Efficacy of linezolid versus a pharmacodynamically optimized vancomycin therapy in an experimental pneumonia model caused by methicillin-resistant Staphylococcus aureus.

OBJECTIVES: The British Thoracic Society, American Thoracic Society and Infectious Diseases Society of America guidelines recommend vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, based on evidence suggesting that a vancomycin AUC0₋24/MIC ratio of 400 predicts clinical success against MRSA pneumonia. The aim of this study was the evaluation of an optimized dose of vancomycin in the treatment of MRSA experimental pneumonia versus linezolid. METHODS: In vitro activities of vancomycin and linezolid were tested using time-kill curves. Experimental pneumonia in neutropenic C57BL/6 mice was achieved using two clinical MRSA strains, MR30 and MR33 (vancomycin and linezolid MICs of 1 and 4 mg/L, respectively). In vivo dosages were 30 and 110 mg/kg vancomycin (obtaining an AUC0₋24/MIC ratio lower and higher than 400, respectively), and 30 mg/kg linezolid. RESULTS: Survival rates in controls, and in the groups treated with 120 mg/kg/day vancomycin, 440 mg/kg/day vancomycin and 120 mg/kg/day linezolid were 85.7%, 92.9%, 76.9% and 100%, and 66.7%, 100%, 75% and 100% for MR30 and MR33, respectively. Sterile blood cultures occurred at rates of 21.4%, 64.3%, 100% and 93.8%, and 40%, 66.7%, 100% and 93.3% for MR30 and MR33 strains, respectively. Finally, the respective bacterial lung concentrations (log10 cfu/g) were 8.93 ±â€Š0.78, 6.67 ±â€Š3.01, 3.25 ±â€Š1.59 and 2.87 ±â€Š1.86 for MR30, and 8.62 ±â€Š0.72, 5.76 ±â€Š2.43, 3.97 ±â€Š1.52 and 1.59 ±â€Š1.40 for MR33. CONCLUSIONS: These results support that a vancomycin AUC0₋24/MIC ratio >400 is necessary to obtain a high bacterial lung reduction in MRSA pneumonia, comparable to that achieved with linezolid and better than that with the low dose of vancomycin tested. Linezolid was more efficacious than the pharmacodynamically optimized vancomycin dose in the pneumonia caused by the most virulent strain (MR33).

Efficacy of rifampin and its combinations with imipenem, sulbactam, and colistin in experimental models of infection caused by imipenem-resistant Acinetobacter baumannii.

There are currently no defined optimal therapies available for multidrug-resistant (MDR) Acinetobacter baumannii infections. We evaluated the efficacy of rifampin, imipenem, sulbactam, colistin, and their combinations against MDR A. baumannii in experimental pneumonia and meningitis models. The bactericidal in vitro activities of rifampin, imipenem, sulbactam, colistin, and their combinations were tested using time-kill curves. Murine pneumonia and rabbit meningitis models were evaluated using the A. baummnnii strain Ab1327 (with MICs for rifampin, imipenem, sulbactam, and colistin of 4, 32, 32, and 0.5 mg/liter, respectively). Mice were treated with the four antimicrobials and their combinations. For the meningitis model, the efficacies of colistin, rifampin and its combinations with imipenem, sulbactam, or colistin, and of imipenem plus sulbactam were assayed. In the pneumonia model, compared to the control group, (i) rifampin alone, (ii) rifampin along with imipenem, sulbactam, or colistin, (iii) colistin, or (iv) imipenem plus sulbactam significantly reduced lung bacterial concentrations (10.6 +/- 0.27 [controls] versus 3.05 +/- 1.91, 2.07 +/- 1.82, 2.41 +/- 1.37, 3.4 +/- 3.07, 6.82 +/- 3.4, and 4.22 +/- 2.72 log(10) CFU/g, respectively [means +/- standard deviations]), increased sterile blood cultures (0% versus 78.6%, 100%, 93.3%, 93.8%, 73.3%, and 50%), and improved survival (0% versus 71.4%, 60%, 46.7%, 43.8%, 40%, and 85.7%). In the meningitis model rifampin alone or rifampin plus colistin reduced cerebrospinal fluid bacterial counts (-2.6 and -4.4 log(10) CFU/ml). Rifampin in monotherapy or with imipenem, sulbactam, or colistin showed efficacy against MDR A. baumannii in experimental models of pneumonia and meningitis. Imipenem or sulbactam may be appropriate for combined treatment when using rifampin.

Efficacy of beta-lactams against experimental pneumococcal endocarditis caused by strains with different susceptibilities to penicillin.

OBJECTIVES: To compare the in vitro and in vivo activity of penicillin, cefotaxime and ceftriaxone, using three strains of Streptococcus pneumoniae with different susceptibilities to penicillin (MICs of 0.015, 0.25 and 2 mg/L, respectively). METHODS: Time-kill curves and an experimental model of endocarditis in rabbits. RESULTS: Penicillin was efficacious in clearing bacteria from vegetations and blood irrespective of whether infections were caused by penicillin-susceptible or penicillin-resistant strains (P < 0.01 with respect to control groups). The same efficacy was shown with cefotaxime and ceftriaxone. Comparing the results of the in vivo model with those obtained in time-kill curves, penicillin showed the best results. CONCLUSIONS: These results confirm that penicillin is efficacious in the treatment of pneumococcal infections, including those produced by strains with MICs < or = 2 mg/L (with the exception of pneumococcal meningitis). These results also suggest that the breakpoints to define susceptibility and resistance of S. pneumoniae to penicillin must be reviewed, as has been done with amoxicillin and third-generation cephalosporins.

Efficacy of cefepime and imipenem in experimental murine pneumonia caused by porin-deficient Klebsiella pneumoniae producing CMY-2 beta-Lactamase.

Previous studies have shown decreased in vitro activity of zwitterionic cephalosporins and carbapenems against porin-deficient Klebsiella pneumoniae expressing a plasmid-mediated AmpC-type beta-lactamase (PACBL). The in vitro and in vivo activities of cefepime and imipenem were evaluated against the porin-deficient strain K. pneumoniae C2 and its CMY-2-producing derivative [K. pneumoniae C2(pMG248)]. The MICs (in micrograms/milliliter) of cefepime and imipenem against K. pneumoniae C2 were 0.125 and 0.25, respectively, while the corresponding values against K. pneumoniae C2(pMG248) were 8 and 16. Cefepime showed a greater inoculum effect than imipenem against both strains. Imipenem showed a significant postantibiotic effect (>2 h) against K. pneumoniae C2(pMG248) at 1x, 2x, 4x, 6x, and 8x MIC. The maximum concentrations of drug in serum of cefepime and imipenem in a pneumonia model using mice were 124.1 and 16.9 mug/ml, respectively. DeltaT/MIC for K. pneumoniae C2 and C2(pMG248) were 1.29 h and 0.34 h for imipenem and 2.96 h and 1.27 h for cefepime. Both imipenem (30 mg/kg of body weight every 3 h) and cefepime (60 mg/kg every 4 h), administered for 72 h, increased the survival rate (86.6% and 100%) compared with untreated control animals (26.6%, P < 0.003) infected with K. pneumoniae C2. For the CMY-2-producing strain, imipenem, but not cefepime, increased the survival rate compared to the controls (86.6% and 40% versus 40%, P < 0.01). Bacterial concentration of the lungs was significantly decreased by both antimicrobials. In conclusion, imipenem was more active in terms of survival than cefepime for the treatment of murine pneumonia caused by a porin-deficient K. pneumoniae expressing PACBL CMY-2.

Activity of tigecycline (GAR-936) against Acinetobacter baumannii strains, including those resistant to imipenem.

We determined the in vitro activities of tigecycline and imipenem against 49 isolates of Acinetobacter baumannii, including those resistant to imipenem. The MIC at which 50% of the isolates were inhibited (MIC(50)) and the MIC(90) for tigecycline and imipenem were 2 and 2 mg/liter and 32 and 128 mg/liter, respectively, with 92 and 20%, respectively, of the strains being susceptible. Tigecycline did not show bactericidal activity in the time-kill studies (n = 9 strains). Imipenem showed bactericidal activity against seven out of nine strains. These in vitro results show that tigecycline has good in vitro bacteriostatic activity against A. baumannii, including strains resistant to imipenem.

Síndrome febril de larga evolución y demencia / Prolonged febrile syndrome and dementia

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