Efficacy of trovafloxacin against penicillin-susceptible and multiresistant strains of Streptococcus pneumoniae in a mouse pneumonia model.

The increasing emergence of penicillin-resistant and multidrug-resistant strains of Streptococcus pneumoniae will create a serious therapeutic problem in coming years. Trovafloxacin is a novel naphthyridone quinolone with promising activity against S. pneumoniae, including penicillin-resistant strains (MIC for 90% of the isolates tested, 0.25 microg/ml). We compared its in vivo efficacy with that of other fluoroquinolones (ciprofloxacin, temafloxacin, and sparfloxacin) and a reference beta-lactam (amoxicillin) in a model of acute experimental pneumonia. Immunocompetent Swiss mice were infected by peroral tracheal delivery of a virulent, penicillin-susceptible strain (MIC, 0.03 microg/ml); leukopenic Swiss mice were infected with three poorly virulent, penicillin-resistant strains (MICs, 4 to 8 microg/ml) and a ciprofloxacin-resistant strain (MIC, 32 microg/ml). Treatments were started 6 h (immunocompetent mice) or 3 h (leukopenic mice) after infection. Doses ranging from 12.5 to 300 mg/kg were given at 12- or 8-h intervals for 3 days. Trovafloxacin (25 mg/kg) was the most effective agent in vivo against penicillin-susceptible and -resistant strains. Corresponding survival rates were 2- to 4-fold higher than with 50-mg/kg sparfloxacin or temafloxacin and 8- to 16-fold higher than with 100-mg/kg ciprofloxacin. The ratios of the area under the concentration-time curve to the MIC in serum and lung tissue were more favorable with trovafloxacin than with the other quinolones. Efficacy in vivo correlated with pharmacokinetic parameters. Trovafloxacin shows potential for the treatment of infections due to penicillin-susceptible and -resistant S. pneumoniae but appears to be ineffective against a ciprofloxacin-resistant strain.

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.

In vivo efficacy of a broad-spectrum cephalosporin, ceftriaxone, against penicillin-susceptible and -resistant strains of Streptococcus pneumoniae in a mouse pneumonia model.

The increasing emergence of penicillin-resistant (Pr) strains of Streptococcus pneumoniae could pose a therapeutic problem in the next few years. Ceftriaxone (CRO), a broad-spectrum cephalosporin, exhibits a smaller increase in MICs against Pr S. pneumoniae strains than amoxicillin (AMO) (usually referred as to the "gold standard" therapy for pneumococcal infections). Therefore, we compared their respective efficacies in a leukopenic Swiss mouse model of pneumococcal pneumonia. Infection was induced with two serotype 19 strains: a penicillin-susceptible (Ps) strain (MICs of < 0.01 for penicillin, 0.03 for AMO, and 0.03 for CRO) and a Pr strain (MICs of 4 for penicillin, 2 for AMO, and 0.5 for CRO). Untreated mice died within 2 or 3 days. Against the Ps strain, the minimal protective dose (two subcutaneous injections at 12-h intervals for 3 days) for both CRO and AMO was 5 mg/kg of body weight (87% survivors). Ten-fold-increased doses of CRO (50 mg/kg) gave similar protection (75% survivors) against the Pr strain, whereas 20- and 40-fold-increased doses of AMO protected 0 and 34% of the animals, respectively, against the Ps strain. CRO had a marked and prolonged antibacterial effect in the lungs (2.7-log-unit reduction of CFU in 24 h after a single 50-mg/kg injection) against the Pr strain in comparison with AMO. A standard dosage of 50 mg of CRO per kg in mice resulted in peak levels in serum and protein binding comparable to those observed with 1 g given intravenously in humans. This dosage remained effective against a highly Pr S. pneumoniae strain in this model. The microbiological activity and pharmacodynamic and pharmacokinetic properties of CRO (time during which concentrations exceed the MIC for the test pathogen [delta t MIC], > or less than 8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: delta t MIC, <2; peak/MIC ratio, <25) against the highly Pr S. pneumoniae strain used in this study.

Kinetics and tolerability of intravitreal pefloxacin in rabbits.

In the treatment of patients with bacterial endophthalmitis, the intravitreal administration of antibiotics is suitable for induction therapy since it provides immediate high concentrations in the vitreous humor. Pefloxacin has been shown to have good intraocular penetration when given systemically. In order to extend the potential routes of administration of this agent, we have assessed the kinetics and toxicity of pefloxacin in rabbit phakic eyes following intravitreal instillation. Kinetic parameters were determined for 12 albino and 12 pigmented rabbits after a single injection of 80 micrograms. Pefloxacin was undetectable in the aqueous humor but high concentrations were found in the chorioretina. The vitreal half-life was short (3 h). These results were consistent with posterior elimination via the chorioretina. Pefloxacin concentrations in the iris and chorioretina of pigmented rabbits were two-fold greater than those in albino rabbits, probably because of binding to the pigmentary apparatus. Toxicity studies, including ophthalmological and histopathological investigations, identified a maximum non-toxic dosage of 400 micrograms. Intravitreal pefloxacin may therefore be suitable for induction therapy in patients with endophthalmitis, although further studies in primates are required to confirm the efficacy and tolerability of this route of administration.

Efficacy and ocular penetration of sparfloxacin in experimental streptococcal endophthalmitis.

Gram-positive cocci are the most common pathogens in severe human eye infections. Streptococcal endophthalmitis is a devastating infection, and intravitreal antibiotic therapy is limited by retinal toxicity. Because few systemic antistreptococcal antibiotics penetrate into the vitreous, sparfloxacin, a newer quinolone with improved antistreptococcal activity, might be of interest. We therefore assessed its efficacy by the intravitreal route in a rabbit model of streptococcal endophthalmitis. The vitreal bacterial count (mean +/- standard deviation log10 CFU per milliliter) was significantly reduced after an intravitreal injection of 800 micrograms of sprafloxacin (4.9 +/- 0.7) relative to the counts in untreated control (7.1 +/- 0.7) and pefloxacin-treated (7.8 +/- 1.2) eyes. After systemic administration to rabbits, the maximum concentration of sparfloxacin in serum was 5.6 micrograms.ml-1 and the half-life was 7.5 h. Sparfloxacin exhibited very good penetration ratios in the vitreous (54%), cornea (76%), and lens (36%). In the vitreous, the levels of sparfloxacin remained greater than the MICs for most gram-positive cocci for up to 18 h. Further experimental studies are warranted to determine the efficacy of systemic sparfloxacin as adjuvant therapy in the treatment of human endophthalmitis.

In vivo efficacy of a new fluoroquinolone, sparfloxacin, against penicillin-susceptible and -resistant and multiresistant strains of Streptococcus pneumoniae in a mouse model of pneumonia.

The increasing emergence of penicillin-resistant and multiresistant strains of Streptococcus pneumoniae may pose a problem in coming years. We therefore compared sparfloxacin, a new fluoroquinolone with improved potency against streptococci, with amoxicillin, the "gold standard" in this setting, and another fluoroquinolone, ciprofloxacin, in a mouse pneumonia model. Their efficacies against penicillin-susceptible (serotype 3), macrolide-resistant (serotype 1), penicillin-resistant (serotype 23), and multiresistant (serotype 6) S. pneumoniae strains were evaluated. Immunocompetent Swiss mice (serotypes 1 and 3) and leukopenic mice (serotypes 6 and 23) were infected by peroral tracheal delivery of 10(4) to 10(6) CFU. Subcutaneous injections of antibiotics were initiated at 6, 18, 48, or 72 h after infection (six injections at 12-h intervals). In the immunocompetent mice, 100% survival was obtained with sparfloxacin (50 mg/kg) and amoxicillin (5 mg/kg) against both penicillin-susceptible and macrolide-resistant strains; ciprofloxacin gave significantly lower survival rates. Two to four injections of sparfloxacin completely cleared bacteria from lungs and blood; the most rapid eradication was achieved with amoxicillin. Sparfloxacin also fully protected leukopenic mice against penicillin-resistant strains. The dose of amoxicillin (50 mg/kg) required to protect mice and eradicate penicillin-resistant and multiresistant strains was 10 times higher than that effective against penicillin-susceptible strains. The microbiological and pharmacokinetic properties of sparfloxacin (e.g., the time during which concentrations exceed the MIC of the test pathogen) accounted for its efficacy against susceptible and resistant strains of S. pneumoniae in this model.

Kinetic disposition of temafloxacin and ciprofloxacin in a murine model of pneumococcal pneumonia. Relevance for drug efficacy.

The authors studied whether pharmacokinetic parameters could explain differences in the in vivo antipneumococcal activity of temafloxacin and ciprofloxacin in a mouse model of pneumonia. The effects of infection on the disposition and clearance mechanisms of the two drugs were evaluated after a single administration (100 mg/kg s.c.) relative to noninfected controls. Effective drug concentrations and possible drug inactivation at sites of infection were assessed using both microbiological (active drug levels) and high-performance liquid chromatography (total drug levels) procedures and by recording bacterial clearance in blood and lung homogenates. Pulmonary bacterial clearance was correlated more closely to concentrations in serum than to those in lung homogenates, probably because they better reflect interstitial fluid concentrations. Neither the serum and lung concentrations nor the clearance of ciprofloxacin were modified greatly by infection. Ciprofloxacin was not inactivated at sites of infection. Temafloxacin exhibited higher serum concentrations and tissue penetration than ciprofloxacin. The differences between the two drugs in noninfected controls were accentuated, with apparent retention of temafloxacin in infected mice resulting in more persistent activity in lung and serum. The renal failure observed in infected mice did not apparently account for the reduction in the total clearance of temafloxacin, suggesting its probable trapping at sites of infection. The observation that serum (and tissue) concentrations of temafloxacin exceeded the minimal inhibitory concentration of the test organism over the whole dosing interval (12 hr), could account for its efficacy in severe pneumococcal disease.

Use of fluoroquinolones for prophylaxis of murine Pneumocystis carinii pneumonia.

We compared the prophylactic activities of six fluoroquinolones against Pneumocystis carinii pneumonia in immunosuppressed rats. Pefloxacin was the only agent which was as effective as the reference drug trimethoprim-sulfamethoxazole. Clinical trials with pefloxacin in patients at risk for P. carinii pneumonia appear to be justified.

Susceptibility of Plasmodium falciparum strains to mefloquine in an urban area in Senegal.

A total of 47 nonimmune febrile patients from Pikine, Senegal, with greater than 1,000 Plasmodium falciparum asexual forms per microliter whole blood were given 12.5 mg per kg body weight of mefloquine in a single oral dose and were followed up daily until day 7 and also on day 14 of the study. Seven of the patients who vomited, four who had 4-aminoquinolines in their blood, and five dropouts were excluded. Fever and parasitaemia were suppressed within four days until day fourteen in 29 of the 31 remaining patients, including 10 with P. falciparum strains that had a low sensitivity to mefloquine. Two failures were due to poor absorption of mefloquine. The presence of P. falciparum strains with low in vitro susceptibility to mefloquine did not affect, within 14 days, the clinical and parasitological efficacy of a single oral dose mefloquine regimen in patients who had received no previous antimalarial treatment and who did not have partial immune protection.

Ocular kinetics of pefloxacin after intramuscular administration in albino and pigmented rabbits.

We determined the ocular kinetics of pefloxacin, a new fluoroquinolone, when administered by the intramuscular route to albino and pigmented rabbits. In serum of albino rabbits, the area under the concentration-time curve (AUC) for the experimental period was 31.4 +/- 1.07 micrograms.h/ml (mean +/- standard deviation); the AUCs in the aqueous and vitreous humors were high (10.5 +/- 1.90 and 12.4 +/- 3.79 micrograms.h/ml, respectively). Pefloxacin was found in the avascular ocular tissues (30.15 +/- 3.79 micrograms.h/ml in the cornea and 6.98 +/- 1.06 micrograms.h/ml in the lens). In the vascularized tissues, the penetration ratio, defined as tissue AUC/serum AUC, was more than 1. The good intraocular diffusion of pefloxacin might be related to its low molecular weight and to its strong lipophilicity and could explain its clinical efficacy in the treatment of endophthalmitis. In pigmented rabbits, pefloxacin levels were high in the iris (1525 +/- 328 micrograms.h/ml, versus 40.2 +/- 5.08 micrograms.h/ml in albino rabbits) and chorioretina (2600 +/- 422 micrograms.h/ml, versus 48.3 +/- 7.52 micrograms.h/ml in albino rabbits), suggesting that it binds to the pigmentary apparatus.

Divided-dose kinetics of mefloquine in man.

The kinetics of mefloquine was investigated following oral divided-doses in 10 healthy Caucasian volunteers. They received 500 or 750 mg followed by 500 mg 8 h later. Unchanged mefloquine (M) and its carboxylic acid metabolite (MM) were measured in whole blood and plasma for 50 days by h.p.l.c. Maximum blood and plasma M concentrations of 1872 +/- 362 ng ml-1 (mean +/- s.d.) and 1900 +/- 434 ng ml-1, respectively, were found within 6-10 h after the second dose. The terminal plasma elimination half-life was 20.1 +/- 3.7 days (mean +/- s.d.) and the oral clearance was 22.3 +/- 6.7 ml h-1 kg-1 (mean +/- s.d.). Plasma concentrations of MM exceeded those of M by 2-3 fold within 2 days. The whole blood concentration of MM was lower than that in plasma but also exceeded the whole blood concentration of M.

Alteration of gentamicin and cefazolin kinetics with control of the hypothyroid state in humans.

We studied the effect of the control of the hypothyroid state in humans on the pharmacokinetic parameters of cefazolin and gentamicin after a single intravenous injection. These two antibiotics were chosen because of their different patterns of binding to serum albumin (0% for gentamicin and 82% for cefazolin). In hypothyroidism, the behavior of cefazolin only was altered, with a decrease in the total body clearance, possibly due to reduced urinary excretion, and a decrease in the volume of distribution without a significant alteration of cefazolin binding to serum protein.

[Treatment of septicemia and endocarditis with pefloxacine. 15 cases]. / Traitement de septicémies et endocardites par la péfloxacine. Quinze observations.

The therapeutic effectiveness of pefloxacin was evaluated in 15 patients admitted to an intensive care unit and suffering from septicaemia or endocarditis. Seven of these patients had a focal infection (acute anterior mediastinitis or epiduritis). Pefloxacin was combined with an aminoglycoside in 13 cases and with rifampicin in 1 case. Blood cultures became or remained negative in all patients. The associated focus of infection was sterilized in 5 patients; a pefloxacin-resistant pathogen was subsequently isolated in 2 other patients. Three patients died some time after the infectious episode. The minimum inhibitory concentration of pefloxacin ranged from 0.25 to 2 mg/l. The bactericidal activity of the serum at peak concentration was greater than or equal to 1/8 in all cases and greater than or equal to 1/32 in 10 cases. No resistant mutants were selected during treatment. However, 8 strains of a species different from that of the initial pathogen were isolated from a site other than the primary focus. Pefloxacin can therefore be used successfully in the treatment of systemic infections, but close monitoring of bacterial ecology is required.

Vancomycin pharmacokinetics in critically ill patients.

Peak and trough vancomycin serum levels were measured in 37 severely ill patients following dosing using the Moellering nomogram. The peak and trough serum concentrations were 61.2 +/- 23 and 22.6 +/- 16.5 mg/l, respectively, and higher than expected. Vancomycin pharmacokinetics obtained from 10 other patients were also studied. In five patients with a creatinine clearance greater than 1 ml min-1 kg-1, a mean plasma elimination half-life of 7.8 +/- 2.8 h was calculated. In the five other patients with markedly reduced renal function (creatinine clearance less than or equal to 1 ml min-1 kg-1), the mean elimination half-life was 18.3 +/- 10.2 h. A correlation was observed between the vancomycin and creatinine clearance. Important inter-patient variations of vancomycin clearance for the same creatinine clearance was also noted. Tubular damage in critically ill patients with severe sepsis may explain our results of the decreased vancomycin elimination.

Cefamandole bone diffusion in patients undergoing total hip replacement.

Cefamandole penetration was studied in 32 normal bone specimens. No antibiotic bone binding was found. Blood contamination of bone samples was measured by the haemoglobin method. Mean corrected levels attained (5.8 micrograms/g) exceed MIC values of sensitive Staphylococcus aureus, Haemophilus influenzae and Enterobacteriaceae. Similar diffusion was observed in cortical and trabecular bone. The results obtained invite further studies on preoperative prophylaxis and treatment of osteomyelitis.

Studies of granulocyte kinetics in normal and granulocytopenic subjects.

Granulopoiesis was studied simultaneously by three methods in normal subjects and in subjects with neutropenia of various aetiologies: in vitro labelling of autologous and homologous granulocytes for the study of peripheral kinetics, in vivo labelling with DF32P (di-isopropyl-flourophosphate 32P) or 75Se-selenomethionine, and bone marrow autoradiography after in vitro labelling with 3H-thymidine for the study of bone marrow granulopoiesis. Three main mechanisms of neutropenia can be distinguished: a) peripheral hyperdestruction, corpuscular or extra-corpuscular, and false leukopenias (change in the distribution of peripheral granulocytes from the circulating to the marginal granulocyte pool; b) quantitative bone marrow insufficiency without qualitative abnormality; c) qualitative abnormality in bone marrow granulopoiesis with cell death in either the maturation stage or the proliferative stage. There is no exact correlation between clinical and kinetic classifications, but most cases of post-infection chronic neutropenias and idiopathic neutropenias fall into the first two categories, and most cases of benzol intoxication and bone marrow insufficiency due to X-irradiation fall into the last category. Some of these last patients developed an acute myeloblastic leukaemia in the two following years and can be considered as preleukaemic states.

Kinetic studies of 51Cr and DF32P labelled granulocytes.

In vivo kinetic studies of granulocytes labelled in vitro with 51Cr and DF32P were carried out in nine haematologically normal subjects by isolation of the cells in the blood samples by the Ficoll-Isopaque flotation method. 51Cr and 32P specific activity of blood samples made of 93-98% granulocytes was studied. Distribution between marginated and circulating granulocyte pools was identical for both labelled cells and the marginated pool was similar to the circulating pool, except that it was lower in one subject who had a previous splenectomy. The half-disappearance time (T 1/2) was 16.1+/-2.2 h for 51Cr-labelled and 5.4+/-2.1 hr for DF32P-labelled granulocytes. In one case of a normal subject who previously received multiple transfusion homologous 51Cr-labelled granulocytes had a T 1/2 of less than 1 h.