Penicillin- and Cephalosporin-Resistant Pneumococcal Meningitis: Treatment in the Real World and in Guidelines.

To report on the therapy used for penicillin- and cephalosporin-resistant pneumococcal meningitis, we conducted an observational cohort study of patients admitted to our hospital with pneumococcal meningitis between 1977 and 2018. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations, we defined pneumococci as susceptible and resistant to penicillin with MIC values of ≤0.06 mg/L and > 0.06 mg/L, respectively; the corresponding values for cefotaxime (CTX) were ≤0.5 mg/L and >0.5 mg/L. We treated 363 episodes of pneumococcal meningitis during the study period. Of these, 24 had no viable strain, leaving 339 episodes with a known MIC for inclusion. Penicillin-susceptible strains accounted for 246 episodes (73%), penicillin-resistant strains for 93 (27%), CTX susceptible for 58, and CTX resistant for 35. Nine patients failed or relapsed and 69 died (20%), of whom 22% were among susceptible cases and 17% were among resistant cases. During the dexamethasone period, mortality was equal (12%) in both susceptible and resistant cases. High-dose CTX (300 mg/Kg/day) helped to treat failed or relapsed cases and protected against failure when used as empirical therapy (P = 0.02), even in CTX-resistant cases. High-dose CTX is a good empirical therapy option for pneumococcal meningitis in the presence of a high prevalence of penicillin and cephalosporin resistance, effectively treating pneumococcal strains with MICs up to 2 mg/L for either penicillin or CTX.

Daptomycin combinations as alternative therapies in experimental foreign-body infection caused by meticillin-susceptible Staphylococcus aureus.

Whilst levofloxacin (LVX) in combination with rifampicin (RIF) is considered the optimal treatment for prosthetic joint infection (PJI) caused by meticillin-susceptible Staphylococcus aureus (MSSA), no therapeutic alternatives have been accurately evaluated. Based on the high effectiveness of the combination of daptomycin (DAP) plus RIF against meticillin-resistant S. aureus (MRSA) in this setting, in this study the efficacy of DAP+RIF and DAP+LVX combinations was tested as alternative therapies for foreign-body infections (FBIs) caused by MSSA. A tissue-cage infection model was performed using an MSSA strain. Male Wistar rats were treated for 7 days with LVX, DAP, RIF or the combinations LVX+RIF, DAP+RIF and DAP+LVX. Antibiotic efficacy was evaluated by bacterial counts from tissue cage fluid (TCF) and the cure rate was determined from adhered bacteria. Resistance was screened. Monotherapies were less effective than combinations (P<0.05), and resistance to DAP and RIF emerged. DAP+RIF (decrease in bacterial counts in TCF, -4.9logCFU/mL; cure rate, 92%) was the most effective therapy (P<0.05). There were no differences between LVX+RIF (-3.4logCFU/mL; 11%) and DAP+LVX (-3.3logCFU/mL; 47%). No resistant strains appeared with combined therapies. In conclusion, the combinations DAP+RIF and DAP+LVX showed good efficacy and prevented resistance. DAP+RIF provided higher efficacy than LVX+RIF. These DAP combinations were efficacious alternatives therapies for MSSA FBI. Further studies should confirm whether DAP+RIF may be useful as a first-line therapy in the setting of PJI caused by MSSA.

High doses of levofloxacin vs moxifloxacin against staphylococcal experimental foreign-body infection: the effect of higher MIC-related pharmacokinetic parameters on efficacy.

OBJECTIVES: Since levofloxacin at high doses was the best therapy in staphylococcal tissue-cage model of foreign-body infection, we hypothesized that moxifloxacin with higher ratio of area under the concentration-time curve to the MIC (AUC/MIC) would provide better results. METHODS: MICs, MBCs, MPCs (mutant prevention concentration) and 24h kill-curves were determined in the log and stationary phases. Using the aforementioned model, we tested the efficacy of levofloxacin 100mg/kg/d, moxifloxacin 40mg/kg/d and moxifloxacin 80mg/kg/d; they were equivalent to human levels for 1000mg/d, 400mg/d and 800mg/d, respectively. We screened for the appearance of resistant strains. RESULTS: MICs and MBCs in logarithmic and stationary phases and MPCs of levofloxacin were 0.5, 1 and 4, 0.8microg/ml, respectively, and those of moxifloxacin 0.12, 0.25 and 2, 0.25microg/ml. AUC/MIC were 234 (levofloxacin), 431 (moxifloxacin 40) and 568 (moxifloxacin 80). Bacterial counts decreases in tissue-cage fluids (means of logCFU/ml) were -1.81 (n=25), -1.31 (23), and -1.46 (20), respectively; for controls it was 0.24 (22). All groups were better than controls (p<0.05); no differences between them existed. CONCLUSIONS: Moxifloxacin with higher AUC/MIC ratio did not improve the efficacy of high doses of levofloxacin.

Efficacy of linezolid alone and in combination with rifampin in staphylococcal experimental foreign-body infection.

OBJECTIVES: The knowledge about efficacy of linezolid alone or in combination with rifampin in device infections is limited. We test their in vitro and in vivo efficacy in a rat model of foreign-body infection by methicillin-susceptible S. aureus. METHODS: In vitro studies for logarithmic and stationary bacteria were performed. In vivo efficacy (decrease in bacterial counts in tissue cage fluid) was evaluated at: (i) after 7-day therapy (groups: linezolid, cloxacillin, rifampin, linezolid-rifampin and cloxacillin-rifampin); and (ii) after 10-day therapy (groups: rifampin and linezolid-rifampin). RESULTS: After 7-day therapy all groups were significantly better than controls; linezolid (Delta log cfu/ml: -0.59, no resistant strains) and cloxacillin (-0.85) were the least effective therapy; linezolid was significantly less active (P<0.05) than rifampin (-1.22, resistance 90%), cloxacillin-rifampin (-1.3) and linezolid-rifampin (-1.14). After 10-day therapy linezolid-rifampin was the most effective treatment (Delta log -1.44, no resistance, P<0.05); in contrast, rifampin resulted ineffective (Delta log 0.1) due to the growth of resistant strains (100%). CONCLUSIONS: Linezolid alone showed moderate efficacy, whereas its combination with rifampin prevented the emergence of rifampin resistance. The efficacy of linezolid-rifampin combination was initially similar to that of rifampin alone, but in contrast to rifampin, it increased over time revealing the impact of protection against rifampin resistance and the benefits of rifampin activity.

Evaluation of ceftriaxone, vancomycin and rifampicin alone and combined in an experimental model of meningitis caused by highly cephalosporin-resistant Streptococcus pneumoniae ATCC 51916.

OBJECTIVES: The aim of the study was to assess the in vitro and in vivo efficacy of ceftriaxone, vancomycin and rifampicin alone and combined against Streptococcus pneumoniae ATCC 51916 (MIC of ceftriaxone: 32 mg/L). METHODS: In vitro killing curves were performed with clinically achievable CSF antibiotic concentrations. In the rabbit model of pneumococcal meningitis, we studied the efficacy of and effects on inflammation of treatment with ceftriaxone 100 mg/kg/day, vancomycin 30 mg/kg/day and rifampicin 15 mg/kg/day, alone and combined, over a 26 h period. RESULTS: Time-kill curves showed that vancomycin was bactericidal, and ceftriaxone and rifampicin produced a bacteriostatic effect. An additive effect was observed when combinations of ceftriaxone plus vancomycin were studied at subinhibitory concentrations. Emergence of resistance to rifampicin was detected both when rifampicin was studied alone and when combined with ceftriaxone or vancomycin. In the rabbit meningitis model, ceftriaxone was bacteriostatic, whereas rifampicin and vancomycin were bactericidal at 24 h. Although not synergistic, the combinations of ceftriaxone plus vancomycin or rifampicin, and vancomycin plus rifampicin, improved the efficacy of any antibiotic tested alone--all combinations were bactericidal from 6 h--and significantly decreased inflammatory parameters in CSF compared with control and ceftriaxone groups. CONCLUSION: Ceftriaxone plus vancomycin, and vancomycin plus rifampicin appeared to be effective in the therapy of experimental pneumococcal meningitis caused by highly cephalosporin-resistant strains such as ATCC 51916. Our results provide an experimental basis for using these combinations as empirical therapy for pneumococcal meningitis, regardless of the degree of cephalosporin resistance of the causative strain.

Antibiotic combinations for serious infections caused by carbapenem-resistant Acinetobacter baumannii in a mouse pneumonia model.

OBJECTIVES: Successful therapy of carbapenem-resistant Acinetobacter baumannii strains has been reported with colistin, but recently we argued against its use as monotherapy because of the poor results obtained in a mouse pneumonia model. Our aim was to identify antibiotic combinations that were valid therapeutic alternatives in the same model. METHODS: We used two carbapenem-resistant A. baumannii strains (D and E; MICs of imipenem, 8 and 512 mg/L, respectively). MICs of tobramycin, rifampicin and colistin for both strains were 8, 8 and 0.5 mg/L, respectively. RESULTS: In infections caused by strain D, lung bacterial counts (log(10) cfu/g, mean +/- s.d.) were: controls (10.86+/-0.25), imipenem (5.99+/-0.59, P < 0.05 versus controls), and colistin (10.43 +/- 1.09); imipenem + tobramycin was the most active combination (5.46+/-0.62, P < 0.05 versus controls). In infections caused by strain E, results were: controls (10.82+/-0.33), rifampicin (5.62+/-0.26, P < 0.05 versus controls), colistin (8.38+/-1.22, P < 0.05 versus controls), and imipenem (11.01+/-0.2); rifampicin + imipenem (3.79+/-0.99) and rifampicin + tobramycin (3.96+/-0.30) were the most active combinations (P < 0.05); results with rifampicin + colistin (5.59+/-1.17) were similar to those with rifampicin alone. CONCLUSIONS: Our data indicate that imipenem can still be the best alternative for carbapenem-resistant A. baumannii infections with moderate levels of imipenem resistance, preferably combined with aminoglycosides. For strains highly resistant to imipenem, a combination of rifampicin with imipenem, tobramycin or colistin may be useful, if resistance to rifampicin is only moderate.

A mouse peritonitis model for the study of glycopeptide efficacy in GISA infections.

In recent years, the emergence of Staphylococcus aureus strains with reduced susceptibility to glycopeptides has raised considerable concern. We studied the efficacy of vancomycin and teicoplanin, as well as cloxacillin and cefotaxime, against the infection caused by four S. aureus strains with different glycopeptide and beta-lactam susceptibilities (strains A, B, C, and D; MICs for vancomycin of 1, 2, 4, and 8 microg/ml respectively), using a modified model of mouse peritonitis. This optimized model appeared to be straightforward and reproducible, and was able to detect low differences in bacterial killing between antibiotics and also between different S. aureus strains. Bactericidal activities in peritoneal fluid for vancomycin, teicoplanin, cloxacillin, and cefotaxime decreased from -2.98, -2.36, -3.22, and -3.57 log(10) cfu/ml, respectively, in infection by strain A (MICs for vancomycin and cloxacillin of 1 and 0.38 microg/ml, respectively) to -1.22, -0.65, -1.04, and +0.24 in peritonitis due to strain D (MICs for vancomycin and cloxacillin of 8 and 1,024 microg/ml). Our data confirm the superiority of beta-lactams against methicillin-susceptible S. aureus and show that bactericidal activity of glycopeptides decreases significantly with slight increases in MICs; this finding suggests a reduced efficacy of glycopeptides in the treatment of serious glycopeptide-intermediate S. aureus infections.

Experimental study of LY333328 (oritavancin), alone and in combination, in therapy of cephalosporin-resistant pneumococcal meningitis.

Using a rabbit model of meningitis, we sought to determine the efficacy of LY333328, a semisynthetic glycopeptide, in the treatment of cephalosporin-resistant pneumococcal meningitis. LY333328 was administered at a dose of 10 mg/kg of body weight/day, alone and in combination with ceftriaxone at 100 mg/kg/day with or without dexamethasone at 0.25 mg/kg/day. The therapeutic groups were treated with LY333328 with or without dexamethasone and LY333328-ceftriaxone with or without dexamethasone. Rabbits were inoculated with a cephalosporin-resistant pneumococcal strain (ceftriaxone MIC, 2 microg/ml; penicillin MIC, 4 microg/ml; LY333328 MIC, 0.008 microg/ml) and were treated over a 26-h period beginning 18 h after inoculation. The bacterial counts in cerebrospinal fluid (CSF), the white blood cell count, the lactic acid concentration, the CSF LY333328 concentration, and bactericidal and bacteriostatic activities were determined at different time points. In vitro, LY333328 was highly bactericidal and its use in combination with ceftriaxone at one-half the MIC was synergistic. In the rabbit model, LY333328 alone was an excellent treatment for cephalosporin-resistant pneumococcal meningitis, with a rapid decrease in colony counts and no therapeutic failures. The use of LY333328 in combination with ceftriaxone improved the activity of LY333328, but no synergistic effect was observed. The combination of LY333328 with dexamethasone was also rapidly bactericidal, but two therapeutic failures were observed. The combination of LY333328 with ceftriaxone and dexamethasone was effective, without therapeutic failures.