William M. M. Kirby

Serum Protein Binding of the Aminoglycoside Antibiotics

The binding of four aminoglycoside antibiotics by human serum was investigated under controlled conditions of physiological pH and temperature, by means of an ultrafiltration technique. No serum binding was demonstrable for gentamicin, tobramycin, or kanamycin, whereas streptomycin was 35% bound. Previous conflicting studies are discussed, and some of the pharmacological implications are considered.

Comparative pharmacokinetics of tobramycin and gentamicin

Blood and urine concentrations of a new aminoglycoside, tobramycin, were compared with those of gentamicin after intravenous and intramuscular administration in healthy adult volunteers. Serum concentrations for the two antibiotics were the same after an intravenous infusion of 100 mg for the first haur (about 4.75 p.g per milliliter), during the steady state attained by infusing 30 mg per hour for the next 2 haurs (about 3.85 p.g per milliliter), and during the elimination phase after the antibiotics were stopped. After a single intramuscular injection of 100 mg, the blood level curves were equal and the peak concentrations at 20 to 45 minutes were the same as those obtained after intravenous infusion of the same dose for 1 hour. Between 80% and 90% of each of the two antibiotics was recovered in the urine within 24 hours. Plasma clearance was not significantly higher than renal clearance, and glomerular filtration seemed to be the main pathway of elimination. The two aminoglycosides had an apparent volume of distribution of about 30% total body weight. Each had a half‐life of 2 hours.

Comparative Clinical Pharmacology of Amoxicillin and Ampicillin Administered Orally

Ampicillin and amoxicillin (α-amino-p-hydroxybenzyl penicillin) were administered orally in 500-mg doses to eight fasting volunteers in a comparative study in which pharmacokinetic techniques were used. The absorption of amoxicillin was significantly better, as demonstrated by a higher mean peak serum concentration of 7.6 μg/ml as compared to 3.2 μg/ml for ampicillin, an average “area under the curve” that was approximately double that of ampicillin, and an 8-hr urinary recovery for amoxicillin of 60% as compared to 34% for ampicillin. Serum half-lives were the same for the two antibiotics, with values of 60.3 (±3.3) min for ampicillin and 61.3 (±5.6) min for amoxicillin. The latter drug gave measurable concentrations in the blood at 8 hr in all of eight volunteers, as compared to only three of eight with ampicillin.

Pharmacokinetics of Metronidazole as Determined by Bioassay

The pharmacokinetics of metronidazole, a drug effective in vitro against most anaerobic bacteria and promising in treating anaerobic infections, are described. Serum and urine levels after single and multiple doses in 10 adult male volunteers were measured by an agar well diffusion bioassay using clostridial species as the test organisms under anaerobic conditions. Peak serum levels averaged 11.5 μg/ml and 6.2 μg/ml after single 500-mg and 250-mg doses, respectively. Renal clearance was only 10.2 ml/min per 1.73 m2, and less than 20% of the administered dose was recovered in the urine as active drug in 24 h. The average serum half-life was 8.7 h, and there was no protein binding as determined by an ultrafiltration method. With multiple doses of metronidazole (500 mg four times a day and 250 mg three times a day), blood levels increased progressively for the first few doses and then leveled off, with no significant accumulation occurring between 3 and 7 days. On 250 mg three times a day, serum levels just before the 8 a.m. dose (12 h after the preceding dose) on the third day averaged 3.9 μg/ml, and before the 8 p.m. dose, 5.7 μg/ml. For the higher, 500-mg dose (four times a day) regimen, the corresponding minimum serum levels were 13.1 μg/ml at 8 a.m. and 21.3 μg/ml at 8 p.m. Peak levels would have been about 10 μg/ml higher, and since the minimum inhibitory concentrations of most anaerobes including Bacteroides fragilis are less than 6 μg/ml, these concentrations should be highly effective therapeutically, even for severe infections.

Comparative pharmacokinetics of amikacin and kanamycin.

Pharmacokinetic parameters of amikacin and kanamycin were compared in a crossover study using healthy adult male volunteers. Following an intravenous infusion of 3.33 mg per kilogram for 1 hour, an infusion of 1.00 mg per kilogram per hour over the next 3 hours produced a steady state with serum levels of approximately 12 mcg per milliliter. The apparent volumes of distribution were about 28% of total body weight, a relatively large value consistent with the observation that neither antibiotic is protein‐bound. Amikacin and kanamycin had serum half‐lives of about 2 hours, and renal clearance of the antibiotics (84 ml per minute) was less than the creatinine clearance (120 per milliliter per minute), indicating tubular reabsorption. Although 94% of the total dose was eventually recovered in the urine, clearance of the antibiotics from the serum was greater than renal clearance (100 versus 84 ml per minute), implying a small component of unidentified distribution or elimination. After single intramuscular injections of 7.5 mg per kilogram (about 0.6 gm), peak blood levels of about 18 mcg per milliliter were found, and the serum half‐life of each antibiotic was again about 2 hours. Thus the pharmacokinetic parameters of amikacin and kanamycin were Virtually identical.

Pharmacokinetics of Fosfomycin

Fosfomycin, an antibiotic discovered in Spain, has a unique chemical structure and pharmacologic features that are promising for clinical therapy. It is only partially absorbed orally, with relatively low blood levels. Intramuscularly, however, absorption is complete with peak blood levels 3-5 times as high as orally, and rapid intravenous injections give serum concentrations almost twice as high as intramuscularly. Some accumulation occurs with all three routes, and concentrations in excess of 1,000 mug/ml are consistently obtained in the urine with parenteral doses every 6 h. The serum half-life is 1.5-2 h, urinary excretion is by glomerular filtration, the antibiotic is not bound to serum proteins, and the volume of distribution is large. Diffusion into tissues and body fluids is good. Thus, the pharmacologic characteristics of fosfomycin along with its low toxicity make it comparable in these respects to other well-established antibiotics.

Relative Inactivation by Staphylococcus aureus of Eight Cephalosporin Antibiotics

These studies extend the recent observation that cefazolin is inactivated to a greater extent than cephaloridine by some strains of penicillinase-producing Staphylococcus aureus, whereas cephalothin undergoes little if any inactivation. In Mueller-Hinton broth (inoculum, 3 × 106) 100 recently isolated strains had minimal inhibitory concentrations (MICs) ≤ 2 μg/ml for cephalothin and cephaloridine, whereas in Trypticase soy broth (TSB) 50% had MICs > 2 μg/ml and 10% (designated “resistant” strains) were >8 μg/ml for cephaloridine but remained ≤2 μg/ml for cephalothin. A large inoculum (3 × 107) of strains with high MICs in TSB almost completely inactivated 50 μg of cefazolin per ml in 6 h, with progressively less inactivation, in the following order, of cephaloridine, cephalexin, cephradine, cephapirin, and cefamandole; cefoxitin and cephalothin underwent little if any inactivation. The greater inactivation in TSB than in Mueller-Hinton broth appeared to be due to a greater production of β-lactamases by each colony-forming unit, since the inoculum size in the two broths was not significantly different. In contrast, “susceptible” strains (MICs ≤ 2 μg/ml in both broths) inactivated cephaloridine more than cefazolin, and equal amounts of powdered bacterial extracts confirmed the fact that qualitatively different β-lactamases were produced by the susceptible and resistant strains. Disk diffusion tests were unreliable in separating the two groups of staphylococci. The clinical significance of inactivation by strains with high MICs is not known but, unless susceptibility can be clearly established, cephalothin appears preferable for severe staphylococcal infections, since it undergoes little if any inactivation by any strains of staphylococci.

Unique Bactericidal Action of Metronidazole Against Bacteroides fragilis and Clostridium perfringens

The comparative bactericidal activity of penicillin G, carbenicillin, clindamycin, and metronidazole against eight susceptible strains of Bacteroides fragilis and four strains of Clostridium perfringens was determined by performing colony counts anaerobically of cultures incubated in brucella broth. With the B. fragilis strains, there was a lag phase of growth of approximately 8 h, during which time metronidazole did not reduce the colony counts. However, within 4 h of the onset of exponential growth, metronidazole caused an abrupt decrease in counts to less than 100 colonies per ml in all strains tested. Moreover, in two strains in which the bactericidal rate was followed hourly, a 3- to 6-log decrease occurred over 1 h or less. In contrast, penicillin G and carbenicillin caused a gradual decline in colony counts from the start of approximately 1 log for each 8-h interval and were bactericidal for all strains tested. Clindamycin demonstrated the slowest bactericidal activity and for 25% of the strains was only bacteriostatic. With the C. perfringens strains, after a lag phase of 4 h, an abrupt decrease in colony counts also occurred with metronidazole, whereas penicillin and clindamycin again demonstrated more gradual killing effects. These studies showed a unique, time-related bactericidal action of metronidazole as compared with the other three antimicrobial agents.

Clinical Pharmacology of Cefamandole as Compared with Cephalothin

We compared the pharmacology of cefamandole and cephalothin in six healthy adult male volunteers. After a 1-g, 20-min intravenous (i.v.) infusion, the average peak blood level of cefamandole was 87.6 versus 64.1 μg/ml for cephalothin. An i.v. infusion of 500 mg/h for 2 h (after a loading dose of 750 mg) gave an average steady-state blood level of 28.5 μg/ml for cefamandole and 18.2 μg/ml for cephalothin. Mean peak serum levels after 1 g intramuscularly were similar for the two antibiotics (about 21 μg/ml), but with cefamandole they persisted longer, and the area under the blood level curve was about 25% greater. The average t½ as determined from both i.v. studies was 34 min for cefamandole versus 30 min for cephalothin. The mean serum clearance for cephalothin, due to its partial conversion to a metabolite, was much greater than for cefamandole (425 versus 272 ml/min per 1.73 m2), but the renal clearances were similar for the two antibiotics (268 versus 257 ml/min per 1.73 m2). Other values for cefamandole and cephalothin were: 24-h urinary excretion, 80 and 66%; serum protein binding, 74 and 70%; and apparent volume of distribution, 12.8 and 18.5 liters/1.73 m2, respectively. Thus, the pharmacology of the two antibiotics was similar. Blood levels were somewhat higher with cefamandole i.v., but the results suggest that dosage regimens should be the same for the two antibiotics.

Staphylococcal Septicemia treated with Methicillin. Report of Twenty-Two Cases.

SINCE the introduction of penicillin into clinical medicine nearly two decades ago, infections due to antibiotic-resistant staphylococci have become an increasingly serious problem. Penicillinase p...