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Biomedical subjects

M A Sande

Publications and source records attributed to M A Sande.

250 records · Page 14Linked to original sources
PubMedDate not supplied

Use of animal models in evaluation of the quinolones.

Discriminative animal models of infection are important in helping to define the role of new antibacterial drugs in the treatment of human diseases. Several animal models have been used to compare the efficacies of quinolones with those of standard therapies against selected bacterial pathogens. In animal models of endocarditis, pefloxacin, enoxacin, and ciprofloxacin have been shown to be equivalent to standard therapies against methicillin-sensitive Staphylococcus aureus and as effective as vancomycin against methicillin-resistant strains. Difloxacillin has been shown to be equivalent to vancomycin in a model of osteomyelitis due to S. aureus. Ciprofloxacin is as effective as the combination of ceftazidime and tobramycin in a model of pseudomonal meningitis, although the levels of ciprofloxacin (6 mg/L) in serum required to produce a bactericidal effect in the cerebrospinal fluid are higher than those usually obtained in humans. Ciprofloxacin and other quinolones are also effective therapy for pseudomonal infections in neutropenic animals with pneumonia, peritonitis, osteomyelitis, and endocarditis. Data obtained from these animal studies suggest that the quinolones may have an important role in the treatment of endocarditis, meningitis, osteomyelitis, and other serious infections in humans caused by S. aureus and Pseudomonas aeruginosa.

Animals↗
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Intermittent or continuous therapy of experimental meningitis due to Streptococcus pneumoniae in rabbits: preliminary observations on the postantibiotic effect in vivo.

The relative effectiveness of bolus vs. constant intravenous administration of equivalent doses of penicillin G in killing bacteria in vivo was studied in a rabbit model of meningitis due to Streptococcus pneumoniae. Samples of cerebrospinal fluid (CSF) and serum were obtained from 30 rabbits at intervals of less than or equal to 8 hr after treatment for determination of antibiotic concentrations and titers of viable bacteria in the CSF. When penicillin G was given by continuous infusion (10(5) units/hr after an initial 10(5)-unit loading dose), concentrations of drug in serum and CSF reached a steady state in 1 hr. With intermittent bolus administration of 4 x 10(5) units every 4 hr, higher peak and lower trough concentrations were achieved, and these concentrations paralleled those in the CSF. Although an initial acceleration in bactericidal rate was observed with the bolus infusion between the first and second hour of therapy, after the second hour the rate of bacterial killing was identical for the two methods of administration. The duration of therapy required for sterilization of the CSF was dependent only on the bacterial count before treatment and not on the mode of drug administration. The effect of single bolus intravenous administration of ampicillin was examined in experimental pneumococcal meningitis. Ampicillin was given at various dosages (3.25-62.5 mg/kg), and frequent samples of CSF were obtained for determination of concentrations of pneumococci and ampicillin. A long postantibiotic effect was observed in the CSF of all animals, and this effect consistently was longer than that observed in vitro.

Adult↗
PubMedDate not supplied

Antibiotic combinations in experimental infections in animals.

The study of experimental infections has afforded the opportunity to examine the response to antimicrobial therapy in the complex milieu of living animals. This review summarizes the information gained from studies of combination antibiotic therapy for experimental endocarditis, meningitis, and other infections in which host defenses are unable to participate in effecting cure. The studies cited suggest that antibiotic combinations that yield rapid microbial killing are more effective in the treatment of these selected infections than are those combinations that do not give enhanced killing. In addition, the relevance of various methods of demonstrating antimicrobial synergy is examined, and in light of the results of treatment of experimental infections, suggestions for the applications of these methods to the evaluation of the efficacy of antibiotic combinations on infections in humans are given.

Animals↗
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Moxalactam therapy vs. standard antimicrobial therapy for selected serious infections.

Moxalactam was studied in a prospective randomized clinical trial in 97 hospitalized patients suspected of having infection caused by moxalactam-susceptible bacteria. Seventy-eight of the 97 patients had clinical and/or bacteriologic evidence of infection, including pneumonia, cellulitis, urinary tract infection, bacteremia, and fever in neutropenic patients. Patients in the control group received antibiotics deemed appropriate by the attending physicians, whereas the moxalactam-treated group received only the study drug. Successful treatment was defined as the resolution of illness sufficient to allow discontinuation of parenteral antibiotic therapy. No significant difference was seen in efficacy with 33 (86.8%) of 38 patients in the moxalactam-treated group and 32 (80%) of 40 in the control group treated successfully (P greater than 0.20). The mean number of febrile days was significantly less in the moxalactam-treated group than in the control group (P less than 0.05). Renal toxicity occurred more frequently in the control group (P = 0.036). Fungal superinfection developed in two patients in the control group and in one in the moxalactam-treated group. An enterococcal superinfection of the bloodstream developed in one patient treated with moxalactam. Thus moxalactam appears to be comparable in efficacy to combinations of antibiotics in the treatment of selected seriously ill patients and may have less renal toxicity.

Anti-Bacterial Agents↗
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Rifampin in experimental endocarditis due to Staphylococcus aureus in rabbits.

Rifampin possesses unique activity against Staphylococcus aureus. It is the most active antistaphylococcal antibiotic currently available and has been shown to be particularly effective in eradicating S. aureus from abscess cavities in experimental infections. However, resistance develops rapidly in vitro and in vivo when large numbers of organisms (10(6)-10(7)) are present, and use of combination therapy has been recommended. The use of combination therapy is complicated by the finding that in vitro the addition of rifampin may reduce (antagonize) the bactericidal effect of the beta-lactam antibiotics. This study examines the in vivo effect of treatment with a beta-lactam agent (cloxacillin), rifampin, or the combination on the eradication of S. aureus from cardiac vegetations in experimental endocarditis. Five different dosage combinations of the beta-lactam agent and rifampin were administered for a three-day period, and an attempt was made to correlate peak serum bactericidal titers with results of quantitative cultures of vegetations after therapy. In two of five regimens the combination of rifampin and cloxacillin produced enhanced efficacy in vivo (synergism); in two regimens the effect was no greater than the effect of either drug alone (indifference), and in one regimen the combination was less effective than either single-drug regimen alone (antagonism). Peak serum bactericidal titers often were predictive of the in vivo effect when high doses of cloxacillin were used but were not consistently predictive of in vivo results when rifampin was the agent responsible for the major therapeutic effect. Rifampin-resistant strains did not emerge in animals receiving combination therapy but were isolated from vegetations from several animals receiving rifampin alone.

Animals↗
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Combination antifungal chemotherapy for experimental disseminated candidiasis: lack of correlation between in vitro and in vivo observations with amphotericin B and rifampin.

Disseminated candidiasis was established in guinea pigs immunosuppressed with high-dose cortisone acetate. After the disease had been characterized by histopathologic study and quantitative culture of selected organs, guinea pigs were given amphotericin B alone or in combination with rifampin. The addition of rifampin to the regimen enhanced the in vitro rate of killing of the strain of Candida albicans used in the studies but was not noticeably beneficial in treatment of the disease in guinea pigs. Thus, the demonstration of an enhanced rate of killing in vitro was not a reliable basis for prediction of the response to the drug in vivo.

Amphotericin B↗
PubMedDate not supplied

Failure of a once-daily regimen of cefonicid for treatment of endocarditis due to Staphylococcus aureus.

Cefonicid, a new long-acting cephalosporin, was evaluated for treatment of endocarditis due to Staphylococcus aureus. Four patients, all with infection of the tricuspid valve, were treated with a single daily injection. By the fifth day of therapy, three of the four patients continued to have spiking fevers and positive blood cultures, and treatment with cefonicid was discontinued. Even though peak concentrations of antibiotic in serum were greater than 20-40 times the minimum inhibitory concentration of the antibiotic for the infecting organism, serum bactericidal titers were less than 1:8 in three patients. Susceptibility testing of 52 clinical isolates in broth confirmed a marked difference between inhibitory and bactericidal concentrations for 40% of these strains. In addition, susceptibility testing performed in serum rather than broth resulted in a sixfold increase in the minimum inhibitory concentration, a result suggesting that protein binding may be in part responsible for these failures of treatment. Cefonicid administered as a single daily dose is inadequate for treatment of endocarditis due to S. aureus and should not be used for treatment of bacteremia or life-threatening infections known or suspected to be caused by this organism.

Adult↗
PubMedDate not supplied

Limitations of animal models in predicting beta-lactam efficacy for endocarditis and meningitis.

Animal models are important in predicting the efficacy in humans of antimicrobial agents for various disease conditions, including endocarditis and meningitis. Screening models are useful in assessing antibiotic effectiveness and toxicity; their advantages include simplicity, a reproducible course of infection, a well-defined therapeutic end point, and low cost. However, the inoculum size, the virulence of the organism, and the production of beta-lactamases can have important effects on outcome and must be considered in the interpretation of data obtained from such models. Discriminative models are those designed to mimic human disease as closely as possible with respect to infectious inoculum, host response, and course of disease. Each drug's pharmacokinetics must be carefully documented before being extrapolated to humans. Rigid criteria must be established to minimize misinterpretation of results from animal studies before conclusions from in vivo animal models are applied to human disease.

Animals↗
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Etiology and antimicrobial treatment of acute sinusitis.

Acute maxillary sinusitis is a disease of varied etiology. Over half of the cases are caused by Streptococcus pneumoniae and Hemophilus influenzae. Anaerobic bacteria account for another 10% of cases and these are usually of dental origin. The rest of the cases are caused by several other bacteria, each of which cause a small proportion. Rhinoviruses, influenza, and parainfluenza viruses also invade the sinuses and probably lead to secondary bacterial infection. Diagnosis of acute sinusitis on clinical grounds is difficult. Sinus transillumination and x-ray are the most valuable routine tests available. Ampicillin, amoxicillin, trimethoprim-sulfamethoxazole, and cefaclor have been shown to be effective treatment for most cases of acute sinusitis. Infection persists when there is inadequate or inappropriate treatment. The patient may become relatively asymptomatic in the face of persistent active infection. Follow-up clinical and x-ray examinations are indicated, when possible, to detect treatment failures. Although not a routine diagnostic procedure, sinus puncture and aspiration may be of value in the seriously ill patient or one who has not responded to treatment.

Acute Disease↗
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Evaluation of antimicrobial agents in the rabbit model of endocarditis.

The placement of a sterile polyethylene catheter in the heart of a rabbit results in nonbacterial thrombotic endocarditis characterized by an accumulation of fibrin strands, erythrocytes, and platelets that adhere to the endothelial surface. These elements form a nidus where a pathogen, when introduced by injection, lodges, multiples, and develops vegetations typical of infective endocarditis. In the rabbit model, endocarditis induced by Staphylococcus aureus or viridans group Streptococcus resembles the human disease in clinical and bacteriologic features and in response to antimicrobial therapy. The rabbit model thus affords a means of evaluating the therapy of endocarditis. The end points of therapeutic response are culture-negative vegetations and failure to relapse. On the basis of these criteria vancomycin was found to be more rapidly effective in curing an infection caused by a single strain of S. aureus than penicillin or cefazolin and as effective as a combination of penicillin and gentamicin.

Aminoglycosides↗