Anti-Helicobacter pylori agents endowed with H2-antagonist properties.

New anti-Helicobacter pylori (H. pylori) agents endowed with H2-antagonists properties were obtained by combining the lamtidine derived pharmacophoric group with the antibiotic calvatic acid. All the compounds were tested for their irreversible H2-antagonist properties and for their ability to inhibit 20 H. pylori strains, two of them metronidazole resistant. The most active derivative (compound 4) displayed antimicrobial activity similar to metronidazole.

Helicobacter pylori: ureA, cagA and vacA expression during conversion to the coccoid form.

As viability of coccoid forms of Helicobacter pylori can only be verified by demonstrating the integrity of the DNA and active protein synthesis, we analysed the expression of ureA, cagA, vacA genes after prolonged incubation in a liquid medium. Exponentially growing and ageing phase cultures were used. Our results showed that, although the coccoid forms had decreased DNA and RNA levels after 31 days, they were not degraded and still expressed the urease, cytotoxic island and vacuolating toxin genes. Coccoid forms are therefore viable and may act as a transmissible agent that plays a crucial role in disease relapses after antibiotic therapy.

Helicobacter pylori: cultivability and antibiotic susceptibility of coccoid forms.

Helicobacter pylori is an actively dividing helical bacterium that changes to coccoid morphology as the culture ages. It has been suggested that the coccoid forms may be involved in transmission of infection and in relapses following antimicrobial therapy. The aim of this investigation was to determine the survival and susceptibility of the coccoid forms to amoxycillin, erythromycin, gentamicin and metronidazole. Colony counts and microscopic examination were performed after 1-4 weeks of culture. At 2 and 4 weeks, identical cultures were treated with the antibiotics for 24 h. Our results showed that 4-week cultures of coccoid forms were cultivable after antibiotic treatment.

'In vitro' development of metronidazole, erythromycin, amoxicillin and gentamicin resistance in Helicobacter pylori.

Serial passage of 37 Helicobacter pylori clinical isolates on increasing concentrations of metronidazole rapidly produced five strains with MICs up to 512 fold higher than those for the original strains. For these five metronidazole-resistant strains the MICs of erythromycin, gentamicin and amoxicillin were unchanged. When they were submitted to the same technique for these last antimicrobial agents, only one strain developed high level resistance to erythromycin and gentamicin having MIC values respectively up to 32 and 64-fold increased. Finally, no amoxicillin-resistant Helicobacter pylori could be obtained.

Activity of amoxicillin, metronidazole, bismuth salicylate and six aminoglycosides against Helicobacter pylori.

The in vitro activity of metronidazole, amoxicillin, bismuth salicylate and some aminoglycosides, such as ribostamycin, gentamicin, amikacin, tobramycin, streptomycin and netilmicin was evaluated against 60 clinical isolates of Helicobacter pylori using the agar dilution technique. All 60 strains were susceptible to amoxicillin, with minimum concentrations able to inhibit 50% (MIC 50) and 90% (MIC 90) of strains equal to 0.031 microgram/ml and 0.25 microgram/ml, respectively. Of the aminoglycosides, ribostamycin, streptomycin and amikacin had a little lower activity (MIC 50 of 2 micrograms/ml, MIC 90 of 4-8 micrograms/ml) than gentamicin, tobramycin and netilmicin, with MIC 50s of 0.125 microgram/ml and MIC 90s of 0.25 microgram/ml. Metronidazole was effective against the majority of the strains, but we found ten resistant strains. Finally, bismuth salicylate showed only slight antibacterial activity.

Susceptibility of Helicobacter pylori and pharmacokinetic properties in mice of new 5-nitroimidazole derivatives devoid of mutagenic activity in the Ames test.

The minimum inhibitory concentrations of metronidazole and four new 5-nitroimidazole derivatives (EU 11100, EU 11102, EU 11103, EU 11104), obtained by the reaction of 1-methyl-5-nitroimidazolyl-2-carboxyaldehyde and terbutyl-phenol, were determined against 25 clinical isolates of Helicobacter pylori. Three of them (EU 11100, EU 11103, EU 11104) exhibited an antibacterial activity higher than that of metronidazole. The last one, the molecule EU 11102, was less active than metronidazole. In mice, after a single equimolar oral administration, the molecules EU 11100 and 11103 were poorly absorbed and poorly excreted in urine. The molecular EU 11104 was well adsorbed and its urinary recovery was slightly lower than that of metronidazole. The substance EU 11102 was not demonstrable in blood and urine. In the Salmonella/microsome mutagenicity test only the molecule EU 11100 showed an increase of mutation frequency in S. typhimurium TA 100.

[Bone marrow cryptococcosis as the first manifestation of AIDS]. / Criptococcosi midollare quale prima espressione di AIDS.

Bone marrow cryptococcosis as initial sign of AIDS. The Authors describe a case of bone marrow cryptococcosis in a patient, female aged 27, in which a toluene-induced aplastic anemia was suspected. The mycosis was at first extracerebral and represented the initial manifestation of unexpected AIDS. The Authors discute the symptomatology and the clinical findings leading to the diagnosis and remark the main point of bone marrow evaluation as aid in diagnosing the infective pathology.

Listeria monocytogenes infections: the organism, its pathogenicity and antimicrobial drugs susceptibility.

L. monocytogenes can induce serious, life-threatening infections. Multiple clinical manifestations of the disease include neonatal and perinatal listeriosis, infections in adult immunocompromised patients as well as in normal hosts, with the CNS as the more frequent site involved. Many outbreaks are believed to be food-borne in origin, but there can be other means of transmission. The susceptibility of L. monocytogenes to different antimicrobial drugs is reviewed. Many drugs that are highly effective in vitro show only a moderate activity in vivo, due either to their poor ability to enter the phagocytes and destroy the engulfed bacteria, as with the beta-lactams, ampicillin and amoxicillin, or to their bacteriostatic rather than bactericidal activity, as with the fluoroquinolones, or their affinity for a serum glycoprotein, as with the macrolide antibiotics. The bacterial killing appears to be enhanced by some synergistic drug associations, the best therapeutic results being achieved by trimethoprim-cotrimoxazole and ampicillin plus gentamicin. Other more recent antimicrobial drugs and drug combinations are still under clinical evaluation.

Antibacterial, antimycotic and trichomonicidal activity of a new nitroimidazole (EU 11100).

The antimicrobial profile of a new nitroimidazole derivative (5-nitro-1-methyl-imidazolyl-2-hydroxy-3 terbutylphenyl carbinol) has been studied. The in vitro activity of the new molecule has been evaluated against both aerobic and anaerobic bacteria, Trichomonas vaginalis, and mycetes, under suitable experimental conditions. The new compound was compared with ampicillin against aerobic bacteria; with metronidazole against anaerobic bacteria, lactobacilli and T. vaginalis; with nistatin and econazole against candida and with econazole and bifonazole against filamentous fungi. The new nitroimidazole derivative has been shown to be moderately active against some anaerobic bacteria belonging to both the Gram-positive and Gram-negative groups. Its inhibitory activity against T. vaginalis was similar to that of metronidazole.

Activity of two benzofuran-imidazoles, IM/B/4-62 and IM/B/4-66, against experimental infections with Candida albicans and Trichophyton mentagrophytes.

The therapeutic activity of two new benzofuran-imidazoles, IM/B/4-62 and IM/B/4-66, formulated as 1% cream, has been evaluated against Candida albicans and Trichophyton mentagrophytes by inducing experimental vaginal candidosis in female rats and dermatophytosis in female guinea pigs. Results of the treatment were compared with those obtained by the same therapeutic regimen carried out with bifonazole. IM/B/4-66 proved to possess superior antimycotic activity to that of IM/B/4-62 and similar to that of bifonazole in both infections. Nmaley vaginal candidosis was cured in all the treated in animals at 6 days post-inoculation and skin lesions were healed in 9 of 10 animals at 15 days after infection, with negative cultures from all the infected sites.

Antifungal activity of two benzofuran-imidazoles in different experimental conditions.

A number of experiments was performed in order to analyze the in vitro activity of two new benzofuran-imidazoles, IM/B/4-62 and IM/B/4-66. Studies included the determination of minimum inhibitory concentrations (MICs) on three culture media, at different pH values and at different inoculum sizes. Furthermore, the killing activity and induced resistance were determined. In all the experiments econazole, clotrimazole and bifonazole were the reference compounds. The best MIC values of the two new imidazoles were observed on modified Sabouraud's medium, at neutral pH and an inoculum size of 10(4) cells/ml. The two substances showed killing activity and no resistance was observed. On the whole, the more favorable results were obtained with the compound IM/B/4-66.

Microbiological patterns of four new imidazole derivatives.

The authors present an in vitro experimental study concerning the microbiological properties of four imidazole derivatives, with a piperazine group between two benzene rings. Seventy strains of Gram-positive and Gram-negative bacteria, 30 of yeasts, 14 of filamentous fungi and 10 strains of Trichomonas vaginalis were tested. The new compounds revealed a good inhibitory activity against Gram-positive bacteria, yeasts and dermatophytes. These results compare well with those obtained with the other known imidazoles. Moreover any mutagenic activity is absent.

Mutagenicity studies on dihydroergocristine.

Dihydroergocristine (DHEC) is an ergot derivative used for the therapy of patients with cerebrovascular insufficiency. It was tested for mutagenicity by means of four tests. In the mutagenicity in vitro assay on Salmonella typhimurium, DHEC was checked at 10,000 micrograms/plate on TA98 and TA1538 strains and at 3000 micrograms/plate on TA1535, TA1537 and TA100 strains with and without metabolic activation. In a quantitative in vitro test for mutagenicity in V79 Chinese hamster cells, DHEC was studied at concentrations between 30 and 0.3 microgram/ml with and without metabolic activation. DHEC was tested for its ability to induce chromosomal damage in human lymphocyte cultures utilizing the concentrations of 10, 3 and 1 microgram/ml. In the in vivo mouse (Swiss strain) micronucleus assay, DHEC was orally administered at two dosages (50% and 16% of LD50) following the schedule of the test. Dihydroergocristine is a drug free of mutagenic activity on the basis of all the results obtained from the above in vitro and in vivo tests.

[Activity of topical flunoxaprofen in nonspecific vaginitis. Comparison with meclocycline sulfosalicylate]. / Attività di flunoxaprofene per uso topico nelle vaginiti aspecifiche. Confronto con meclociclina solfosalicilato.

A trial was performed in 30 patients affected by non-specific vaginitis. The results show that the topical application (by vaginal washings) of flunoxaprofen produces a high therapeutic activity like that of meclocycline. Contrary to meclocycline, flunoxaprofen does not possess bactericidal and bacteriostatic properties. Therefore, the normalization of vaginal flora, with a remarkable increase of Döderlein bacillus, is exclusively due to local antiphlogistic activity of flunoxaprofen. Contrary to meclocycline, flunoxaprofen induces a precocious increase of Döderlein bacillus, necessary for a definitive normalization and to limit the possibility of relapses.

Effect of cefotetan in clindamycin-induced enterocolitis in hamsters.

In hamsters the administration of clindamycin provokes a fatal diarrhea and death in 1-2 days. This study was performed in order to assess the possible protective effect of three cephalosporins in clindamycin-induced enterocolitis in these laboratory animals. The efficacy of cefotetan was compared with that of cefoxitin and latamoxef: the hamsters were treated twice daily for 5 days with clindamycin (10 mg/kg) by oral route, and cefotetan, cefoxitin and latamoxef (100 mg/kg) were given subcutaneously. All animals developed "wet-tail syndrome", but cefotetan and latamoxef were able to protect a large percentage of hamsters from death and to prolong the survival time.

Treatment of experimental cystitis in the rat with a single dose of fosfomycin trometamol.

The therapeutic effectiveness of a single oral dose (60 and 200 mg/kg body weight) of fosfomycin trometamol (FT), norfloxacin, trimethoprim sulfamethoxazole (Bactrim) and pipemidic acid against experimental cystitis in the rat were compared. Infections were produced with clinical isolates of Klebsiella pneumoniae, Proteus mirabilis and Escherichia coli in a total of 135 Sprague-Dawley albino rats. Oral treatment with all four drugs consistently lowered the numbers of CFU in bladder tissue, especially E. coli and P. mirabilis. Fosfomycin trometamol appeared to be as effective as norfloxacin for treatment of E. coli cystitis even thoughs its minimal inhibitory concentration (MIC) in vitro is 100 times greater than that of the quinolonic antibiotic. Fosfomycin trometamol, pipemidic acid and Bactrim were equally effective against P. mirabilis infection, but FT was less active than norfloxacin or Bactrim for treatment of K. pneumonia cystitis. In conclusion, single dose treatment with fosfomycin trometamol was effective for treatment of experimental cystitis in the rat and might, by extrapolation, be of use in clinical practice for single dose treatment of uncomplicated urinary tract infections.

Antibacterial activity in human urine of fosfomycin trometamol in an in vitro model of the urinary bladder.

The urinary concentrations of fosfomycin trometamol, norfloxacin, pipemidic acid and cotrimoxazole were studied at various times after oral administration of drugs in healthy volunteers. Using the same urine, the bactericidal activity of four antimicrobial agents against Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae in an in vitro model simulating the treatment of bacterial cystitis was also evaluated. The results obtained show that very high concentrations of the drugs were achieved in urine particularly after the oral administration of the fosfomycin trometamol. In the bladder model bactericidal activity of fosfomycin trometamol, norfloxacin and pipemidic acid were higher than that of cotrimoxazole; no resistant mutants to drugs were selected over a period of 24 h.