Comparative Incidence of Phlebitis Due to Buffered Cephalothin, Cephapirin, and Cefamandole

Buffered cephalothin, cefamandole, and cephapirin were compared with respect to their tendency to produce phlebitis. Two grams of each agent was administered every 6 h for 4 days to 12 healthy volunteers in a double-blind crossover fashion. Approximately 50% of intravenous sites developed mild (grade 1) phlebitis and 25% developed moderate (grade 2) phlebitis. The frequency of grade 1 inflammation did not differ significantly among the three cephalosporins. The proportion of individuals eventually exhibiting grade 2 phelebitis was highest with cefamandole, lowest with cephalothin (P = 0.07), and intermediate with cephapirin; however, cephapirin required a substantially greater number of doses to produce grade 2 phelebitis than did the other two drugs. These findings, together with the results of other reports, suggest that interpretation of the phlebitogenic potential of these antibiotics must be made with caution.     

Comparison of Phlebitis Produced by Cephapirin and Cephalothin

In a single-blinded study involving 120 patients neither the incidence nor severity of phlebitis observed with cephapirin and cephalothin was significantly different.     

Comparative Pharmacokinetics and Metabolism of Cephapirin in Laboratory Animals and Humans

Comparative drug disposition studies in mice, rats, dogs, and humans indicate that cephapirin, a new semisynthetic cephalosporin antibiotic that exhibits broad-spectrum antimicrobial activity, is metabolized to desacetylcephapirin in these species. Pharmacokinetic analyses of the concentrations of cephapirin and desacetylcephapirin in plasma and urine reveal that the rate and extent of deacetylation decreases from rodents to dogs to humans. The kinetic analyses also suggest that the kidney performs a role not only in the excretion but also in the metabolism of cephapirin to desacetylcephapirin.     

Excretion of Cefamandole, Cefazolin, and Cephalothin into T-Tube Bile

The biliary tract excretion of cefamandole, cefazolin, and cephalothin was measured in eight patients with T-tubes inserted into their common ducts after ductal exploration for biliary tract stones. Each patient received 1.0 g intravenously of each cephalosporin on 3 separate days; T-tube bile and serum were collected at selected time intervals thereafter. In seven patients, bile and urine were collected for 6 h after the administration of each drug. Mean peak levels of cefamandole, cefazolin, and cephalothin in bile were 352, 46, and 12 μg/ml, respectively. The respective mean peak serum levels were 55.0, 92.8, and 32.4 μg/ml. Despite the fact that peak serum levels of cefazolin were 1.5 times those of cefamandole, levels in bile of cefamandole were about 8 times those of cefazolin. Over a 6-h period, almost three times as much cefamandole was excreted into bile as was cefazolin. Therefore, in those patients with biliary tract sepsis, in whom a cephalosporin is indicated for therapy, cefamandole appears to be the drug of choice.     

Penetration of Cefamandole, Cephalothin, and Desacetylcephalothin into Fibrin Clots

The conversion of cephalothin into a less active metabolite (desacetylcephalothin) might influence its distribution in tissues. An experimental rabbit model devised to determine concentrations of antibiotics in subcutaneous fibrin clots was used in this study. Groups of five to six animals received 100-mg/kg intravenous injections of either cefamandole or cephalothin. One hour after the injection, the concentration of cefamandole in serum was 20 times higher than that of cephalothin. Whereas cephalothin was undetectable at 4 h, cefamandole was still detectable at the end of the experiment. The half-lives of cephalothin and cefamandole in serum were 16 and 27 min, respectively. The concentration of cefamandole found in fibrin clots was severalfold higher than that of cephalothin. The half-life of cefamandole in clots (81 min) was superior to that of cephalothin (38 min). Although concentrations of both antibiotics were higher in serum than in clots at 1 h, the concentrations of these drugs in the clots persisted at higher levels throughout the next 5 h of the experiment. The extent of binding of cefamandole (87%) to rabbit serum was greater than that of cephalothin (50%). At least 55% of cephalothin was metabolized in vivo into its less active metabolite desacetylcephalothin. This metabolite was found in higher proportion in the serum (75%) than in the clots (55%). Whereas only 12% of the free (unbound) cephalothin reached the clots, 78% of the free cefamandole was found in the clots. This lower level of penetration of unbound cephalothin might be explained by the short half-life of this antibiotic, not permitting equilibrium to occur.     

Safety and Pharmacokinetics of the Antiorthopoxvirus Compound ST-246 following Repeat Oral Dosing in Healthy Adult Subjects

ST-246, a novel compound that inhibits egress of orthopoxvirus from infected cells, is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, placebo-controlled, escalating multiple-dose study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose of 250, 400, or 800 mg for 21 days to nonfasting healthy human volunteers. ST-246 appeared to be well tolerated, with no serious adverse events (AEs). Headache, for which one subject in the 800-mg group discontinued the study, was the most commonly reported AE in all treatment groups. The multiple-dose pharmacokinetics of ST-246 was well characterized. The day 21 mean elimination half-lives were calculated at 18.8, 19.8, and 20.7 h for each of the 250-, 400-, and 800-mg/day dose groups, respectively. Steady state was reached by day 6 (within 3 to 5 half-lives), saturable absorption was observed at the 800-mg dose level, and the fraction of parent drug excreted in the urine was very low. Based on these results, administration of 400 mg/day ST-246 can be expected to provide plasma concentrations above the efficacious concentration demonstrated in nonhuman primate models in earlier studies.Human orthopoxviruses cause a spectrum of diseases ranging from severe disseminated lesional disease characteristic of the most common type of variola virus infection (variola major) to localized lesional infection caused by vaccinia virus. Of the several species of orthopoxvirus known to infect humans, variola virus, the etiological agent of smallpox, causes far more serious infections than the other species of poxviruses (3). While variola virus no longer exists in the environment, other orthopoxviruses continue to circulate and cause disease. Monkeypox virus, which is endemic in some areas of the Democratic Republic of the Congo, causes a zoonotic disease that is characterized by a generalized infection resembling a milder version of smallpox (7). Vaccinia-like viruses have been isolated from patients in Brazil presenting with localized lesions of the hands and arms (10), and cowpox virus infections are increasing in certain parts of Europe (11). These viruses are believed to be maintained in the population through rodent reservoirs, and zoonotic disease is thought to arise from contact with infected animals or through an intermediate species such as cattle or domestic pets (7, 11). Disease severity in all cases is influenced by the status of the host immune system, with individuals who suffer from certain skin disorders or who are immunocompromised developing the most severe infections (2, 3).There are currently no U.S. Food and Drug Administration-approved therapies other than early vaccination that can alter the outcome of disease or potentially prevent disease in a population that has been exposed to pathogenic orthopoxviruses (4, 6). Because vaccination has a lag period for antibody formation and carries the risk of certain severe side effects, and because it is not universally available to all who might potentially need it, there is clearly a need for a safe, small-molecule, oral medication that is highly active against variola virus and possibly other zoonotic poxviruses, such as monkeypox, cowpox, and vaccinia-like viruses.ST-246 is a low-molecular-weight compound {Tecovirimat; 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide} that was discovered through a deliberate effort to develop orally available antiviral drugs for use in biodefense (1, 12). ST-246 is chemically unrelated to any substance currently approved for human use for human or veterinary applications. In a number of animal studies, oral administration of ST-246 not only protected nonhuman primates from variola and monkeypox viruses but also protected mice from lethal infection with vaccinia virus, cowpox virus, and ectromelia virus (8, 12) and squirrels from severe monkeypox disease (9), implying that ST-246 could also be used to control vaccination complications and to prevent or treat zoonotic poxvirus disease.Safety pharmacology studies of mice and nonhuman primates demonstrated that ST-246 was well tolerated after a 28-day multiple-dose administration with a no-observable-effect level (NOEL) of 2,000 mg/kg and 300 mg/kg for mice and nonhuman primates, respectively. A phase I clinical study was conducted to determine the safety, tolerability, and clinical pharmacokinetics (PK) of ST-246 administered orally as a single dose of 500, 1,000, or 2,000 mg (fasting) or 1,000 mg (nonfasting) to healthy human volunteers (5). The study concluded that ST-246 at these dose levels was safe and well tolerated. The pharmacokinetics in plasma showed dose proportionality over 500- and 1,000-mg dose levels but not over 1,000- and 2,000-mg dose levels. At the 1,000-mg dose level, nonfasting subjects had greater apparent maximum concentration of drug in serum (C_max), time to maximum concentration of drug in serum (T_max), and area under the curve from zero hour to infinity (AUC_0-∞) than fasting subjects (5).Based on these results, and given the variability in exposure levels in both monkeys and humans in the nonfasting and fasting states, it has been predicted that doses of 400 mg and 800 mg for humans who are nonfasting will encompass plasma drug exposure levels comparable to those that provide protective efficacy in the nonhuman primate model of orthopoxvirus disease. The purpose of this study was to determine the safety, tolerability, and clinical pharmacokinetics of ST-246 when administered orally as a single dose of 250, 400, or 800 mg every day for 21 days to nonfasting healthy human volunteers.     

In Vitro Comparison of Cefoxitin, Cefamandole, Cephalexin, and Cephalothin

The in vitro effect of cefoxitin, cefamandole, cephalexin, and cephalothin was tested against 645 strains of bacteria recently isolated from clinical sources. Against gram-positive organisms cephalothin and cefamandole were the most effective, generally being three- to fourfold more active than cephalexin or cefoxitin. Enterococci were not inhibited by less than 25 μg of any of the antibiotics per ml. Against Enterobacteriaceae, cefoxitin and cefamandole were the most active. An exception was the Enterobacter strains, against which cefoxitin was the least effective. None of the Pseudomonas aeruginosa strains were susceptible to 100 μg of any of the cephalosporins per ml. Cefamandole was the most active agent against Neisseria meningitidis and Neisseria gonorrhoeae. It was also the most effective agent against Haemophilus influenzae, even when taking into account a threefold inoculum effect.     

Bacampicillin, Ampicillin, Cephalothin, and Cephapirin Levels in Human Blood and Interstitial Fluid

The diffusibility of bacampicillin, ampicillin, cephalothin, and cephapirin into human interstitial fluid was investigated by using crossover studies. We compared bacampicillin with ampicillin and found that bacampicillin was better absorbed after oral administration. Blood, interstitial fluid, and urine levels were consistently higher in volunteers who received bacampicillin. We compared cephalothin with cephapirin and found that blood and interstitial fluid levels were comparable throughout the study.     

Effect of Rifampin on the Pharmacokinetics of Ertugliflozin in Healthy Subjects

Purpose

Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor being developed for the treatment of type 2 diabetes mellitus. The primary enzyme involved in the metabolism of ertugliflozin is uridine diphosphate-glucuronosyltransferase (UGT) 1A9, with minor contributions from UGT2B7 and cytochrome P450 (CYP) isoenzymes 3A4, 3A5, and 2C8. Rifampin induces UGT1A9, UGT2B7, CYP3A4, and CYP3A5. Because concurrent induction of these enzymes could affect ertugliflozin exposure, this study assessed the effect of multiple doses of rifampin on the pharmacokinetic properties of single-dose ertugliflozin.

Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

Dolutegravir (DTG) is an HIV integrase inhibitor (INI) with demonstrated activity in INI-naive and INI-resistant patients. The objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established “no-effect” boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered at ClinicalTrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT01209065","term_id":"NCT01209065"}}NCT01209065.)     

Double-Blind Controlled Comparison of Phlebitis Produced by Cephapirin and Cephalothin

In a double-blind study with each patient as his own control cephapirin and cephalothin were administered to 20 patients in opposite arms for a period of 48 hr each. Neither the incidence of phlebitis nor the degree of phlebitis was significantly different with the two drugs, and there was no difference in the time of onset of pain or phlebitis.     

Safety,Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects

PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compound''s MIC is between 0.015 and 0.25 μg/ml for drug-sensitive strains and between 0.03 and 0.53 μg/ml for drug-resistant strains. In addition, it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approximately 3 μg/ml (1,500-mg dose) in the single-dose study and 3.8 μg/ml (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approximately 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compound for the treatment of tuberculosis.According to the World Health Organization, there were 9.27 million new tuberculosis (TB) cases worldwide in 2007, which claimed the lives of approximately 1.77 million people, including 456,000 patients coinfected with human immunodeficiency virus (11). In addition, global increases in cases of multidrug-resistant TB and, more recently, extensively drug-resistant TB pose serious treatment challenges (12). New anti-TB drugs are needed that can shorten the duration of treatment, improve the treatment of resistant disease, facilitate the treatment of TB patients coinfected with human immunodeficiency virus, and shorten the treatment of latent TB infection.The 4-nitroimidazo-oxazoles (a subclass of nitroimidazoles) have potent sterilizing activity against Mycobacterium tuberculosis, as first demonstrated in 1993 (1). The further investigation of nitroimidazoles in an anaerobic model of M. tuberculosis dormancy demonstrated that metronidazole is active against slow-growing M. tuberculosis, suggesting the potential for the treatment of latent TB infection and for shortening the treatment of active TB disease (10). The further development of the nitroimidazole class by Pathogenesis, Inc., led to the discovery of another subclass, 4-nitroimidazo-oxazines, with promising activity against M. tuberculosis. PA-824, with the full chemical name (S)-2-nitro-6-[4-(trifluoromethoxy)benzyloxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine), was identified as the lead 4-nitroimidazo-oxazine. Stover et al. (8) reported that the MIC of PA-824 under aerobic conditions against a variety of drug-sensitive clinical isolates was similar to the MIC of isoniazid (MIC of PA-824, 0.015 to 0.25 μg/ml; MIC of isoniazid, 0.03 to 0.06 μg/ml). PA-824 also was found to be active against all single-drug- and multidrug-resistant clinical isolates of M. tuberculosis tested, with MICs of 0.03 to 0.53 μg/ml. Additional studies using microaerophilic and anaerobic culture models indicated that PA-824 also is active against both replicating and nonreplicating or infrequently replicating M. tuberculosis isolates (3, 8).Like metronidazole, PA-824 requires metabolic activation by M. tuberculosis through an F420-dependent nitroreduction (4, 5, 8). Although not thoroughly elucidated at this time, PA-824''s novel mechanism of action involves the inhibition of the synthesis of both protein and lipids but not nucleic acid. Studies by Stover et al. (8) demonstrated that PA-824 inhibits the oxidation of hydroxymycolate to ketomycolate, an essential lipid for M. tuberculosis cell wall function. Recent work by Singh et al. (7) indicates that the reduction of PA-824 to its des-nitroimidazole metabolite by a deazaflavin (F420)-dependent nitroreductase is associated with the generation of reactive nitrogen species, including nitric oxide, which may represent important effectors of PA-824 killing of M. tuberculosis under anaerobic conditions. In an experimental mouse model of infection, Tyagi et al. (9) demonstrated that, at a dose of 100 mg/kg of body weight, PA-824 has substantial bactericidal activity during both the initial and continuation phases of TB treatment. Using a short-course mouse infection model that employs 9 days of the drug treatment of gamma-interferon knockout mice infected with M. tuberculosis 14 days before treatment initiation, Lenaerts et al. (3) found that at 100 mg/kg PA-824 was as active as isoniazid at 25 mg/kg, rifampin (rifampicin) at 10 mg/kg, and moxifloxacin at 100 mg/kg. Additional studies of a mouse model of TB examined the activity of PA-824 administered in combination with current TB drugs. When substituted for isoniazid in standard therapy, PA-824 resulted in significantly fewer CFU after 2 months of therapy and a higher rate of conversion to culture negativity than that of the standard drug combination. Relapse rates after 6 months of treatment were not different in the experimental and control treatment arms in this study, but the study design was such that an improved relapse rate relative to the control could not have been demonstrated (6). Pharmacokinetic analyses reported by Nuermberger et al. (6) demonstrated in mice that the standard rifampin-isoniazid-pyrazinamide regimen does not affect core PA-824 pharmacokinetic parameters, such as C_max (maximum concentration observed), AUC_0—24 (total area under concentration-time curve from 0 to 24 h), or t_1/2 (half-life). Further nonclinical studies are under way to characterize PA-824''s activity and interactions in novel drug combinations.     

Effect of Nifedipine on the Steady-State Pharmacokinetics and Pharmacodynamics of Irbesartan in Healthy Subjects

BACKGROUND: In clinical practice, nifedipine has the potential to alter the pharmacokinetics, and therefore possibly the pharmacodynamics and efficacy or safety, of irbesartan. The objectives of the current study were to determine the effects of concomitant administration of nifedipine on the steady-state pharmacokinetics and pharmacodynamics of irbesartan in 12 healthy subjects. METHODS AND RESULTS: This was an open-label, randomized, crossover study. Each subject received irbesartan 300 mg once daily for 4 days in one period and irbesartan 300 mg once daily plus long-acting nifedipine (Procardia XL, Pratt Pharmaceuticals, New York, NY) 30 mg once daily for 4 days in the other period. The order of treatment periods was randomized, and a minimum 7-day washout phase separated the two periods. Steady state was achieved by day 3. On day 4, no significant differences were observed between the two treatments with respect to maximum concentration of irbesartan at the end of the dosing interval (C(max)) or the area under the plasma concentration versus time curve during a dosing interval (AUC(tau)) of irbesartan. Steady-state C(max) and AUC(tau) met the criteria for bioequivalence when irbesartan was administered alone or with nifedipine. On day 4, mean plasma renin activity was somewhat higher at every point but one when irbesartan was administered with nifedipine; however, no significant difference was observed between the two treatments in mean 24-hour AUC values. On day 4, there was a modest overall decrease from baseline in mean blood pressure for both treatments. No significant differences were observed between the two treatments in mean 24-hour AUC values for seated diastolic or systolic blood pressure. No serious adverse events were reported. CONCLUSIONS: Concomitant administration of nifedipine 30 mg with irbesartan 300 mg for 4 days in healthy subjects (1) does not alter the steady-state pharmacokinetic parameters of irbesartan, (2) results in C(max) and AUC(tau) values for irbesartan that meet the criteria for bioequivalence, and (3) is well tolerated.     

Relative Incidence of Phlebitis Caused by Continuous Intravenous Infusion of Cephapirin and Cephalothin

In a single-blinded study, two groups of 10 healthy subjects were given cephapirin or cephalothin by continuous intravenous infusion for 5 days, 0.5 g every 6 hr for the first day and then 1.0 g every 6 hr for 4 days. Eight of the cephalothin subjects and two of the cephapirin subjects developed phlebitis. Phlebitis was more severe in the cephalothin group and developed more rapidly, necessitating vein changes six times more often than in the cephapirin group. The less irritating properties of cephapirin demonstrated in this study indicate it may be the more useful cephalosporin analogue for intravenous therapy.     

Effect of Gender and Menopausal Status on the Pharmacokinetics of Tirilazad Mesylate in Healthy Subjects

The pharmacokinetics of tirilazad were assessed in men ages 40--60 years, women <40 years of age, premenopausal women ages 40--60, and postmenopausal ages 40--60. Eight subjects in each group received single 3.0 mg kg(minus sign1) intravenous infusions of tirilazad mesylate over 10 min. Plasma concentrations of tirilazad and U-89678, an active metabolite, were measured by high-performance liquid chromatography. Tirilazad administration was well tolerated in all groups. Mean tirilazad clearance was 59.6% higher in young women compared to the middle-aged men (35.6 plus minus 8.04 L h(minus sign1) vs. 22.3 plus minus 8.40 L h(minus sign1)). Mean tirilazad clearance in middle-aged women was 30.7% higher than in middle-aged men. Mean clearance in postmenopausal women (26.1 plus minus 4.21 L h(minus sign1)) was not significantly different than that in middle-aged men, but clearance corrected for body weight was significantly different between the men and postmenopausal women. Clearance in premenopausal middle-aged women (32.2 plus minus 7.60 L h(minus sign1)) was not significantly different from that in young women and was 44% greater than that in middle-aged men. Mean AUC(0minus signinfty infinity) and C(max) values for U-89678 were significantly higher in men than in all of the female groups. Among the women, values for U-89678 AUC(0minus signinfty infinity) were lowest in young women (467 plus minus 345 ng h ml(minus sign1), 8.8% of male value) and highest in postmenopausal women (1565 plus minus 1382 ng h ml(minus sign1), 29.4% of male value). The absolute values for U-89678 AUC(0minus signinfty infinity) must be interpreted with caution, as limited assay sensitivity and low plasma concentrations in the latter portion of the concentration-time profile in women precluded accurate determination of the terminal half-life and AUC(0minus signinfty infinity). Regardless, these results show that women, particularly premenopausal women, have lower concentrations of U-89678, an active metabolite of tirilazad, than are achieved in men. The gender differences in tirilazad and U-89678 pharmacokinetics are of sufficient magnitude that they may impact the clinical response of male and female patients to tirilazad treatment.     

Pharmacokinetics of Cefamandole in Infants and Children

In infants less than 3 months of age, the serum concentration of cefamandole during therapy was higher and more prolonged than that in children older than 1 year. A dosage of 37 mg/kg administered intravenously at 6-h intervals provided a serum concentration in excess of the minimum inhibitory concentrations of common bacterial pathogens for 4 h, and in young infants for 5 h, after dosing.     

Pharmacokinetics,Tolerability, and Bioequivalence of Two Formulations of Rotigotine in Healthy Chinese Subjects

Purpose

The pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature–stable (PR2.2.1) formulations of rotigotine in healthy Chinese men.

Treatment of Experimental Staphylococcus aureus Abscesses: Comparison of Cefazolin, Cephalothin, Cefoxitin, and Cefamandole

Cefazolin (CZ), cephalothin (CF), cefoxitin (CX), and cefamandole (CM) were evaluated in therapy of Staphylococcus aureus infection produced in perforated table tennis balls placed intraperitoneally in rabbits. Four weeks after placement of two balls in each rabbit, a beta-lactamase producing strain of S. aureus was injected into one of the balls. Twenty-four hours later therapy was initiated with 40 mg of CZ or 80 mg of CF, CX, or CM per kg intramuscularly every 6 h. After 24 h of treatment, the mean log(10) colony-forming units per ml were 7.1 for CZ, 6.7 for CF, 6.5 for CX, and 7.2 for CM. After 72 h the mean log(10) colony-forming units per ml were 5.0 for CZ, 4.1 for CF, 3.6 for CX, and 5.6 for CM. After 8 days, the titers were 1.6/ml for CZ, 1.0 for CF, 1.9 for CX, and 3.6 for CM. CZ serum levels were about double CF and CX levels and about two-thirds of CM levels. In sterile ball fluid CZ and CM levels were more than double CF or CX concentrations. Concentrations of all four antibiotics were lower in infected balls.     

Comparison of the In Vitro Activities of HR756 with Cephalothin, Cefoxitin, and Cefamandole

The in vitro activity of HR756, a new semisynthetic cephalosporin, was compared with the activities of cephalothin, cefoxitin, and cefamandole against 1,535 isolates of gram-positive and gram-negative bacteria. HR756 was less active than cephalothin and cefamandole and twofold more active than cefoxitin against Staphylococcus. All four of the antibiotics were inactive against the enterococcus group of Streptococcus; however, HR756 was the most active antibiotic against the other isolates of Streptococcus. HR756 was also more active against isolates of Enterobacteriaceae, including 84 to 95% of the isolates resistant to one or more of the other three antibiotics. HR756, at a concentration of 12.5 μg/ml, inhibited 86, 75, and 100% of the isolates of Pseudomonas aeruginosa, other Pseudomonas species, and Acinetobacter, respectively. The minimal inhibitory concentrations and minimal bactericidal concentrations of HR756 were within one twofold dilution for 11 of 21 gram-positive cocci and 119 of 125 gram-negative bacilli tested.     

Comparison of Cephalothin and Cefamandole Prophylaxis During Insertion of Prosthetic Heart Valves

Cefamandole nafate (CM) and cephalothin sodium (CP) were administered as prophylaxis in a randomized, prospective study to 30 consecutive patients undergoing prosthetic cardiac valve insertion. A single dose of 20 mg/kg was given intramuscularly during anesthesia induction, and serial plasma antibiotic concentrations, atrial muscle and cardiac valve tissue antibiotic levels, plasma bactericidal activity against pathogenic staphylococci, and infectious complications were determined and compared for the two drugs. Both antibiotics produced high plasma levels (>20 mug/ml 30 min after injection) which fell less than 25% during the period of cardiopulmonary bypass. However, CM levels were significantly higher at most time periods (P<0.05) than CP levels. CP levels were undetectable in atrial muscle from 14 of 15 patients and in valves from 10 of 15 patients. In contrast, CM bioactivity was found in all tissues. Differences in tissue antibiotic concentration could not be accounted for by differences in plasma concentrations or by CP tissue binding and were assumed to be caused by differences in penetration. Plasma bactericidal activity against staphylococci was equal for the two drugs (median titer, 1:16). No infections were seen in either group. CM appeared to be an effective and perhaps preferable prophylactic antibiotic for use during cardiac surgery.