Kinetics of netilmicin and gentamicin.

The kinetic parameters of netilmicin were studied in normal human subjects. In the intravenous study a steady-state was obtained in 4 subjects by the constant infusion of 2 mg/kg of netilmicin during the first hour followed by 0.5 mg/kg/hr for each of three successive hours. Creatinine clearance was greater than the simultaneous serum and renal clearance of netilmicin. In the intramuscular study 6 subjects received a single injection of 1 mg/kg of netilmicin followed by the same dose of gentamicin 1 wk later. A mean peak serum levels of 3.9 microgram/ml was found for both antibiotics, but the mean serum half-life of netilmicin was shorter than that of gentamicin. Doubling the intramuscular dose of netilmicin approximately doubled the peak serum level. In both studies 75% to 90% of the netilmicin was recovered in the urine within the first 24 hr. Netilmicin appears to be primarily excreted by glomerular filtration. The apparent volume of distribution was similar to that reported for other related aminoglycosides. Netilmicin and gentamicin have similar kinetic parameters. There were wide individual differences among normal subjects with both drugs.

Cefotaxime kinetics after intravenous and intramuscular injection of single and multiple doses.

The kinetics of cefotaxime, a cephalosporin with an unusually broad antibacterial spectrum, were examined in humans after intravenous bolus injection, intravenous infusion every 6 hr for 14 days, and intramuscular injection every 8 hr for 10 days. Mean peak serum level after bolus injection of 500 mg was 37.9 microgram/ml; after 1 gm, 102.4 microgram/ml; and after 2 gm, 214.1 microgram/ml. The half-life (t1/2) was 1 hr for the 3 doses. Total serum clearance was the same for all doses. Overall excretion was 50% to 60%; part of the drug was excreted as the desacetyl derivative. After multiple intravenous infusion the elimination rate constants and t1/2 were the same on days 1 and 15. Assayable levels were present on all days 5 min before injection of a dose. Multiple intramuscular injections of 500 mg produced serum levels of 9.2 to 11.9 microgram/ml. The t1/2 was 0.93 hr. Mean serum levels at 8 hr ranged from 0.08 to 0.55 microgram/ml. Serum levels produced by intravenous infusion or intramuscular injection were inhibitory for most (90%) aerobic gram-positive and gram-negative organisms susceptible to cefotaxime.

Pharmacokinetics of ceftriaxone after intravenous infusion and intramuscular injection.

The pharmacokinetics of ceftriaxone were evaluated in eight adults after doses of 1 g administered by intravenous infusion and 1 and 0.5 g administered by intramuscular injection. Mean peak plasma concentrations were 168 micrograms/ml for 1 g given intravenously, 81 micrograms/ml for 1 g given intramuscularly, and 46 micrograms/ml for 0.5 g intramuscularly. Plasma concentrations were similar by both high pressure liquid chromatographic and microbiologic methods. The plasma half-lives were 7.6 and 8.3 hours, respectively, for the intravenous infusion and intramuscular injection. Plasma concentrations were equal for the 1 g intravenous and intramuscular routes by 2.5 hours. Plasma concentrations exceeded the minimal inhibitory concentrations (MICs) of most aerobic gram-positive and gram-negative organisms with the exception of Pseudomonas aeruginosa and Acinetobacter species for 24 hours. Urinary concentrations exceeded 100 micrograms/ml for 24 hours for the 1-g doses and for 12 hours for the 0.5-g dose. Urinary recovery of ceftriaxone within 24 hours was 40 percent for intravenous infusion and 33 and 34 percent for the intramuscular injection. A single 1-g dose daily will exceed the MICs of most staphylococcal and streptococcal species and Enterobacteriaceae for 12 to 24 hours.

Clinical evaluation of netilmicin therapy in serious infections.

Netilmicin, a new semisynthetic aminoglycoside, was evaluated in the therapy of 33 episodes of infection in 30 patients. Eighteen patients had documented bacteremia. Infection sites included pulmonary, urinary tract and soft tissue areas. A complete bacteriologic and clinical cure rate of 85 per cent was achieved. No treatment failures occurred in the bacteremic group. Although netilmicin is less effective than gentamicin in vitro against Pseudomonas, it was clinically and bacteriologically effective. Netilmicin bacteriologic cures occurred in patients whose organisms were inhibited by 6.2 microgram/ml or less of netilmicin. Despite a uniform dosing protocol, a wide range of netilmicin serum levels was obtained. Adverse effects were limited to one case of transient nephrotoxicity and one Candida urinary suprainfection. Netilmicin appears to be an effective, safe agent for the therapy of serious infections.

In vitro activity of l-ofloxacin against norfloxacin-resistant coagulase-negative staphylococci.

The in vitro activity of l-ofloxacin was determined against coagulase-negative staphylococci that were induced to norfloxacin resistance. l-Ofloxacin was the most active agent tested with an MIC90 of 4 micrograms/ml compared with greater than 128, 32, and 128 micrograms/ml for norfloxacin, ciprofloxacin, and enoxacin, respectively. Rifampin-resistant, coagulase-negative staphylococci were not cross-resistant to the quinolones tested. Among the rifampin-resistant organisms tested, l-ofloxacin was also the most active agent with an MIC90 of 0.25 micrograms/ml.

The postantibiotic suppressive effect of L-ofloxacin, an optically active isomer of ofloxacin.

The postantibiotic suppressive effect (PAE) of L-ofloxacin was studied and compared with those of ciprofloxacin and norfloxacin. The PAE of L-ofloxacin was observed against all Gram-positive organisms tested: Staphylococcus aureus, S. epidermidis, and Enterococcus faecalis. At the achievable serum concentrations L-ofloxacin showed a longer PAE than ciprofloxacin and norfloxacin. Exposure of organisms to 4 micrograms/ml of L-ofloxacin for 2 hr produced a 3.1 and 4.2 hr PAE for methicillin-sensitive and methicillin-resistant staphylococci, respectively. Against E. faecalis and S. epidermidis, the PAEs of L-ofloxacin were 1.9 and 1.6 hr, respectively.

Disposition of a novel recombinant tissue plasminogen activator, delta 2-89 TPA, in mice.

The pharmacokinetic characteristics of delta 2-89 tPA, characterized by the deletion of the first 89 amino acids at the NH2-terminus of tPA, were evaluated and compared to those of recombinant tPA (rtPA). When they were administered intravenously to mice, a biexponential disposition curve was observed for both tPAs. The plasma half-lives of lambda 1 and lambda 2 phases of delta 2-89 tPA were 15 minutes and 180 minutes which are significantly higher than those of rtPA. A zymogram of mouse plasma taken at various time intervals showed that delta 2-89 tPA retained fibrinolytic activity up to 30 minutes, whereas rtPA could be detected only up to 5 minutes after injection. Autoradiography revealed that most of 125I-delta 2-89 tPA was associated with plasma protein complex.

Clearance of a novel recombinant tissue plasminogen activator in rabbits.

The pharmacokinetic properties of hPA(B), characterized by the insertion of a urokinase kringle coding region before the double kringle of tPA plus the complete tPA coding region, were investigated and compared to those of melanoma tPA (mtPA). Mean peak plasma concentrations at the end of infusion were 4.7 micrograms/ml for hPA(B) and 4.6 micrograms/ml for mtPA. The pharmacokinetics of both hPA(B) and mtPA showed a biexponential disappearance from plasma which is consistent with a two-compartment model of t 1/2 (lambda 1) = 2 minutes, t 1/2 (lambda 2) = 58 minutes for hPA(B), and t 1/2 (lambda 1) = 2.2 minutes, t 1/2 (lambda 2) = 61 minutes for mtPA. However, this very fast decaying lambda 1 phase of mtPA lasted five times longer than that of hPA(B) which resulted in very low concentrations of mtPA. Thus, hPA(B) exhibited larger AUC, slower clearance rate, and smaller volume of distribution (P less than 0.01) than those of mtPA. The fibrinolytic activity of hPA(B) in rabbit plasma as determined by zymography lasted up to 120 minutes after the end of infusion as compared to that of 2 minutes for mtPA. This indicates that mtPA, despite its t 1/2 (lambda 2) being similar to that of hPA(B), is no longer at physiologically meaningful concentrations at the start of the lambda 2 phase.

The comparative beta-lactamase resistance and inhibitory activity of 1-oxa cephalosporin, cefoxitin and cefotaxime.

The beta-lactamase stability and inhibitory activity of 1-oxa cephalosporin, (6R,7R)-7-[[carboxy(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, was investigated and compared to that of cefoxitin and cefotaxime. There was no detectable beta-lactamase hydrolysis of 1-oxa cephalosporin, cefotaxime and cefoxitin when incubated with beta-lactamases of plasmid or chromosomal origin which were primarily cephalosporinases or enzymes which hydrolyzed both penicillins and cephalosporins. The beta-lactamase inhibitory activity of 1-oxa cephalosporin was comparable to that of cefoxitin and cefotaxime. At equal molar concentration of substrate and inhibitor, cefoxitin, cefotaxime and 1-oxa cephalosporin effectively inhibited cephalosporinase hydrolysis of cephaloridine. Cefoxitin and cefotaxime were more effective inhibitors than the 1-oxa cephalosporin against a Providencia enzyme, whereas cefotaxime and 1-oxa cephalosporin were more effective inhibitors of a Citrobacter cephalosporinase.

The comparative synergistic activity of amikacin, gentamicin, netilmicin and azlocillin, mezlocillin, carbenicillin and ticarcillin against Serratia marcescens.

The synergistic activities of netilmicin, gentamicin and amikacin combined with carbenicillin, ticarcillin, azlocillin and mezlocillin were investigated against 32 Serratia marcescens isolates. Synergy could be demonstrated by killing curve technique, isobologram plots as susceptibility data with any of the aminoglycosides and penicillins combinations. No antagonism was shown with any of the combinations. The majority of the isolates were resistant to the aminoglycosides and penicillins. Combination of either ureido-penicillin or carbenicillin with gentamicin or netilmicin did not reduce the MIC values to levels achievable in serum but did reduce the MIC levels of both agents to those achievable in urine. The combination of ureido-penicillins or carbenicillin and ticarcillin with amikacin reduced the inhibitory levels of all isolates to levels achievable in both serum and urine.

1-N HAPA gentamicin B, a new aminoglycoside active against gentamicin resistant isolates--activity compared to other aminoglycosides.

1-N HAPA gentamicin B is a new aminoglycoside active against most Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. Among 504 clinical isolates at a concentration of 12.5 microgram/ml all Staph. aureus, Escherichia coli, Klebsiella, Enterobacter, Proteus rettgeri, Providencia and 78% of Pseudomonas, 86% of Proteus morganii were inhibited. Like other aminoglycosides, the activity was greatest at an alkaline ph and reduced by high cations concentrations. 1-N HAPA gentamicin B was equal in activity to amikacin against both gentamicin-sensitive and resistant isolates. It inhibited bacteria containing many of the aminoglycoside inactivating enzymes. When combined with carbenicillin it inhibited in a synergistic manner many Gram-negative bacteria, particularly Pseudomonas and Serratia.

Purification and properties of a beta-lactamase from Proteus penneri.

A cephalosporin-hydrolyzing enzyme from strains of Proteus penneri resistant to beta-lactam antibiotics was purified and characterized. The enzyme gave a single protein band on SDS-polyacrylamide gel electrophoresis with a molecular weight of 30,000. This cephalosporinase has an isoelectric point of 6.8, a pH optimum of 6.5 and a temperature optimum of 45 degrees C. The enzyme hydrolyzed cephaloridine, cephalothin, cefuroxime, and cefotaxime more rapidly than penicillins. The relative rate, with cephaloridine as 100, were: cephalothin, 50; cefuroxime, 93; cefotaxime, 48; ceftriaxone, 23; cefoperazone, 11; benzylpenicillin, 3; ampicillin, 9; and carbenicillin, less than 1. Cephamycins had low affinities for the enzyme. However, clavulanic acid and sulbactam, with high affinities for the enzyme, were inhibitors of this enzyme.

Experimental efficacy of apalcillin and cefpiramide compared with that of six other antipseudomonal agents in Pseudomonas aeruginosa burn infections.

The therapeutic efficacy of cefpiramide and apalcillin was evaluated and compared with that of six other antipseudomonal beta-lactam antibiotics in an experimental mouse burn infection due to Pseudomonas aeruginosa. Both cefpiramide and apalcillin were as potent as cefsulodin and more potent than carbenicillin, cefotaxime, cefoperazone, piperacillin and gentamicin in protecting the infected mice from fatal bacteraemia and in eradicating Ps. aeruginosa from the infected site.

In vitro and in vivo antidermatophytic activity of saperconazole, a new fluorinated triazole.

The in vitro activity of saperconazole against selected isolates of dermatophytes and its in vivo efficacy in a guinea pig dermatophytic infection model using Trichophyton mentagrophytes were evaluated. Susceptibility testing was determined with an agar dilution method in three media: yeast nitrogen base agar (YNBA), brain heart infusion agar (BHIA) and Sabouraud dextrose agar (SDA). An inoculum of 1 x 10(5) CFU of T. mentagrophytes spores was placed onto the surface of these agars. Incubation was at 32 degrees C for 72 h. The MIC of saperconazole against all isolates was less than 1 microgram/ml, whereas the MIC ranged from 0.1 to > 128 micrograms/ml for fluconazole. The MIC range of saperconazole against Trichophyton species was < or = 0.002 to 0.25 micrograms/ml; against Microsporum species it was < 0.001 to 0.1 microgram/ml; and against Epidemophyton species was < or = 0.002 to 0.25 micrograms/ml. These data showed that saperconazole was the most active compound tested against these selected dermatophytes. The activities of saperconazole against T. mentagrophytes, T. rubrum and M. canis were not affected by the medium. The MICs against these organisms were < or = 0.008 micrograms/ml in SDA, YNBA or BHIA. There were 2- to 4-fold decreases in activity for fluconazole at the same conditions. In vivo, topical treatment with saperconazole at concentrations of 0.125% and 0.25% resulted in 50% and 75% microbiological cure rates, respectively, in the guinea pig topically infected with T. mentagrophytes.

Therapeutic efficacy and pharmacokinetic properties of ciprofloxacin in intra-abdominal abscesses caused by Bacteroides fragilis and Escherichia coli.

Experimental intra-abdominal abscesses were produced in mice by intraperitoneal injections of Bacteroides fragilis and Escherichia coli. The therapeutic efficacy of ciprofloxacin was investigated in this mixed intra-abdominal abscess model and was compared with that of rifampicin. Treatment with ciprofloxacin at 0.2 to 20 mg/kg or rifampicin at 20 mg/kg prevented all mice from death, as compared to the 60% mortality rate observed in the vehicle-treated controls. Rifampicin concentrations at 10 and 20 mg/kg were effective in preventing abscess formation and eradicated bacterial abscess. Ciprofloxacin at all the levels tested neither reduced the incidence of abscess nor eradicated Bact. fragilis from abscesses. However, ciprofloxacin at levels of 20, 10, 5, and 1 mg/kg reduced significantly the number of E. coli cells in the abscess. The peak serum level of ciprofloxacin at the oral dose of 20 mg/kg was 0.43 mg/l which was well above the MIC values for E. coli but not for Bact. fragilis.

Interaction of clavulanic acid, sulbactam and cephamycin antibiotics with beta-lactamases.

The inhibitory effects of clavulanic acid, sulbactam and cephamycin antibiotics on chromosomally-mediated or plasmid-mediated beta-lactamases were investigated. The inhibition constants were determined by a non-linear regression analysis. Clavulanic acid and sulbactam had high affinities for the purified plasmid-mediated beta-lactamases such as SHV-1, TEM-1 and PSE-4, and were potent inhibitors as shown by their low Ki values. Except for Bacteroides beta-lactamase, which is sensitive to inhibition by cephamycin antibiotics, clavulanic acid and sulbactam were found not to be as effective against chromosomally-mediated beta-lactamases. The cephamycin antibiotics were better inhibitors of chromosomally-mediated beta-lactamases than those that are plasmid mediated. Except for P99 beta-lactamase, against which sulbactam and clavulanic acid were inactive, the cephamycin antibiotics were less effective inhibitors than sulbactam and clavulanic acid.

Experimental efficacy and pharmacokinetic properties of cefpiramide, a new cephalosporin.

The in vivo therapeutic efficacy of cefpiramide was investigated and compared with that of cefoperazone. Cefpiramide was more potent than cefoperazone against infections produced by both beta-lactamase-producing and non-beta-lactamase-producing S. aureus. The protective activity of cefpiramide against experimental infections with selected members of Enterobacteriaceae was lower than that of cefoperazone. Against carbenicillin-resistant P. aeruginosa infections, cefpiramide was as active as gentamicin and aztreonam and three times more potent than cefoperazone, cefotaxime and piperacillin. The pharmacokinetic properties of cefpiramide in mice and rats were superior to those of cefotaxime and cefoperazone. The peak serum concentrations of cefpiramide, administered subcutaneously at a dose of 50 mg/kg, were 76 micrograms/ml in mice and 174 micrograms/ml in rats and the corresponding serum half-lives of cefpiramide were 87 min and 49 min in mice and rats respectively.

Comparative inhibition beta-lactamases by novel beta-lactam compounds.

The beta-lactamase-inhibiting activity of CP-45,899, 3,3-dimethyl-7-oxo-4-thia-1-azabicylo(3,2,0)heptane-2-carboxylic acid, 4,4-dioxide [2S-(2alpha,5alpha)], was investigated and compared with the beta-lactamase-inhibiting activity of clavulanic acid and dicloxacillin. CP-45,899 was an effective inhibitor of Staphylococcus aureus beta-lactamase and of those beta-lactamases of gram-negative bacteria which are primarily active against penicillins or equally active against penicillins and cephalosporins. The reaction of CP-45,899 with beta-lactamases was a concentration- and time-dependent event. CP-45,899 acted as a competitive inhibitor of plasmid-mediated S. aureus, Escherichia coli, and Shigella sonnei beta-lactamases and inducible Klebsiella beta-lactamase. CP-45,899 was a poor inhibitor of inducible or constitutive chromosomally mediated beta-lactamases of indole-positive Proteus, Citrobacter, and Enterobacter. CP-45,899 had lower kinetic constants for inhibition of hydrolysis than did clavulanic acid against many of the beta-lactamases which both inhibited.

Cefaclor: in vitro spectrum of activity and beta-lactamase stability.

The in vitro activity of cefaclor against 556 clinical isolates of gram-positive and gram-negative bacteria was compared with that of other cephalosporins. Cefaclor had activity similar to that of cephalexin against gram-positive bacteria. It showed greater activity against Haemophilus strains than did cephalexin and inhibited beta-lactamase-producing Haemophilus isolates. Cefaclor was more active than cephalexin or cephalothin against Escherichia coli, Salmonella, and Shigella isolates but did not act against Serratia, Acinetobacter, indole-positive Proteus, or Bacteroides isolates. Cefaclor was resistant to type III (TEM) beta-lactamases but was destroyed by type I beta-lactamases and, to a lesser degree, by type IV and type V beta-lactamases.