Treatment of Experimental Staphylococcus aureus Endocarditis: Comparison of Cephalothin, Cefazolin, and Methicillin

The effectiveness of cefazolin in Staphylococcus aureus endocarditis has been questioned because of in vitro inactivation by staphylococcal beta-lactamase. Cefazolin, although inactivated in vitro by S. aureus beta-lactamase, was as effective as cephalothin in the treatment of left-sided S. aureus endocarditis in rabbits. Cefazolin (20 mg/kg every 6 or 8 h), cephalothin (40 mg/kg every 6 h), and methicillin (40 mg/kg every 6 h), administered intramuscularly, were compared in the treatment of left-sided endocarditis caused in rabbits by a highly penicillin-resistant strain of S. aureus. The three antibiotics were all effective in reducing titers in vegetations. However, at the dose used, methicillin reduced the titers more rapidly than cephalothin or cefazolin. Cefazolin concentrations in serum were about double those achieved with cephalothin or methicillin. However, cefazolin was only half as active as methicillin and one-eighth as active as cephalothin in vitro in a serum assay. The half life in serum of cefazolin, cephalothin, and methicillin were each about 30 min. Serum bactericidal activities of the three antibiotics were very similar.     

Co-trimoxazole versus nafcillin in the therapy of experimental meningitis due to Staphylococcus aureus

Co-trimoxazole was compared with nafcillin against Staphylococcus aureus in vitro and in the therapy of experimental Staph. aureus meningitis in rabbits. Co-trimoxazole (trimethoprim:sulphamethoxazole in a 1:20 ratio) was synergistic against 22/24 strains of Staph. aureus in vitro. The MBC90 of co-trimoxazole and nafcillin were 0.156-3.12 mg/l and 0.25 mg/l, respectively, concentrations below those achievable in purulent cerebrospinal fluid. The rate of bacterial killing (Staph. aureus) by co-trimoxazole and nafcillin were similar in both broth and pooled CSF in vitro. However, the MBC increased and the rate of bactericidal activity of both agents declined when tested in CSF at a higher inoculum (10(7) cfu/ml). During continuous intravenous infusion therapy of a reproducible, uniformly fatal (if untreated) model of experimental Staph. aureus meningitis, serum concentrations of all agents closely approximated those found in humans receiving standard parenteral regimens. The mean percent penetration into CSF ([CSF]/[serum] X 100) was 2.9, 35.6 and 27.1% for nafcillin, trimethoprim and sulphamethoxazole, respectively. Although both nafcillin and co-trimoxazole therapy reduced CSF Staph. aureus concentrations significantly more rapidly (P less than 0.001) when compared to untreated controls, the bactericidal rate was modest. The CSF was rendered sterile in 0/64 animals treated with either regimen for 8 h. Nafcillin was more rapidly bactericidal in vivo (P less than 0.03) than co-trimoxazole in this model. Caution is advised in the use of co-trimoxazole for infections of the central nervous system caused by Staph. aureus.     

Rosaramicin Versus Penicillin G in Experimental Pneumococcal Meningitis

Rosaramicin, a new macrolide antibiotic, was compared with penicillin G in the treatment of pneumococcal meningitis in rabbits. Animals were infected intracisternally with 10(4) colony-forming units of Streptococcus pneumoniae type III (rosaramicin minimal inhibitory/bactericidal concentrations, 0.25/0.5 mug/ml; penicillin G minimal inhibitory/bactericidal concentrations, 0.03/0.06 mug/ml). Treatment was instituted 96 h later. Infusion of rosaramicin at 25 mg/kg per h intravenously for 8 h produced a peak cerebrospinal fluid (CSF) drug concentration of 1.54 mug/ml (range, 0.87-3.6 mug/ml). During this infusion the numbers of pneumococci in CSF decreased from 6.2 +/- 0.5 to 3.36 +/- 1.12 log(10) colony-forming units per ml. Penicillin G, infused at 30 mg/kg per h for 8 h, reached a similar concentration in CSF but caused a greater reduction (P < 0.01) in CSF bacteria, from 6.4 +/- 0.36 to 1.3 +/- 0.67 log(10) colony-forming units per ml. Penicillin G, at 100 mg/kg per day intramuscularly for 5 days, cured 7 of 10 rabbits with pneumococcal meningitis. A higher dose, 300 mg/kg per day for 5 days, was no more efficacious: 11 of 14 rabbits were cured. Rosaramicin at 100 mg/kg per day intramuscularly for 5 days cured only 5 of 15 rabbits with meningitis, but a higher dosage regimen of that drug (250 mg/kg per day intramuscularly) produced acute, fulminant enterocecitis and death within 48 h in seven of eight rabbits. No cytotoxin was detected in the feces of one rabbit with acute enterocecitis. Thus the efficacy of rosaramicin in experimental pneumococcal meningitis, measured by bacterial clearance from CSF and by treatment outcome, was less than that of penicillin G. In addition, high-dose parenteral rosaramicin caused acute, fulminant enterocecitis in a high proportion of treated rabbits.     

BMS-284756 in experimental cephalosporin-resistant pneumococcal meningitis

BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial activity, including Streptococcus pneumoniae. The purpose of this study was to evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae (CRSP). Meningitis was induced in rabbits by intracisternal inoculation of CRSP. BMS-284756 was given intravenously 16 h after intracisternal inoculation in single doses of 2.5 (n = 5 animals), 5 (n = 6), 10 (n = 6), 20 (n = 8), and 30 mg/kg (n = 6), in two doses of 10 mg/kg each separated by 5 h (n = 4), and as a 20-mg/kg dose followed 5 h later by 10 mg/kg (n = 5). The MICs and MBCs of BMS-284756, ceftriaxone, and vancomycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 microg/ml, respectively. After single doses of 10, 20, and 30 mg/kg, the maximum concentrations in cerebrospinal fluid (CSF) (mean +/- standard deviation) were 0.32 +/- 0.12, 0.81 +/- 0.38, and 1.08 +/- 0.43 microg/ml, respectively; the elimination half-life in CSF was 4.5 to 6.3 h. The CSF bacterial killing rates (BKR) at 5 h of the single-dose regimens of 10, 20 and 30 mg/kg were -0.84 +/- 0.48, -1.09 +/- 0.32, and -1.35 +/- 0.05 Deltalog(10) CFU/ml/h. The BKR(0-5) of the divided regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was -0.82 +/- 0.52 and -1.24 +/- 0.34 Deltalog(10) CFU/ml/h, respectively. The BKR(0-5) of the combined therapy with vancomycin and ceftriaxone was -1.09 +/- 0.39 Deltalog(10) CFU/ml/h. The penetration of BMS-284756 into purulent CSF relative to plasma was 14 to 25%. The bactericidal effect of BMS-284756 in CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or divided dose was as effective as standard therapy with vancomycin and ceftriaxone.     

Concentrations in plasma, urinary excretion, and bactericidal activity of linezolid (600 milligrams) versus those of ciprofloxacin (500 milligrams) in healthy volunteers receiving a single oral dose

In a randomized crossover study, 12 volunteers (6 males, 6 females) received a single oral dose of 600 mg of linezolid or 500 mg of ciprofloxacin to assess the concentrations in plasma (up to 24 h), urinary excretion (by high-pressure liquid chromatography), and bactericidal titers in urine (UBT) at intervals up to 120 h. The mean maximum concentration of linezolid in plasma was 13.1 mg/liter, and that of ciprofloxacin was 2.46 mg/liter. The median cumulative levels of renal excretion of the administered dose of the parent drug were 44% for linezolid (range, 28 to 47%; mean +/- standard deviation, 40% +/- 7.8%) and 43% for ciprofloxacin (range, 20 to 56%; mean +/- standard deviation, 40% +/- 9.3%). The UBTs, i.e., the highest twofold dilution (with antibiotic-free urine used as the diluent) of urine that was still bactericidal, were determined for a reference strain and five gram-positive clinical uropathogens for which the MICs of linezolid and ciprofloxacin were as follows: Staphylococcus aureus ATCC 27278, 2 and 0.25 mg/liter, respectively; Staphylococcus aureus (methicillin susceptible), 1 and 16 mg/liter, respectively; Staphylococcus aureus (methicillin resistant), 2 and 64 mg/liter, respectively; Staphylococcus saprophyticus (methicillin susceptible), 1 and 0.25 mg/liter, respectively; Enterococcus faecalis, 2 and 1 mg/liter, respectively; and Enterococcus faecium, 2 and 1 mg/liter, respectively. The median UBTs of linezolid measured within the first 6 h were 1:96 for each of the two enterococcal strains and between 1:128 and 1:256 for the four staphylococcal strains. The median UBTs of ciprofloxacin were 1:64 for the two enterococcal strains; between 1:384 and 1:512 for the two ciprofloxacin-susceptible strains; and 1 (bactericidal activity of undiluted urine only) and 1:2 for the two resistant staphylococcal strains, respectively. The areas under the UBT-time curve (AUBT) for linezolid and ciprofloxacin showed no statistically significant (P<0.05) differences except for a better AUBT for linezolid for the two ciprofloxacin-resistant staphylococcal strains. For linezolid there were no statistically significant differences in UBTs or AUBTs for ciprofloxacin-susceptible and -resistant strains. Thus, the bactericidal activities of linezolid and ciprofloxacin against susceptible strains in urine were comparable, whereas linezolid also exhibited the same good bactericidal activity against ciprofloxacin-resistant strains. Therefore, linezolid should be tested for use as empirical treatment for complicated urinary tract infections due to gram-positive uropathogens in an appropriate clinical trial.     

Penetration of cefuzoname into the cerebrospinal fluid of rabbits.

Concentrations of cefuzoname in cerebrospinal fluid (CSF) were determined in a total of 16 rabbits, 5 with healthy meninges, 5 with Staphylococcus aureus meningitis, and 6 with Escherichia coli meningitis. Mean percentages of the maximum concentration of the drug in CSF versus that in serum were 0.57, 3.37, and 4.40% for healthy rabbits, those with staphylococcal meningitis, and those with E. coli meningitis, respectively. The percentages of the area under the concentration-time curve of cefuzoname in CSF versus that in serum were, in the order of healthy group, staphylococcal meningitis group, and E. coli meningitis group, 0.61, 4.99, and 8.04% at 15 to 60 min, 1.44, 7.09, and 12.7% at 15 to 120 min, and 1.87, 8.07, and 15.8% at 15 to 180 min after administration, showing significant differences between the healthy and meningitis groups. All of the values in the E. coli meningitis group were greater than those of the staphylococcal meningitis group, but the differences were not significant. The ratios of the half-life of cefuzoname in CSF to that in serum were 2.10, 1.98, and 3.37 for the healthy, staphylococcal meningitis, and E. coli meningitis groups, respectively, with no significant difference between the three groups. Cefuzoname seems to be among the middle ranks of beta-lactam agents as far as penetration rate is concerned; however, when its potent antibacterial activity and broad spectrum are taken into account, the concentrations in CSF in patients with meningitis seem worth examining.     

Anti-staphylococcal activity of indolmycin, a potential topical agent for control of staphylococcal infections

OBJECTIVES: We sought to investigate the anti-staphylococcal activity of indolmycin, with particular emphasis on comparing its activity with fusidic acid and mupirocin. METHODS: Established procedures were used to examine the activity of indolmycin against a range of clinical isolates, including strains resistant to fusidic acid and mupirocin. Indolmycin-resistant mutants were recovered and characterized phenotypically and genotypically. RESULTS: Indolmycin was bacteriostatic and demonstrated good activity against MSSA (methicillin-susceptible Staphylococcus aureus), MRSA (methicillin-resistant S. aureus) and VISA (vancomycin-intermediate S. aureus), including strains resistant to mupirocin or fusidic acid. Spontaneous indolmycin-resistant mutants occurred at a lower frequency than those selected by mupirocin or fusidic acid and exhibited no cross-resistance with the comparative drugs. High-level resistance (indolmycin MIC 128 mg/L) that was associated with an H43N mutation in tryptophanyl-tRNA synthetase (TrpS), the target enzyme of indolmycin, resulted in loss of bacterial fitness. However, the locus responsible for low-level indolmycin resistance (indolmycin MICs 8-32 mg/L) was not identified. CONCLUSIONS: Indolmycin is a potent anti-staphylococcal agent, which exhibits activity against mupirocin- and fusidic acid-resistant strains. Indolmycin might be a candidate for development as a topical agent in the treatment of staphylococcal infections and nasal carriage of MRSA.     

Pharmacodynamic interaction between RP 59500 and gram-positive bacteria infecting fibrin clots.

The fibrin clot penetration and in vivo bactericidal activity of RP 59500, a new semisynthetic streptogramin, for two Staphylococcus aureus strains (one methicillin resistant and the other methicillin susceptible), two Staphylococcus epidermidis strains (one methicillin resistant and the other methicillin susceptible), and one Enterococcus faecalis strain were evaluated. The clots, inserted subcutaneously, were infected with a mean of 10(8) CFU of the pathogen per g. For each strain, groups of four rabbits received a single intravenous injection of 50 mg of RP 59500 per kg of body weight over 30 min. The mean peak level of RP 59500 in serum in the infected rabbits was 61.9 +/- 6.3 micrograms/ml. The drug was detectable in serum at a level of 0.8 micrograms/ml up to 4 h after administration. The mean peak fibrin clot drug level at 1 h was 3.3 +/- 0.1 micrograms/g. At 6 h, the level in clots was 1.2 +/- 0.1 micrograms/g. The mean half-life in serum in infected rabbits was 0.34 +/- 0.01 h, while in clots the drug exhibited a longer half-life of 3.8 +/- 0.4 h. In vivo, this new streptogramin sterilized the clots infected with the two S. aureus strains studied in less than 1 h and induced a marked reduction in colony counts of the two S. epidermidis strains studied for up to 24 h. The activity of the streptogramin against E. faecalis was limited. These results suggest that RP 59500 should be further evaluated for the treatment of infection with methicillin-resistant staphylococci.     

Mutation frequencies for resistance to fusidic acid and rifampicin in Staphylococcus aureus

Frequencies at which mutants resistant to fusidic acid and/or rifampicin arose in vitro were determined in Staphylococcus aureus strains including methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate resistant S. aureus (VISA) and hetero-VISA. The concentrations of fusidic acid (30 and 15 mg/L) and rifampicin (16 and 1 mg/L) used for selection were equal to the expected maximum and minimum serum concentrations after an oral regimen of rifampicin 900 mg od, together with fusidic acid 500 mg tds. Resistant mutants arose at a frequency of around 10(-8) for selections with rifampicin, but were undetectable (frequency <10(-11)) for selections with fusidic acid. Mutants were not recovered (frequency <10(-11)) after selections in the presence of both fusidic acid and rifampicin at 30/16 and 15/1 mg/L. Our results suggest that these antibiotics, when used in combination, could have a wider role in the management of staphylococcal infections.     

Different ratios of the piperacillin-tazobactam combination for treatment of experimental meningitis due to Klebsiella pneumoniae producing the TEM-3 extended-spectrum beta-lactamase.

We evaluated the pharmacokinetics and therapeutic efficacies of piperacillin and tazobactam, a beta-lactamase inhibitor, given either alone or in different combinations (80:10, 200:10, and 80:25 mg/kg/h), in experimental meningitis due to a strain of Klebsiella pneumoniae producing the TEM-3 extended-spectrum beta-lactamase. Treatment was administered intravenously as a 7-h constant infusion preceded by a bolus of 20% of the total dose. The mean (+/- standard deviation) rates of penetration into the cerebrospinal fluid (CSF) of infected animals were 6.7 +/- 3.9% for piperacillin given alone and 36.3 +/- 21.9% for tazobactam given alone. Combination treatment significantly magnified the concentration of either drug in CSF. Concentrations of bacteria in CSF increased throughout therapy in animals given either drug alone, even at high dosages. In animals given the combination at dosages of 80:10 and 200/10 mg/kg/h, only a suboptimal reduction of CSF bacterial titers was obtained in vivo, i.e. -0.49 +/- 0.34 and -0.73 +/- 0.49 log CFU/ml/h, respectively. An increase in the tazobactam dosage within the combination (80:25 mg/kg/h) was required in order to obtain a significantly faster elimination of viable organisms from the CSF (-0.97 +/- 0.35 log CFU/ml/h). The study shows that tazobactam is able to provide effective protection against piperacillin hydrolysis by the TEM-3 enzyme within the CSF. Appropriate dosage regimens of various beta-lactam-tazobactam combinations may deserve comparative studies in experimental meningitis caused by organisms producing extended-spectrum beta-lactamases.     

Anti—Interleukin-6 Antibodies Attenuate Inflammation in a Rat Meningitis Model

OBJECTIVES: Interleukin-6 (IL-6) is elevated in the cerebrospinal fluid (CSF) of humans and animals with bacterial meningitis. This study's hypothesis was that anti-IL-6 antibodies will attenuate meningeal inflammation in a rat model of bacterial meningitis. METHODS: 14 male Sprague-Dawley rats were inoculated intracisternally (IC) with 0.1 mL of heat-killed pneumococci. At one hour post-inoculation, the rats received intraperitoneal doses of either 1.0 mL phosphate-buffered saline (PBS treatment group, n = 7) or 70 microg anti-IL-6 antibodies in 1.0 mL PBS (anti-IL-6 antibody treatment group, n = 7). Nine rats (normal group, n = 9) had no inoculation, and four rats (surgical sham group, n = 4) had IC inoculations of saline. At six hours post-inoculation, all the animals had CSF removed via IC tap. The CSF protein and white blood cell (WBC) count measures were compared using a t-test. RESULTS: Mean CSF WBC for the anti-IL-6 treatment group was 2,458/microL, versus the PBS controls' mean of 9,697/microL (p = 0.007). Mean CSF protein for the anti-IL-6 group was 180 mg/dL, versus 296 mg/dL for the controls (p = 0.032). The surgical sham and normal animals had normal CSF WBC and protein values. CONCLUSIONS: In this rat meningitis model, systemic treatment with anti-IL-6 antibodies after the induction of meningitis suppressed both CSF WBC count and CSF protein level, two important indices of meningeal inflammation.     

Garenoxacin (BMS-284756) and moxifloxacin in experimental meningitis caused by vancomycin-tolerant pneumococci

The emergence of multidrug-resistant strains of Streptococcus pneumoniae drives the development and evaluation of new antipneumococcal agents, especially for the treatment of bacterial meningitis. The aims of the present study were to assess the antibacterial effectiveness of two new quinolones, garenoxacin (BMS; BMS-284756) and moxifloxacin (MOX) in experimental meningitis caused by a vancomycin (VAN)-tolerant S. pneumoniae strain and to compare the results with those obtained by therapy with VAN and ceftriaxone (CRO) in combination. Meningitis was induced in young male New Zealand White rabbits by intracisternal inoculation of a VAN-tolerant pneumococcal strain (strain Tupelo) from a child with meningitis. Sixteen hours after inoculation, therapy was given by intravenous administration of BMS at 20 mg/kg of body weight, followed 5 h later by administration at a dosage of 10 mg/kg (n = 9 animals) or MOX as two doses of 20 mg/kg every 5 h (n = 8 animals). For comparison, we studied the following groups: (i) animals treated with VAN (20 mg/kg every 5 h, three doses) and CRO (125 mg/kg, one dose) (n = 9), (ii) animals infected with a VAN-tolerant strain but not treated (n = 8), (iii) animals infected with a VAN-tolerant pneumococcus isolated from the nasopharynx of a carrier and treated with BMS (n = 8), and (iv) animals infected with a cephalosporin-resistant type 6B S. pneumoniae strain and treated with BMS (n = 6). The MICs of penicillin, CRO, VAN, BMS, and MOX for the Tupelo strain were 2, 1, 0.5, 0.06, and 0.03 micro g/ml, respectively. The rates of killing of strain Tupelo (the change in the log(10) number of CFU per milliliter per hour) in cerebrospinal fluid at 5 h were -0.70 +/- 0.35, -0.61 +/- 0.44, and -0.49 +/- 0.36 for BMS, MOX, and VAN-CRO, respectively. Therapy with BMS and MOX was as effective as therapy with VAN-CRO against VAN-tolerant pneumococcal meningitis in rabbits.     

Efficacy of gatifloxacin alone and in combination with cefepime against penicillin-resistant Streptococcus pneumoniae in a rabbit meningitis model and in vitro

Gatifloxacin penetrated well into cerebrospinal fluid (CSF) (49 +/- 11%), measured by comparison of AUC(CSF)/AUC(serum), and showed good bactericidal activity (leading to a decrease of 0.75 +/- 0.17 log10 cfu/mL/h) in the treatment of experimental meningitis in rabbits caused by a penicillin-resistant pneumococcal strain (MIC 4 mg/L). It was significantly more effective than the standard regimen, ceftriaxone with vancomycin, which led to a decrease of 0.53 +/- 0.17 log10 cfu/mL/h. The addition of cefepime to gatifloxacin slightly improved the killing rates (giving a decrease of 0.84 +/- 0.14 log10 cfu/mL/h). In vitro, synergy was demonstrated between cefepime and gatifloxacin by the chequerboard method (fractional inhibitory concentration index = 0.5) and by viable counts over 8 h.     

Penetration of aztreonam into cerebrospinal fluid and brain of noninfected rabbits and rabbits with experimental meningitis caused by Pseudomonas aeruginosa.

This study examined the penetration of aztreonam into the cerebrospinal fluid (CSF) and brain in noninfected rabbits and rabbits with experimental meningitis caused by Pseudomonas aeruginosa. Animals received either 600 or 1,200 mg of aztreonam administered intravenously over 6 h. Aztreonam did not readily enter the CSF in the absence of meningitis. In noninfected animals, mean concentrations in the CSF ranged from 1.1 to 3.0 micrograms/ml with the 600-mg dose and from 2.3 to 4.7 micrograms/ml with the 1,200-mg dose. In contrast, mean concentrations of aztreonam in the CSF were significantly higher (P less than 0.01) at each sampling time in rabbits with experimental meningitis caused by P. aeruginosa. They ranged from 10.2 to 14.6 micrograms/ml with the 600-mg dose and from 29 to 40 micrograms/ml with the 1,200-mg dose. Although concentrations in the brain measured at 6 h tended to be higher in infected rabbits, this difference was not statistically significant. Aztreonam therapy produced a substantial decline in CSF bacterium counts over 6 h: mean CSF counts decreased 2.4 log10 CFU/ml in the 600-mg dose group and 3.0 log10 CFU/ml in the 1,200-mg dose group. The results of this study suggest that aztreonam may be useful in the therapy of meningitis caused by P. aeruginosa.     

Effectiveness of Nafcillin, Methicillin, and Cephalothin in Experimental Staphylococcus aureus Endocarditis

Nafcillin, methicillin, and cephalothin (40 mg/kg every 6 h) were all effective in reducing the number of Staphylococcus aureus in vegetations in rabbits with endocarditis. Nafcillin and methicillin reduced the number of S. aureus at a significantly faster rate than did cephalothin. Nafcillin and methicillin also reduced titers of the S. aureus more rapidly than did cephalothin in vitro, both in broth and in rabbit serum.     

Resistance to methicillin in isolates of Staphylococcus aureus from blood and cerebrospinal fluid in Wales, 1993-1997

Surveillance data for organisms isolated from blood cultures and cerebrospinal fluid (CSF) specimens has been gathered electronically in Wales since 1993. Over this period the proportion of total reported organisms from blood cultures and CSF represented by methicillin-resistant staphylococci (MRSA) has risen steadily. This has corresponded to a rise in rates of methicillin resistance amongst Staphylococcus aureus isolated from blood cultures and CSF from 4 to 43%. In certain age/gender groups in 1997, more than 50% of isolates of S. aureus were resistant to methicillin, suggesting that a change in empirical treatment may be necessary for suspected staphylococcal sepsis.     

Pharmacokinetics of florfenicol in cerebrospinal fluid and plasma of calves.

Florfenicol, a fluorinated analog of thiamphenicol, is of great value in veterinary infectious diseases that formerly responded favorably to chloramphenicol. In view of the treatment of meningitis in calves, we studied its pharmacokinetics in the cerebrospinal fluid (CSF) and plasma of six animals. To this end, a new high-performance liquid chromatography method was developed which, unlike previous ones, uses solid-phase instead of double-phase extraction to isolate the drug. After a single intravenous dose of 20 mg/kg of body weight, a maximum concentration in CSF of 4.67 +/- 1.51 microg/ml (n = 6) was reached, with a mean residence time of 8.7 h. The decline of florfenicol in both CSF and plasma fitted a biexponential model with elimination half-lives of 13.4 and 3.2 h, respectively. Florfenicol penetrated well into CSF, as evidenced from an availability of 46% +/- 3% relative to plasma. The levels remained above the MIC for Haemophilus somnus over a 20-h period. Our results provide evidence indicating the effectiveness of florfenicol in the treatment of bacterial meningitis of calves.     

Effectiveness of treatment with mezlocillin, ampicillin and latamoxef (moxalactam) of experimental group B beta-haemolytic streptococcal meningitis in rabbits

This study compared the effectiveness of treatment with various antibiotics in rabbits with experimental group B beta-haemolytic streptococcal meningitis. Groups of nine infected rabbits each received the following treatments intramuscularly, three times per day: (1) control--no treatment; (2) mezlocillin--400 mg/kg/day; (3) mezlocillin--400 mg/kg/day + gentamicin--15 mg/kg/day; (4) ampicillin--400 mg/kg/day; (5) ampicillin--400 mg/kg/day + gentamicin 15 mg/kg/day; (6) latamoxef (moxalactam)--100 mg/kg/day. Bacterial counts in the cerebrospinal fluid (CSF) and drug levels in the serum and CSF were measured each hour for 7 h and at 24, 48 and 72 h after start of therapy. Percent penetration values (CSF concentration/serum concentration X 100) for the drugs were calculated and effectiveness of bacterial clearing from the CSF was determined. Over the 72 h period, the most effective therapy was mezlocillin + gentamicin, followed by ampicillin + gentamicin, mezlocillin, ampicillin and latamoxef in order of effectiveness in clearing bacteria from the CSF.     

Experience with teicoplanin in the treatment of neonatal staphylococcal sepsis

We aimed to evaluate retrospectively the clinical and bacteriological efficacy and potential side-effects of teicoplanin treatment in neonates with proven staphylococcal infection. There were 37 episodes of staphylococcal septicaemia in neonates with a mean gestational age of 34.2 +/- 2.3 weeks; 26 were caused by coagulase-negative staphylococcal (CoNS) sepsis and 11 by Staphylococcus aureus sepsis. All episodes were treated with teicoplanin (intravenous loading dose 16 mg/kg followed by a maintenance dose of 8 mg/kg daily). The methicillin resistance and antibiotic susceptibilities of both micro-organisms were evaluated. Bacterial eradication was achieved in 89.1% of cases and mortality was 16.2%. The mean duration of treatment of the survivors was 11.6 +/- 2.3 days. There were no drug-related adverse events and the biochemical and haematological tests showed no clinically significant changes in relation to teicoplanin therapy. Our results suggest that teicoplanin is highly effective in neonatal staphylococcal sepsis.     

Evaluation of cefepime alone and in combination with vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model and in vitro

Cefepime, a broad-spectrum, fourth-generation cephalosporin, showed excellent CSF penetration with levels ranging between 10 and 16 mg/L after two intravenous injections (100 mg/kg). The bactericidal activity of cefepime (-0.60 +/- 0.28 Deltalog(10) cfu/mL/h) was superior to that of ceftriaxone (-0.34 +/- 0.23 Deltalog(10) cfu/mL/h, P < 0.05) and vancomycin (-0.39 +/- 0.19 Deltalog(10) cfu/mL/h, P < 0.05) in the treatment of rabbits with meningitis caused by an isolate highly resistant to penicillin (MIC of penicillin G: 4 mg/L). The addition of vancomycin to both cephalosporins did not significantly increase the killing rate compared with monotherapies (P > 0.05). Similar results were obtained in time-killing experiments in vitro.