefazolin into Pleural Fluid

Single doses of cefazolin, 500 mg intramuscularly and 1 g intravenously, were administered to 16 patients having lung pathology who were scheduled for thoracic fluid aspiration. Pleural fluid and serum samples were taken at intervals of 30 to 240 min for determination of cefazolin levels. The levels obtained were variable; however, the levels of cefazolin in pleural fluid generally exceeded the reported minimal inhibitory concentration values for Staphylococcus pneumoniae and Staphylococcus, and group A beta-hemolytic streptococcus. In addition, the pleural fluid levels exceeded the minimal inhibitory concentration for cefazolin against most of the Klebsiella and Haemophilus influenzae strains. These data show that cefazolin, despite its comparative high protein binding, produces levels in the pleural fluid capable of inhibiting the organisms commonly found in respiratory tract infections.     

Penetration of Cefamandole into Spinal Fluid

Twelve patients, aged 6 months to 62 years, with proven bacterial meningitis, were given a single intravenous dose of cefamandole (33 mg/kg) 75 to 140 min before a routine lumbar puncture. Infecting organisms included Haemophilus influenzae (eight cases), Streptococcus pneumoniae (two cases), and Neisseria meningitidis and β-hemolytic streptococcus (one each). Cerebrospinal fluid (CSF) was analyzed by microbiological assay for cefamandole. The median concentration was 0.60 μg/ml, ranging from undetectable to 7.4 μg/ml. CSF cefamandole concentrations correlated with CSF protein: in six patients with CSF protein less than 100 μg/dl, the range of drug concentration was 0 to 0.62 μg/ml; and in six patients with CSF protein above 100 mg/dl, the range was 0.57 to 7.4 μg/ml. No significant correlation was noted between severity of illness, type of organism involved, or patient age and concentration of drug achieved.     

Penetration of Amoxicillin into Cerebrospinal Fluid

The penetration of amoxicillin into cerebrospinal fluid (CFS) in the presence of meningeal inflammation was evaluated in patients with tuberculous meningitis. Serum and CSF concentrations of amoxicillin were measured at 2 h in nine patients who received a 1-g oral dose and at 1.5 and 4 h in ten patients who received a 2-g intravenous injection of sodium amoxicillin. After the oral dose, CSF concentrations ranged from 0.1 to 1.5 μg/ml. After the intravenous injection, CSF concentrations ranged from 2.9 to 40.0 μg/ml at 1.5 h and from 2.6 to 27.0 μg/ml at 4 h. These data on penetration suggest that parenterally administered sodium amoxicillin may be of value in the therapy of acute bacterial meningitis.     

Penetration of Colistin into Cerebrospinal Fluid

Colistin penetration into the cerebrospinal fluid (CSF) was studied in five critically ill adult patients receiving colistin methanesulfonate for infections by multiresistant gram-negative bacilli. Colistin concentrations were determined in paired serum and CSF samples, with the latter taken by lumbar puncture, with the exception of one patient with an external ventriculostomy. CSF-to-serum ratios (0.051 to 0.057) for all study patients coincided at all sampling times. The low level (5%) of penetration suggests inadequate bactericidal colistin concentrations in the CSF.Several case reports have described the successful treatment of central nervous system (CNS) infections with colistin (in the form of colistin methanesulfonate [CMS]) administered intravenously and/or either intrathecally or intraventricularly (2, 7-11, 16). However, initial data derived from colistin concentrations measured by microbiological assay suggested poor drug penetration into the cerebrospinal fluid (CSF), which was not enhanced in the presence of meningeal inflammation (5), while more recently, a 25% peak CSF-to-serum concentration ratio (8) and a ∼15% ratio of areas under the CSF/serum concentration-time profiles were reported (9). These findings raise concerns about the effectiveness of intravenous (i.v.) CMS monotherapy. Furthermore, as the data (5, 8, 9) relating to the penetration of colistin into the CSF are based solely on unreliable bioassay measurements, these have to be confirmed by high-performance liquid chromatography, which is now considered to be the only valid approach for quantifying colistin levels (12).In order to determine the CSF penetration of colistin after i.v. administration of CMS, we performed a prospective study of five nonconsecutive critically ill adult patients treated with i.v. CMS for serious gram-negative infections (not necessarily CNS infections) (Table ​(Table1).1). All patients had CSF withdrawn either for diagnostic reasons (suspected meningitis or ventriculitis) or for the follow-up of a documented CSF infection. The study was approved by the Hospital Ethics and Research Committee and performed in accordance with good clinical practice guidelines. Informed consent was waived.

TABLE 1.

Characteristics of the patients investigated^a

Gentamicin and Tobramycin Penetration into Synovial Fluid

The penetration of gentamicin and tobramycin into the synovial fluid of 12 patients with nontraumatic joint effusions was studied. Simultaneous serum and synovial fluid specimens taken after the intramuscular or intravenous administration of an antimicrobial agent were assayed. Synovial fluid levels of antibiotic were >50% of serum levels in all subjects studied. In five patients, synovial fluid levels were equal to or exceeded simultaneous serum values. These results suggest that intra-articular injection of aminoglycoside antibiotics is not necessary in the treatment of infectious arthritis.     

Comparative Penetration of Various Cephalosporins into Inflammatory Exudate

A rabbit sterile peritonitis model was used to determine the relative penetration of four cephalosporin antibiotics into exudate fluid. Male New Zealand white rabbits were given 120 ml of sterile saline intraperitoneally, and peritonitis developed over the following 8 h, with exudate fluid containing a mean of 17,188 granulocytes per mm(3) at 8 h. Each antibiotic was administered intramuscularly at a dose of 30 mg/kg 3 h after peritonitis was initiated, and serum and peritoneal concentrations were measured 0.5, 1, 2, and 4 h later. Cefamandole gave the highest mean peak serum level (26.8 mug/ml), and cephalothin, cephacetrile, and cephradine all gave peak serum levels between 13 and 15 mug/ml. When peak peritoneal exudate concentration was expressed as a percentage of peak serum concentration, cephradine developed 28.5% of the peak serum level, cephacetrile 27.7%, cephalothin 14.0%, and cefamandole 12.5%. These percentages of exudate penetration were inversely proportional to the degree of serum protein binding: cephradine 26.6%, cephacetrile 36.3%, cephalothin 50%, and cefamandole 88%.     

Pharmacokinetics and Inflammatory-Fluid Penetration of Moxifloxacin following Oral or Intravenous Administration

A single 400-mg oral or intravenous (i.v.) dose of moxifloxacin was given to each of eight healthy male volunteers, and 6 weeks later the dose was administered by the other route. The concentrations of the drug in plasma, cantharidin-induced inflammatory fluid, and urine were measured over the subsequent 24 h. The mean maximum concentrations observed in plasma were 4.98 microg/ml after oral dosing and 5.09 microg/ml after i.v. dosing. The mean maximum concentrations attained in the inflammatory fluid were 2.62 and 3.23 microg/ml, respectively. The mean elimination half-lives from plasma were 8.32 and 8.17 h, respectively. The overall penetration into the inflammatory fluid was 103.4 and 104.2%. Over 24 h 15% of the drug was recovered in the urine when administered by either route.     

Penetration of Daptomycin into Bone and Synovial Fluid in Joint Replacement

Daptomycin exhibits clinical activity in the treatment of infections with Gram-positive organisms, including infections due to methicillin-resistant Staphylococcus aureus. However, little is known about its penetration into bone and synovial fluid. The aim of our study was to assess the penetration of daptomycin into bone and synovial fluid after a single intravenous administration. This study was conducted in 16 patients who underwent knee or hip replacement and received a single intravenous dose of 8 mg of daptomycin per kg of body weight prior to surgery. Plasma daptomycin concentrations were measured 1 h after the end of daptomycin infusion and when bone fragments were removed. Daptomycin concentrations were also measured on bone fragments and synovial fluid collected at the same time during surgery. All samples were analyzed with a diode array–high-performance liquid chromatography (HPLC) method. After a single-dose intravenous infusion, bone daptomycin concentrations were above the MIC of daptomycin for Staphylococcus aureus in all subjects, and the median bone penetration percentage was 9.0% (interquartile range [IQR], 4.4 to 11.4). These results support the use of daptomycin in the treatment of Staphylococcus aureus bone and joint infections.     

Pharmacokinetics of Liposomal Amphotericin B in Pleural Fluid

We report the penetration of liposomal amphotericin B into the pleural fluid of a patient with pulmonary zygomycosis and empyema. The ratio of area under the concentration-versus-time curve in pleural fluid (AUC_{pleural fluid}) to that in serum (AUC_serum) for liposomal amphotericin B over 24 h was 9.4%, with pleural fluid concentrations of 2.12 to 4.91 μg/ml. Given the relatively low level of intrapleural penetration of liposomal amphotericin B, chest tube drainage may be warranted for successful treatment of zygomycotic empyema.Invasion of the pleural space is a serious complication of fungal pneumonias (9). There is limited information on the penetration of liposomal amphotericin B (LAmB) into the pleural fluid of humans (20). We report herein a detailed pharmacokinetic sampling and analysis of the penetration of LAmB into the pleural fluid of a patient with pulmonary zygomycosis (mucormycosis) and empyema.     

Comparative Activities of Clinafloxacin against Gram-Positive and -Negative Bacteria

Activities of clinafloxacin, ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, piperacillin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, ceftazidime, and imipenem against 354 ciprofloxacin-susceptible and -intermediate-resistant organisms were tested by agar dilution. Clinafloxacin yielded the lowest quinolone MICs (≤0.5 μg/ml against ciprofloxacin-susceptible organisms and ≤16.0 μg/ml against ciprofloxacin-intermediate-resistant organisms) compared to those of levofloxacin, trovafloxacin, and sparfloxacin. Ceftazidime, piperacillin alone or combined with tazobactam, trimethoprim-sulfamethoxazole, and imipenem usually yielded higher MICs against ciprofloxacin-resistant strains.     

Clinafloxacin pharmacokinetics in subjects with various degrees of renal function

As the primary route for elimination of clinafloxacin is renal clearance (CL(R)) of unchanged drug, studies were conducted to determine the pharmacokinetic profile of clinafloxacin following administration to young and elderly subjects, subjects with various degrees of renal function, and subjects requiring dialysis. These were open-label studies in which subjects received single oral clinafloxacin doses. Sixteen young subjects (18 to 35 years old) and 16 elderly subjects (>65 years old) were enrolled in a study comparing pharmacokinetic profiles of clinafloxacin in young and elderly subjects. Twenty subjects having various degrees of renal function were enrolled into one of three groups based on degree of renal function as measured by creatinine clearance (CL(CR)). Twelve subjects with severe renal impairment requiring dialysis enrolled in a third study. Clinafloxacin was generally well tolerated by all subjects. Clinafloxacin pharmacokinetic profiles in elderly subjects were dependent only on age-related decreases in renal function. Clinafloxacin maximum concentrations in plasma, areas under the concentration-time curves, and terminal elimination half-life values increased with decreasing CL(CR) values. Total apparent body clearance of clinafloxacin from the plasma after oral administration (CL(oral)) and CL(R) were dependent on CL(CR) according to the following relationships: CL(oral) = 2.3. CL(CR) + 77 and CL(R) = 1.74. CL(CR). Hemodialysis had no significant effect on clinafloxacin clearance. Based on the relationship between CL(CR) and clinafloxacin CL(oral) and CL(R) values, the clinafloxacin dose should be halved in patients having a CL(CR) of <40 ml/min. Further dose adjustment is not warranted in patients requiring hemodialysis.     

Penetration of Cefazolin, Cephaloridine, and Cefamandole into Interstitial Fluid in Rabbits

We compared the penetration of three cephalosporins into interstitial fluid. Interstitial fluid was obtained in rabbits from Silastic tissue cages. Cefazolin, cephaloridine, and cefamandole were administered by the intramuscular route (30 mg/kg per injection). Peak blood levels and interstitial concentrations were studied after a single injection. Interstitial levels were also compared in a three-injection study (one injection every 12 h) and in a cumulative effect study (six injections), in which the interval between injections was established for each drug on the basis of its common therapeutic use. After a single injection, cephaloridine activity was detected more rapidly and attained higher levels than the other two drugs within the first 4 h. However, 2 h after the third injection, cefazolin levels in tissue fluid were higher than with cephaloridine. Cefamandole consistently gave the lowest interstitial levels. With all three drugs, detectable concentrations were present in interstitial fluid at a time when no detectable antibiotic was found in serum. In the six-injection study, the interstitial levels obtained with cefazolin were significantly higher than those observed with the other drugs. Our data suggest that cefazolin is a drug of choice due to its high extravascular levels.     

Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation

Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for ≥50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for between-subject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (≥90%) probabilities of target attainment (PTAs) for MICs of ≤12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.Osteomyelitis is difficult to diagnose and treat and may cause irreversible damage. Antibiotic treatment over weeks to months is required, often in addition to surgical debridement. To reduce the incidence of infections after orthopedic surgery, perioperative prophylaxis is standard practice. Each year more than a million hip replacements are done worldwide. Prosthetic devices are particularly susceptible to infections, more than 50% of which are due to Staphylococcus aureus or coagulase-negative staphylococci, such as S. epidermidis (38). It is vitally important that adequate surgical prophylaxis be used and that sufficient concentrations of antibiotic with activity against frequently encountered pathogens in bone be achieved.Amoxicillin (amoxicilline) in combination with clavulanic acid is active against pathogens commonly found in prosthesis-related bone infections (MICs at which 90% of bacteria are inhibited [MIC₉₀s], 1 mg/liter for methicillin-susceptible S. aureus [MSSA] and 8 mg/liter for S. epidermidis [28]). Successful treatment of infections with amoxicillin-clavulanic acid after molar extraction (22), peri-implantitis (52), osteomyelitis due to diabetic foot infections (40), prophylaxis of infections after orthognathic surgery (6), and staphylococcal osteomyelitis in a rat model (23) has been reported. The combination was recommended for the treatment of osteomyelitis caused by mixed anaerobic and aerobic pathogens (39).Bone tissue is less vascularized than, for example, the lungs or the skin. Therefore, it is especially important to study the bone penetration of an antimicrobial drug before a clinical effectiveness trial is performed. For the timing of perioperative prophylaxis and surgery, it seems critical to know how fast efficacious concentrations are achieved and how long they are maintained. Modeling of the time course of bone concentrations for penicillins is important, since the shape of the concentration-time curve affects the time above the MIC.The concentrations of amoxicillin and clavulanic acid in bone were studied in the 1980s (1, 3, 24, 54), and only the bone concentration/serum concentration ratios were reported. As these bone concentration/serum concentration ratios change over time, they are a suboptimal measure of the extent of tissue penetration (36, 47). For patients undergoing joint replacement surgery, only one bone sample is most commonly available per patient. Population pharmacokinetic (PK) modeling offers the advantage that it can fit the full time course of the bone and serum concentrations on the basis of the data for all patients simultaneously. The extent of bone penetration is best described by the ratio of the area under the curve (AUC) for bone/AUC for serum. We are not aware of any reports on population pharmacokinetic-pharmacodynamic (PK-PD) models for beta-lactams in bone.Our first objective was to investigate the amoxicillin and clavulanic acid concentrations in cancellous and cortical bone in patients undergoing hip replacement by using a standardized and validated analytical method for bone and serum. The second objective was to develop a PK model which describes the time course of the amoxicillin and clavulanic acid concentrations in bone as well as the drug exposure in bone relative to that in serum. The third objective was to evaluate the PD profile of amoxicillin in serum, cortical, and cancellous bone (16, 19) against pathogens commonly encountered in bone infections, such as MSSA and S. epidermidis.     

Ascitic Fluid Cephalosporin Concentrations: Influence of Protein Binding and Serum Pharmacokinetics

Mongrel dogs with ascites created by inferior vena cava ligation were given cephalothin, cephaloridine, cefazolin, and cefamandole to evaluate the effect of protein binding and serum pharmacokinetics on the distribution of cephalosporins into ascitic fluid. Antibiotics were given intramuscularly (15 mg/kg) every 4 h for a total of eight doses. Antibiotic binding to dog serum and ascitic fluid was measured by ultracentrifugation. Binding of the cephalosporins to dog serum ranged from 31% for cephaloridine to 46% for cephalothin, considerably lower than human serum binding for cefazolin, cephalothin, and cefamandole. Antibiotic binding to ascitic fluid was only slightly lower than that to serum. Ascitic fluid antibiotic concentrations, which approached equilibrium at 16 to 28 h, were significantly higher for cefazolin and cephaloridine than for cephalothin and cefamandole. However, serum concentrations were also higher for cefazolin and cephaloridine, and percent penetration (ratio of serum peak to ascites peak × 100) was not statistically different among the four drugs. Binding of these cephalosporins to extravascular fluid protein was an important factor that determined the total ascitic fluid antibiotic level achieved. A formula utilizing the log mean serum level and binding to serum and extravascular fluid protein was used to accurately predict ascitic fluid drug levels at equilibrium.