Successful prophylaxis of experimental streptococcal endocarditis with single doses of sublethal concentrations of penicillin.

Penicillin prophylaxis against experimental endocarditis due to a strain of Streptococcus intermedius isolated from a patient with endocarditis was studied in rats. The minimum bactericidal concentration of penicillin for this strain was more than 64 mg/l and was higher than the peak penicillin serum level obtained in rats 30 min after the iv injection of 60 mg/kg, and in man after an oral dose of 2 g of phenoxymethyl penicillin. Moreover timed kill curves performed in the presence of 64 mg/l of penicillin showed no decrease in the number of colony-forming units during the first 6 h of incubation and only a 95% decrease after 24 h. In addition, no bactericidal activity could be detected in the serum 30 min after penicillin injection, that is at the time of bacterial challenge. Using the minimum bacterial inoculum needed to produce endocarditis in 90% of control animals (ID90), penicillin successfully prevented endocarditis due to this strain. We conclude that penicillin may prevent streptococcal endocarditis by other mechanisms than bacterial killing

In-vitro activity of temafloxacin for gram-positive pathogens.

The antimicrobial activity of temafloxacin against aerobic Gram-positive cocci was compared to that of ciprofloxacin, ofloxacin, fleroxacin and pefloxacin using the broth microdilution technique. Temafloxacin was more active than the other four fluoroquinolones, particularly for viridans streptococci and Streptococcus pneumoniae. The MIC90 of temafloxacin was at least four-fold lower than that of ciprofloxacin and ofloxacin for viridans streptococci and penicillin-susceptible pneumococci. The MIC50s and MIC90s of temafloxacin were equal to or lower than those of the other fluoroquinolones for methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and methicillin-susceptible and methicillin-resistant coagulase-negative staphylococci. Temafloxacin was more active against all the other Gram-positive aerobes (except Enterococcus faecalis) tested than the other fluoroquinolones

Comparative study of imipenem in severe infections.

Forty patients with severe bacterial infections due to micro-organisms known or presumed to be sensitive to both study antibiotics, were randomized to receive either imipenem with cilastatin, 500 mg/500 mg iv tid (20 patients), or cefotaxime, 2 g iv tid (20 patients). The types of infections observed were equally distributed between the 2 groups, and consisted of 18 complicated urinary tract infections, 9 pneumonia, 7 bone and soft tissue infections, 4 septicaemia of unknown origin and 2 intravenous-catheter-related septicaemia. In the imipenem group, 12 patients were bacteraemic, compared to 10 in the cefotaxime group. The micro-organisms observed were evenly distributed with Escherichia coli (22 cases) and Klebsiella pneumoniae (6 cases) being the most frequent. Sixteen patients were cured in the imipenem group and 15 in the cefotaxime group, while 2 and 2 improved, 2 and 1 relapsed and 0 and 2 did not respond to the therapy, respectively. In the imipenem group, no clinical side effects were observed while 5 patients had mild reactions in the cefotaxime group (2 fever, 1 skin rash, 1 oral candidiasis and 1 diarrhoea). Imipenem thus appeared as effective and well tolerated as cefotaxime in the treatment of severely infected patients

Successful single-dose amoxicillin prophylaxis against experimental streptococcal endocarditis: evidence for two mechanisms of protection.

Amoxicillin prophylaxis against experimental endocarditis due to one nontolerant and two tolerant strains of streptococci was studied in rats. Single-dose amoxicillin protected against the two tolerant strains in animals challenged with the 90% infective dose (ID90), but protection diminished with increasing inoculum sizes. Protection against the nontolerant strain was successful with inocula that were 100- and 1,000-fold larger than the ID90. Close correlation existed between the speed of bacterial killing in vitro, the time of exposure to bactericidal levels in vivo, and the range of inocula against which prophylaxis was effective. Amoxicillin seemed to protect by at least two mechanisms. (1) When in vitro tests indicated adequate bacterial killing, protection was independent of the inoculum size and was probably conferred by bacterial killing. (2) When in vitro tests indicated bacterial inhibition but not killing, protection was inoculum-dependent and was probably mediated by inhibition of bacterial adherence

Antibiotic treatment of experimental endocarditis due to methicillin-resistant Staphylococcus epidermidis.

The natural history and treatment of experimental endocarditis due to heterogeneous and homogeneous methicillin-resistant Staphylococcus epidermidis was investigated. Amoxicillin/clavulanate or vancomycin were administered for 3 days via a computerized pump to mimic human drug kinetics in animals. After challenge with the minimum inoculum producing 90% of infections (ID90), bacteria in the vegetations grew logarithmically for 16 h. Then, bacterial densities stabilized (at approximately 10(8) cfu/g) and growth rates sharply declined. Both regimens cured > or = 60% of endocarditis (due to heterogeneous or homogeneous bacteria) when started 12-16 h after infection, although the bacterial densities in the vegetations had increased by 20 times in between. In contrast, treatment started after 24 h failed in most animals, while bacterial densities had not increased any more. Thus, while both regimens were equivalent, the therapeutic outcome was best predicted by growth rates in the vegetations, not by bacterial densities. These observations highlight the importance of phenotypic tolerance developing in vivo

Cefepime monotherapy for the empirical treatment of fever in granulocytopenic cancer patients.

In a pilot study, we evaluated the efficacy and the safety of cefepime, a new cephalosporin with extended-spectrum activity against both Gram-positive and Gram-negative bacteria, as empirical monotherapy for 108 febrile episodes in 84 granulocytopenic cancer patients. Cefepime (2 g tds) was given for a minimum of 7 days or until resolution of infection. Of the 108 episodes, 91 were evaluable. Microbiologically documented infections occurred in 25 patients (27%) (18 Gram-positive, 7 Gram-negative), of whom 18 had bacteraemia. Infection was clinically documented in 47 patients (52%) and fever was unexplained in 19 (21%). Overall, 71% (65/91) of the infections resolved. Response rates were 86% (6/7) for Gram-negative infections, 44% (8/18) for Gram-positive infections (57% for cefepime-susceptible Gram-positive bacteria), 77% (36/47) for clinically documented infections and 79% (15/19) for unexplained fevers. Of the 26 patients (29%) whose primary infections did not improve with cefepime monotherapy, 23 responded after the addition of other antibiotics. Sixteen patients (18%) developed secondary infections of which 13 were microbiologically documented; Gram-positive bacteria were isolated from seven patients, Gram-negative bacteria from two, fungi from three and a virus from one. Adverse effects were mild and did not require premature discontinuation of therapy except for one patient who developed an immediate allergic reaction after the first dose of cefepime from which he recovered fully. The survival rate after resolution of granulocytopenia was 96%; three patients died of primary bacterial infection and one from secondary disseminated candidiasis. In this pilot study, cefepime monotherapy appeared safe and effective as empirical therapy for fever in cancer patients with granulocytopenia. Whether cefepime is superior to other advanced-generation cephalosporins for the treatment of Gram-positive infections will require evaluation in a larger comparative study

Incidence of gallbladder lithiasis after ceftriaxone treatment.

Ceftriaxone has potent activity against a broad range of Gram-positive and Gram-negative bacteria. While it is eliminated mainly by the kidney, 10-20% of the drug is eliminated in the bile and ceftriaxone salt precipitates have been described in the gallbladder of animals dosed with ceftriaxone. The purpose of the present study was to investigate the incidence of biliary lithiasis 6 and 12 months after treatment with ceftriaxone and to compare it with that in patients treated with amoxycillin/clavulanate. Biliary ultrasonography was performed at the start of treatment, at 6 months and at 12 months after the beginning of the study. One hundred patients were randomized and 74 were evaluable: 34 were given amoxycillin/clavulanate, 40 ceftriaxone. Gallbladder lithiasis developed in one patient 12 months after the amoxycillin/clavulanate treatment and in none in the ceftriaxone treatment arm. Biliary precipitate during ceftriaxone treatment was not looked for because this phenomenon was not known at the beginning of the study, but gallbladder precipitation that was seen in two patients given ceftriaxone during and at the end of treatment, respectively, resolved spontaneously. In conclusion, ceftriaxone treatment does not appear to lead to gallstone formation more often than an antibiotic that is not eliminated through the bile