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The postantibiotic effect (PAE) in vivo of imipenem, cefoperazone and latamoxef was investigated in a neutropenic mouse thigh model. Two hours after inoculation of 10(6) cfu of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa into each thigh, the neutropenic mice were treated with single doses of 50-200 mg/kg imipenem, 40-1200 mg/kg cefoperazone and 50-100 mg/kg latamoxef. Serum levels exceeded the MIC for 1.1-2.9 h. Cefoperazone and latamoxef induced PAEs of 2.1-5.6 h for S aureus, but no significant PAEs were induced for the Gram-negative bacilli. In contrast imipenem produced PAE of 0.9-4.6 h with P. aeruginosa. However, strain variation was observed in the duration of the PAE after imipenem. These data are in concordance with the PAEs of the antimicrobials under study when these are determined in vitro. The implications of these findings for clinical use of these drugs need further evaluation.

The therapeutic failure of aminoglycosides in leukopenic mice was studied. Pseudomonas aeruginosa isolated from experimentally infected leukopenic mice was analyzed for susceptibility to gentamicin. Bacterial population analyses were performed before, during, and after therapy with high doses of gentamicin. Inocula from numerous strains, including P. aeruginosa strain ATCC 27853, harbored slowly growing aminoglycoside-resistant subpopulations. In leukopenic mice (in contrast to normal mice) receiving gentamicin, the breakthrough growth of these subpopulations occurred 6 hr after treatment. Resistance to gentamicin reversed in vivo when gentamicin treatment was stopped. The emergence of gentamicin-resistant subpopulations was successfully suppressed by a combined treatment regimen of gentamicin and ticarcillin. Gentamicin-ticarcillin synergy in these infections is due, in part, to antimicrobial suppression of slowly growing aminoglycoside-resistant subpopulations of bacteria.

Two patients had streptococcal myositis. Both patients developed extensive muscle necrosis and overwhelming sepsis after trivial skin trauma. Death occurred within 48 hours of hospital admission despite aggressive surgical and medical treatment. Review of the literature is included to highlight the fulminant nature of this unusual infection and to contrast streptococcal myositis with other soft-tissue streptococcal infections.

Erythromycin pharmacokinetics were examined following intravenous infusion to male subjects. The biological half-life of erythromycin in serum was 2 hr in individuals with normal renal function. The half-life varied in cases of reduced renal function, with values of 3.9 and 7.0 hr occurring in two subjects with severe renal impairment. Postinfusion serum erythromycin levels were adequately described by two-compartment model kinetics, and values for the distribution volume of the central compartment and the overall distribution are described. Estimated erythromycin distribution volumes in normal individuals may facilitate calculation of absorption efficiencies of erythromycin and its salts after oral doses.

The impact of acidification and alkalinization of the urine on the pharmacokinetics of cinoxacin was examined after single 500-mg oral doses were administered to nine healthy male volunteers. Acidic and alkaline conditions were achieved by repeated oral doses of ammonium chloride or sodium bicarbonate, respectively. Plasma cinoxacin levels in all subjects were adequately described in terms of one-compartment-model kinetics with first-order absorption and elimination. Acidification and alkalinization treatment had no effect on cinoxacin absorption or distribution. The mean elimination half-life of cinoxacin in plasma was 1.1, 2.0, and 0.6 h in control subjects and with acidification and alkalinization of urine, respectively. Recovery of intact cinoxacin in samples of urine collected 0 to 36 h after cinoxacin administration represented 65% of the dose in control subjects and urine acidification and 80% of the dose with alkalinization of urine. The mean renal clearance of cinoxacin was 76, 118, and 278 ml/min with acidification, control, and alkalinization, respectively, and renal clearance was highly correlated with urinary pH. Urine concentrations of cinoxacin were significantly higher with alkalinization compared with control values during the first 4 h after drug administration. Urine cinoxacin concentrations were reduced somewhat by acidification, but these tended not to be significantly different from control values. Changes in cinoxacin elimination owing to urine pH are less pronounced in humans than in dogs. The antibacterial activity of cinoxacin against some common urinary tract pathogens was pH dependent. A four- to eightfold reduction in cinoxacin activity was generally observed at pH 8 compared with lower pH values. However, in view of the high levels of cinoxacin which are obtained in both acidic and basic urine, the impact of urine pH on cinoxacin antibacterial efficacy would be of minor clinical importance.

Examples are presented to demonstrate that in-vitro determinations of the minimal inhibitory concentration of antibiotics do not take into account factors of presumable in-vivo significance: pH and divalent cations in the medium, protein binding of antimicrobials, and the bacterial inoculum effect.

The pharmacokinetics of cefoperazone in normal subjects and in patients with hepatic and renal dysfunction are reviewed. Peak serum concentrations and areas under serum level-time curves are linearly related to dose. The range of mean peak serum concentrations after a 2-g dose of cefoperazone is 202-375 micrograms/ml with iv injection or infusion and 111 micrograms/ml with im injection. The serum half-life is 1.6-2.6 hr. Urinary excretion is rapid, but only 15%-37% of the dose is recovered in urine. The drug is not metabolized significantly. Levels of drug in bile are many times higher than serum levels, and biliary excretion represents the major pathway of cefoperazone elimination. Serum kinetics of cefoperazone are not significantly altered by renal impairment. However, hepatic dysfunction is associated with a two- to fourfold increase in serum half-life. Even in these patients, drug accumulation was not observed after repeated administration of 1 g of cefoperazone at 12-hr intervals. Major dosage modification should only be required with concomitant renal and hepatic dysfunction.

Persistent suppression of bacterial growth following exposure of both gram-positive and gram-negative bacteria to numerous antimicrobial agents was studied. The persistent, or postantibiotic, effect was quantitated by periodic counts of colony-forming units after removal of the drug by washing, dilution, or inactivation with penicillinase. Although a postantibiotic effect was observed with all drugs studied, there were marked differences among drugs in their postantibiotic effects on certain organisms. With gram-positive organisms, concentrations of beta-lactam antibiotics near the minimal inhibitory concentration produced persistent effects lasting 1-3 hr. With gram-negative organisms much higher concentrations were required to elicit a postantibiotic effect. Inhibitors of protein and RNA synthesis produced the longest persistent suppression of growth, which was of comparable duration in gram-positive and gram-negative bacteria. Only a short persistent effect of gentamicin was observed with Staphylococcus aureus and Escherichia coli, but a postantibiotic effect lasting 1.6-2.6 hr was observed with Pseudomonas aeruginosa. The duration of the postantibiotic effect was related linearly to concentration of drug and duration of exposure up to a point of maximal response. Persistent effects following exposure to antibiotics were also demonstrated in 90% human serum.

The influence of various test meals and fluid volumes on the relative bioavailability of commercial formulations of doxycycline hyclate and tetracycline hydrochloride was studied in healthy human volunteers. Serum levels of tetracycline were uniformly reduced by approximately 50% by all test meals, whereas serum levels of doxycycline were reduced by 20%. The reduction of tetracycline serum levels will likely be of clinical significance. The bioavailability of each drug was almost identical from an oral solution and from capsules in fasted subjects. The rate of doxycycline absorption was reduced when capsules were administered with a small volume of water, but the overall efficiency of absorption of both drugs was essentially independent of co-administered fluid volume. The use of 8-h serum data provides a reliable estimate of drug bioavailability for tetracycline and, to a lesser extent, for doxycycline.

Pretreatment with multiple doses of polymyxin B and colistimethate was evaluated as to its ability to sequester sufficient antibiotic in tissues to neutralize the effects of endotoxin in three animal models. Animals were challenged with endotoxin 24, 48, or 72 h after the last dose of antibiotic when there was minimal or not detectable drug in serum. Pretreatment with polymyxin B was successful in preventing the generalized Shwartzman reaction in rabbits and reducing endotoxin lethality in mice; however, large doses (20 mg per kg per day for 2 or 4 days) were required. Prolongation by more than 24 h of the interval between the last dose of polymyxin B and endotoxin challenge resulted in reduction or loss of protection. Dogs were unable to tolerate the high polymyxin B dosage which was protective in the mouse and rabbit. Lower, nontoxic doses of polymyxin B in dogs did not prevent endotoxin shock and lethality, even when challenged as soon as 1 h after the last dose. Pretreatment with colistimethate was ineffective in all three animal models.

The pharmacokinetics of 14C-labeled glyburide were studied in 13 men with varying degrees of renal impairment. Patients received a single, 5 mg oral dose of glyburide as a solution (10 microCi/ml/mg) after a high-carbohydrate breakfast. Serial plasma and breath samples were collected for 48 hours and urine and feces were collected for 5 to 7 days. Patients with normal to moderately impaired renal function (creatinine clearance [CLCR] of 29 to 131 ml/min/1.7 m2) had glyburide plasma t1/2 values of 2.0 to 5.0 hours, with no relationship between CLCR and glyburide clearance. One subject with severe renal impairment (CLCR = 5 ml/min/1.7 m2) had decreased glyburide clearance that resulted in a t1/2 of 11 hours. The elimination of metabolites was more dependent on renal status but was only significantly affected in the patient with severe renal impairment.

Persistent suppression of bacterial growth by certain antibiotics was tested by periodic counts of viable organisms in a culture of Staphylococcus aureus that had been incubated in media containing drugs for limited periods of time and then removed by centrifugation. During short (2 hr) periods of exposure of test cultures to penicillin G, cephalothin, erythromycin, clindamycin, vancomycin, and tetracyline, effects on the growth of S. aureus were produced that persisted after removal of the drug for periods of 1.7-4.1 hr. A persistent antibiotic effect was not observed with gentamicin. The persistent effects of penicillin G and erythromycin were directly related to duration of exposure and concentration of drug, up to a point of maximal response. The maximal durations of bacterial suppression after exposure to penicillin G and erythromycin were approximately 2 and 5 hr, respectively. These effects were observed over a wide range of inocula.

The influence of various test meals and fluid volume on the relative bioavailability of ampicillin and amoxicillin was studied in healthy human subjects. Serum amoxicillin levels were somewhat, but not always, significantly higher than those of ampicillin from equivalent oral doses. Food ingested immediately before dosing reduced serum levels and urinary excretion of both antibiotics to a similar extent. Reduction of dosed water volume caused a marked decrease in serum amoxicillin levels in fasted subjects.

A few studies have suggested that the inhibitory effect of serum on activity of broad-spectrum cephalosporins is less than that predicted by the degree of protein binding. Microdilution MICs of ceftriaxone, cefoperazone, moxalactam, and ceftizoxime were therefore determined against ATCC and clinical strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus in Mueller-Hinton broth containing either human albumin (as 0, 2.5, or 5% solution) or heat-inactivated human serum (as 0, 25, 50, or 95% solution). Arithmetic linear dilutions were used to improve accuracy. For standard bacterial strains, MICs in the presence of 5% albumin were higher than in broth alone by multiples of 10.9 to 21 for ceftriaxone, 5.5 to 16.4 for cefoperazone, 1.9 to 3.7 for moxalactam, and 1.1 to 1.4 for ceftizoxime, as expected by their protein binding. MICs in the presence of 95% serum were similar to those in 5% albumin for all four drugs against S. aureus and P. aeruginosa but were 2.2- to 4.8-fold lower (P less than 0.001) against E. coli and K. pneumoniae. Similar findings were observed at lower protein concentrations and with clinical isolates, except that for some strains of P. aeruginosa MICs were lower in serum than in albumin. Individual sera from five subjects gave comparable results. The addition of serum ultrafiltrate to albumin-containing solutions reduced MICs of ceftriaxone and cefoperazone 1.6- to 7.4-fold against E. coli and K. pneumoniae (P less than 0.01) but did not alter the MICs for S. aureus. Serum may contain an ultrafiltrable component(s) that enhances the activity of third-generation cephalosporins against many gram-negative bacilli.

The safety and clinical efficacy of dosing twice a day with bacampicillin was evaluated in clinical trials conducted at various locations in Latin America, Switzerland, and Scandinavia, Bacampicillin (200, 400, 600, or 800 mg) given twice a day was compared with bacampicillin (400 mg) or ampicillin (500 or 556 mg) administered three times a day in eight double-blind and six open randomized trials involving 750 patients with respiratory and urinary tract infections. In a noncomparative study, 47 additional patients were treated with 600 mg of bacampicillin twice a day. High rates of clinical cure or improvement were achieved for all types of infections investigated. Microbiologic cure was observed in greater than 90% of respiratory infections due to beta-hemolytic streptococci, Streptococcus pneumoniae, or Hemophilus influenzae. There were no significant differences between the responses of groups treated twice and those treated three times a day. Adverse effects of both regimens of bacampicillin were similar and occurred less frequently than in patients treated with ampicillin. Dosing twice daily with bacampicillin appears to be effective against numerous gram-positive and gram-negative bacteria in a variety of mild clinical infections. Studies comparing identical dosage regimens of bacampicillin and other aminopenicillins are needed to determine whether bacampicillin given twice a day has a therapeutic advantage.

The postantibiotic effect (PAE) is the suppression of bacterial growth that persists after limited exposure of organisms to antimicrobial agents. We demonstrated and standardized the in vivo PAE in a thigh infection model in neutropenic mice. Inhibitors of protein and nucleic acid synthesis induced PAEs of 1.4-7.5 h against aerobic gram-negative bacilli, whereas beta-lactam antibiotics did not induce significant PAEs. Against aerobic gram-positive cocci, cell wall-active agents and inhibitors of protein and nucleic acid synthesis induced PAEs of 1.2-7.1 h, except for penicillins, which did not induce PAEs against streptococci. With few exceptions the in vivo PAE correlated well with the PAE reported in prior in vitro studies. Residual drug in thigh tissue did not cause the PAE. Theoretically, the presence of a PAE may allow antimicrobial agents to be given more intermittently without organism regrowth after drug levels fall below the minimal inhibitory concentration.

Assessment of antimicrobial activity from standard in vitro minimum inhibitory and minimum bactericidal concentration determinations alone is incomplete. Rate of bacterial killing, effect of increasing concentration, sub-MIC effects, and degree of suppression of bacterial growth after limited exposure (post-antibiotic effect) more precisely describe the course of antimicrobial activity. Aminoglycoside antibiotics exhibit concentration-dependent bactericidal activity and a prolonged post-antibiotic effect. beta-Lactam antibiotics demonstrate more time-dependent killing and lack post-antibiotic effects, except with staphylococci. Most bacteriostatic antimicrobial agents also produce post-antibiotic suppression of growth. Studies in different animal infection models with a variety of organisms suggest that beta-lactams are more efficacious with continuous dosing, whereas the efficacy of aminoglycosides is relatively independent of dosing regimen, even when administered once daily. Knowledge of the kinetics of antimicrobial action is useful in predicting optimal dosage regimens.

An attempt was made in vitro and in vivo to clarify the significance of aminoglycoside-resistant subpopulations that can be isolated from gentamicin-susceptible Pseudomonas aeruginosa. Population analyses revealed bacterial subpopulations resistant to greater than or equal to 8 micrograms/ml gentamicin in 23 of 24 gentamicin-susceptible strains tested. These subpopulations could easily be selected in a single exposure of high inocula of P. aeruginosa to two times the MIC of gentamicin for 24 to 48 hr. The increased gentamicin resistance was associated with slower growth and formation of smaller colonies. In serial subcultivations, most of the selected variants were unstable regarding gentamicin resistance and colony morphology. Stable SCV representing the extreme form of gentamicin-resistant subpopulations were further studied. In comparison to the corresponding PS, they were fourfold to sixfold less susceptible to five aminoglycosides tested; their susceptibility to eight antipseudomonal beta-lactam drugs, however, was usually retained. SCV proved to be less pathogenic than PS for normal and moderately leukopenic mice. Agranulocytic mice, in contrast, were invariably killed after i.p. injection of less than 20 organisms of PS or SCV, although death occurred 24 to 48 hr later in mice infected with SCV. After injection into the thigh muscle of agranulocytic mice, SCV were not affected by therapeutic plasma levels of gentamicin, whereas ticarcillin was highly effective. Aminoglycoside-resistant subpopulations of P. aeruginosa could contribute to the high number of treatment failures of Pseudomonas injections in agranulocytic patients and may account, in part, for the superiority of combined antipsuedomonal chemotherapy in this clinical situation.

Protein binding of numerous drugs, primarily organic acids, is decreased in sera from uremic patients. The defect in binding is (1) greater than can be accounted for by hypoalbuminemia alone; (2) unchanged by prolonged in vitro dialysis; (3) transferred in the protein but not the ultrafiltrate fraction of uremic serum; and (4) not reproduced by addition of low and middle molecular weight compounds known to accumulate in uremia. However, treatment with activated charcoal at pH3 was found to significantly increase drug protein binding in uremic sera. This effect was studied with six different drugs in sera from groups of 6 normal subjects and 8 patients on chronic hemodialysis. The percentage of sulfamethoxazole, dicloxacillin, diphenylhydantoin, salicylate, and digitoxin bound to protein in normal sera (65.9, 97.1, 93.1, 96.7, and 92.7, respectively) was unchanged by charcoal treatment. In contrast, charcoal treatment significantly (p less than 0.01) increased the percentage of drug bound to protein in uremic sera from 41.7 to 59.0 for sulfamethoxazole, 90.7 to 96.3 for dicloxacillin, 84.3 to 90.8 for diphenyhydantoin, 86.4 to 93.8 for salicylate, and 89.5 to 90.9 for digitoxin. Charcoal treatment significantly (p less than 0.05) reduced penicillin protein binding in normal sera and failed to correct the binding defect for penicillin in uremic sera. The effect of charcoal can be explained by removal of an inhibitor which accumulates in uremia and (1) occupies the binding site of certain drugs, (2) changes the configuration of the albumin molecule, or (3) both. Free fatty acid (FFA) concentrations in uremic patients were similar to those in normal subjects and were not the cause of the binding defect.

Binding of antimicrobials to serum proteins and tissue affects their distribution, elimination and antimicrobial activity. Penetration of drugs into most tissues and interstitial and inflammatory fluids correlates with level of free drug in serum. Serum protein binding can increase or decrease the rate of drug elimination depending on whether total or free drug is available to the excretory or metabolic routes of elimination. Binding to soluble intracellular proteins (ligandin and fatty acid binding protein) appears to be important in the cellular transport and elimination of antimicrobials by renal tubular secretion and hepatic extraction. Although only free, unbound drug is antimicrobially active, the lack of well designed studies has prevented precise quantitation of the influence of binding on therapeutic efficacy in vivo. Pharmacokinetic considerations predict that serum binding greater than 80% would be necessary to significantly reduce free levels of drug in the body. However, extensive protein binding is often compensated for by greater intrinsic activity of lipophilic antimicrobials.

The pharmacokinetics of minocycline have been studied after single intravenous infusions and repeated oral doses to human subjects with varying degrees of renal impairment. There was no evidence of reduced drug clearance with reduced renal function after intravenous doses although there appeared to be an increase in the tissue distribution of antibiotic in the body in uremia. After identical multiple oral dosage regimens serum levels of antibiotic were comparable in normal and mildly uremic subjects. There was no evidence of renal toxicity in normal or uremic subjects with the repeated dosage regimen used.

The pharmacokinetics of ceftizoxime (CZM) were determined in 16 non-infected CAPD patients. Patients received either 500 mg or 1000 mg CZM by i.v. bolus. The dialysate exchange volume was 2 l. Serum CZM concentrations at 10 min were 69.7 +/- 19.7 micrograms/ml (1000 mg dose) and 39.2 +/- 8.4 micrograms/ml (500 mg dose), and declined to 33.7 +/- 13.9 micrograms/ml and 16.9 +/- 3.2 micrograms/ml respectively at 360 min. Dialysate CZM levels at 10 and 360 min were 1.8 +/- 1.3 and 19.9 +/- 6.6 micrograms/ml respectively (1000 mg dose) and 1.4 +/- 0.9 and 12.6 +/- 3.5 micrograms/ml (500 mg dose). The half-time of CZM was 14.1 +/- 4.6 h. Peritoneal clearance of CZM was low and equilibrium was not achieved in 6 h. However peritoneal CZM concentrations were adequate within 1 h for the treatment of most organisms which cause CAPD-related peritonitis.

The influence of various test meals and ingested fluid volumes on the bioavailability and pharmacokinetics of propoxyphene and its major metabolite norporpoxyphene has been studied in healthy human subjects. The absorption of drug was delayed by all test meals, but the overall efficiency of absorption was either not affected or was slightly increased. Increased fluid volume intake decreased propoxyphene bioavailability. Plasma levels of metabolite correlated well with levels of unchanged drug, particularly in the first 2 hr after dosing, but were not markedly influenced by treatments.

Current antimicrobial dosing regimens are designed to maintain active drug levels for most of the dosing interval and are based on 40-y-old observations. With use of numerous multiple-dosing regimens in an animal model, this study is the first to successfully minimize the interdependence between pharmacokinetic parameters and thereby determine, by stepwise multivariate regression analysis, that the time that serum levels exceeded the minimum inhibitory concentration (MIC) was the most significant parameter determining efficacy for beta-lactams and erythromycin against various pathogens, whereas the log area under the curve was the major parameter for aminoglycosides. Optimal dosing intervals were no greater than the time that serum levels exceeded the MIC plus the duration of the postantibiotic effect. Careful application of these concepts should allow other investigators to use more optimally dosed regimens than those previously used in preclinical trials and to design studies to improve on current dosing regimens for humans.

Netilmicin, the 1-N-ethyl derivative of sisomicin, is a new aminoglycoside antibiotic that was recently marketed in the United States. Its role in therapeutics is not yet established. The pharmacokinetic profile of netilmicin is very similar to that of gentamicin. Its antimicrobial spectrum and clinical efficacy is similar to that of gentamicin, tobramycin and amikacin. It is less active in vitro against Pseudomonas aeruginosa that gentamicin and tobramycin, but in clinical trials the efficacy of netilmicin against the organism has been similar to other aminoglycosides. Netilmicin is active against some gentamicin and tobramycin-resistant strains of gram-negative bacilli, particularly those harboring adenylating and phosphorylation enzymes. Most of these strains are sensitive to amikacin as well, and amikacin is also active against most netilmicin-resistant strains of these bacteria. Therefore, amikacin remains the aminoglycoside of choice against gentamicin tobramycin and netilmicin-resistant gram-negative bacilli. In comparison to other currently available aminoglycosides, a lower frequency of nephrotoxicity and ototoxicity has been observed in laboratory animals given netilmicin. This has not been unequivocally demonstrated in humans. The frequency of nephrotoxicity in humans has been similar to that of other aminoglycosides. The frequency of ototoxicity associated with netilmicin in humans has been low but not significantly less than in other aminoglycosides, except in one trial. If further studies document a significantly lower frequency of ototoxicity with netilmicin, it may become the aminoglycoside of choice for patients with significant risk factors for ototoxicity, such as advanced age, renal impairment, concomitant ototoxic drug therapy and prolonged aminoglycoside administration.

Serum protein binding of weakly acidic drugs is impaired in uremia, but that of basic drugs tends to be normal. Treatment of uremic serum with anion exchange resin (Amberlite CG-400, acetate form) corrected binding defects for three acidic drugs (nafcillin, salicylate and sulfamethoxazole) but did not affect the binding of two basic drugs (trimethoprim and quinidine). Resin treatment of normal human serum did not alter the binding of these five drugs. Extraction of the acetate buffer eluate from resin exposed to uremic serum with n-butyl chloride at acidic pH (3.0) resulted in a fraction that could induce similar binding defects in normal human serum. The factor(s) responsible for binding defects in uremia appears to be lipid soluble, weakly acidic, and dialyzable. It is believed to be tightly bound to albumin at physiologic pH, but dissociates from it at acidic pH. These findings further support the previously proposed hypothesis that drug-binding defects in uremia are due to accumulation of certain endogenous metabolic product(s).

The relative efficacy of different aminoglycosides or of different dosage schedules of the same aminoglycoside should be quantitated and related to relative toxicity. Quantitative experimental indicators of efficacy should not only include MIC and MBC, but also the postantibiotic effect in vitro and in vivo, the emergence of resistance in in-vitro and in-vivo models, and the relationship between plasma concentration profiles and efficacy. Parameters of clinical efficacy are to be related to pharmacokinetic parameters such as the ratio between the peak serum concentration and the MIC. Toxicity in clinical trials should be assessed by the most sensitive methods available. Experimental and clinical studies have shown cortical uptake to be a sensitive indicator of renal toxicity. As far as ototoxicity is concerned endolymph and perilymph pharmacokinetics are not clearly related. Clinical ototoxicity should be assessed by sensitive methods, such as high frequency tone audiometry. Finally, risk factors for nephrotoxicity and ototoxicity (e.g., duration of treatment, associated nephrotoxic drugs, dehydration) should be assessed in the evaluation of clinical trials.

The influence of dosing intervals on the activity of gentamicin and ticarcillin against Pseudomonas aeruginosa was studied in vivo. Granulocytopenic mice infected with P. aeruginosa in the thigh muscle were treated with 1-hr or 3-hr injections of gentamicin, ticarcillin, or gentamicin-ticarcillin. Plasma pharmacokinetics of the drugs were correlated with antibacterial activity. Gentamicin injected every 1 hr tended to be less active than gentamicin injected at longer intervals. In contrast, ticarcillin given every 1 hr was significantly more efficacious than equivalent total doses injected every 3 hr. The dosing schedule of gentamicin-ticarcillin was again important for ticarcillin but did not appreciably affect the antibacterial activity of gentamicin. Thus, antimicrobial chemotherapy of P. aeruginosa infections in the granulocytopenic host might be improved by administering ticarcillin rather than gentamicin as a constant infusion.

The influence of various test meals, and of fluid volumes, on the bioavailability of theophylline from a solid dosage form has been studied in healthy male volunteers. Absorption of a drug was faster after dosing immediately following a high protein meal than after a high fat or a high carbohydrate meal. Absorption from a solution was faster than from a solid dosage form in all treatments; areas under serum level time curves after dosing were also significantly higher up to 12 hr. Areas up to 12 hr after dosing also tended to be higher after the high protein meal and after dosing with 500 ml water on an empty stomach than after other solid dose treatments.

Three fasted, male subjects received single 10-, 30-, and 50-mg oral doses of hydrocortisone tablets on separate occasions. Endogenous hydrocortisone was suppressed by giving 2 mg of dexamethasone 9 hr prior to dosing. Plasma samples obtained serially for 8 hr after hydrocortisone dosing were assayed by reversed-phase high-pressure liquid chromatography (HPLC) with UV detection and by normal-phase HPLC with fluorescence detection of the dansylhydrazine derivative of hydrocortisone. The two assay methods yielded equivalent plasma hydrocortisone concentrations. Metabolite interference was absent in both assay methods. Drug concentrations in plasma from all three doses of hydrocortisone were described by one-compartment open-model kinetics, with first-order absorption and elimination, and an absorption lag time. Mean Cmax values of 199, 393, and 419 ng/ml were obtained at 1.0, 1.0, and 1.7 hr following the 10-, 30-, and 50-mg doses, respectively. Hydrocortisone was cleared from plasma with an elimination half-life of approximately 1.5 hr. Within the dosage range studied, plasma levels of hydrocortisone were related, but not directly proportional, to dose size. This apparent lack of proportionality may be due to reduced drug availability or altered distribution with increasing dose.

Serum protein binding of antimicrobials can reduce antimicrobial activity, restrict tissue distribution, and delay drug elimination. Binding percentages of 80 per cent or more have the potential to significantly reduce free drug levels and affect therapeutic efficacy in patients. However, binding-induced alterations in drug elimination and differences in intrinsic antibacterial activity can often compensate for the inhibitory effect of high serum protein binding. Knowledge of the extent of protein binding does allow one to estimate, for a given level of total drug, the concentration of active drug in serum and most extravascular fluids.

Several new methods for detection of bacteriuria were studied to evaluate their usefulness as screening procedures. A new filter paper device incorporating dehydrated media and tetrazolium was found to be reliable when compared with the standard pour plate method in the laboratory and with the dip-slide method in a field test. It failed to detect yeasts and slowly growing streptococci. Antibiotics blocked the test when susceptible organisms were present. An agar-cup method was found to be quite reliable, but could be improved by use of differential media. The Griess test was confirmed in a small trial to be highly specific when used in conjunction with a first morning specimen, but of little value with random specimens. Phenzopyridine was found to give false positive reactions. The subnormal glucose test, although highly sensitive and specific, gave too many false positive tests to be useful other than as a screening method.

A new dip-inoculum method for quantitative urine culture is described which utilizes a dual-chambered plastic "paddle" housing both a general purpose and differential medium. Comparative bacterial counts of 1,000 clinical specimens using the pour plate and this device were identical in 82.9% and within a factor of five in 95.6%. The "paddle" detected all but 19 of 258 specimens (92.6%) with 100,000 or greater colonies per ml. This simple, convenient method should allow more extensive use of quantitative urine culture in the diagnosis and follow-up of patients with urinary tract infections in office practice. It should not be considered as a substitute for the more definitive pour plate method or for standard methods for characterization of bacteriological species when more exact information is required.