fosfomycin and Pneumococcal-Infections

Topics: Ceftriaxone; Debridement; Fasciitis, Necrotizing; Fasciotomy; Fosfomycin; Humans; Immunocompromised Host; Male; Middle Aged; Penicillin Resistance; Pneumococcal Infections; Salvage Therapy; Streptococcus pneumoniae; Treatment Outcome

Fosfomycin targets the first step of peptidoglycan biosynthesis in Streptococcus pneumoniae catalyzed by UDP-N-acetylglucosamine enolpyruvyltransferase (MurA1). We investigated whether heteroresistance to fosfomycin occurs in S. pneumoniae. We found that of 11 strains tested, all but 1 (Hungary(19A)) displayed heteroresistance and that deletion of murA1 abolished heteroresistance. Hungary(19A) differs from the other strains by a single amino acid substitution in MurA1 (Ala(364)Thr). To test whether this substitution is responsible for the lack of heteroresistance, it was introduced into strain D39. The heteroresistance phenotype of strain D39 was not changed. Furthermore, no relevant structural differences between the MurA1 crystal structures of heteroresistant strain D39 and nonheteroresistant strain Hungary(19A) were found. Our results reveal that heteroresistance to fosfomycin is the predominant phenotype of S. pneumoniae and that MurA1 is required for heteroresistance to fosfomycin but is not the only factor involved. The findings provide a caveat for any future use of fosfomycin in the treatment of pneumococcal infections.

Topics: Alkyl and Aryl Transferases; Anti-Bacterial Agents; Crystallization; Drug Resistance, Bacterial; Fosfomycin; Humans; Hungary; Microbial Sensitivity Tests; Models, Molecular; Molecular Sequence Data; Mutation; Pneumococcal Infections; Sequence Analysis, DNA; Streptococcus pneumoniae

We report a rare case of multiple vertebral osteomyelitis due to Streptococcus pneumoniae. A 73-year-old man admitted for back pain and a low-grade fever was found in laboratory studies to have severe leukocytosis and increased C-reactive protein, but neither computed tomography (CT) nor vertebral magnetic resonance imaging (MRI) clarified the cause of infection in the painful hip lesion, and paralysis developed. in the left leg MRI eventually indicated a vertebral abscess involving multiple lesions at C4-7 and L4-5. We had started antibiotics before blood culture clarified Streptocccus pneumonaie, and antibiotics acted more effectively thereafter. The clinical course was good, little paralysis remained.

Topics: Aged; Anti-Bacterial Agents; beta-Alanine; Cervical Vertebrae; Clindamycin; Drug Therapy, Combination; Fosfomycin; Humans; Lumbar Vertebrae; Male; Meropenem; Osteomyelitis; Penicillin Resistance; Pneumococcal Infections; Streptococcus pneumoniae; Thienamycins; Treatment Outcome

The rate of penicillin-resistant Streptococcus pneumoniae isolates in Spain is high. At present, penicillin and ceftriaxone are two drugs chosen for treating serious infections. In this study the bactericidal activity of four antimicrobial regimens against ten clinical isolates of S. pneumoniae (five with an intermediate resistance to penicillin and five highly resistant ones), was determined by means of kill kinetics studies using either penicillin, or ceftriaxone, in combination with vancomycin, or fosfomycin. The concentrations of the antimicrobial regimens (MICs 4x, 1x and 1/4x) were within possible physiological levels. While the combinations of penicillin, or ceftriaxone, plus vancomycin showed a significant increase in bactericidal activity, the bacterial reductions obtained in combination with fosfomycin were greater, achieving synergistic effects. These results suggest that in vivo trials with a regimen composed of ceftriaxone and fosfomycin would be worthwhile.

Topics: Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; Drug Interactions; Drug Therapy, Combination; Fosfomycin; Kinetics; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Pneumococcal Infections; Streptococcus pneumoniae; Vancomycin

Using a clinical pneumococcal strain for which MICs were 4, 2, and 32 mg/liter for penicillin, amoxicillin, and fosfomycin, respectively, we studied the efficacies of these antibiotics alone and their combinations in the treatment of prolonged (48-h) experimental fibrin clot infection in rabbits. Treatments were as follows: amoxicillin IV at 20 mg/kg of body weight in one dose (Amo20), 50 mg/kg in one dose (Amo50), or two doses 6 h apart (Amo20 x 2 and Amo50 x 2); fosfomycin IV at a fixed dose of 50 mg/kg in one dose (Fos50) or two divided doses 6 h apart (Fos50 x 2); or the combinations of amoxicillin and fosfomycin with the same schedules. Maximum concentrations in clots were 2.03 +/- 1.02 and 2.13 +/- 0.33 mg/liter for Amo20 regimens, 3.7 +/- 1.9 and 4 +/- 1.3 mg/liter for Amo50 regimens, and 24 +/- 7 and 40 +/- 8 mg/liter for fosfomycin regimens, respectively. The mean half-lives of elimination from clots were between 2 and 3 h for amoxicillin regimens and between 5 and 7 h for fosfomycin. We observed the highest bacterial reductions (log10 CFU/gram) for Amo50 in two divided doses with or without fosfomycin. A significantly higher bacterial reduction than that with each monotherapy was observed when Amo20 was combined with fosfomycin in either one dose or two doses 6 h apart (0.16 +/- 0.8 and 1.64 +/- 1.6 log10 CFU/g for Amo20 in one and two doses, respectively, and 0.93 +/- 0.81 and 0.61 +/- 0.56 log10 CFU/g for fosfomycin in one and two doses, respectively, versus 3.46 +/- 1.26 and 3.16 +/- 1.31 log10 CFU/g for Amo20 plus fosfomycin in one and two doses, respectively [P < 0.001]). A time-dependent effect was observed with amoxicillin regimens. The time of regrowth was significantly delayed when amoxicillin was combined with fosfomycin. By using a multivariate analysis, we demonstrated that the most important parameter correlated to efficacy of the combination amoxicillin-fosfomycin was the length of the period during which the concentration of amoxicillin remained above the MIC. We demonstrated that the in vivo efficacy of the combination of amoxicillin and fosfomycin gave higher antibacterial effect than each monotherapy.

Topics: Amoxicillin; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Drug Therapy, Combination; Fibrin; Fosfomycin; Half-Life; Humans; Penicillin Resistance; Penicillins; Pneumococcal Infections; Rabbits; Streptococcus pneumoniae