We investigated the relationships between changes in CD4 lymphocytes counts over 24 weeks after the initiation of therapy with indinavir at dosages of > or = 2.4 g/day (n = 15) in human immunodeficiency virus-positive patients and compared them to the baseline values. Starting CD4 count were linked to the time-weighted average CD4 cell count (return) through a nonlinear effect model. The diminution of destruction of CD4 cells after the initiation of indinavir therapy was estimated by fitting simultaneous differential equations to the data by using a linked lymph node (LN)-blood (BL) (two-compartment) system in which there is a constant rate of generation (R), first-order transfer rate constants (KLN-BL and KBL-LN) of compartment exchange, and first-order rate constants of CD4 destruction in the absence and presence of indinavir (KLN-OUT1 and KLN-OUT2). The half-life of CD4 lymphocytes was calculated from the rate constants by standard two-compartment methods. The CD4 lymphocyte counts at the start and return were linked in a sigmoid-Emax model were the maximal effect (Emax) was at 574.6 cells/microliters and 50% of the effect occurred at 157.1 cells/microliters (r2 = 0.94; P < 0.001). The mean +/- standard deviation (median) KLN-OUT2 was 0.574 +/- 0.202 (0.589), indicating that indinavir decrease the destruction of CD4 cells by circa 41 to 42%. The mean (median) CD4 half-life was 11.5 +/- 5.72 day (10.3 days). In multivariate analysis, KLN-OUT2 was significantly correlated with starting the CD4 cells count and the change in the CD4 cell count on therapy. The relationship between CD4 lymphocyte half-life and the starting CD4 lymphocyte count was hyperbolic, with a rapid increase in half-life as the CD4 count decreased. On the basis of the calculated half-life, the average production (destruction) of CD4 lymphocytes was approximately 3 x 10(9) cells/day, with an individual variation of 44-fold. These findings suggest that (i) the CD4 lymphocyte cell count at the start is significantly correlated to both the decrease in the destruction rate of CD4 cells and the degree of change in the CD4 lymphocytes on therapy, (ii) the lower the initial CD4 lymphocyte count, the higher the amount of CD4 lymphocyte turnover and the lower the ability of the immune system to increase absolute CD4 lymphocyte levels after viral suppression, consistent with a decreased regenerative capacity with progression of disease; and (iii) the increase in CD4 lymphocytes is likely secondary to the expansion of proliferating pool of cells since our determinations are based on 24 weeks of effect.

The therapeutic utility of a human immunodeficiency virus type 1 (HIV-1) protease inhibitor may depend on its intracellular concentration, which is a property of its uptake, metabolism, and/or efflux. Previous studies in our laboratory indicated that the addition of alpha 1 acid glycoprotein (alpha 1 AGP) to the medium markedly increased the amount of the drug required to limit infection in vitro. In this study, physiologically relevant concentrations of alpha 1 AGP and a radiolabeled inhibitor, A-80987, were used to determine both the uptake and activity of the agent in HIV-1-infected human peripheral blood mononuclear cells and cell lines. Both the uptake and efflux of 14C-labeled A-80987 were rapid (t1/2, < 5 min). Uptake of the drug was linearly dependent on the concentration but insensitive to the metabolic inhibitors KF, sodium cyanide, or CCCP (carbonyl cyanide m-chlorophenyl hydrazone). The amount of A-80987 which entered the cells was inversely proportional to the concentration of alpha 1 AGP (r2, 0.99) and directly proportional to the amount of extracellular non-protein-bound drug (r2, 0.99). Most importantly, the antiviral activity of the drug in HIV-1-infected peripheral blood mononuclear cells and MT-2 cells was directly related to the amount of intracellular A-80987. This study demonstrates that A-80987 binds to alpha 1 AGP, resulting in a free fraction below 10%. Cellular uptake of A-80987 is proportionally decreased in the presence of alpha 1 AGP, which results in less-than-expected antiviral activity. Importantly, we demonstrate for the first time that the inhibition of HIV protease is highly correlated with the amount of intracellular inhibitor.

We propose a method for the selection of doses and dosing schedule for drugs to be used in combination. This approach uses the simulation of steady-state concentrations of the drugs in the combination and overlays these concentrations onto a three-dimensional effect surface. The MacSynergy II program is used to construct the three-dimensional drug interaction surface from the direct evaluation of drug combination effect in vitro. The study examined the combination of an inhibitor of the human immunodeficiency virus protease, A-77003, and the nucleoside analog zidovudine. Zidovudine concentrations from a steady-state interval were simulated on the basis of the administration of 100 mg every 12 h by mouth, while for A-77003 simulation profiles were for intravenous administration of 800 mg every 4 h as well as a continuous infusion of 200 mg/h. The average percentage of the maximal effect was taken as a measure of regimen effectiveness. Three different schedules of administration were examined. If both drugs were to be administered simultaneously, the model predicts a mean maximal effect of a steady-state interval (12 h) of 67%. If the drug doses were offset by 2 h, the mean maximal effect predicted was 71%. If A-77003 was to be given by continuous infusion, the mean maximal effect predicted was 90%. This method holds promise as a way of quickly evaluating potential combinations of agents that takes into account the drug interaction in a mathematically robust way and that allows the evaluation of the effect of each drug's pharmacokinetic profile.

A-77003, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is effective for both acute and chronic infection in vitro and was evaluated clinically by continuous intravenous infusion administration. The minimum effective dose (the concentration required to completely inhibit viral replication) was determined in vitro in a population of uninfected (99%) and HIV-infected (1%) cells exposed to A-77003 by continuous infusion in hollow-fiber bioreactors. The production of infectious HIV and release of p24 antigen from infected cells were completely inhibited in cultures exposed to A-77003 at or above a concentration of 0.5 microM. Measurement of unintegrated HIV-1 DNA synthesis and flow cytometric analysis for cells expressing HIV p24 antigen demonstrated that the spread of HIV to uninfected cells was also blocked at 0.5 microM A-77003. Dose deescalation to 0.25 microM or removal of A-77003 resulted in the limited spread of the virus throughout the culture, the resumption of viral DNA synthesis, and release of p24. HIV produced after exposure to 0.5 microM A-77003 was noninfectious for a period of 72 h after the removal of the drug. Addition of 1 mg of alpha 1-acid glycoprotein per ml to this in vitro system completely ablated the anti-HIV effect of 0.5 microM A-77003. These data suggest that determination of the minimum effective dose under conditions which simulate human pharmacodynamic patterns may be useful in determining the initial dose and schedule for clinical trials. However, other factors, such as serum protein binding, may influence the selection of a therapeutic regimen.

We examined the pharmacokinetics of ganciclovir in different populations of cytomegalovirus (CMV)-infected patients through the use of nonlinear mixed-effects modelling. As expected, patient weight and estimated creatinine clearance were shown to be important covariates in the serum ganciclovir clearance. Unexpectedly, major differences in ganciclovir clearance between different populations of patients were found. Human immunodeficiency virus (HIV)-infected patients with CMV retinitis cleared ganciclovir 41% faster than HIV-infected patients only shedding CMV into the urine. Solid-organ transplant patients had a serum clearance one-fourth that of HIV-infected patients, even with correction for creatinine clearance. These findings require prospective validation and may have important implications for ganciclovir dosing in different populations of CMV-infected patients.

Robust determination of the concentration-time profile of anti-infective agents in certain specialized compartments is often limited by the inability to obtain more than a single sample from such a site in any one subject. Vitreous humor and cerebrospinal fluid are obvious examples for which the determination of concentrations of anti-infective agents is limited. Advances in pharmacodynamics have pointed out the importance of understanding the profiles of drugs in the plasma and in specialized compartments in order to dose the drugs to obtain the best patient outcomes. Advances in population pharmacokinetic modeling hold the promise of allowing proper estimation of drug penetration into the vitreous (or other specialized compartment) with only a single vitreous sample, in conjunction with plasma sampling. We have developed a rabbit model which allows multiple samples of vitreous to be obtained without breaking down the blood-vitreous barrier. We have employed this model to test the hypothesis that robust estimates of vitreous penetration by the fluoroquinolone ciprofloxacin can be obtained from a traditional intensive plasma sampling set plus a single vitreous sample. We studied 33 rabbits which were receiving 40 mg of ciprofloxacin per kg of body weight intravenously as short infusions and from which multiple plasma and vitreous samples were obtained and assayed for ciprofloxacin content by high-performance liquid chromatography. Data were analyzed by the iterative two-stage population modeling technique (IT2S), employing the iterative two-stage program of Forrest et al. (Antimicrob. Agents Chemother. 37:1065-1072, 1993). Two data sets were analyzed: all plasma and vitreous samples versus all plasma samples and the initially obtained single vitreous sample. The pharmacokinetic parameter values identified were used to calculate the percent vitreous penetration as the ratio of the area under the concentration-time curve for the vitreous to that for the plasma. The values identified, 4% penetration for the full data set versus 3% penetration for the single vitreous sample data set, and their corresponding estimates were not statistically significantly different. We conclude that population modeling holds promise for the analysis of penetration of antimicrobiol agents into specialized spaces from which only single samples can be obtained, particularly for patients with whom robust plasma sampling can be performed.

We examined the relationship between the concentrations of zidovudine in plasma given by continuous intravenous infusion to human immunodeficiency virus-positive pediatric patients and a surrogate marker of outcome (measured by the increase in the number of CD4-positive T cells) as well as drug-mediated toxicity (change in granulocyte count). The return of CD4-positive T cells was most strongly related to the number of these cells present at the start of therapy. Drug concentration data added little explanatory power to this relationship, indicating that the effect of zidovudine was near maximal throughout the range of concentrations examined. The change in granulocyte count was significantly correlated with zidovudine concentration both from weeks 1 through 8 and from weeks 8 through 12. These findings imply that it may be wise to stratify phase I antiretrovirus drug trials for the entry level of CD4-positive T cells if pharmacodynamic relationships with this marker as the dependent variable are to be sought. Continued efforts need to be made to derive quantitative relationships between drug exposure and measures of both efficacy and toxicity so that the maximal amount of information is derived from small phase I studies.

We sought to validate an in vitro system which could predict the minimal effect dose of antiretroviral agents. Mixtures of uninfected CEM cells and CEM cells chronically infected with human immunodeficiency virus (HIV) type 1 MN were exposed to 2',3'-didehydro-3'-deoxythymidine (D4T) in vitro in a hollow-fiber model which simulates the plasma concentration-time profile of D4T in patients. Drug concentration was adjusted to simulate continuous intravenous infusion, or an intravenous bolus administered twice daily. The effect of the dosing regimen was measured with viral infectivity, p24 antigen, and reverse transcriptase or PCR for unintegrated HIV DNA. Dose deescalation studies on a twice-daily dosing schedule predicted a minimum effect dose of 0.5 mg/kg of body weight per day which correlated with the results of a clinical trial. Antiviral effect was demonstrated to be independent of schedule for every 12-h dosing versus continuous infusion. Finally, at or near the minimal effect dose, efficacy appeared to depend on the viral load. The ability of this in vitro pharmacodynamic model to assess the response of HIV-infected cells to different doses and schedules of antiviral agents may be useful in the design of optimal dosing regimens for clinical trials but requires validation with other types of antiretroviral agents.

We studied the impact of zidovudine (AZT) in Cas-Br-M murine leukemia virus-infected NFS-N mice after administration by once-daily bolus or continuous infusion. While higher peak concentrations of AZT were achieved by once-daily dosing, continuous AZT infusion at 25 micrograms/h maintained levels > 1 microM in plasma and > 0.2 microM in the brain. Continuous infusion provided significantly better viral inhibition, even though total doses were only one-third that of the once-daily therapy group.

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Foscarnet is an antiviral agent used for the treatment of cytomegalovirus retinitis and acyclovir-resistant herpes simplex virus infections in AIDS patients. Renal impairment has been reported for many patients treated with foscarnet. We have studied the effects of foscarnet on the viability (estimated by neutral red inclusion) and ultrastructure of cultures of human renal proximal tubule cells (HRPTC) isolated from the kidneys of five cadavers and cultured. The degree of foscarnet-induced toxicity was dose dependent and varied among the HRPTC cultures. The data obtained by using the in vitro system of HRPTC mimic the data of the clinical trials in that there is a dose-dependent individual variation among human cases in response to foscarnet treatment. Thus, these cultures are extremely well-suited to investigations of the mechanism of toxicity at the subcellular level.

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We examined the impact of dose fractionation and altered MICs on survivorship in a neutropenic rat model of Pseudomonas aeruginosa sepsis employing the new fluoroquinolone antibiotic lomefloxacin. Once-daily administration of a drug dose which produced a high peak concentration/MIC (peak/MIC) ratio (ca. 20/1) produced significantly better survivorship compared with regimens employing the same daily dose but on a more fractionated schedule. The use of a smaller dose, producing lower (< 10/1) peak/MIC ratios, did not show this effect, as once-daily and twice-daily regimens produced equivalent results (the area under the concentration-time curve/MIC ratio was linked to survivorship). Challenge with resistant mutants selected for altered MICs of fluoroquinolones (two and four times the MIC for the parent strain, respectively) resulted in markedly diminished survivorship. Challenge with the parent strain and use of a drug dose which produced a peak/MIC ratio identical to that for animals challenged with the mutant for which the MIC was four times that for the parent strain and treated with the larger drug dose produced survivorship curves which were not different. For this animal model, peak/MIC ratio was linked to survivorship, particularly when high ratios (10/1 to 20/1) were obtained. At lower doses, producing peak/MIC ratios < 10/1, the area under the concentration-time curve relative to the MIC appeared to be most closely linked to outcome. The time that levels in plasma exceeded the MIC did not influence survivorship. The hypothesis most likely to explain these findings is that higher peak/MIC ratios can suppress the parent strain and mutant organisms (gyrA and transport mutants) for which the MIC is higher but limited (no more than eight times that for the parent strain).

A synthetic, symmetry-based inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, A77003, was evaluated for antiviral activity and cytotoxicity in vitro in human peripheral blood lymphocytes or cell lines H9, CEM, and U937. Toxicity and antiviral activity of the HIV-1 protease inhibitor were compared with those of the reverse transcriptase inhibitors zidovudine and 2',3'-dideoxy-2',3'-didehydrothymidine and human recombinant alpha and beta interferons. Production of infectious virus particles, cell-free p24 antigen, and cell-associated viral proteins was reduced 50% by the HIV-1 protease inhibitor at concentrations of 0.12 to 0.26 microM (50% effective concentration [EC50]) in acute infection and 0.2 to 1.7 microM (EC50) in persistent infection. Fluorescence-activated cell sorter analysis of U937 cells persistently infected with HIVIIIB using a monoclonal antibody to HIV also showed a reduction of cell-associated viral protein in A77003-treated cells. Furthermore, toxicity of A77003 assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was not observed at greater than 100 times the EC50. A77003 was more effective in persistent HIV-1 infection than alpha and beta interferons (1,000 U/ml), while zidovudine and 2',3'-dideoxy-2',3'-didehydrothymidine were not active.

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The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodeficiency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P much less than 0.01). For doses of less than or equal to 5.1 mg/kg given every 12 h (10.2 mg/kg/day), bioavailability was 41%. We conclude that once-daily administration results in lower mean bioavailability, probably because of a saturation of the absorption process similar to that seen with acyclovir. This difference in bioavailability on the basis of the administration schedule explains the different short-term maximal tolerated doses identified in phase I trials of this agent.

The effect of renal function on the bioavailability of ciprofloxacin was studied in 21 subjects with measured creatinine clearances ranging from 0 to 8.99 liters/h per 1.73 m2. Each subject received ciprofloxacin, 200 mg intravenously and 750 mg orally, separated by at least 1 week. Serial (12 to 15) blood samples were obtained over 24 to 48 h. Concentrations in serum were assayed by high-pressure liquid chromatography. Area under the curve was calculated by the trapezoidal rule with extrapolation to infinity. Bioavailability was calculated as the ratio between the dose-normalized area under the curve of oral and intravenous administrations. The overall mean (standard deviation) bioavailability observed was 63.4% (14.6%), similar to that observed in those with normal renal function (69.0% [15.7%]). The mean bioavailability in the subgroup of subjects with renal insufficiency was 59.9% (13.3%). The observed range in bioavailability was 33.9 to 91.4%. Linear regression did not reveal a correlation between creatinine clearance and bioavailability. Renal insufficiency does not appear to affect ciprofloxacin bioavailability.

Interpretation of the majority of data on the disposition of clindamycin is confounded by the presence of active metabolites, which may interfere with commonly employed bioassays. We undertook a multiple-dose study of the disposition of clindamycin phosphate and clindamycin, given either as 600 mg intravenously every 6 h or 1,200 mg intravenously every 12 h for five and three doses, respectively, in six healthy volunteers. Concentrations in serum and urine were analyzed by a specific gas chromatography assay. Maximum and minimum clindamycin concentrations in serum and the area under the serum concentration-time curve following the first dose were similar to those observed at the steady state. The mean and standard deviation of the maximum, 1-h postdose, and minimum concentrations in serum at steady state for the 600-mg dose given every 6 h were 16.8 +/- 6.0, 7.6 +/- 0.7, and 2.3 +/- 0.9 microgram/ml, whereas for the 1,200-mg dose given every 12 h they were 17.2 +/- 3.5, 9.8 +/- 1.5, and 0.6 +/- 0.3 microgram/ml, respectively. For the 12-h regimen, clindamycin concentrations in serum remained above 2 micrograms/ml for 7 h. The decay of clindamycin phosphate levels in serum was rapid, with virtually 100% of the phosphate eliminated within the first 1.5 h following the dose. Approximately 0.35 and 4.5% of the administered dose were recovered in the urine as clindamycin phosphate and clindamycin, respectively. Further pharmacokinetic evaluation of the 12-hourly dosage regimen should be done before clinical evaluation in infected patients is undertaken.

The relationships between creatinine clearance (CLCR) and the pharmacokinetics of oral ciprofloxacin were characterized. On the basis of these data, a dosage adjustment strategy, which incorporates the severity of infection and the size and renal function of the patient, was developed. An adaptive (feedback) control algorithm is proposed. A total of 32 subjects (8 normal, 8 anuric, and 16 with CLCR between 0.53 and 4.3 liters/h per 1.73 m2) were given a single 750-mg tablet of ciprofloxacin by mouth. Serial serum and urine samples were collected, assayed by high-pressure liquid chromatography, and comodeled. The population relationship between total apparent ciprofloxacin clearance (CL/f) and CLCR, both measured in liters per hour per 1.73 m2, was CL/f = 2.83 x CLCR + 21.8 (r = 0.69; P less than 0.001). The mean terminal half-life was not significantly related to CLCR but was much more variable in subjects with CLCR less than 3 liters/h per 1.73 m2 (F = 4.8; P less than 0.005). We conclude that patients with CLCR less than 1.2 liters/h per 1.73 m2 should receive two-thirds of the normal daily dose and that the dose interval should not be lengthened.

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The emergence of resistance to imipenem by Pseudomonas aeruginosa was investigated with four pairs of isolates. Each pair represented pretherapy (susceptible) and posttherapy (resistant) specimens. In all cases, the imipenem-resistant isolates did not demonstrate changed susceptibilities to other beta-lactams. Agarose gel electrophoresis revealed no change in plasmid profiles between any pair of isolates. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the Sarkosyl-insoluble membrane protein revealed the loss of an outer membrane protein of apparent molecular mass 48 to 49 kilodaltons in posttherapy strains when grown with imipenem selection (5 micrograms/ml). There was no significant difference in the binding of [14C]imipenem to the penicillin-binding proteins of the pre- and posttherapy strains. Trichloroacetic acid precipitation of membranes isolated after growth in the presence of [14C]imipenem revealed that significantly less drug was bound to Sarkosyl-soluble membrane protein in three of the four posttherapy strains than the membrane proteins of the respective pretherapy strains. beta-Lactamase activity against imipenem at 100 or 3 microM was not detected in any isolate either with or without induction. These data suggest that resistance to imipenem is associated with the loss of a 48- to 49-kilodalton outer membrane protein accompanied by, in three of four cases, decreased penetration of the antibiotic across the outer membrane.

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We ascertained the pharmacokinetics of imipenem in febrile granulocytopenic cancer patients. The values observed were both different from and significantly more variable than those observed in normal volunteers. Free drug concentrations exceeded the MIC for 90% of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus strains for greater than 6 h. The MIC for 90% of Pseudomonas aeruginosa strains was exceeded for 4 h. Because imipenem induces a 2-h postantibiotic effect in P. aeruginosa, it is promising as single-agent empiric therapy in this setting.

We compared ciprofloxacin (200 mg) with cefotaxime (2 g) when each was administered intravenously over a 30-min period to six volunteers in a crossover manner 1 week apart. To integrate the pharmacologic and microbiologic activity, inhibitory and bactericidal activities in serum were obtained for both antibiotics 1 and 6 h after administration against 10 strains of Escherichia coli, 10 strains of Klebsiella pneumoniae, 15 strains of Pseudomonas aeruginosa, and 10 strains each of methicillin-susceptible and -resistant Staphylococcus aureus. Geometric mean bactericidal titers for E. coli 1 h after the infusion were 1:60 for ciprofloxacin and 1:252 for cefotaxime, and for K. pneumoniae they were 1:20 and 1:256, respectively. However, geometric mean titers were poor for both antibiotics against methicillin-susceptible S. aureus (less than 1:2 for ciprofloxacin versus 1:5 for cefotaxime) and methicillin-resistant S. aureus (less than 1:2 for both antibiotics), as well as against P. aeruginosa (1:3 for ciprofloxacin versus 1:2 for cefotaxime). These data suggest that ciprofloxacin may be useful for the treatment of serious infections caused by E. coli and K. pneumoniae. However, caution is suggested when this dose of ciprofloxacin is used in situations in which septicemia is caused by P. aeruginosa or S. aureus and originates outside the urinary tract.

We evaluated the bioavailability of ciprofloxacin at two dose sizes in eight healthy volunteers. Each volunteer was given 200 mg of ciprofloxacin both orally and intravenously in a randomized crossover fashion and 750 mg orally. Bioavailability at the two doses was similar: 69 and 69.1% for the 200- and 750-mg doses, respectively. However, the bioavailability observed with the 750-mg dose was significantly more variable than that observed with the 200-mg dose. Between 375 and 700 mg of ciprofloxacin reached the systemic circulation after administration of the 750-mg dose, with no evidence of adverse reactions.

We examined the pharmacokinetic behavior of 200 mg of ciprofloxacin administered intravenously to 32 volunteers whose renal function as measured by creatinine clearance ranged from 0 to 8.99 liters/h per 1.73 m2. Serum clearances (mean +/- standard deviation) were 26.8 +/- 5.7 and 15.4 +/- 4.3 liters/h per 1.73 m2 in normal and anephric volunteers, respectively. The half-life (mean +/- standard deviation) increased from 4.3 +/- 0.8 h in normal volunteers to 8.6 +/- 3.3 h in anephric volunteers. There was good correlation between normalized creatinine clearance and both normalized serum and renal clearance. The regression equation for serum clearance (CLS) versus creatinine clearance (CLCR) was CLS = 1.97 X CLCR + 13.23, where r = 0.697; for renal clearance versus creatinine clearance, the equation was CLR = 2.26 X CLCR, where r = 0.845. On the basis of these data, we recommend a maximum 50% reduction in dose when ciprofloxacin is instituted at a renal function of 1.2 to 1.8 liters/h per 1.73 m2 (20 to 30 ml/min per 1.73 m2). Because of the observed variation in ciprofloxacin half-life in our anephric volunteers, we also recommend that a schedule of administration every 12 h be maintained, even for patients without urine output.

The combinations of imipenem plus ciprofloxacin and imipenem plus amikacin were investigated for their activity against Pseudomonas aeruginosa and other bacterial pathogens. For imipenem-susceptible P. aeruginosa, synergy of imipenem plus ciprofloxacin and imipenem plus amikacin was observed against 36 and 45% of the strains, respectively. The incidence of synergy against imipenem-resistant isolates of P. aeruginosa was 10% for both combinations. Antagonism was not observed with either combination.

We evaluated the absolute bioavailability of ciprofloxacin, a new quinoline carboxylic acid, in 12 healthy male volunteers. Doses of 200 mg were given to each of the volunteers in a randomized, crossover manner 1 week apart orally and as a 10-min intravenous infusion. Half-lives (mean +/- standard deviation) for the intravenous and oral administration arms were 4.2 +/- 0.77 and 4.11 +/- 0.74 h, respectively. The serum clearance rate averaged 28.5 +/- 4.7 liters/h per 1.73 m2 for the intravenous administration arm. The renal clearance rate accounted for approximately 60% of the corresponding serum clearance rate and was 16.9 +/- 3.0 liters/h per 1.73 m2 for the intravenous arm and 17.0 +/- 2.86 liters/h per 1.73 m2 for the oral administration arm. Absorption was rapid, with peak concentrations in serum occurring at 0.71 +/- 0.15 h. Bioavailability, defined as the ratio of the area under the curve from 0 h to infinity for the oral to the intravenous dose, was 69 +/- 7%. We conclude that ciprofloxacin is rapidly absorbed and reliably bioavailable in these healthy volunteers. Further studies with ciprofloxacin should be undertaken in target patient populations under actual clinical circumstances.

We evaluated the pharmacokinetics of 100- and 200-mg doses of ciprofloxacin, with the 200-mg dose administered either as a 30-min infusion or as a 100-mg loading dose followed by a 4-h constant infusion of 25 mg/h in six normal volunteers. No significant differences were seen in the dose-normalized area under the curve when the 100- and 200-mg 30-min administrations were compared. Differences that approached statistical significance were seen when data from either of these trials were compared with data from the constant-infusion arm. Serum clearances averaged 23.0 +/- 9.1 liters/h per 1.73 m2 for the 100-mg dose and 23.7 +/- 5.1 liters/h per 1.73 m2 for the 200-mg dose. Renal clearance accounted for approximately two-thirds of the serum clearance in each instance. Half-lives were slightly longer than 4 h. For the constant-infusion arm, serum clearance was 28.9 +/- 2.7 liters/h per 1.73 m2, with renal clearance accounting for 58% of serum clearance. Although no nonlinearities were apparent in the 100- to 200-mg dose range, larger doses, particularly in the multiple-dosing situation, may uncover nonlinearity in the disposition of ciprofloxacin.