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Antimycobacterial drugs acting efficiently against Mycobacterium avium complex have in common low MICs and MBC/MIC ratios. The recently reported clinical efficacy of some of the newer drugs is also clearly linked to their pharmacokinetic properties such as higher serum level and/or intracellular concentrations and half-life. In the present investigation, comparative postantibiotic effects (PAEs) of amikacin, rifampin, sparfloxacin, clofazimine and clarithromycin were investigated. Bacteria were exposed to MIC, MIC x 4 and MIC x 8 concentrations of each drug for 2 h, the drug was removed by centrifugation and cells were thoroughly washed and resuspended in drug-free medium. Growth was compared to control organisms which underwent a similar treatment (but without drugs) and PAEs were assessed using the equation "T-C", where T equals the time required for colony counts to increase by 1 log10 in test samples after antibiotic exposure and C equals the time for 1 log10 growth in control. Our results underlined two distinct patterns concerning PAE: pattern I included drugs for which PAE (in hours) was dose-dependent and varied (for MIC, MIC x 4 and MIC x 8 concentrations) for amikacin (10.3 +/- 1.7, 14.7 +/- 1.9 and 17.7 +/- 4.1), rifampin (28.0 +/- 7.6, 62.0 +/- 18.5 and 71.0 +/- 3.2) and clarithromycin (2.6 +/- 1.0, 15.0 +/- 4.0 and 22.0 +/- 4.0), whereas pattern II included drugs with a stable PAE, relatively independent of the drug concentrations: sparfloxacin (11.0 +/- 2.5, 12.3 +/- 6.4 and 13.0 +/- 2.1) and clofazimine (26.0 +/- 2.8, 28.8 +/- 2.5 and 27.3 +/- 1.3). These results may be useful for guidance in scheduling of drug administration in M. avium-infected AIDS patients overburdened with too many drugs given for various opportunistic infections.

We determined cefotaxime and desacetyl-cefotaxime concentrations in children with bacterial meningitis receiving high-dose cefotaxime (300 mg/kg of body weight/day) and concomitant dexamethasone therapy. The median peak cerebrospinal fluid cefotaxime and desacetyl-cefotaxime concentrations were 4.7 and 8.1 microg/ml, respectively. In vitro bactericidal activity (>99.9% killing in 6 h) was found in 17 (94%), 13 (72%), and 8 (44%) of 18 cerebrospinal fluid specimens against cefotaxime-susceptible, -intermediate (MIC, 1 microg/ml), and -resistant (MIC, 4 microg/ml) strains, respectively. High-dose cefotaxime, while safe, is not reliably sufficient therapy for cephalosporin-nonsusceptible pneumococcal meningitis, and combination therapy is recommended.

Twelve volunteers received 300 mg of clindamycin intravenously (i.v.) or orally (p.o.) administered every 8 h (q8h) or q12h by random assignment over four study periods. Serum bactericidal titers were determined for each regimen against two isolates each of Staphylococcus aureus, Streptococcus pneumoniae (one penicillin-sensitive isolate and one penicillin-resistant isolate), and Bacteroides fragilis. The duration of measurable bactericidal activity over the dosing interval (expressed as a percentage of the dosing interval) was determined for each isolate. No significant differences in the duration of activity were observed between i.v. and p.o. regimens dosed according to the same interval (P > 0.05). All regimens provided bactericidal activity against S. pneumoniae for 100% of their respective dosing intervals. Against B. fragilis, bactericidal activity was observed for greater than 80% of the dosing interval for each of the regimens. Although a statistically significant difference favoring the q8h i.v. regimen (P < 0.05) was detected, this difference is not believed to be clinically significant. The q8h and q12h regimens provided measurable bactericidal activity against S. aureus for greater than 85 and 50% of the dosing intervals, respectively (P < 0.001). Clindamycin dosed at 300 mg i.v. or p.o., q8h or q12h, provides adequate coverage against S. aureus, S. pneumoniae, and B. fragilis.

Owing to the broad spectrum of activity afforded by beta-lactam-beta-lactamase inhibitor preparations, these agents are frequently selected as empiric therapy for the treatment of mixed infections such as intra-abdominal and diabetic foot infections, either alone or in combination with an aminoglycoside. Twelve healthy volunteers were enrolled in a randomized, open-label, four-way crossover trial comparing the bactericidal activities of piperacillin-tazobactam, ticarcillin-clavulanate, and ampicillin-sulbactam against microorganisms commonly isolated from mixed infections. Subjects received the following regimes: (i) 3.375 g of piperacillin-tazobactam intravenously (i.v.) every 6 h (q6h) (ii) 4.5 g of piperacillin-tazobactam i.v. q8h, (iii) 3.1 g of ticarcillin-clavulanate i.v. q6h, and (iv) 3.0 g of ampicillin-sulbactam i.v. q6h. Serum bactericidal titers were determined and used to calculate the duration of measurable bactericidal activity over the dosing interval of each of the regimens against two clinical isolates of Bacillus fragilis, Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa. The percentage of the dosing interval over which drug concentrations in serum remained above the MIC for each organism was determined and compared with the observed duration of bactericidal activity was noted (r = 0.78; P < 0.001). All of the regimens demonstrated good activity against B. fragilis and E. coli. Against E. faecalis and P. aeruginosa, however, all of the regimens provided bactericidal activity for less than 50% of the respective dosing intervals. These data suggest that use of shorter dosing intervals or continuous-infusion regimens should be considered in combination with an aminoglycoside to improve the bactericidal profiles of these agents for E. faecalis and P. aeruginosa.

Nontypeable Haemophilus influenzae (NTHI) frequently causes recurrent infections of the respiratory tract in humans. Previous indirect evidence suggested that a strain-specific immune response occurs following infection and that this immune response is directed at an immunodominant epitope on the bacterial surface. To test this hypothesis, mice and rabbits were immunized with whole cells of a strain of NTHI and the antiserum was characterized to identify the antigens to which antibodies were directed. All animals made a prominent antibody response to the loop 5 region of the P2 molecule, which is the major outer membrane protein. Rabbit serum showed complement-dependent bactericidal activity. Adsorption of the immune serum with the loop 5 fusion peptide removed bactericidal activity and also abolished reactivity to P2 detected by an immunoblot assay, an enzyme-linked immunosorbent assay, and a radioimmunoprecipitation assay. These data indicate that immunization with whole cells of NTHI results in a prominent antibody response which is directed at epitopes on the loop 5 region of the P2 molecule. Thus, a strain-specific immune response to NTHI occurs as a result of the expression of an immunodominant epitope on the P2 molecule.

Summary Life history parameters appear to be traded off against each other, but the physiological mechanisms involved remain unclear. One hypothesis is that potentially energetically costly processes such as immune function, and protection from oxidative stress, may be compromised during reproductive attempts because of selective resource allocation. Lower temperatures also impose energy costs, and hence allocation decisions might be more pronounced when animals are forced to reproduce in the cold. Here, we experimentally tested whether reproduction at different ambient temperatures was associated with elevated oxidative stress and suppressed immune function in Mongolian gerbils (Meriones unguiculatus). Using a variety of different markers for both immune function and oxidative stress we found that some measures of immune function (serum bactericidal capacity and size of the thymus) were significantly suppressed, while some measures of oxidative protection (serum superoxide dismutase (SOD) activity and glutathione peroxidase (GPx) activity) were also reduced, and a marker of oxidative damage (protein carbonyls in serum) was increased, in lactating compared with non-reproductive gerbils. These changes were in line with the selective resource allocation predictions. However, the PHA response and serum total immunoglobulin (IgG) were not suppressed, and other markers of oxidative damage (malonaldehyde MDA (TBARS) and protein carbonyls in the liver) were actually lower in lactating compared with non-reproductive gerbils, consistent with increased levels of SOD activity and total antioxidant capacity (T-AOC) in the liver. These latter changes were opposite the expectations based on resource allocation. Furthermore other measures of protection (GPx levels in the liver and protein thiols in both serum and liver) and damage (MDA (TBARS) in serum) were unrelated to reproductive status. Ambient temperature differences did not impact on these patterns. Collectively, our results indicated that the infra-red effects of reproduction on immunosuppression and oxidative damage, and hence support or otherwise for particular physiological mechanisms that underpin life history trade-offs, are critically dependent on the exact markers and tissues used. This may be because during reproduction individuals selectively allocate protection to some key tissues, but sacrifice protection of others.

Proteus sp. strains isolated from patients with urinary tract infection (UTI) are often insensitive to the bactericidal action of normal human serum (NHS) which poses a clinical problem. The swarming phenomenon is an especially important factor in cases of UTIs gained through the ascending route. Both these virulence factors are connected with the cell surface components of bacteria, including lipopolysaccharide (LPS).The resistance of Proteus bacilli to the bactericidal activity of NHS and the swarming phenomenon were investigated as well as the possible relationships between these virulence factors and the chemical structure of LPS.The research was carried out on P. penneri and P. vulgaris species. Two preparations of sera were tested with respect to the bactericidal action of NHS. The ability of bacteria to swarm was checked on broth agar plates. The length of the O-specific part of LPS was estimated after poliacrylamide gel electrophoresis (PAGE) and staining with silver nitrate.Among the 62 tested Proteus strains, over 62% of Proteus vulgaris and 50% of Proteus penneri strains were sensitive to the bactericidal action of NHS. However, the number of resistant strains grew dramatically when serum with blocked complement activation via the alternative pathway was used. From 102 of the Proteus sp. Strains, only few were unable to swarm over the solid surface of the media. The remaining showed diverse ability to translocate.There was no definite correlation between the chemical structure of the O-specific chains of lipopolysaccharides and sensitivity or resistance of the Proteus sp. strains to NHS. Also, no significant relationships were found between the length or the chemical structure of the O-specific chains of the bacterial LPSs and the swarming phenomenon.

To develop a hyperdynamic sepsis model in rats, four Escherichia coli strains were used, which differed in the presence or absence of a capsule or K antigen (K1 and K-, respectively) and/or in O serogroup (O9 and O18). Of the two clinical isolates, O9K- did not survive in rat serum, whereas O18K1 and two isogenic laboratory strains (O18K1 and O18K-) were able to resist serum bacteriolysis. Pentobarbital-anesthetized rats (n = 21) received an intravenous bolus of 10(9) bacteria. In contrast to the two noncapsulated strains, both capsulated strains induced hyperdynamic shock; arterial lactate rose from a mean value of .91 to 3.09 mmol.L-1, systemic vascular resistance dropped from 1.15 to .78 mmHg.min.mL-1, and cardiac output transiently increased from 98 to 115 mL.min-1; renal plasma flow remained at 3-4 mL.min-1, whereas glomerular filtration rate decreased from 1.3 to .7 mL.min-1. Laparotomy, which is often performed to study kidney function, completely abolished the hyperdynamic condition, while glomerular filtration rate was still decreased. We conclude that in rats, in contrast to humans, capsulated bacteria are required to induce a hyperdynamic septic shock; the hyperdynamic characteristics of the shock do not occur in animals subjected to a laparotomy.

The serum bactericidal activities of ceftizoxime and ceftriaxone against organisms commonly implicated in community-acquired and nosocomial pneumonias were studied. Ceftizoxime 1 g (as the sodium salt) every 12 hours for two doses and ceftriaxone 1 g (as the sodium salt) every 24 hours for two doses were administered to 20 healthy volunteers in a crossover fashion. Blood samples were drawn immediately before and 2,4,6,8,10, and 12 hours after the second ceftizoxime dose and immediately before and 8,12,16,18,20, and 24 hours after the second ceftriaxone dose. Serum drug concentrations were determined by validated high-performance liquid chromatography. Serum bactericidal titers were determined in duplicate for each serum sample against four clinical isolates of each of the following organisms: Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae, and Serratia marcescens. The median duration of serum bactericidal activity during the dosage interval was significantly different between antimicrobial regimens only for S. pneumoniae (92% of the dosage interval for ceftizoxime, versus 100% for ceftriaxone). This difference does not appear to be clinically important since ceftizoxime provides adequate serum bactericidal activity for more than 50% of the dosage interval and its effectiveness against pneumococcal pneumonia has been supported in clinical trials. The ceftriaxone and ceftizoxime regimens did not differ significantly in their duration of serum bactericidal activity against six of the seven organisms tested.

Sparfloxacin, a new fluorinated quinolone, exhibits higher in vitro activity against pneumococci than do ciprofloxacin and ofloxacin. Since up to 30% of cases of pneumococcal pneumonia are associated with bacteremia, and since an increasing percentage of pneumococci are resistant against penicillin, we studied the serum bactericidal activity of sparfloxacin against pneumococci in eight healthy, middle-aged volunteers. Pharmacokinetics in serum and urine after a 400-mg oral dose of sparfloxacin were comparable to those described by other authors. Inhibitory and bactericidal activities in serum were measured for four pneumococcal isolates representing penicillin-susceptible (one isolate), intermediately resistant (two isolates), and highly resistant (one isolate) strains. Geometric mean inhibitory titers ranged between 1:2.4 and 1:6.3 and bactericidal titers ranged between 1:1.3 and 1:3.6 during a time period of 1 to 6 h after drug intake. Although such titers were not sufficient to predict a clinical response based on previous pharmacodynamic studies using quinolone antibiotics, data obtained with volunteers may only partially reflect the clinical situation in which a rise of humoral antibodies directed against pneumococcal antigens may help to reinforce the bactericidal action of the antibiotic.

The pharmacodynamics and pharmacokinetics of ceftazidime administered by continuous infusion and intermittent bolus over a 4-day period were compared. We conducted a prospective, randomized, crossover study of 12 critically ill patients with suspected gram-negative infections. The patients were randomized to receive ceftazidime either as a 2-g intravenous (i.v.) loading dose followed by a 3-g continuous infusion (CI) over 24 h or as 2 g i.v. every 8 h (q8h), each for 2 days. After 2 days, the patients were crossed over and received the opposite regimen. Each regimen also included tobramycin (4 to 7 mg/kg of body weight, given i.v. q24h). Eighteen blood samples were drawn on study days 2 and 4 to evaluate the pharmacokinetics of ceftazidime and its pharmacodynamics against a clinical isolate of Pseudomonas aeruginosa (R288). The patient demographics (means +/- standard deviations) were as follows: age, 57 +/- 12 years; sex, nine males and three females; APACHE II score, 15 +/- 3; diagnosis, 9 of 12 patients with pneumonia. The mean pharmacokinetic parameters for ceftazidime given as an intermittent bolus (IB) (means +/- standard deviations) were as follows: maximum concentration of drug in serum, 124.4 +/- 52.6 micrograms/ml; minimum concentration in serum, 25.0 +/- 17.5 micrograms/ml; elimination constant, 0.268 +/- 0.205 h-1; half-life, 3.48 +/- 1.61 h; and volume of distribution, 18.9 +/- 9.0 liters. The steady-state ceftazidime concentration for CI was 29.7 +/- 17.4 micrograms/ml, which was not significantly different from the targeted concentrations. The range of mean steady-state ceftazidime concentrations for the 12 patients was 10.6 to 62.4 micrograms/ml. Tobramycin peak concentrations ranged between 7 and 20 micrograms/ml. As expected, the area under the curve for the 2-g q8h regimen was larger than that for CI (P = 0.003). For IB and CI, the times that the serum drug concentration was greater than the MIC were 92 and 100%, respectively, for each regimen against the P. aeruginosa clinical isolate. The 24-h bactericidal titers in serum, at which the tobramycin concentrations were < 1.0 microgram/ml in all patients, were the same for CI and IB (1:4). In the presence of tobramycin, the area under the bactericidal titer-time curve (AUBC) was significantly greater for IB than CI (P = 0.001). After tobramycin was removed from the serum, no significant difference existed between the AUBCs for CI and IB. We conclude that CI of ceftazidime utilizing one-half the IB daily dose was equivalent to the IB treatment as judged by pharmacodynamic analysis of critically ill patients with suspected gram-negative infections. No evaluation comparing the clinical efficacies of these two dosage regimens was performed.

Penetration of ceftriaxone into heart tissues (valves, myocardium, auricles, and pericardium) and mediastinal tissues (fat and sternal bone) was evaluated after two regimens of ceftriaxone administration. Ten patients (group 1) were given 1,000 mg of ceftriaxone intravenously 30 min before anesthesia. Ten other patients (group 2) received the same dose and then a second 1,000-mg dose at the time of initiation of cardiopulmonary bypass. Similar and very satisfactory penetrations of ceftriaxone into tissue were observed for both groups. During opening and closure of the thorax, mean ceftriaxone concentration was in excess of the MIC at which 90% of the potential pathogens were inhibited (> or = 4 micrograms/g) in the thoracic fat, the sternal bone, and the pericardium. No significant differences between the two administration regimens in penetration of ceftriaxone into tissue were observed. During cardiopulmonary bypass, the ceftriaxone concentration was > or = 4 micrograms/g in the myocardium, the endocardium, and the auricle. The regimen of ceftriaxone administration did not significantly influence penetration of the drug into heart tissues. However, for some patients in the two groups and mainly in the sternal bone at the time of thorax closure (6 patients in group 1 and 5 patients in group 2), ceftriaxone levels in tissues were less than the MICs (4 micrograms/g) for some potential pathogens (methicillin-susceptible Staphylococcus aureus and methicillin-susceptible Staphylococcus epidermidis). During the different steps of the surgical procedures, all (10 of 10) patients in each group had tissue ceftriaxone levels greater than the MICs for gram-negative aerobic bacilli (0.1 microgram/g), except for Pseudomonas spp.

Ten patients were treated with conventional dosing (CD) and continuous-infusion (CI) vancomycin therapy in this prospective, randomized, crossover study. Patients were randomized to receive either CD or CI therapy for 2 consecutive days and then crossed over to receive the opposite regimen for 2 days. CD therapy consisted of 1 g of vancomycin every 12 h. CI therapy consisted of a 500-mg loading dose followed by 2 g infused over 24 h. Ten serum samples were obtained on the second day of each therapy for pharmacokinetic and pharmacodynamic analyses. Two clinical isolates of Staphylococcus aureus, one methicillin sensitive (MSSA 1199) and one methicillin resistant (MRSA 494), were chosen for pharmacodynamic evaluation of both regimens. The patient demographics (means +/- standard deviations [SD]) were as follows: sex, six males, four females; age, 36 +/- 11 years; and serum creatinine, 0.72 +/- 0.18 mg/dl. Mean pharmacokinetic parameters +/- SD for CD therapy were as follows: elimination rate constant, 0.16 +/- 0.07 h-1; half-life, 5.6 +/- 3.5 h; volume of distribution, 33.7 +/- 25 liters, 0.5 +/- 0.2 liters/kg; maximum concentration in serum, 53.4 +/- 19.3 micrograms/ml; and minimum concentration, 8.4 +/- 5.9 micrograms/ml. The steady-state concentration for CI was 20.2 +/- 11.1 micrograms/ml. Overall, both regimens resulted in the MIC being exceeded 100% of the time. The mean CD trough serum bactericidal titer (SBT) was 1:8, and the average CI SBTs were 1:16 for both isolates. Even though there was no statistically significant difference between CD trough and CI SBTs, the CI SBTs remained > 1:8 for 100% of the time versus 60% of the time for CD therapy. During CI therapy, 20 and 40% of the patients maintained SBTs of > 1:32 throughout the dosing interval for MSSA 1199 and MRSA 494, respectively. During CD therapy, however, only 10% of patients maintained SBTs of > 1:32 during the entire dosing interval for both isolates. The mean areas under the bactericidal titer-time curve (AUBC24s) +/- SD for MSSA 1199 were 528 +/- 263 for CD therapy and 547 +/- 390 for CI therapy. The mean AUBC24s +/- SD against MRSA 494 were 531 +/- 247 for CD and 548 +/- 293 for CI therapy. Similar to the AUBC24, the mean area under the concentration-time curve for a 24-h dosing interval divided by the MIC (AUC/MIC24) ratios +/- SD were 550.0 +/- 265.7 for CD and 552.6 +/- 373.4 for CI therapy, respectively. No statistically significant differences were found between any of the pharmacodynamic parameters for CD and CI therapy. In addition, no adverse effects with either CD or CI therapy were observed during the study. We conclude that CI and CD vancomycin therapy demonstrated equivalent pharmacodynamic activities. Although CI therapy was more likely to result in SBTs that remained above 1:8 for the entire regimen, the clinical impact of this result is unknown. Serum drug concentration variability was observed with both treatment regimens but to a lesser extent with CI administration. CI administration of vancomycin should be further evaluated to determine the clinical utility of this method of administration.

Although serum vibriocidal activity is used extensively as a marker of immunity to O1 Vibrio cholerae, there are limitations in this assay to detect instances of reexposure. We define the conditions operative in producing secondary vibriocidal responses in North American volunteers primed with either wild-type V. cholerae 1, 4, or 6 months later. Secondary serum vibriocidal responses occurred under two distinct secondary challenge conditions. The first occurred when secondary challenge produced a breakthrough in clinical protection. Following secondary exposure, 14 of 22 (64%) and 1 of 29 (3%) subjects with and without vibrio stool excretion, respectively, had secondary responses (P < 0.001); 5 of 6 (83%) and 10 of 45 (22%) subjects with or without diarrhea, respectively, mounted a secondary response (P = 0.006). The second condition occurred in the presence of full clinical protection but was dependent on the time interval between exposure. No subject (0 to 17) vaccinated with CVD 103-HgR and given homologous wild-type challenge within 4 months mounted a secondary vibriocidal response (P = 0.0009). The majority of the serum vibriocidal activity was of the immunoglobulin M (IgM) isotype, seen in 96 and 73% of subjects following primary and secondary exposure, respectively. Vibriocidal activity in the IgG fraction following primary and secondary exposures occurred with < or = 50% of volunteers; lipopolysaccharide (LPS)-specific IgG1 and IgG3 subclass responses supported the vibriocidal isotype data. However, following primary exposure, IgG4 LPS responses predominated, occurring in 81% of responding volunteers. These data suggest that, under certain conditions of secondary exposure to V. cholerae O1 antigens, when there is sufficient active local immunity present, there is a block of vibrio antigen resampling at the M cell level. We discuss the implications of and possible explanations for these findings.

Since beta-lactam antibiotics have concentration-independent killing, bacterial eradication is a function of the time the serum drug concentration remains above the drug's MIC (T > MIC). We compared the serum bactericidal titers (SBTs) of ceftazidime given by continuous infusion (CI) or by intermittent bolus dosing (BD) against two clinical isolates each of Pseudomonas aeruginosa and Escherichia coli to determine if CI would allow lower daily dosing while still providing equal bactericidal activity compared with BD. This was an open-labeled, randomized, steady-state, four-way crossover study with 12 healthy volunteers. The ceftazidime regimens were 1 g every 8 h (q8h) BD, 1 g q12h BD, 3 g over 24 h CI, and 2 g over 24 h CI. The areas under the bactericidal curves were calculated by the trapezoidal rule using the reciprocal of the SBT. For all organisms the areas under the bactericidal curves for intermittent versus the CI regimens were the same for equal doses (P > 0.05). For both strains of E. coli all four regimens provided SBTs of > or = 1:2 over the dosing interval and 100% T > MIC. The 1-g q8h BD and q12h BD regimens provided T > MIC of 82 and 52%, respectively, for both P. aeruginosa isolates (MICs, 4 micrograms/ml). In comparison, the 2- and 3-g CI regimens always maintained SBTs of > or = 1:2 and T > MIC over the 24-h period as serum drug concentrations were 12.8 +/- 3.0 and 18.2 +/- 4.5 micrograms/ml, respectively. CI optimizes the pharmacodynamic and pharmacoeconomic profile of ceftazidime by providing adequate antibacterial activity over the 24-h dosing period with a reduction in the total daily dose of the antimicrobial agent.

Brucellosis is a zoonotic disease caused by Brucella spp. and is still a serious problem of public health for some regions around the world such as the Mediterranean Sea, Middle East, Latin America, and Asia. (Published: 14 February 2013) Citation: Libyan J Med 2013, 8 : 20417 - http://dx.doi.org/10.3402/ljm.v8i0.20417

There are reports of failure of extended-spectrum cephalosporin treatment in pneumococcal meningitis. On the basis of in vitro and animal experimental studies, the addition of vancomycin or rifampin to an extended-spectrum cephalosporin has been recommended for empiric treatment of these patients. Cerebrospinal fluid (CSF) was taken from 31 children with bacterial meningitis randomized to receive ceftriaxone alone (n = 11), ceftriaxone plus rifampin (n = 10), or ceftriaxone plus vancomycin (n = 10). The CSF from children receiving ceftriaxone alone was unable to kill intermediately ceftriaxone-resistant or fully resistant strains when the concentration of ceftriaxone in the CSF was less than 5 micrograms/ml. At higher concentrations bactericidal activity was present. We have shown that vancomycin penetrates reliably into the CSF of children with acute meningitis, which is in contrast to previous studies with adults. The addition of vancomycin or rifampin to ceftriaxone resulted in significantly enhanced CSF bactericidal activity compared with that of ceftriaxone alone against these resistant strains. Our data suggest that the addition of rifampin or vancomycin to ceftriaxone may be useful for the treatment of cephalosporin-resistant pneumococcal meningitis.

In a randomized crossover study, the protein binding and serum bactericidal activities (SBAs) of vancomycin and teicoplanin against Staphylococcus aureus and Streptococcus pyogenes were investigated in six healthy volunteers. Total concentrations in serum 1 h postadministration of vancomycin and teicoplanin were 25.5 +/- 2.7 and 10.8 +/- 8.9 mg/liter, respectively; mean free concentrations were 14.6 +/- 2.0 and 0.6 +/- 0.9 mg/liter, respectively. Protein binding for vancomycin was 36.9% +/- 2.87%, and that for teicoplanin was 97.4% +/- 2.6%. SBA determined in pooled human serum at 1 h against S. aureus ranged from 1:8 to 1:32 for both vancomycin and teicoplanin. Against S. pyogenes SBA at 1 h ranged from 1:16 to 1:128 for vancomycin and 1:256 to 1:2,048 for teicoplanin. In vitro kill curve studies showed that vancomycin is slowly bactericidal and that teicoplanin is bacteriostatic. Despite having less in vitro cidal activity against the study isolates and having low or unrecordable levels of free drug in serum, teicoplanin demonstrated a similar or better SBA than vancomycin. SBA was more closely related to the total drug level (r = 0.77 for S. aureus and r = 0.79 for S. pyogenes) than the free level of teicoplanin (r = 0.59 for S. aureus and r = 0.56 for S. pyogenes). The high level of protein binding of teicoplanin did not seem to impair its antibacterial activity as measured by its SBA.

Bovine herpesvirus-1 (BHV-1) is an important pathogen of respiratory infections in cattle. Its continuing importance lies in its ability to predispose infected hosts to bacterial infections (e.g., Pasteurella haemolytica). In this study we determined whether the immunoregulatory effects induced by recombinant bovine interleukin-1 (rbIL-1) could stimulate appropriate host defense mechanisms to influence the course of BHV-1 and P. haemolytica infection in cattle. We first evaluated the effect of multiple doses (5 doses of 300 ng/kg) of rbIL-1 in normal cattle. An increase in polymorphonuclear (PMN) cells, as well as monocytes, in peripheral blood was observed during the course of IL-1 administration. In addition, the phagocytic activity of monocytes was increased. Although the phagocytic and oxidative burst activities in PMN decreased during the course of rbIL-1 treatment, no changes were observed in the bactericidal capacity of these cells. Lymphocyte numbers in peripheral blood remained unchanged; however, the functional activity of these cells, as measured by IFN-gamma production upon in vitro stimulation, was decreased. In the bovine respiratory disease model, multiple administration of IL-1 did not influence significantly the progression of BHV-1/P. haemolytica infection in cattle. Thus, our results demonstrated that IL-1, although not therapeutically effective, could be administered safely as an adjuvant, even during the course of BHV-1/P. haemolytica infection.

The interaction between clinicians and microbiology laboratory staff has to be one of mutual benefit. The more the laboratory personnel know about your patients, the more meaningful and thorough will be the results. Communication is the key to success. Visit the microbiology laboratory and get to know the staff. The clinician also needs to be familiar with and use the most commonly used diagnostic tests for individual bacterial pathogens appropriately.

Despite its clinical efficacy on intracellular pathogens, the in-vitro intracellular antimicrobial activity of azithromycin, has been shown to be absent or lower than expected from the intracellular concentrations reached. To test the possibility that the high intracellular concentrations of the drug could damage phagocytes, the present study evaluated the effects of azithromycin on (a) the intracellular killing of Staphylococcus aureus by human blood neutrophils (PMNs) and (b) the viability and the respiratory burst of PMNs. Using a fluorochrome assay, we assessed the phagocytosis and intracellular killing of S. aureus by PMNs preloaded with azithromycin, or by PMNs unloaded but with the drug in the culture medium. In addition, possible drug-induced damage to PMNs was evaluated measuring: (a) hydrogen peroxide (H2O2) production and (b) the percentages of PMNs dead at the end of the phagocytosis process. Compared to control PMNs without drug, a time-dependent enhancement in the intracellular killing was observed which was statistically significant after 60 min incubation. The increased intracellular killing was higher in suspensions of unloaded PMNs and azithromycin (P < 0.01) that in suspensions of preloaded PMNs (P < 0.05). This increased intracellular killing was not associated with increased proportions of dead phagocytes, either in preloaded or unloaded PMNs (P < 0.05, each comparison). Similarly no changes in the production of H2O2 by PMNs were observed in the presence of azithromycin. Thus, azithromycin induces a time-dependent increase in the bactericidal activity of human PMNs, without increasing the phagocyte self-killing or modifying H2O2 production.

The bactericidal activity of RP 59500, a semisynthetic streptogramin, was compared with that of vancomycin against Staphylococcus aureus. This activity was evaluated in vitro by the kill curve method and in vivo using a model of mouse septicaemia. In vitro, RP 59500 (MIC = 0.12 mg/L) was more rapidly bactericidal against S. aureus IP 8203 than was vancomycin (MIC = 1 mg/L). In vivo, RP 59500 (120 mg/kg) was bactericidal against staphylococci in the blood of infected mice 1 h after administration, an effect which lasted for up to 7 h, whereas vancomycin at the same dose was bactericidal only 4 h after administration. The serum concentrations of vancomycin were higher than those of RP 59500 for at least 4 h after administration, and the Cmax and AUC of vancomycin were 4.8 and 8.3 times higher, respectively, than those of RP 59500 (Cmax = 13.2 mg/L; AUC0(-1) = 15.2 mg/L/h), although the agents had similar elimination half-lives (about 0.5 h). RP 59500 was also administered to mice as a fractionated dose (30 mg/kg x 4, 40 mg/kg x 3, 60 mg/kg x 2). The onset of its bactericidal effect was delayed by fractionating the dose, but the suppression of bacteria in the blood was prolonged.

In recent decades considerable data have been acquired concerning the complex interactions of the organism-antimicrobial-host triad. Using the current understanding of drug disposition in the body, pharmacokinetics, and in vitro microbiologic activity, optimal dosing strategies can be derived to maximize clinical efficacy and minimize potential toxicities. This article discusses pharmacokinetics, pharmadynamics, and the application of this principle in clinical practice.

Soon after antimicrobial drugs became available, it was recognized that they were being overused and misused. Reasons for concern about the inappropriate use of antimicrobials include the emergence of resistant nosocomial bacteria, which have been identified in every hospital nationwide. The presence of resistant nosocomial bacteria presents the physician with a clinical problem and increases the cost of therapy. It is clear that methods need to be implemented to help physicians improve prescribing of antimicrobial agents. As health care practitioners in all fields strive to make patient care more cost-effective, one observation has become evident: The successfully treated patient consumes fewer resources and subsequently costs the hospital less than an otherwise similar, unsuccessfully treated patient. The goal in the 1990s is to provide optimal, cost-effective care for patients without compromising quality. This goal can be achieved by collaborative efforts of physicians, pharmacists, and microbiologists working together as a team to promote quality patient care.

In addition to MIC and MBC tests in this study the serum bactericidal activity of 3.1 µg/ml of moxifloxacin or 5.2 µg/ml of levofloxacin was determined against ten susceptible strains of S. aureus, S. epidermidis, E. coli and K. pneumoniae. Moxifloxacin achieved markedly better activity against S. aureus and S. epidermidis as compared to levofloxacin. Activity of moxifloxacin against E. coli and K. pneumoniae was excellent but not superior to levofloxacin. In conclusion both fluorquinolones are highly effective against E. coli and K. pneumoniae, moxifloxacin being superior with respect to gram-positives like S. aureus and S. epidermidis.

In recent years, an increase of systemic Candida infections was noted. Thus, identification and susceptibility testing to antifungals became of considerable importance. The technique of dilution in liquid medium developed by « National committee for clinical laboratory standards » NCCLS or more recently named CLSI « Clinical and laboratory standards institute » is the reference method most used. The European committee "European committee on antibiotic susceptibility testing" or EUCAST has made progress by determining the susceptibility of strains within a shorter time. However, the use of these techniques is limited especially in clinical microbiology laboratories. Other techniques for determining antifungal sensitivity have been developed such as those based on agar diffusion (E-test and disk diffusion), on microdilution (Sensititre yeastOne, Vitek 2 AST-YS01), on flow cytometry techniques and the MALDI-TOF.

To analyze the levels of human serum antibody against Neisseria meningitidis serogroup C measured by serum bactericidal assay (SBA) and ELISA.SBA and a modified ELISA were applied to measure the serum bactericidal titer and the specific concentration of immunoglobulin G (IgG) against meningococcal serogroup C in sera samples. Seventy-five sera were from healthy adults without undertaking vaccination while another 429 and 388 pre- and post-vaccinated sera were from 143 infants and 194 young children immunized with conjugate vaccine or polysaccharide vaccine, respectively. Correlation between serum bactericidal titer and the concentration of specific IgG against meningococcal serogroup C was analyzed.The concentration of meningococcal serogroup C specific IgG in healthy adults showed a strong correlation (r=0.814 33, P0.001) with serum bactericidal titer through linear regression analysis. Weak correlation was observed between SBA titers and IgG concentration in pre vaccinated sera of infants and children (conjugate/polysaccharide vaccine) (infants: r=0.140 64, P0.100/r=0.2899, P0.05; children: r=0.540 40, P0.05/r=0.194 36, P0.05). After immunization with 2-dose conjugate vaccine in infants and 1-dose in children, a strong correlation between the two panels of results was observed (r=0.809 38, P0.001 and r=0.837 23, P0.001 respectively). However after immunization with polysaccharide vaccine, the correlation between serum bactericidal titer and concentration of specific IgG was weak (r0.50000).Among healthy adults and post vaccinated infants or young children immunized with conjugate vaccine, the concentration of specific IgG was comparable to the serum bactericidal titer against meningococcal serogroup C. However, it was not unfavorable to use ELISA as the principal means of measuring serum antibody responses to polysaccharide vaccine for infants under 1 year old.

International audience; A meningococcal B:14:P1.7,16 outbreak in Normandy (France) was recently controlled using MenBvac, an outer membrane vesicle vaccine previously designed against the B:15:P1.7,16 strain. The further emergence of a new B:14:P1.7,16 outbreak in another district in Normandy led us to explore immunity against B:14:P1.7,16 before and after the MenBvac campaign using a 2+1 (day 0, week 6, month 8) schedule. Children (1-5 years) were sampled before, during and up to one year after vaccination. Serum bactericidal activity against B:14:P1.7,16 was titrated using human complement (hSBA) and immune response was defined by hSBA titer ≥4 as a surrogate for protection. The percentage of hSBA titer ≥4 was 10.8% before vaccination, raised to 84.1% 6 weeks after the completion of the schedule, but declined to 39.7% one year later. This level is lower than the targeted 60% level and suggests only short-term persistence of response against B:14:P1.7,16 using this schedule.

Antibiotic therapy is administered intravenously to children with bacterial meningitis to achieve the highest possible blood and cerebrospinal fluid (CSF) concentrations. However, intravenous access for the entire duration of therapy may be difficult in some children. Intramuscular therapy offers a more versatile option; however, CSF concentrations and bactericidal activity following im injection in children concurrently treated with dexamethasone have not been studied. We prospectively evaluated 37 children given an im dose of ceftriaxone on either the 3rd, 6th or 9th day of antibiotic therapy while receiving dexamethasone for the first 4 days of treatment. All children were required to have normal peripheral perfusion at the time of im injection. Four to 6 hours after im injection CSF was obtained. The average age of study patients was 28 months; Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b were responsible for 95% of all infections. All children studied had detectable CSF ceftriaxone concentrations, with mean (+/- SD) concentrations (microgram/ml) on Days 3, 6 and 9 of therapy of 5.7 +/- 5.5 (n = 12), 5.2 +/- 5.0 (n = 14) and 2.0 +/- 2.6 (n = 10), respectively. All CSF bactericidal titers for N. meningitidis, S. pneumoniae and H. influenzae type b, regardless of day of im injection, were > or = 1:64. Intramuscular ceftriaxone therapy of bacterial meningitis may be a reasonable therapeutic option for the convalescing child with good peripheral perfusion.

The activity of ceftriaxone plus metronidazole against pathogens usually involved in intra-abdominal infections was studied. Metronidazole 1 g and ceftriaxone 1 g (as the sodium salt) were simultaneously administered i.v. over 30 minutes every 24 hours to 12 healthy volunteers for three doses. Serum samples were collected at baseline, just before the last dose, and 12, 16, 20, 22, and 24 hours after the start of infusion of the last dose. Serum bactericidal titers (SBTs) were performed in duplicate for each serum sample from 12 hours on. Serum ceftriaxone and metronidazole concentrations were determined by high-performance liquid chromatography, and the elimination rate and half-life were calculated for each antimicrobial in each volunteer. The minimum inhibitory concentrations (MICs) of each antibiotic for two strains each of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Bacteroides fragilis were determined by microdilution. Eleven volunteers completed the study. Ceftriaxone and metronidazole maintained SBTs of at least 1:4. Serum ceftriaxone concentrations remained above the MICs for E. coli, P. mirabilis, and K. pneumoniae, and serum metronidazole concentrations remained above the MIC for B. fragilis throughout the study. Ceftriaxone combined with metronidazole resulted in intense and prolonged activity against E. coli, P. mirabilis, K. pneumoniae, and B. fragilis.

Rifampin at a maximally effective dose was less active than ceftriaxone (both drugs at 10 mg/kg of body weight.h) in a rabbit model of pneumococcal meningitis (delta log10 CFU/ml.h, -0.40 +/- 0.13 versus -0.77 +/- 0.18; P < 0.01). The bactericidal activity of rifampin decreased at concentrations in cerebrospinal fluid greater than those that are clinically achievable, and use of rifampin in combination with ofloxacin had no synergistic or additive effect.

Previous studies have suggested that group A streptococcal strains from southeast Asia, serotypically different from temporally related North American and European isolates, may represent unrecognized M serotypes. Sixty non-M typeable group A streptococcal upper respiratory tract isolates from Thailand were evaluated for the presence of M protein using a modification of the direct serum bactericidal test. Of them, 59 (98%) grew rapidly in human blood. Typeability by T agglutination and opacity factor production did not influence their growth in blood. It was concluded that these isolates produce M protein and likely represent previously uncharacterized M serotypes. Identification of such non-M typeable strains is important in understanding the epidemiology and pathogenesis of group A streptococcal infections and their sequelae in areas of the world where they remain a significant health problem and will also be necessary in the development of a vaccine with global efficacy.

Plasma concentration of cefminox and serum bactericidal activity against four ATCC strains (Escherichia coli 25992, Klebsiella pneumoniae 13833, Serratia marcescens 8100 and Bacteroides fragilis 25285), were determined over a 24 h period after administration of cefminox 1 and 2 g to six healthy volunteers in a randomized, cross-over, single blind study. The increase observed in the area under the bactericidal curve (AUBC) with the 2 g dose was at least 3.5 times that seen with the 1 g dose for all four test strains and was larger than predicted by the corresponding increase (1.84 times) in the area under the serum concentration versus time curve (AUC); a correlation (r = 0.88, P = 0.0001) between the cefminox concentration and the serum bactericidal titres was, however, observed with all four strains tested. The MBC6h showed a better association with the serum bactericidal titre (P < 0.01) than did the MIC or MBC.

Bactericidal activity of grass carp (Ctenopharyngodon idella) serum was significantly enhanced when pre-treated with 15 mg l(-1) or 3 mg l(-1) of berberine hydrochloride, an effective component of several commonly used herbal medicines in aquaculture. The complement consumption experiment demonstrated that berberine hydrochloride can certainly activate fish complement system. The results of both experiments suggested that berberine hydrochloride could enhance the serum bactericidal activity in grass carp by activating the complement system and indicating the potential in the prevention or treatment of fish diseases. (C) 2012 Elsevier Ltd. All rights reserved.

Imipenem, cefaperazon-sulbactam and cefepime are the antibiotics of choice for the treatment of soft tissue infections due to Acinetobacter baumannii. In this study, it was aimed to determine the invivo and invitro efficacy of, these antibiotics against drug susceptible and multidrug resistant A.baumannii in an experimental abscess model. Abscess models were established in Wistar-Albino type female rats. Susceptibility tests were performed by E-test. Rats were divided randomly into four groups with eight rats in one group. Standard absorbent paper discs containing 6 log10 CFU microorganisms were used to form an abscess model. The first group was regarded as the control group and the other three groups were the study group each treated with one of the test antibiotics. Cardiac blood samples for serum antibiotic efficacy test, were obtained on the fourth day of treatment and 30 minutes after the last dose. The number of live bacteria at the area of infection was determined by colony count method. All of the three antibiotics reached sufficient concentration in sera of rats and there were no statistically important difference between the efficacies of these antibiotics (p= 0.778). In all of the antibiotic-treated groups, the weight of the abscess material were less, macroscopic views were smaller and the colony counts per gram of abscess tissue were less than the control group (p0.001). All antibiotics were effective against susceptible and resistant strains in vitro. No resistance was detected against imipenem, cefaperazon-sulbactam and cefepime in the course of therapy. Cefaperazone-sulbactam and cefepime were as effective as imipenem against susceptible and multi-drug resistant A.baumannii both in vivo and in vitro. Since irrational use of extended spectrum cephalosporins are frequently associated with the emergence of carbapenem resistant strains, the use of relatively narrow spectrum antibiotics should better be considered in the empirical treatment of A.baumannii infections.

In order to evaluate the efficacy of an antibacterial therapy, three basic PK/PD indexes were defined: the ratio between the maximum drug concentration obtained after a single dose and minimum inhibitory concentration MIC (CMAX/MIC), the ratio between the area under the curve of dependence between the drug concentration in blood and time within 24 hours to MIC (AUC24/MIC), and the time when the concentration of the drug in blood is higher than MIC (TMIC). The aim of the study was an analysis of the pharmacokinetics of ciprofloxacin and the PK/PD: CMAX/MIC index in patients with cystic fibrosis. Six patients with cystic fibrosis, with the identified microbiological factor were subjected to the examination. The patients received ciprofloxacin in the dose of 400 mg/12 h (i.v.). Plasma drug concentration was measured by HPLC-UV method after the first dose (Cmax1) and at steady state (Cssmax, Cssmin). The following mean values of ciprofloxacin blood concentrations were obtained from the analyzed patients: Cmax1 = 2.34 (+/- 1.15) microg/mL, Cssmax = 2.49 (+/- 1.44) pg/mL, Cssmin = 0.42 (+/- 0.22) pg/mL. The mean values of the Cmax1/MIC and Cssmax/MIC indexes were 3.66 +/- 2.34) and 3.38 (+/-1.73), respectively. Low values of the Cmax/MIC index for ciprofloxacin in the analyzed patients may indicate too low concentrations of the drug in the blood in relation to the MIC value of pathogens and the need to verify the assumed administration scheme.

Several generic piperacillin/ tazobactam formulations have been approved by Thai Food andDrugAdministration, Ministry of Public Health. Piperacillin/ tazobactam is a parenteral drug. Therefore, a study demonstrating a biological equivalence of generic piperacillin/ tazobactam is not required for drug registration in Thailand.The study was to determine microbiological equivalence of serum bacteriostatic and bactericidal activities of the sera from healthy volunteers receiving generic piperacillin/ tazobactam (PipertazA) and original piperacillin/tazobactam (Tazocin).This was a randomized crossover study in 16 adult healthy volunteers. Each subject received 4.5 grams of Pipertaz and Tazocin in 50 ml of normal saline via intravenous infusion for 30 minutes. The blood samples were drawn at baseline prior to receiving the study drug, at 30 minutes after initiating infusion, and at 8 hours after initiating infusion. The serum bacteriostatic activity against E. coli ATCC 25922, K. pneumoniae, P aeruginosa ATCC 27853 and A. baumannii was performed by disk diffusion The serum bactericidal activity against E. coli ATCC 25922 was performed by Serum Bactericidal Titre.The average inhibition zone diameter of the serum samples from the subjects while receiving Pipertaz against each tested organisms was1 mm smaller than that while receiving Tazocin and such difference was not significantly different. All serum samples collected at 30 minutes after initiating Tazocin and Pipertaz had bactericidal titres 1:64 to 1:256 against E. coli ATCC 25922. All serum samples collected at 8 hours after initiating Tazocin and Pipertaz had bactericidal titres1:2 against E. coli ATCC 25922. The differences of serum bactericidal titres of the serum samples collected at 30 minutes (p = 0.7) and 8 hours (p = 1.0) after initiating Tazocin and Pipertaz were not statistically significant.The sera from healthy volunteers receiving Pipertaz contain bacteriostatic and bactericidal activities not significantly different from those receiving Tazocin.

In order to study the immunomodulatory effects of decaffeinated green tea extract on rainbow trout, a study with a 30-day feeding trial was conducted. Commercial diets with graded levels of decaffeinated green tea extract, 20 mg (T1), 100 mg (T2), 500 mg (T3) per kg feed were prepared. 120 rainbow trout (35 ± 3 g) were randomly assigned to 4 groups in triplicates and fed one of the 3 experimental diets formulated or control diet. After feeding trial, 12 fish from each group were sampled for analysis of some immunological parameters. Remaining fish were injected with 0.5 ml of chicken red blood cell (C-RBC) suspension (2%) intraperitoneally on days 5 and 15 after feeding trial. Results of the current study showed that the inclusion of 20 mg kg-1 green tea (T1) in fish diet enhanced the serum bactericidal activity against Yersinia ruckeri, while significant elevation of lysozyme activity was shown in T2 group. Anti-trypsin activity due to α1-antiprotease was significantly higher in T1 and T2 groups while peroxidase content showed significant increase in all treatment groups compared to control group. Hemagglutination antibody titer against C-RBC was significantly higher in fish administered with 100 mg kg(-1) green tea (T2). Our findings showed that decaffeinated green tea in lower doses of administration could be optimum to enhance the immunity of rainbow trout.

Serum bactericidal activity (SBA) was determined against ten strains each of Staphylococcus aureus, Klebsiella pneumoniae, Proteus vulgaris and Enterobacter cloacae in six volunteers 1 h and 4 h after intravenous infusion of 1 g and 2 g cefotaxime and cefmenoxime, and 2 g flomoxef, and against ten strains of Pseudomonas aeruginosa after infusion of 1 g and 2 g ceftazidime. Flomoxef showed the highest SBA against methicillin-susceptible Staphylococcus aureus. All cephalosporins had high SBA against gram-negative rods. Cefotaxime had the highest SBA against Klebsiella pneumoniae and Enterobacter cloacae. The SBA against Pseudomonas aeruginosa after 1 g and 2 g doses of ceftazidime was very similar.

Plasma and epiploic fat drug concentrations and fat penetration of ceftriaxone and ornidazole given for antimicrobial prophylaxis were studied in 11 patients scheduled for liver transplantation. Ceftriaxone (1 g) and ornidazole (500 mg) were infused during 30 min after the induction of anesthesia. Arterial blood and epiploic fat samples were collected at 30, 60, and 120 min and then every 90 min following the end of the infusion until closure of the peritoneum. Blood samples were immediately centrifuged, and plasma and fat were stored at -35 degrees C until analysis. Ceftriaxone and ornidazole concentrations were determined by high-performance liquid chromatography. Surgery lasted 440 +/- 84 min and required a mean of 9.5 units of packed erythrocytes and 13 units of fresh frozen plasma. Plasma ceftriaxone concentrations decreased from 89 +/- 34 to 41 +/- 16.5 micrograms/ml from the beginning of the operation until the time of closure of the peritoneum. Corresponding levels in epiploic fat decreased from 8.7 +/- 3.3 to 4.5 +/- 3.5 micrograms/g. Ornidazole concentrations ranged, respectively, between 8.7 +/- 2.5 and 4.9 +/- 1.7 micrograms/ml in plasma samples and 4.6 +/- 1.2 and 2.5 +/- 1.1. micrograms/g in fat samples. Rates of penetration into the omentum remained at about 9% for ceftriaxone and between 50 and 70% for ornidazole. Tissue ceftriaxone concentrations were, in all cases, greater than typical MICs for 90% for Escherichia coli and Klebsiella isolates tested (MIC90S). They were insufficient in 40% of patients after 60 min with regard to the MIC90S for Staphylococcus aureus. Tissue ornidazole concentrations were not superior to MIC90S for anaerobes after 30 min in 50% of patients. These results show that a single dose of 1 g of ceftriaxone provides adequate coverage against gram-negative bacteria and that 1 g instead of 500 mg ornidazole may provide a protective effect against anaerobes during liver transplantation. Prophylaxis against S. aureus and Streptococcus faecalis requires more specific antibiotics. Prophylaxis for patients with significant blood loss or initial severe renal or hepatic failure needs further evaluation.

We performed experiments in rats aimed at determining whether a combination of ceftriaxone (CRO) and netilmicin (NET), by using once-daily administration in rats, which simulated profiles of drug in human serum, was more effective than either agent alone in the treatment of endocarditis caused by viridans group streptococci. A programmable infusion pump system enabled the production of profiles of CRO in serum that simulate those found in humans after the intravenous administration of 2 g. The subcutaneous administration of 18 mg of NET per kg of body weight produced levels in the sera of rats comparable to those after the intravenous administration of a dose of 5 mg of NET per kg in humans. Rats with catheter-induced aortic vegetations were infected intravenously with two test strains, a CRO-susceptible Streptococcus sanguis strain (MICs of CRO and NET, 0.064 and 8 mg/liter, respectively) and a relatively CRO-resistant Streptococcus mitis strain (MICs of CRO and NET, 2 and 8 mg/liter, respectively). Against both strains, the combination of CRO and NET was synergistic in vitro as determined by time-kill curves. Treatment of rats was started 48 h postinfection and lasted for 3 days. CRO alone was effective against the susceptible strain (P < 0.001 compared with control animals) but was not effective against the resistant organism. A significantly enhanced antibacterial activity of the CRO-NET combination in reducing the valvular bacterial counts was observed with both test strains (P < 0.001). The synergistic effect was obtained with a single daily injection of NET which provided detectable levels in serum for only 8 h, suggesting that in vivo synergism in the treatment of infections caused by viridans group streptococci can be obtained without 24 h of aminoglycoside coverage. These experimental data might provide a rationale for clinical trials of a once-a-day dosing regimen in the treatment of streptococcal but nonenterococcal endocarditis.

The combination of novobiocin and rifampin is effective in eliminating colonization due to methicillin-resistant Staphylococcus aureus (MRSA) and in treating experimental MRSA soft tissue infections. To evaluate novobiocin, rifampin, and the combination of the two agents for potential oral therapy in patients with MRSA infections, we measured the serum inhibitory and bactericidal activity from four volunteers against 20 MRSA strains obtained from seven different institutions. When Stratton-Reller methods employing 50% human serum were used to perform the assay, rifampin produced peak mean serum inhibitory titers of 1:40, whereas novobiocin alone produced essentially no inhibitory activity. The combination of novobiocin plus rifampin had similar inhibitory activity as rifampin alone. The bactericidal titers produced by the three regimens were significantly less than inhibitory titers. In additional studies, involving serum from five volunteers tested against seven representative strains, peak mean serum inhibitory activity of novobiocin was 1:232 when Mueller-Hinton broth was used as the diluent compared with1:2 when 50% human serum was used. We conclude that despite the high degree of activity of novobiocin in broth, its activity against MRSA in serum is minimal, probably related to the high degree of protein binding of that antibiotic.

In a prospective, randomized trial, 205 febrile episodes in granulocytopenic cancer patients were treated with ceftazidime with or without tobramycin (C±T), both agents being administered only if the initial granulocyte count was below 200/μl, or ceftazidime plus piperacillin (C+P). The overall response rate was 71% (39 of 60 for C±T and 45 of 58 for C+P). Logistic regression analyses documented no evidence of a significant difference between the two regimens in overall treatment effect after accounting for the linear effects of potentially important variables, such as infection type and granulocyte count. Although the response rates for the subgroup of patients with bacteremias was better with the C+P regimen (P=0.06), there was no difference in response for patients with bacteremia and profound (

We examined the effects of sub-MICs of erythromycin (EM) and other macrolide antibiotics on the serum sensitivity of Pseudomonas aeruginosa. P. aeruginosa S-6 grown for 36 and 48 h on agar with 10 micrograms of EM per ml (1/10th the MIC) showed significantly increased sensitivity to human serum bactericidal activity compared with those of bacteria grown on agar without EM (P < 0.05). No changes in serum sensitivity were observed in bacteria grown for less than 24 h. This increased sensitivity was apparent even at a concentration of 1.5 micrograms of EM per ml (1/67th the MIC) in bacteria grown for 48 h (P < 0.01). Among the other macrolide antibiotics tested, clarithromycin also enhanced sensitivity to serum, but there were no changes in the sensitivities of bacteria grown on agar with kitasamycin, josamycin, rokitamycin, or oleandomycin even at a concentration of 12 micrograms/ml (1/16th, 1/16th, 1/8th, and 1/33rd the MICs, respectively). P. aeruginosa S-6 grown on agar with subinhibitory concentrations of EM showed decreased cell surface hydrophobicity in a dose-dependent manner, whereas oleandomycin and rokitamycin, even at a concentration of 12 micrograms/ml, induced a slight decrease in hydrophobicity which was approximately equivalent to that of 1.5 micrograms of EM per ml. Among six other strains of the nonmucoid phenotype, three strains became more sensitive to serum by exposure to 10 micrograms of EM per ml for 48 h. In contrast, no evident correlation between EM treatment and a change in serum sensitivity was observed in six strains of the mucoid phenotype, as judged by the results of experiments with both 2 and 0.4% serum. These results show that EM at subinhibitory concentrations enhances the serum sensitivity of some P. aeruginosa strains. Since induced serum sensitivity was accompanied by a decrease in bacterial cell surface hydrophobicity, EM may render P. aeruginosa more serum sensitive by changing the cell surface structure(s) of this organism.

Pefloxacin pharmacokinetics and serum bactericidal activities (SBA) against Escherichia coli and Staphylococcus aureus were compared after intravenous infusion of either a single 800-mg dose or twice-daily 400-mg doses into 16 healthy volunteers. Plasma pefloxacin concentrations were measured for up to 60 h, and SBAs were determined 1, 12, and 24 h after the start of the infusion. The mean areas under the concentration-versus-time curve for plasma were not different (138 versus 136 h.mg/liter). The mean clearances, volumes of distribution, and half-lives were also comparable. The mean (+/- standard deviation) maximal concentration after the 800-mg infusion was 12.11 +/- 1.35 versus 6.51 +/- 0.73 mg/liter after the first 400-mg infusion and 7.42 +/- 0.76 mg/liter after the second 400-mg infusion. Mean trough concentrations at 24 h were significantly different: 2.77 +/- 0.63 (800 mg) versus 1.93 +/- 0.49 (400 mg twice) mg/liter (P = 0.0007). Mean SBAs against E. coli after 800 mg of pefloxacin were higher than 1/128 (1 h), 1/32 (12 h), and 1/16 (24 h). Mean SBAs against S. aureus under the same conditions were higher than 1/64 (1 h), 1/16 (12 h), and 1/8 (24 h). Mean SBAs at 1 and 12 h were significantly higher after the 800-mg infusion than after the 400-mg infusion but were similar at 24 h for both regimens. Comparison of SBAs according to National Committee for Clinical Laboratory Standards criteria showed a similar adequacy at 24 h for both regimens against both strains. Administration of 800 mg of pefloxacin once a day is bioequivalent to 400 mg twice a day, and bactericidal activity of the 800-mg infusion is not less than that of two 400-mg infusions.

Elimination kinetics following a single dose of teicoplanin in rats pre-treated with morphine sulphate (MS), phenobarbital sodium (Pb), and normal saline (NS) were determined. A microbioassay was used to measure teicoplanin levels. A significant increase in the total clearance of teicoplanin was found in rats pre-treated with MS as compared to controls (P < 0.048). Wide variability was observed in the renal and non-renal clearances of teicoplanin. The mean renal clearance for rats pre-treated with MS, Pb and NS was 0.61 +/- 0.07.mL/min/kg, 0.60 +/- 0.13 mL/min/kg, and 0.46 +/- 0.02 mL/min/kg, respectively; the mean non-renal clearance was 0.33 +/- 0.18 mL/min/kg, 0.17 +/- 0.15 mL/min/kg, and 0.08 +/- 0.03 mL/min/kg, respectively. The differences among the groups for renal and non-renal clearance were not statistically significant. The mean apparent volume of distribution of teicoplanin at steady state was significantly lower in the Pb-pre-treated rats as compared to controls (P < 0.043). The mean half-life for MS-, Pb-, and NS pre-treated groups was 8.1 +/- 3.1 h, 5.9 +/- 3.3 h, and 34.6 +/- 20.7 h, respectively. The differences in mean half-life among the groups achieved statistical significance (P < 0.016). The increase in the total clearance of teicoplanin can best be explained by an increase in both renal elimination and hepatic metabolic pathways.

To gain additional data concerning the anti-anaerobic activity of tigecycline in serum, we analyzed blood samples from six patients with a complicated skin/soft tissue infection who were receiving IV tigecycline 50 mg every 12 h. Venous blood samples were obtained after multiple doses of tigecycline at 1, 6 and 12 h after the initiation of a 1 h IV infusion. Sera from these samples were tested to determine serum inhibitory and bactericidal activity over time against 4 anaerobic bacteria (Bacteroides fragilis, Peptoniphilus asaccharolyticus, Prevotella bivia and Finegoldia magna). An analysis of serum titers found that tigecycline exhibited early (1 h) and prolonged (12 h) inhibitory activity against each study isolate. Moreover, it provided bactericidal activity for 12 h against these strains with the exception of F. magna. Tigecycline was found to exhibit antibacterial activity at serum concentrations below the MICs of the anaerobic bacteria tested. This finding further supports that the antimicrobial activity of tigecycline can be greater than that suggested by the free fraction of drug and that serum appears to enhance this antibacterial activity.