A pooled analysis of telithromycin in the treatment of community-acquired respiratory tract infections in adults.

BACKGROUND: Thirteen multinational, Phase III studies were conducted to establish the efficacy of telithromycin 800 mg once daily in the treatment of community-acquired respiratory tract infections (RTIs). PATIENTS AND METHODS: Data were analyzed from 4,743 adult patients participating across four indications: community-acquired pneumonia (CAP) of mild to moderate severity, acute exacerbations of chronic bronchitis (AECB), acute maxillary sinusitis (AMS) and tonsillitis/pharyngitis. RESULTS: Treatment with telithromycin for either 5 days (AECB, AMS and tonsillitis/pharyngitis) or 7-10 days (CAP and AMS) provided high rates of clinical and bacteriologic cure (5-day, 87.0% and 86.0%, respectively; 7 to 10-days, 90.3% and 90.5%, respectively) that were equivalent to those of a 10-day course of comparator antibacterials (86.5% and 86.5%, respectively). The clinical efficacy of telithromycin extended to high-risk CAP and AECB patients and to all key respiratory pathogens, including Streptococcus pneumoniae strains resistant to penicillin or erythromycin and atypical/intracellular pathogens. Telithromycin was generally well-tolerated across patient groups. CONCLUSION: These findings support the use of telithromycin as an effective therapy for the treatment of community-acquired RTIs.

Activities of the combination of quinupristin-dalfopristin with rifampin in vitro and in experimental endocarditis due to Staphylococcus aureus strains with various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics.

We evaluated the activities of quinupristin-dalfopristin (Q-D), alone or in combination with rifampin, against three strains of Staphylococcus aureus susceptible to rifampin (MIC, 0.06 microg/ml) and to Q-D (MICs, 0.5 to 1 microg/ml) but displaying various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics: S. aureus HM1054 was susceptible to quinupristin and dalfopristin (MICs of 8 and 4 microg/ml, respectively); for S. aureus RP13, the MIC of dalfopristin was high (MICs of quinupristin and dalfopristin for strain RP13, 8 and 32 microg/ml, respectively); and S. aureus HM1054R was obtained after conjugative transfer of macrolide-lincosamide-streptogramin B constitutive resistance to HM1054, and the MIC of quinupristin for this strain was high (MICs of quinupristin and dalfopristin, 64 and 4 microg/ml, respectively). In vitro time-kill curve studies showed an additive effect [corrected] between Q-D and rifampin, at a concentration of four times the MIC, against the three strains. Rabbits with aortic endocarditis were treated 4 days with Q-D, rifampin, or their combination. In vivo, the combination was highly bactericidal and synergistic against strains susceptible to quinupristin (HM1054 and RP13) and sterilized 94% of the animals. In contrast, the combination was neither synergistic nor bactericidal against the quinupristin-resistant strain (HM1054R) and did not prevent the emergence of mutants resistant to rifampin. We conclude that the in vivo synergistic and bactericidal activity of the combination of Q-D and rifampin against S. aureus is predicted by the absence of resistance to quinupristin but not by in vitro combination studies.

Differential selection of multidrug efflux mutants by trovafloxacin and ciprofloxacin in an experimental model of Pseudomonas aeruginosa acute pneumonia in rats.

The ability of trovafloxacin and ciprofloxacin to select efflux mutants in vivo was studied in a model of acute Pseudomonas aeruginosa pneumonia in rats. Twelve hours after intratracheal inoculation of 10(6) CFU of P. aeruginosa strain PAO1 enmeshed in agar beads, two groups of 12 rats were treated by three intraperitoneal injections of each antibiotic given every 5 h. Dosing regimens were chosen to obtain a comparable area under the concentration-time curve from 0 to infinity/MIC ratio of 27.9 min for trovafloxacin (75 mg/kg of body weight) and of 32.6 min for ciprofloxacin (12.5 mg/kg). Twelve rats were left untreated and served as controls. Rats were sacrificed 12 h after the last injection (34 h after infection) for lung bacteriological studies. Selection of resistant bacteria was determined by plating lung homogenates on Trypticase soy agar plates containing antibiotic. In untreated animals, the frequency of resistant colonies was 10-fold higher than in agar beads. Compared to controls, both treatment regimens resulted in a 2-log reduction of lung bacterial load. The frequency of resistant colonies was 10-fold less with trovafloxacin than with ciprofloxacin at twice the MIC (7.4 x 10(-5) versus 8.4 x 10(-4), respectively) (P < 0.05) and at four times the MIC (6.2 x 10(-4) versus 5.0 x 10(-5), respectively) (P < 0.05). A multidrug resistance phenotype typical of efflux mutants was observed in all 41 randomly tested colonies obtained from treated and untreated rats. In agreement with in vitro results, trovafloxacin and ciprofloxacin preferentially selected MexCD-OprJ and MexEF-OprN overproducers, respectively. These results demonstrate the differential ability of trovafloxacin and ciprofloxacin to select efflux mutants in vivo and highlight the rapid emergence of those mutants, even without treatment.

In vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia.

We evaluated the in vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia using a susceptible strain and one with low-level resistance (MIC/MBC of levofloxacin: 0.06/0.06 and 4/4 mg/L, respectively). As demonstrated previously with other pathogens, the AUC/MIC ratio predicted the efficacy of fluoroquinolones against A. baumannii. This parameter correlated with bactericidal effect and survival. Combination therapy did not enhance the efficacy of levofloxacin.

Activity of LY333328 combined with gentamicin in vitro and in rabbit experimental endocarditis due to vancomycin-susceptible or -resistant Enterococcus faecalis.

We investigated the activity of LY333328 alone and combined with gentamicin, both in vitro and in a rabbit model of experimental endocarditis, against the susceptible strain Enterococcus faecalis JH2-2 and its two glycopeptide-resistant transconjugants, BM4316 (VanA) and BM4275 (VanB). MICs of LY333328 and gentamicin were 2 and 16 microgram/ml, respectively, for the three strains. In vitro, LY333328 alone was bactericidal at 24 h against JH2-2 at a concentration of 2 microgram/ml and against BM4316 and BM4275 at a concentration of 30 microgram/ml. The combination of LY333328 and gentamicin (4 microgram/ml) was synergistic and bactericidal after 24 h of incubation against the three strains at LY333328 concentrations of 2 microgram/ml for JH2-2 and 8 microgram/ml for BM4275 and BM4316. The combination of LY333328 and gentamicin was the only regimen demonstrating in vitro bactericidal activity against BM4316. In vivo, intravenous treatment with LY333328 alone, providing peak and trough serum levels of 83.3 +/- 1.3 and 3.8 +/- 0.2 microgram/ml, respectively, was inactive against BM4316 and BM4275 and selected mutants resistant to LY333328 in half of the rabbits infected with the VanA-type strain (MICs, 8 to 20 microgram/ml). However, the LY333328-gentamicin combination was active against the three strains and prevented the emergence of mutants resistant to both components of the combination. We conclude that the LY333328-gentamicin combination might be of interest for the treatment of enterococcal infections, particularly against VanA-type strains.

Influence of resistance to streptogramin A type antibiotics on the activity of quinupristin-dalfopristin in vitro and in experimental endocarditis due to Staphylococcus aureus.

We evaluated the activity of quinupristin-dalfopristin (Q-D) against three clinical strains of Staphylococcus aureus susceptible to Q (MIC, 8 microg/ml) and Q-D (MICs, 0.5 to 1 microg/ml) but displaying various levels of susceptibility to D. D was active against S. aureus HM 1054 (MIC, 4 microg/ml) and had reduced activity against S. aureus RP 13 and S. aureus N 95 (MICs, 32 and 64 microg/ml, respectively). In vitro, Q-D at a concentration two times the MIC (2xMIC) produced reductions of 4.3, 3.9, and 5.8 log(10) CFU/ml after 24 h of incubation for HM 1054, RP 13, and N 95, respectively. Comparable killing was obtained at 8xMIC. Q-D-resistant mutants were selected in vitro at a frequency of 2 x 10(-8) to 2 x 10(-7) for the three strains on agar containing 2xMIC of Q-D; no resistant bacteria were detected at 4xMIC. Rabbits with aortic endocarditis were treated for 4 days with Q-D at 30 mg/kg of body weight intramuscularly (i.m.) three times a day (t.i.d.) or vancomycin at 50 mg/kg i.m. t.i.d. In vivo, Q-D and vancomycin were similarly active and bactericidal against the three tested strains compared to the results for control animals (P < 0.01). Among animals infected with RP 13 and treated with Q-D, one rabbit retained Q-D-resistant mutants that were resistant to Q and to high levels of D (MICs, 64, >256, and 8 microg/ml for Q, D, and Q-D, respectively). We conclude that the bactericidal activity of Q-D against strains with reduced susceptibility to D and susceptible to Q-D is retained and is comparable to that of vancomycin. Acquisition of resistance to both Q and D is necessary to select resistance to Q-D.

In vivo efficacies of combinations of beta-lactams, beta-lactamase inhibitors, and rifampin against Acinetobacter baumannii in a mouse pneumonia model.

The effects of various regimens containing combinations of beta-lactams, beta-lactam inhibitor(s), and rifampin were assessed in a recently described mouse model of Acinetobacter baumannii pneumonia (M. L. Joly-Guillou, M. Wolff, J. J. Pocidalo, F. Walker, and C. Carbon, Antimicrob. Agents Chemother. 41:345-351, 1997). Two aspects of the therapeutic response were studied: the kinetics of the bactericidal effect (treatment was initiated 3 h after intratracheal inoculation, and bacterial counts were determined over a 24-h period) and survival (treatment was initiated 8 h after inoculation, and the cumulative mortality rate was assessed on day 5). Two clinical strains were used: a cephalosporinase-producing strain (SAN-94040) and a multiresistant strain (RCH-69). For SAN-94040 and RCH-69, MICs and MBCs (milligrams per liter) were as follows: ticarcillin, 32, 64, 256, and >256, respectively; ticarcillin-clavulanate, 32, 64, and 512, and >512, respectively; imipenem, 0.5, 0.5, 8, and 32, respectively; sulbactam, 0.5, 0.5, 8, and 8, respectively; and rifampin, 8, 8, 4, and 4, respectively. Against SAN-94040, four regimens, i.e., imipenem, sulbactam, imipenem-rifampin, and ticarcillin-clavulanate (at a 25/1 ratio)-sulbactam produced a true bactericidal effect (>/=3-log10 reduction of CFU/g of lung). The best survival rate (i.e., 93%) was obtained with the combination of ticarcillin-clavulanate-sulbactam, and regimens containing rifampin provided a survival rate of >/=65%. Against RCH-69, only regimens containing rifampin and the combination of imipenem-sulbactam had a true bactericidal effect. The best survival rates (>/=80%) were obtained with regimens containing rifampin and sulbactam. These results suggest that nonclassical combinations of beta-lactams, beta-lactamase inhibitors, and rifampin should be considered for the treatment of nosocomial pneumonia due to A. baumannii.

Low dosage and long treatment duration of beta-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae.

CONTEXT: The spread of drug-resistant Streptococcus pneumoniae in the community is a public health problem in developed and developing nations, but whether antibiotic use is responsible for the increase in drug resistance is not known. OBJECTIVE: To analyze the relationship between penicillin-resistant S pneumoniae (PRSp) pharyngeal carriage and characteristics of beta-lactam use. DESIGN: Observational study of children attending 20 randomly sampled schools. SETTING: The Loiret, in the center of France. PARTICIPANTS: A total of 941 children, 3 to 6 years old. MAIN OUTCOME MEASURE(S): Pharyngeal carriage of S pneumoniae, antibiotic use, and medical events during the preceding 30 days. Pneumococcal penicillin G sodium minimal inhibitory concentrations and serotyping were performed. RESULTS: Medical illnesses and the use of antibiotics were not associated with PRSp carriage. However, oral beta-lactam use was associated with an increased risk of PRSp carriage (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.1-8.3; P=.03). Children treated by low daily doses of an oral beta-lactam (defined as lower than clinical recommendations) had an increased risk of PRSp carriage, as compared with children who did not (OR, 5.9; 95% CI, 2.1-16.7; P=.002). A treatment of long duration (>5 days) with a beta-lactam was associated with an increased risk of PRSp carriage (OR, 3.5; 95% CI, 1.3-9.8; P=.02). CONCLUSIONS: Our results suggest that a low daily dose and a long duration of treatment with an oral beta-lactam contribute to the selective pressure in promoting pharyngeal carriage of PRSp.

Influence of inducible cross-resistance to macrolides, lincosamides, and streptogramin B-type antibiotics in Enterococcus faecium on activity of quinupristin-dalfopristin in vitro and in rabbits with experimental endocarditis.

The influence of inducible cross-resistance to macrolides, lincosamides, and streptogramin B (MLS(B)) type antibiotics (inducible MLS(B) phenotype) on the activity of quinupristin-dalfopristin was investigated against Enterococcus faecium in vitro and in rabbits with experimental endocarditis. In vitro, quinupristin-dalfopristin displayed bacteriostatic and bactericidal activities against a MLS(B)-susceptible strain similar to those against two strains with the inducible MLS(B) phenotype. In addition, induction of the two MLS(B)-resistant strains with quinupristin (0.016 to 1 microg/ml) or quinupristin-dalfopristin (0.08 to 0.25 microg/ml) increased the MICs of quinupristin from 8 microg/ml to 32 to > 128 microg/ml, but did not modify the MIC of dalfopristin (2 microg/ml) or quinupristin-dalfopristin (0.5 microg/ml). In a rabbit endocarditis model, quinupristin-dalfopristin was as active as amoxicillin against the MLS(B)-susceptible E. faecium strain. In contrast, the activity of quinupristin-dalfopristin was significantly decreased in animals infected with either of the two inducible MLS(B)-resistant strains (P < 0.05), although no mutants resistant to quinupristin-dalfopristin were detected. Against the clinical strain with the inducible MLS(B) phenotype, quinupristin-dalfopristin was not effective and was less active than amoxicillin (P < 0.001); however, the activity of the combination of amoxicillin and dalfopristin-quinupristin was superior to that of amoxicillin (P < 0.01). The different impact of the inducible MLS(B) phenotype in E. faecium on the activity of quinupristin-dalfopristin in vitro and in experimental endocarditis may be related to the reduced diffusion of dalfopristin compared with that of quinupristin into cardiac vegetations that we previously reported. This result emphasizes the importance of the constant presence of dalfopristin at the site of infection to ensure synergism with quinupristin.

Efficacies of cefotaxime and ceftriaxone in a mouse model of pneumonia induced by two penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniae.

We previously demonstrated the efficacy of ceftriaxone (CRO), at 50 mg/kg of body weight every 12 h, against a highly penicillin-resistant (MIC, 4 micrograms/ml) Streptococcus pneumoniae strain with low-level resistance to CRO (MIC, 0.5 microgram/ml) in a leukopenic-mouse pneumonia model (P. Moine, E. Vallée, E. Azoulay-Dupuis, P. Bourget, J.-P. Bédos, J. Bauchet, and J.-J. Pocidalo, Antimicrob. Agents Chemother. 38:1953-1958, 1994). In the present study, we assessed the activity of CRO versus those of cefotaxime (CTX) and amoxicillin (AMO) against two highly penicillin- and cephalosporin-resistant S. pneumoniae strains (P40422 and P40984) (MICs of 2 and 8 for penicillin, 2 and 4 for AMO, and 4 and 8 for CRO or CTX, respectively). Against both strains, a greater than an 80% cumulative survival rate was observed with CRO at a dose of 100 or 200 mg/kg every 12 h (dose/MIC ratio, 25). With CTX, a high dosage of 400 mg/kg (dose/MIC ratio, 100 or 50) administered every 8 h (TID) was needed to protect 66 and 75% of the animals, respectively, with no statistically significant differences versus CRO. Against the P40422 strain, CRO (100 mg/kg) produced the greatest bactericidal effect, from the 8th to the 24th hour after a single injection (1.8-log-unit reduction over 24 h), and the fastest bacterial pulmonary clearance during treatment; with CTX, only multiple injections at a high dosage, i.e., 400 mg/kg TID, demonstrated a significant bactericidal effect. AMO in a high dosage, 400 mg/kg (dose/MIC ratio, 200) TID, showed good activity only against the P40422 strain. Despite the identical MICs of CTX and CRO, the longer time (3.6 to 4.6 h) that serum CRO concentrations remained above the MICs for the pathogens at a dose of 100 mg/kg resulted in greater efficacy versus CTX against highly penicillin- and cephalosporin-resistant S. pneumoniae strains.

Efficacy of single-dose ceftriaxone in experimental otitis media induced by penicillin- and cephalosporin-resistant Streptococcus pneumoniae.

We used a gerbil model of otitis media to assess the efficacy of single-dose ceftriaxone against three Streptococcus pneumoniae strains highly resistant to penicillin (MICs, 4 to 8 micrograms/ml) and with various susceptibilities to ceftriaxone (MICs, 0.5, 4, and 8 micrograms/ml). Middle ear infection was induced by bilateral transbullar challenge with 10(7) bacteria per ear. Antibiotic treatment was administered subcutaneously at 2 h postinfection. Infection status was checked 2 days later by counting the bacteria in middle ear and cerebrospinal fluid samples. With the cefriaxone-susceptible strain (MIC, 0.5 microgram/ml), we tested doses of 5 to 100 mg/kg of body weight. With a dose of 50 mg/kg, treatment outcome was equivalent to that with amoxicillin, which was used as a reference (25 mg/kg, two injections); no bacteria were recovered from 82% of the middle ear samples, and the rate of cerebrospinal fluid culture positivity was significantly reduced to 6%, relative to 59% for the untreated controls. Similar efficacy was obtained with a dose of 100 mg/kg against the two ceftriaxone-resistant strains. Pharmacokinetic study indicates that the values of the parameters in plasma after the administration of a dose of 100 mg/kg (peak level of total drug, 268 +/- 33 micrograms/ml; elimination half-life, 0.8 h; area under concentration-time curve, 488 micrograms.h.ml-1) were still suboptimal compared with the values of the parameters measured in pediatric patients after intravenous or intramuscular administration of a dose of 50 mg/kg. Our results indicate the efficacy of ceftriaxone against experimental cephalosporin-resistant pneumococcal otitis and provide a basis for the clinical use of single-dose ceftriaxone against pneumococcal otitis media.

Efficacy of sparfloxacin and autoradiographic diffusion pattern of [14C]Sparfloxacin in experimental Staphylococcus aureus joint prosthesis infection.

Using a new rabbit model of methicillin-susceptible Staphylococcus aureus knee prosthesis infection, we compared the efficacies of sparfloxacin (50 mg/kg of body weight subcutaneously, twice a day) and pefloxacin (50 mg/kg subcutaneously, twice a day). A partial knee replacement was performed with a silicone implant fitted into the intramedullary canal of the tibia, and 5 x 10(7) CFU of methicillin-susceptible S. aureus was injected into the knee. The 7-day treatment regimen was started 15 days later. The MICs and MBCs of sparfloxacin and pefloxacin were, respectively, 0.06 and 0.25 microgram/ml (MIC) and 0.25 and 1 microgram/ml (MBC). The peak levels of sparfloxacin and pefloxacin in serum were 3.6 and 21 micrograms/ml, respectively. Three weeks after the end of treatment, animals were sacrificed and tibias were removed, pulverized, and quantitatively cultured. In contrast to pefloxacin (3.61 +/- 1.64 log10 CFU/g of bone), sparfloxacin significantly reduced the bacterial density (2.12 +/- 1.1 log10 CFU/g of bone) (P = 0.01) in comparison with the level in controls (4.59 +/- 1.21 log10 CFU/g of bone), without selection of resistant variants. Sparfloxacin was significantly more effective than pefloxacin (P = 0.025). The autoradiographic pattern of [14C]sparfloxacin diffusion was studied in noninfected animals with prostheses and in infected animals 15 days after inoculation. Sixty minutes after completion of infusion of 250 microCi of [14C]sparfloxacin, in infected animals the highest levels of radioactivity were detected around the prosthesis, in femoral cartilage, and in articular ligaments. Radioactivity was slightly less intense in bone marrow and muscles and was very weak in compact bone. The distribution of sparfloxacin in uninfected rabbits was similar. Thus, sparfloxacin may represent a valid alternative therapy in these infections provided that it is carefully monitored for potential side effects.

Synergy between amoxicillin and gentamicin in combination against a highly penicillin-resistant and -tolerant strain of Streptococcus pneumoniae in a mouse pneumonia model.

In vivo synergy with beta-lactam antibiotics and aminoglycosides has been studied only with penicillin-susceptible Streptococcus pneumoniae strains. We evaluated the interaction between amoxicillin (AMX) and gentamicin (GEN) on the basis of in vitro checkerboard and time-kill curves and of findings in a mouse model of acute bacteremic pneumonia due to a highly penicillin-resistant and -tolerant S. pneumoniae strain of serotype 19 (penicillin and AMX MICs of 4 micrograms/ml; gentamicin MIC of 16 micrograms/ml). Checkerboard results at 18 h of incubation showed indifference. With regard to AMX alone, in vitro time-kill curves demonstrated synergy between AMX (1 microgram/ml) and GEN (16 micrograms/ml) at 5 and 8 h of incubation and for AMX (16 micrograms/ml) in combination with GEN (16 micrograms/ml) at 3, 5, and 8 h of incubation. In leukopenic mice, pulmonary killing curves after a single drug injection demonstrated that AMX (100 mg/kg of body weight) with GEN (16 mg/kg) was more effective than AMX alone (P = 10(-4). With repeated-dose treatment, a synergy was apparent at 8 h after four injections with AMX (100 mg/kg) in combination with GEN (8 or 16 mg/kg) (P < or = 0.05). The cumulative survival rate with AMX (100 mg/kg) every 8 h, combined with GEN (4 or 8 mg/kg) every 8, 12, or 24 h, was better than with AMX alone. Combined use of AMX and GEN may be a valuable therapeutic alternative for pneumococcal pneumonia due to highly penicillin-resistant S. pneumoniae strains.

[Streptococcus pneumoniae bacteremia and HIV infection. Retrospective study of 41 episodes in 30 patients]. / Bactérièmies à Streptococcus pneumoniae et infection par le VIH. Etude rétrospective de 41 épisodes chez 30 malades.

OBJECTIVES: Pulmonary infections and bacteraemia, essentially due to Streptococcus pneumoniae and Haemophilus influenzae, are frequently reported in patients infected with the human immunodeficiency virus (HIV). We retrospectively analyzed episodes of bacteraemia in HIV-infected patients to determine whether supplementary risk factors could be ascertained and whether it would be advisable to propose vaccination. METHODS: From June 1986 to February 1992, 41 episodes of bacteraemia in 30 HIV-infected patients were observed in 7 different wards. Data on age, sex, risk group, Centers for Disease Control classification, CD4 counts and clinical outcome were recorded. RESULTS: There were 18 males and 12 females, mean age 34 years (range 26-67 years) in CDC class II (n = 11), III (n = 5) and IV (n = 16). There were 17 intravenous drug users (56.6%). There were 8 heterosexuals (26%), 3 homosexuals or bisexuals (n = 3) and 2 patients infected after blood transfusions (6%). All the heterosexual patients were of black-African or Carabean ethnic origin. Mean CD4 count was 239 mm3 (range 2-1148) during the episode of bacteraemia which occurred during an upper respiratory tract infection in 96% of the patients. Recurrent episodes were observed in 7 patients. Outcome of the infectious episode was favourable in 35/41 cases after antibiotic therapy. Six patients (all CDC class IV) died during the episode of bacteraemia. CONCLUSIONS: These observations showed that intravenous drug use and black-African ethnic origin are supplementary risk factors for S. pneumoniae infection in HIV-infected patients. The frequency of upper respiratory tract infections in these patients suggests that anti-S. pneumoniae vaccination should be evaluated further.

Influence of antimicrobial therapy on kinetics of tumor necrosis factor levels in experimental endocarditis caused by Klebsiella pneumoniae.

The kinetics of tumor necrosis factor (TNF) levels in serum during therapy with cell wall-active agents (ceftriaxone, imipenem) and gentamicin were investigated in rabbits with experimental endocarditis caused by an isogenic pair of Klebsiella pneumoniae strains: a TEM-3 beta-lactamase-producing strain (KpR) or its susceptible variant (KpS). In vitro, KpR was resistant to ceftriaxone and was susceptible to gentamicin and imipenem, while KpS was susceptible to all three antibiotics. Serum TNF levels were determined in control rabbits hourly after bacterial inoculation and then daily; they were determined in treated animals hourly after the first antibiotic injection and then daily during a 4-day therapy with either imipenem (60 mg/kg of body weight four times daily), ceftriaxone (75 mg/kg once daily), or gentamicin (4 mg/kg once daily) alone or in combination with ceftriaxone. After a transient peak (10.2 +/- 3.1 ng/ml) at 90 min following bacterial challenge, serum TNF levels remained low and stable in control animals. The peak in the serum TNF levels occurred 4 h after the first antibiotic injection and with ceftriaxone was significantly higher (P < 0.05) against KpS (1.99 +/- 0.52 ng/ml) than against KpR (1.40 +/- 0.17 ng/ml). Against the KpR strain, the levels observed with ceftriaxone were significantly higher (P < 0.05) than those obtained with the other therapeutic regimens (0.70 to 0.80 ng/ml). On the day of sacrifice, effective regimens were associated with low TNF levels. We concluded that TNF production depends on (i) the antiobiotic's mechanism of action and the susceptibility of the strain at the early phase of therapy, without any effect of the rapidity of bacterial killing, and (ii) the final reduction of the bacterial count at a later stage of therapy.

Dextranase enhances antibiotic efficacy in experimental viridans streptococcal endocarditis.

In endocarditis, exopolysaccharide production by viridans streptococci has been associated with delayed antimicrobial efficacy in cardiac vegetations. We compared the efficacies of temafloxacin alone and in combination with dextranase, an enzyme capable of hydrolyzing 20 to 90% of the bacterial glycocalyx, in a rabbit model of endocarditis. In in vivo experiments, rabbits were infected intravenously with 10(8) Streptococcus sanguis organisms and were treated 6 days later with temafloxacin (50 mg/kg of body weight intramuscularly twice a day) alone or combined with dextranase (1,000 U per rabbit per day intravenously). After 4 days of treatment (day 11), the animals were sacrificed and vegetations were quantitatively cultured. For ex vivo experiments, rabbits were infected as stated above and, on day 11, vegetations were excised aseptically and incubated in vitro in rabbit serum alone (control) or with temafloxacin or temafloxacin plus dextranase at concentrations similar to peak levels in plasma. In vitro, dextranase alone had no antimicrobial effect. In vivo and ex vivo, temafloxacin combined with dextranase was more effective than temafloxacin alone (P < 0.05). Our results suggest that dextranase is able to increase the effects of temafloxacin by reducing the amount of bacterial glycocalyx in infected vegetations, as confirmed in vitro by electron microscopy showing a markedly reduced amount of glycocalyx and a more clearly visible fibrin matrix.

Investigation of the potential role of Enterococcus faecalis in the pathophysiology of experimental peritonitis.

Two nonfatal models of peritonitis differing by the duration and the severity of the disease were studied in rats by implantation of Escherichia coli and Bacteroides fragilis with or without increasing concentrations of Enterococcus faecalis. Results were evaluated at 3 or 6 days after inoculation. The highest enterococcal concentrations (10(9) cfu/mL) enhanced the severity of the infection, evident by increased emaciation, increased peritoneal counts of E. coli and B. fragilis, and increased frequency of E. coli and B. fragilis bacteremia compared with enterococcus-free animals. Six therapeutic regimens (low-dose amoxicillin + low-dose gentamicin, high-dose amoxicillin + high-dose gentamicin, pefloxacin, ornidazole, pefloxacin + ornidazole, imipenem + gentamicin) were tested. All treatments failed to eradicate E. faecalis except the combination pefloxacin + ornidazole, which achieved a significant reduction of local bacterial counts and suppressed bacteremia. Enterococcus played an important role in the mechanisms of bacterial synergy in experimental peritonitis. However, eradication of enterococcus did not seem possible by conventional antienterococcal therapy.

Conditions for the emergence of resistance to cefpirome and ceftazidime in experimental endocarditis due to Pseudomonas aeruginosa.

The conditions for the emergence of resistance to cefpirome and ceftazidime were studied in rabbits with experimental aortic endocarditis due to Pseudomonas aeruginosa. The MIC of cefpirome was 16 mg/L and that of ceftazidime was 4 mg/L. Resistant mutants with MICs of > or = 64 mg/L were obtained in vitro to cefpirome after a single passage and to ceftazidime after five passages. A single dose of 50 mg/kg intramuscularly gave mean peak serum concentrations of 110.0 +/- 31.7 mg/L for cefpirome compared with 67.7 +/- 21.4 mg/L for ceftazidime and the half-lives were 1.2 +/- 0.1 h and 2.1 +/- 0.4 h, respectively. After treating infected rabbits for 4 days with various dosing regimens, resistant strains were only detected in those animals in which the time that the serum concentration exceeded the MIC was less than half of the dosing interval. There was no evidence of emergent resistance when the serum concentrations exceeded the MIC for a longer period nor when amikican was combined with the cephalosporins on the first day of therapy. Moreover, once differences in MICs and pharmacokinetics were taken into account, both antibiotics had a similar propensity to induce resistance.

Quinolones in the treatment of lower respiratory tract infections in adult patients.

The potential role of quinolones is discussed on the basis of data obtained during the past 2 years from epidemiological studies, in vitro investigations, animal experiments and clinical trials. Although the newest compounds exhibit good activity against Streptococcus pneumoniae and intracellular pathogens in animal models, the role of quinolones as first line therapy in community-acquired pneumonia is still debatable and may be modified according to clinical presentation and the rate of resistance of pneumococci to beta-lactams and macrolides. Cost-utility and cost-benefit studies are required to delineate precisely the role of quinolones in the treatment of acute exacerbations of chronic bronchitis. In addition, promising results indicating a possible future for the clinical use of quinolones in the therapy of mycobacterial infections have been obtained.

Daptomycin or teicoplanin in combination with gentamicin for treatment of experimental endocarditis due to a highly glycopeptide-resistant isolate of Enterococcus faecium.

Using an experimental endocarditis model, we studied the activity of daptomycin used alone or in combination with gentamicin against an Enterococcus faecium strain that was highly resistant to glycopeptides and susceptible to gentamicin. In vitro, the MIC of daptomycin was 1 micrograms/ml. In vivo, daptomycin appeared to be effective only when it was used in a high-dose regimen, i.e., 12 mg/kg of body weight every 8 h (-2.5 log10 CFU/g versus controls; P < 0.05), particularly when it was combined with gentamicin (-5.0 log10 CFU/g versus controls; P < 0.01). Since the distribution of daptomycin into cardiac vegetations, as evaluated by autoradiography, appeared to be homogeneous, the poor in vivo activity of daptomycin was considered to be related to its high degree of protein binding, as suggested by killing curves studies. Since the MIC of teicoplanin for the vancomycin-resistant E. faecium strain used in the study was only 64 micrograms/ml and since an in vitro synergy between teicoplanin at high dose and gentamicin was observed, a high-dose regimen of teicoplanin, i.e., 40 mg/kg every 12 h, was also assessed in vivo. This treatment provided marginal activity only when it was combined with gentamicin (-2.3 log10 CFU/g versus controls; P < 0.05). These results suggest that the levels of daptomycin or teicoplanin in serum required to cure experimental endocarditis caused by a highly glycopeptide-resistant strain of E. faecium would not be achievable in humans.