Reduced immunotoxicity and preservation of antibacterial activity in a releasable side-chain carbapenem antibiotic.

A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.

Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin.

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.

Use of acetylacetone to prepare a prodrug of cycloserine.

Several derivatives of cycloserine (1) were prepared and it was found that (R)-4-[(1-methyl-3-oxo-1-butenyl)-amino]-3-isoxazolidinone (11), the condensation product of acetylacetone and cycloserine (1), was an efficacious prodrug of increased stability under aqueous conditions.

In vivo evaluation of three acid-stable azalide compounds, L-701,677, L-708,299 and L-708,365 compared to erythromycin, azithromycin and clarithromycin.

L-701,677, L-708,299 and L-708,365 are novel azalide derivatives of erythromycin that exhibit improved acid stability over erythromycin, azithromycin and clarithromycin. The half-life in aqueous solution at pH = 2.1 of these compounds ranged from 0.3 hour for erythromycin to 16.2 hours for L-708,299. The rank order of half-life in acid solution from most to least stable was L-708,299 > L-701,677 > L-708,365 > azithromycin = clarithromycin > erythromycin. In a disseminated Streptococcus pyogenes mouse infection model, azithromycin and L-708,365 were slightly more efficacious than clarithromycin, L-701,677 and L-708,299; all 5 compounds being more active than erythromycin. In a Klebsiella pneumoniae pulmonary challenge mouse model, azithromycin, L-701,677, L-708,299 and L-708,365 were all equal in efficacy and at least four-fold more active than clarithromycin and erythromycin. Clarithromycin, L-708,365 and interestingly erythromycin, showed greater bacterial clearance than azithromycin, L-701,677 and L-708,299 in a localized infection model that measured clearance of Staphylococcus aureus from mouse thigh tissues. Our results indicate that L-701,677, L-708,299 and L-708,365 exhibit improved acid stability and were at least equally efficacious as presently marketed macrolide/azalide antibiotics.

[An ophthalmologic image databank on the Internet]. / Eine ophthalmologische Bilddatenbank im Internet.

The Internet has become a powerful, international source for information, and it has shown an exponential growth because of the ease of access and the immediate availability of information. We introduced a new ophthalmological atlas including ICD coding on the World Wide Web. So far, more than 500 lantern slides of typical and interesting ophthalmological findings have been selected and digitized. These pictures were integrated in a data base, which was arranged for ease and speed of search and retrieval. In its background, the data base contains a list of over 4700 ICD-encoded diagnoses to which the picture-documented findings are linked. Comments on pictures can be added by the author or by users. The data base contains several lists, such as a list of ICD codes and diagnoses, a list of all pictures with corresponding diagnoses, a list of all diagnoses and number of pictures, a list of those diagnoses for which the corresponding picture is available, as well as a list of comments on each picture. Special program scripts handle the user's search key words for diagnoses and extract the required information out of the data base, using Windows NT. Search results are presented on an automatically built-up webpage. To provide fast speed of search all pictures initially are shown in a small format (thumbnails) with little amount of data. The related full-size picture is retrieved by a single mouse click. Moreover, the name and institution of the author, diagnostical hints and comments on pictures by the author or by users are offered for each diagnosis available. The Giessen Ophthalmological Picture Atlas can be reached under www.med.unigiessen.de in the Internet. It allows a fast search free of charge from all over the world and, therefore, offers an additional option to obtain specific ophthalmological information for various purposes.

[Selection of resistant variants by broad spectrum beta-lactam antibiotics: to what extent is there cross resistance between imipenem and other beta-lactam antibiotics?]. / Zur Selektionierung resistenter Varianten durch "Breitspektrum"-beta-Laktamantibiotika: Inwieweit besteht zwischen Imipenem und anderen beta-Laktamen eine Kreuzresistenz?

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.

[Clinical trials with mercapto polycytidylic acid in the treatment of acute childhood leukemia (author's transl)]. / Behandlungsversuche mit Mercaptopolycytidylsäure bei akuten Leukämien des Kindes.

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.

beta-Lactam antibiotic-induced release of free endotoxin: in vitro comparison of penicillin-binding protein (PBP) 2-specific imipenem and PBP 3-specific ceftazidime.

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.

[Prevention of varicella in children on immunosuppressive therapy (author's transl)]. / Varizellen-Prophylaxe während immunosuppressiver Therapie.

The mortality rate due to varicella in patients on cytostatic therapy is high. However, during the first 72 hours after infection, an effective protection can be given with Varicella/Zoster-Immunoglobulin (ZIG). This article deals with 172 cases with malignant diseases. These children who were on polychemotherapy contacted varicella. They were treated with ZIG 0,2 ml/kg per body weight in 15% concentration. After triple dilution ZIG was administered intravenous to 151 patients and undiluted intramuscular to 21 patients. ZIG was well tolerated. Only 3 children had varicella and even this was in a mild form. The donors of ZIG were selected through a screening program.

[Interstitial pneumonia in children with malignancies during cytotoxic therapie. Clinical picture, analysis of promoting factors, and detailed discussion of etiology (author's transl)]. / Interstitielle Pneumonien bei Kindern mit einer malignen Systemerkrankung unter zytostatischer Therapie. Klinisches Erscheinungsbild, Analyse der begünstigenden Faktoren und Versuch einer ätiologischen Klärung.

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.

Metabolism of thienamycin and related carbapenem antibiotics by the renal dipeptidase, dehydropeptidase.

Thienamycin (THM), the N-formimidoyl thienamycin derivative MK0787, and related carbapenem antibiotics were metabolized extensively in mice, rats, rabbits, dogs, rhesus monkeys, and chimpanzees. Urinary recovery of THM ranged from a low of 5% in dogs to 58% in rhesus monkeys. Renal clearance rates in dogs and chimpanzees were unusually low, less than glomerular filtration rates. The reduction in clearance of THM and MK0787 from plasma of rats and rabbits after ligation of renal arteries indicate that the kidneys are responsible for 35 and 92%, respectively, of metabolic drug clearance. Degradation was detected only in kidney homogenates. The enzyme activity was membrane bound and sensitive to inhibitors of Zn-metalloenzymes such as EDTA. A renal dipeptidase, dehydropeptidase-I (DHP-I), EC 3.4.13.11, was found to be responsible for the metabolism of the THM-class antibiotics, which exhibit a structural homology to dehydropeptides. A parallel increase in specific activity against THM and the substrate of DHP-I, glycyldehydrophenylalanine, was observed during solubilization and purification of the enzyme from porcine and human renal cortex. DHP-I was found to catalyze the hydrolysis of the beta-lactam ring in THM and MK0787. The products of the enzyme reaction were identical by high-powered liquid chromatography to their respective metabolites found in the urine. Nonbasic N-acylated THM and natural N-acylated carbapenems (epithienamycins and olivanic acids) were degraded 4- to 50-fold faster than THM when exposed to the enzymatic hydrolysis of DHP-I. Good correlations were obtained between the increased susceptibility of the carbapenem antibiotics to DHP-I as measured in the in vitro enzyme assay and the generally lower recoveries of active antibiotic in the urine of test animals. Despite this unusual degree of metabolism localized in the kidney, the plasma half-life of MK0787 and its efficacy against experimental systemic infections in animals remain satisfactory.

Pharmacokinetics of L-749,345, a long-acting carbapenem antibiotic, in primates.

L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation. Levels of binding to protein, in the range of clinically relevant concentrations in serum, are virtually equivalent for L-749,345 and CTX in humans. Results of a crossover bioassay versus those of a high-pressure liquid chromatography assay of 1-g human samples showed that there were no bioactive metabolites of L-749,345. The extended half-life at elimination phase of L-749,345 allows consideration of single daily dosing. In contrast to results with IPM, the improved stability of L-749,345 with respect to hydrolysis by the renal dehydropeptidase I (0.25 times the rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.

MK0787 (N-formimidoyl thienamycin): evaluation of in vitro and in vivo activities.

The practical application of thienamycin, a novel beta-lactam antibiotic with a broad activity spectrum, was compromised by problems of instability. MK0787, N-formimidoyl thienamycin, does not have this liability. As reported, bacterial species resistant to most beta-lactam antibiotics, such as Pseudomonas aeurginosa, Serratis, Enterobacter, Enterococcus, and Bacteroides spp., are uniformly susceptible to MK0787, usually at one-half the inhibitory level of thienamycin. Bactericidal activity usually occurs at the minimal inhibitory concentration endpoint. Activity was reduced only at the highest inoculum densities tested and by a lessor factor than was observed with reference beta-lactam antibiotic active against P. aeruginosa and beta-lactamase-bearing strains. MK0787 exhibits a broad spectrum of in vivo activity when evaluated parenterally for efficacy against systemic infections in mice. The order of potency in vivo, 0.03 to 0.06 mg/kg for gram-positive species and 0.65 to 3.8 mg/kg for gram-negative infections including Pseudomonas, exceeded that of thienamycin and was at least 10-fold superior to reference beta-lactam antibiotics including two recently developed agents with antipseudomonal activity, cefotaxime and LY127935.

[Interstitial pneumonia in children on cystostatic treatment for malignant systematic disease (author's transl)]. / Interstitielle Pneumonien bei Kindern mit einer malignen Systemerkrankung unter zytostatischer Therapie

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.

Antibacterial activity of imipenem: the first thienamycin antibiotic.

Imipenem (N-formimidoyl thienamycin) is the first representative of a new class of beta-lactam antibiotics--the carbapenems. Imipenem has an unusually broad spectrum, high potency, and no cross-resistance with other beta-lactam antibiotics. Susceptible gram-negative species include Pseudomonas aeruginosa, Serratia, and Enterobacter. Activity is high against Staphylococcus aureus, most group D streptococci, and Staphylococcus epidermidis but is variable against methicillin-resistant S. aureus. Imipenem is more active against Bacteroides than are other beta-lactam agents, chloramphenicol, metronidazole, and clindamycin. The minimal inhibitory concentrations (MICs) for 98% of 30,655 isolates--excluding those of the three resistant species (Pseudomonas maltophilia, Pseudomonas cepacia, and Streptococcus faecium)--were less than 8 micrograms/ml, the susceptibility breakpoint adopted for clinical trials. Imipenem is bactericidal (minimal bactericidal concentrations (MBCs] less than twice the MICs). For P. aeruginosa, MBCs of imipenem are less influenced by high inoculum density rather than are MBCs of antipseudomonal penicillins and cephalosporins. Stability of imipenem to diverse classes of plasmid-mediated and chromosomal beta-lactamases accounts for its lack of cross-resistance with other beta-lactam antibiotics. Imipenem is also active against P. aeruginosa with non-lactamase-mediated resistance to classical beta-lactam agents. Efficacy of imipenem was shown in animal models, including septicemia in normal and neutropenic rodents and P. aeruginosa pneumonia. Imipenem also has a unique postantibiotic effect against P. aeruginosa in vivo.

[Varicella-zoster-immunoglobulin as a safe prophylaxis of varicella (author's transl)]. / Zur Sicherheit der Varizellenprophylaxe mit Varizellen-Zoster-Immunglobulin.

The occurrence of varicella in the course of immunosuppressive therapy is always a hazard to life. Up till now, passive immunization is the only method which provides reliable protection. We have had an immunoglobulin compound at our disposal during the last 5 years. This compound was obtained by screening a plasmapool for high-titre varicella antibodies, which were then fractionated. Varicella immunoglobulin was injected on 298 occasions to children incubated with varicella. There were no serious side effects after i.v. administration. These children were on polychemotherapy because of malignant diseases. Only 4 children developed varicella, 3 of them very mildly and none of them was later disabled due to varicella in any form. The protective value of this varicella-immunoglobulin compound is much greater than any other known so far [16].

[Prevention of cytomegalic inclusion disease in leukemia patients with a cytomegalovirus hyperimmune globulin preparation]. / Zytomegalie-Prophylaxe bei Leukämiepatienten mit einem Zytomegalie-Hyperimmunglobulinpräparat.

In a randomised study the efficacy of a cytomegalic hyperimmune globulin preparation (CMV-HIGP) which had been treated with beta-propiolactone was analysed. The study included 85 patients with acute lymphoblastic leukemia (ALL) and Non-B-Non-Hodgkin-lymphoma (NHL) who were treated initially or underwent a relapse therapy. During the intense chemotherapeutical period within leukemia treatment the patients were passively immunised by the intravenous route with CMV-HIGP (1 ml per kilogram of body weight) every two to three weeks at the latest. In the initial stages the basic immunisation protection was achieved by the application of double dose CMV-HIGP. The Frankfurt patients were recruited from the BFM-ALL- and the NHL-study since october 1982. When they were admitted their CMV serostatus was determined by means of the ELA-ELISA or IFA-method. Seronegative patients were given the passive immunisation immediately or 48 hours after the first blood transfusions at the latest. The patients who had become CMV-IgG-positive by passive immunisation were randomised when reaching long-term therapy according to the protocol. Because of a 30% cytomegaly disease incidence rate in our patient population a randomisation was unwarrantable at the beginning of leukemia treatment. During randomisation one group of patients were immunised by the intravenous route with CMV-HIGP (2 ml per kg body weight one time in four weeks), the second group was a control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of L-671,329 in rhesus monkeys and DBA/2 mice.

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.