Biomedical subjects
Publications and source records attributed to H Kropp.
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The relative effects of two beta-lactam antibiotics, penicillin-binding protein (PBP) 2-specific imipenem and PBP 3-specific ceftazidime, upon in vitro induction of lipopolysaccharide (LPS) release were investigated against smooth- and rough-LPS mutant isolates of Pseudomonas aeruginosa. Free LPS liberated from both isolates are 10- to 40-fold higher for ceftazidime-exposed cultures than control or imipenem-treated cultures after 4-8 h at 35 degrees C despite equivalent MICs. Lethalities of filtrates in mice correlated with in vitro endotoxin assay results. Sub-MIC levels of ceftazidime induced filamentation and LPS release without significant bacterial lysis. Amounts released not only matched the quantities achieved at inhibitory concentrations (e.g., 1-, 2-, and 50-times MIC) of ceftazidime but significantly exceeded levels of LPS liberated by exposure to imipenem, less than or equal to 100 times its MIC. Sub-MIC levels of imipenem released relatively small amounts of free LPS while reducing colony counts approximately 2 logs more than equivalent amounts of ceftazidime after 2 h. Data suggest that ceftazidime-induced filamentation releases larger quantities of bioreactive LPS than nonfilamentous fast-lysing imipenem.
The time course of plasma drug levels and urinary recovery for two lipopeptide antifungal antibiotics, L-671,329 and cilofungin, were measured in male rhesus monkeys (Macaca mulatta) and in female DBA/2 mice. The antibiotics were administered intravenously at 10 mg/kg of body weight in phosphate-buffered saline-26% polyethylene glycol for the rhesus monkeys and in 5% dimethyl sulfoxide for the mice. Plasma and urine drug concentrations were determined by high-pressure liquid chromatography and/or a microbiological assay versus Aspergillus niger, and pharmacokinetic parameters were determined for both species. In each of the two rhesus crossover tests as well as in the mouse studies, the pharmacokinetics of the two compounds were similar; however, a marked difference was evident between species. The half-lives of L-671,329 and cilofungin in plasma were 39 and 34 min in the mice and averaged 1.8 and 2 h in the rhesus monkeys, respectively. In mice and rhesus monkeys, urinary recovery was less than 4% for both compounds.
Resistant variants can be selected in the presence of most of the recently developed beta-lactam antibiotics thus resulting in cross resistance between penicillin-, cephalosporin- and monocyclic derivatives except for imipenem. Among the Enterobacteriaceae-resistant so-called beta-lactamase-overproducing variants can be selected in some species in the presence of various broad-spectrum beta-lactams except for imipenem. However, imipenem-resistant variants can be selected from clinical Pseudomonas aeruginosa isolates in a frequency comparable to those obtained for other beta-lactams. Imipenem resistance in Pseudomonas aeruginosa is presently understood to be independent of either enzymatic degradation or an alteration of the penicillin-binding proteins; moreover, it has to be attributed to characteristic changes of the outer membrane proteins, thus explaining imipenem resistance due to impaired penetration. Consequently, resistance to imipenem in Pseudomonas aeruginosa has to be considered independent of resistance to other beta-lactams.
The discovery of Streptomyces cattleya and its antibiotic product, thienamycin, has ushered in a new era of beta-lactam agents, the carbapenems. Numerous carbapenems were subsequently discovered; however, none had the potency, broad-spectrum activity, and lack of cross-resistance exhibited by thienamycin. Chemical instability encountered with thienamycin was overcome by the N-formimidoyl derivative, imipenem. Imipenem is distinguished from other beta-lactams by its outstanding activity against gram-positive organisms as well as against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides. However, development was hindered by extensive renal metabolism of imipenem, resulting in low urinary concentrations of antibiotic. A renal dipeptidase, dehydropeptidase-I, was responsible for hydrolyzing imipenem and other carbapenems. To counter its action, a specific inhibitor, cilastatin, was developed. Coadministered with imipenem in a one-to-one ratio, cilastatin provides prolonged, reversible blockade of imipenem metabolism, dramatically improving urinary recoveries to therapeutically significant levels. Cilastatin also contributes to the safety of imipenem, since its coadministration prevents proximal tubular necrosis which has been observed in sensitive animals receiving imipenem alone in high doses. Thus, the combination imipenem and cilastatin overcame the pharmaceutical and metabolic challenges presented by thienamycin, and allowed for the evaluation in humans of the outstanding antimicrobial activity of this new class of beta-lactam antibiotics.
Mercapto Polycytidylic acid (MPC) is a potent inhibitor of oncornaviral reverse transcriptase. The fact that this enzyme has been found in human leukemic cells, has let to the clinical trials of MPC in the treatment of childhood acute leukemia. This report discribes the first pilot clinical trial on 23 patients. The results are encouraging, and have let to a second pilot study including other clinical centers on the clinical efficacy of MPC in the treatment of leukemia.
This communication documents a study of 35 patients with systemic malignant diseases between 1964 and 1973. All these patients developed interstitial pneumonia (int.pn.), and in two cases recurrence of int.pn. was observed after several months. Of these 35 patients 29 were diagnosed of acute lymphoblastic leukemia (ALL). In particular the occurrence of int.pn. was very frequently noticed under the more aggressive therapeutic regimes mentioned in the Memphis protocol VII. The statistical analysis revealed that the most critical period of occurrence is between 8 and 11 weeks after the induction therapy or 6-9 weeks after the reinduction or relapse therapy. These observations indicate the dependency of this disease during the intensive phase of therapy. The prognosis of int.pn. was improved significantly after the pentamidine treatment. The etiology of the int.pn. is discussed in detail. The post mortem examination of 6 patients revealed that 5 of them had pneumocystes carinii.
The radiologic appearances of interstitial pneumonia are described as they appeared in 39 children treated with immunosuppressive and cytostatic substances given for malignant systemic disease. At the time most of the children were in a stage of remission of their basic illness. In most of them there may have been a pneumocystis carinii infection. 15 children died of this pneumonia. In the majority of post-mortem examinations pneumocysts could be detected.
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Cephamycin A was found to be more active in vivo than cephamycin B. In comparison with cephamycin C, cephamycin A was more active against gram-positive organisms but less active against gram-negative organisms. Given subcutaneously, cephamycin C had good in vivo gram-negative activity, comparing favorably with cephalothin and cephaloridine against cephalosporin-susceptible organisms. In general, against the gram-negative organisms, it was more active than cephalothin or cephalosporin C and about as active as cephaloridine. In addition, cephamycin C protected mice against beta-lactamase-producing Proteus cultures, including clinically isolated strains. The compound is remarkably nontoxic. Cephamycin C was detected in the serum and recovered from the urine of treated mice to about the same extent as cephaloridine. Like cephaloridine and cephalosporin C, cephamycin C must be excreted mainly by glomerular filtration, because the use of probenecid did not enhance the therapeutic effectiveness nor concentrations of these agents in the sera of treated mice.
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