Biomedical subjects
Publications and source records attributed to M J Ingerman.
This article provides background information on the pharmacokinetics of antimicrobial agents in patients with normal and impaired renal function. Tables are provided to allow quick determination of appropriate dosages for varying degrees of renal failure. Specific mention is made of aminoglycoside dosing, dosage adjustment in dialysis, and antibiotic toxicity in renal failure.
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Interest in vancomycin has been rekindled by the emergence of resistant gram-positive pathogens and the improvement in drug purity. The antimicrobial activity, pharmacokinetics, clinical indications, dosing schedules, and adverse reactions of vancomycin are summarized.
The efficacy and toxicity of ciprofloxacin, an orally administered fluoroquinolone, were evaluated in 24 infections in 23 patients with osteomyelitis caused by aerobic gram-negative bacilli. The diagnosis was confirmed by surgical findings and the results of bone biopsy and culture of bone or deep soft tissue. The aerobic gram-negative bacilli were Pseudomonas aeruginosa (15 isolates), Serratia marcescens (five isolates), Escherichia coli (three isolates), Enterobacter species (three isolates), Proteus mirabilis (one isolate), Pseudomonas fluorescens (one isolate), and Klebsiella pneumoniae (one isolate). Minimal bactericidal concentrations (MBCs) were 1.56 micrograms/ml or less for all but one isolate. Nine infections were polymicrobial, involving aerobic gram-positive cocci or anaerobes in addition to aerobic gram-negative bacilli. Additional antibiotics to which the aerobic gram-negative bacilli were resistant were given when the additional organisms were resistant to ciprofloxacin. Patients received 750 mg of ciprofloxacin twice daily for a mean of 62 days. Peak serum levels of ciprofloxacin were at least threefold higher than the MBCs in 20 of 24 patients. Twenty of 22 infections in which a full course of therapy was completed were without evidence of active disease at one to 17 months posttreatment. A sternotomy wound infection relapsed after eight weeks of therapy with a newly resistant S. marcescens strain, and an infection of a compound fracture relapsed two months posttreatment with a still sensitive P. aeruginosa strain. Toxicity was minimal in most patients: eosinophilia (six patients), nausea (eight patients), mild elevation in transaminase levels (three patients), pruritus (one patient), diarrhea (two patients), thrush (two patients), rash (two patients), and mild leukopenia (one patient). Two additional patients had severe side effects (vertigo in one and acute renal failure in another) that required discontinuation of ciprofloxacin therapy. Overall, ciprofloxacin is a promising agent for the oral treatment of gram-negative bacillary osteomyelitis.
The efficacy of ciprofloxacin, BMY-28142, and ceftazidime was compared in vitro and in experimental left-sided endocarditis due to Pseudomonas aeruginosa in the rat. The dose, dosing interval, and duration of therapy were varied, and the resulting antibiotic levels in serum and vegetations were correlated with bacterial clearance from vegetations. These studies demonstrated that beta-lactams such as BMY exhibited a slow rate of bactericidal action and had no postantibiotic effect against P. aeruginosa in vitro or in vivo. As a consequence, BMY had to be given in multiple doses at relatively short intervals during which concentrations of antibiotics in vegetations were continuously in excess of the MBC for the pathogen. The earlier onset of rapid bactericidal action and the prolonged postantibiotic effect of ciprofloxacin (demonstrated in vivo and in vitro) were, in all likelihood, the factors that allowed the successful use of fewer doses of this antimicrobial agent at relatively longer dosing intervals.
A second strain of enterococcus (PA) producing beta-lactamase (Bla+ phenotype) was compared with the previously reported Bla+ enterococcus, strain HH22. As with the original strain, there was a marked inoculum effect when PA was tested with penicillin, ampicillin, and piperacillin; no difference was noted with methicillin, cephalothin, imipenem, or vancomycin; the difference with ticarcillin was intermediate. High-level gentamicin resistance (Gmr) transferred from PA to an enterococcal recipient strain at a frequency approximately 100-fold lower than for HH22; all Gmr transconjugants from both strains were Bla+, but only PA showed linkage of Gmr and Bla+ with transfer of resistance to streptomycin, tetracycline, and chloramphenicol. EcoRI digestion of plasmid DNA from Gmr Bla+ transconjugants showed no similarities between the two strains. A 5.1-kilobase EcoRI Bla+-encoding fragment derived from HH22 was cloned into an Escherichia coli cloning vector and shown to hybridize to a 10.2-kilobase EcoRI fragment derived from PA; both fragments hybridized to an 840-base-pair staphylococcal Bla+ gene probe. These data indicate that the penicillinases are similar but encoded on different or differently arranged plasmids. The fact that both are transferable emphasizes the potential for this new streptococcal resistance determinant to disseminate.