The role of schedule in antibiotic therapy of the neutropenic patient

Pharmacological studies of moxalactam were conducted with 37 cancer patients. Intramuscular administration of 500 mg of moxalactam to 10 patients produced a mean peak serum concentration of 12.4 ,ug/ml. The serum terminal-phase halflife was 3.9 h. Intravenous administration of 500 mg of moxalactam over 5 min to the same 10 patients produced a mean serum concentration of 42.0 ,ug/ml at 15 min, which decreased to 3.3 ,ug/ml at 6 h. A dose of 1 g of moxalactam was given in an identical manner to the same 10 patients. The mean serum concentration was 69.6 ,ug/ml at 15 min and 7.4 ,ug/ml at 6 h. The mean proportions of drug recovered in the urine by 12 h after administration were 59% after the intramuscular dose and 61 and 55% after the single intravenous doses. Multiple-dose intravenous studies were also conducted. The serum terminal-phase half-life varied from 2.0 to 3.2 h. Continuous infusion studies were perforned for up to 9 days by using a loading dose of 1 g over 0.5 h, followed by 2 g every 6 h. Serum concentrations were maintained at about 30.0 Ag/ml during the study period.Moxalactam is a semisynthetic fi-lactam antibiotic with a spectrum of activity which includes most gram-positive cocci, the Enterobacteriaceae, and Pseudomonas aeruginosa. Although several substituent groups in combination are thought to contribute to these properties, the replacement of sulfur with oxygen in the sixmember ring of the conventional cephem nucleus is believed to be especially important. When the activity of moxalactam was compared with the activities of cephalothin, cefamandole, cefoxitin, carbenicillin, mezlocillin, and piperacillin against gram-negative organisms (11), moxalactam demonstrated the greatest potency and broadest spectrum, inhibiting a majority of isolates of all organisms except P. aeruginosa at concentrations below 6.25 ,ug/ml. It was the most active antibiotic against the Enterobacteriaceae and was also active against P. aeruginosa, inhibiting 50% of these organisms at a concentration of 25.0 ug/ml. Others have reported very similar results (1,3,4,10,12). Preliminary data for animals and humans have indicated very little toxicity. Because ofthese properties, moxalactam is of potential clinical utility in cancer patients since these patients have significant mortality and morbidity from bacterial infections, especially infections caused by gram-negative bacilli (5). Accordingly, we conducted pharmacological studies of moxalactam in a group of patients with malignant diseases. MATERIALS AND METMODSWe conducted a total of 41 studies with 37 cancer patients who ranged in age from 19 to 71 years (median, 46 years). The body surface area of these patients varied from 1.4 to 2.4 m2 (median, 1.9 m2), and their weight varied from 40 to 111 kg (median, 70 kg). All patients but one had normal serum creatinine levels. The exception was a male with an initial serum creatinine level of 1.6 mg/dl, in whom the level decreased to 1.1 mg/dl by the second study day; thereafter, this patient continued to have normal values. T...

Section: Materials and Metmodsmentioning

confidence: 69%

Clinical pharmacology of moxalactam in patients with malignant disease

Estey¹,

Weaver²,

Ho³

et al. 1981

“…Some investigators have suggested that the most effective mode of treatment should provide tissue concentrations of antibiotic continuously in excess of the minimal concentration inhibiting the pathogen (13, 23). Continuously maintained bactericidal levels are particularly important to effect cure in cases of invasive infections such as bacterial endocarditis (35), meningitis (24), or infections in neutropenic or cancer patients (8,9,14,37), in whom host defenses may be impaired. Other investigators have demonstrated that these constant bactericidal levels of drug may not be necessary (7,28,29) and that frequent administration of antibiotics at short intervals is as effective as constant infusion, since it results in significant accumulation of drugs in interstitial fluid (17) and tissues (1, 4).…”

mentioning

confidence: 99%

“…Any mode of administration producing higher penetration into extravascular sites may be clinically advantageous, since most infections, including those caused by Haemophilus influenzae, occur outside the bloodstream. It is likewise difficult to define the influence of the concentration obtained in the extravascular compartment on the bactericidal activity of antibiotics since most investigators have only evaluated the pharmacology of antibiotics (2,11,33), or have studied the bacteriological outcome of therapy (9,14,23), without specifically analyzing tissue penetration of drugs and the kinetics of bacterial killing at the site of infection.…”

mentioning

confidence: 99%

Influence of four modes of administration on penetration of aztreonam, cefuroxime, and ampicillin into interstitial fluid and fibrin clots and on in vivo efficacy against Haemophilus influenzae

Lavoie¹,

Bergeron²

1985

The extravascular penetration and bactericidal activity of aztreonam, cefuroxime, and ampicillin against ,-lactamase-positive and -negative Haemophilus influenzae strains were compared in a rabbit model. All groups of animals received an identical total dose of 100 mg of either antibiotic per kg given by four different intravenous modes of administration including a single large injectiorl, four intermittent injections, a continuous infusion, and an injection followed by an infusion. Aztreonam had a higher degree of penetration in interstitial fluid and fibrin clots and was the most effective agent against 13-lactamase-positive and -negative H. influenzae. A single large injection of either drug resulted in sigitificantly higher peak levels and higher initial area under the curves of concentrations of drugs in serum, the interstitial fluid, and fibrin clots than those by other modes of administration. Continuous infusions of antibiotics resulted in poor in vivo bactericidal activity. Other modes of administration exhibited good antibacterial activity within the first 6 h of the study.Thereafter, a single large injection of aztreonam resulted in a much more rapid killing of H. influenzae than that by injection of the other drugs. Aztreonam and cefuroxime showed good in vivo stability to ,3-lactamase produced by H. influenzae while ampicillin was rapidly hydrolyzed in vivo.The influence of the mode of administration on the penetration and efficacy of antimicrobial agents is still a matter of controversy (2,4,20,33). Some investigators have suggested that the most effective mode of treatment should provide tissue concentrations of antibiotic continuously in excess of the minimal concentration inhibiting the pathogen (13, 23). Continuously maintained bactericidal levels are particularly important to effect cure in cases of invasive infections such as bacterial endocarditis (35), meningitis (24), or infections in neutropenic or cancer patients (8,9,14,37), in whom host defenses may be impaired. Other investigators have demonstrated that these constant bactericidal levels of drug may not be necessary (7,28,29) and that frequent administration of antibiotics at short intervals is as effective as constant infusion, since it results in significant accumulation of drugs in interstitial fluid (17) and tissues (1, 4). Any mode of administration producing higher penetration into extravascular sites may be clinically advantageous, since most infections, including those caused by Haemophilus influenzae, occur outside the bloodstream. It is likewise difficult to define the influence of the concentration obtained in the extravascular compartment on the bactericidal activity of antibiotics since most investigators have only evaluated the pharmacology of antibiotics (2, 11, 33), or have studied the bacteriological outcome of therapy (9, 14, 23), without specifically analyzing tissue penetration of drugs and the kinetics of bacterial killing at the site of infection.In an effort to clarify these issues, we compared simultaneously t...

“…In patients with impaired host defense mechanisms, maintenance of concentrations above the minimal inhibitory concentration may be important because of the propensity of gram-negative organisms to resume proliferation quickly once serum concentrations fall below this level (3). From our data, it appears that a schedule of ceftriaxone consisting of 2 g every 8 h by continuous i.v.…”

Section: Antimicrod Agents Chemothermentioning

confidence: 79%

Clinical Pharmacology of Ceftriaxone in Patients with Neoplastic Disease

Salvador

Smith

Weinfeld

et al. 1983

Pharmacological studies of ceftriaxone, a new semisynthetic cephalosporin, were conducted in 35 cancer patients. This antibiotic was administered in a variety of doses and schedules with no observed toxicity. Intramuscular administration of 500 mg of ceftriaxone to seven patients produced mean peak serum concentrations of 32.9 μg/ml 2.0 h after administration. The terminal serum half-life was 10.9 h. Intravenous infusion of 500 mg of ceftriaxone over 5 min to the same group of seven patients produced a mean peak concentration of the drug in serum of 83 μg/ml at the end of administration which decreased to 16.8 μg/ml at 8 h. A dose of 1 g of ceftriaxone given in identical fashion to the same group of seven patients produced mean peak concentrations in serum of 130 μg/ml at the end of administration and 17.3 μg/ml at 12 h. The mean percentages of drug recovered in urine 12 h after single intravenous doses of 500 mg and 1 g were 30 and 20%, respectively. A 1-g dose of ceftriaxone was administered every 8 h to 10 patients, and a 2-g dose was administered every 12 hours to 9 patients. Drug concentrations in serum were measured for each patient after drug administration on day 1, day 3 or 4, and day 7 or 8. The 1-g dose produced an observed mean peak concentration of 154 μg/ml and a mean terminal-phase half-life of 5.6 h on day 3 or 4. The 2-g dose produced a mean peak concentration in serum of 262 μg/ml and a terminal-phase serum half-life of 6.3 h on day 3 or 4. Continuous infusion studies were performed in nine neutropenic patients for up to 8 days by using a loading dose of 1 g over 30 min, followed by 2 g every 8 h. Mean concentrations in serum were maintained at about 135 μg/ml during the infusion period.