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Vancomycin and a new antibiotic, daptomycin (LY146032), were tested in vitro and in vivo against Staphylococcus aureus. In vivo tests were performed with rabbits with kaolin-induced hydrocephalus. Five groups of rabbits were studied: untreated ventriculitis, intraventricular vancomycin only, and ventriculitis treated with intraventricular vancomycin (30 micrograms or 120 micrograms) or daptomycin (7.5 micrograms). Results of this study were as follows. (i) S. aureus demonstrated static growth in cerebrospinal fluid in vitro and in ventriculitis at a maximum titer of 10(5) to 10(6) CFU/ml. (ii) In vitro time kill curves in cerebrospinal fluid matched those in vivo. (iii) Single-dose intraventricular vancomycin did not lower S. aureus concentrations over 8 h, whereas daptomycin did. (iv) Ventriculitis did not significantly alter the clearance of intraventricular vancomycin. (v) Intraventricular half-lives were approximately 2.8 h (maximum) for vancomycin and 4.5 h for daptomycin. (vi) Vancomycin was detectable in the periventricular white matter only in the presence of ventriculitis. Daptomycin was also detectable in the periventricular white matter of rabbits with ventriculitis, but in amounts too small to quantitate. We concluded that daptomycin achieved greater bactericidal activity, more rapid killing kinetics, and a longer half-life in the ventricle than vancomycin did in this model.

To review recent advances in the understanding of pathogenic and pathophysiologic mechanisms underlying bacterial meningitis that may lead to the development of adjunctive strategies for treating this disorder.Studies published from 1975 to 1989 were identified using Index Medicus and by reviewing the bibliographies of identified articles.We reviewed the experimental and human studies evaluating pathogenesis, pathophysiology, and antimicrobial treatment of bacterial meningitis, as well as those reviews that have contributed to our understanding of meningitis.We evaluated the data on the pathogenesis, pathophysiology, and treatment of bacterial meningitis and considered in depth the information from animal models that may have potentially important applications in the treatment of human disease.Penicillin and ampicillin remain the drugs of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis. The third-generation cephalosporins have revolutionized the treatment of gram-negative bacillary meningitis; one such agent, ceftazidime, is also useful for treating Pseudomonas aeruginosa meningitis. Modification of subarachnoid space inflammation by anti-inflammatory agents may lessen many of the pathophysiologic consequences of bacterial meningitis. A recent study of adjunctive dexamethasone therapy in infants and children with bacterial meningitis showed that the incidence of long-term neurologic sequelae was lower in the corticosteroid group.Future therapy for bacterial meningitis will use recent developments in the understanding of pathogenic and pathophysiologic mechanisms underlying this disease. Additional studies using monoclonal antibodies against specific virulence factors and investigations into the production of inflammatory cytokines in response to bacterial cell products may lead to additional treatments that decrease the high morbidity and mortality in patients with bacterial meningitis.

We have examined the pharmacokinetics of moxalactam (LY127935) in 36 subjects with various degrees of renal dysfunction. Creatinine clearance (Ccr)/1.73 m2 ranged from zero to 135.8 ml/min. After a 1-g administration of moxalactam intravenously, the volume of distribution was 20.6 /+- 9.5 liters (0.28 liter/kg), and the mean half-life ranged from 3.1 h for subjects with Ccr greater than 65 ml/min to 19.3 h for subjects with Ccr less than 10 ml/min. The moxalactam clearance was closely correlated to Ccr (r = 0.93, P less than 0.0001) and excretion of antibiotic was 73.6 +/- 13% in normal subjects. Renal clearance accounted for 90% of moxalactam clearance in the normal subjects. A dosage schedule for administering moxalactam to patients with various degrees of renal dysfunction is provided.

The influence of leukocytes and Haemophilus influenzae type b (Hib) capsule on blood brain barrier permeability (BBBP) to circulating 125I-albumin in normal and leukopenic rats was assessed after intracisternal inoculation of encapsulated (Rd-/b+/02) or unencapsulated (Rd-/b-/02) isogenic strains of Hib. Both normal and leukopenic animals had increased BBBP 18 h after inoculation, with normal rats demonstrating significantly increased BBBP after challenge with the encapsulated strain. Despite cerebrospinal fluid (CSF) pleocytosis in normal rats, CSF bacterial concentrations were not lower. Normal rats cleared unencapsulated Rd-/b-/02 more effectively than leukopenic rats, with BBBP correlating with CSF bacterial density and not leukocyte concentrations. Challenge with heat-killed Rd-/b+/02 resulted in increased BBBP in both normal and leukopenic rats, with greater BBBP at higher bacterial concentrations. The data suggest: (a) significant increases in BBBP occur in the near absence of CSF leukocytes; (b) CSF leukocytes can augment changes in BBBP; (c) type b capsule inhibits host clearance mechanisms within the CSF; and (d) BBBP appears to correlate with bacterial concentrations within the CSF.

The influence of preformed antibody on the induction of experimental Candida albicans endocarditis was investigated by both in vitro and in vivo techniques. Preincubation of C. albicans with immune serum (raised in rabbits by intravenous injection of Formalin-killed yeast cells) decreased adhesion to the constituents of nonbacterial thrombotic endocarditis, e.g., fibrin plus platelets, in vitro. Two different methods, with radiolabeled or viable yeast cells, were confirmatory and demonstrated decreased adhesion of immune serum-treated C. albicans cells to 0 to 7.8% of control values (P less than 0.001). These results correlated with protection from the development of C. albicans endocarditis in the immunized rabbits. The mean (+/- standard deviation) infectious dose for 50% of the animals was 10(5.29) +/- 10(0.07) in 48 control animals versus 10(7.11) +/- 10(0.22) in 37 immunized rabbits (P less than 0.001). These studies suggest that humoral antibody may protect against C. albicans endocarditis, perhaps through inhibition of adhesion, a crucial early step in the pathogenesis of endocarditis.

Bacterial adhesion to the constituents of nonbacterial thrombotic endocarditis (NBTE) is important in the pathogenesis of endocarditis. Subinhibitory concentrations (subMIC) of some antibiotics decrease bacterial adhesion to epithelial cells in vitro. We utilized an in vitro assay system to study the effect of subMIC of various antibiotics on streptococcal adhesion to a fibrin-platelet matrix (simulating NBTE). The results were (a) bacterial adhesion of Streptococcus sanguis and Streptococcus faecalis to NBTE was significantly reduced by vancomycin, penicillin, tetracycline, chloramphenicol and streptomycin (P less than 0.01 vs. controls) but not rifampin or trimethoprimsulfametrole; (b) the effect was dose-dependent and increased with duration of exposure to antibiotic; (c) reduction in bacterial adhesion did not correlate with altered retention by hydrophobic-interaction chromatography. This reduction in adhesion correlated with a diminished capacity of subMIC exposed Streptococcus sanguis (1/4 vancomycin minimum inhibitory concentration (MIC) X 4 h) to produce endocarditis in vivo. After intravenous inoculation of 10(6) colony-forming units of preincubated organisms into rabbits with traumatized aortic valves, 6 of 22 developed endocarditis vs. 17 of 22 controls (P = 0.03). These results may be relevant to prophylaxis of endocarditis since exposure of bacteria to subMIC of various antibiotics may reduce bacterial adherence both, to mucosal surfaces, and to damaged cardiac valves.

Increasing resistance to antibiotics in meningeal pathogens has stimulated a search for new antimicrobial agents for the treatment of bacterial meningitis. Moxalactam penetrates well into infected cerebrospinal fluid (CSF) and is highly active against most gram-negative bacteria. The clinical efficacy and safety of moxalactam in the treatment of childhood meningitis caused by Haemophilus influenzae (25 patients) or Neisseria meningitidis (five patients) was evaluated in a random, uncontrolled study. The penetration of the antibiotic into CSF was also evaluated in these patients and in another five children with bacterial meningitis. The clinical results were excellent, with 29 of 30 cases cured. The single adverse clinical reaction noted was the development of a wound hematoma in a postoperative patient; this problem may have been related to moxalactam therapy. The levels of moxalactam achieved in CSF greatly exceeded the minimal bactericidal concentrations for the infecting organisms. Moxalactam appears to be safe and effective as primary therapy for meningitis caused by H influenzae or N meningitidis. Haemophilus influenzae and Neisseria meningitidis are common meningeal pathogens in children. Penicillin is currently recommended for the treatment of meningitis caused by N meningitidis and ampicillin and chloramphenicol for the treatment of meningitis caused by H influenzae. The emergence of ampicillin- and chloramphenicol-resistant strains of H influenzae [1] and concern over the hematopoietic toxicity of chloramphenicol have prompted a search for alternative agents. The successful treatment of meningitis caused by H influenzae requires an antimicrobial agent that is bac

The influence of preformed, anti-whole organism antibody on the development of Streptococcus sanguis endocarditis was examined in both in vivo and in vitro systems. Antibody prevented, rather than potentiated, endocarditis in rabbits. The infectious dose in 30 control animals was 10(6.5) +/- 0.33 (mean +/- standard deviation); this increased to 10(7.71 +/- 0.05 in 36 immunized animals (P less than 0.01). No differences in bacterial clearance mechanisms were apparent between groups. Antibody also prevented the adherence of S. sanguis to the constituents of nonbacterial thrombotic endocarditis (fibrin and platelets) in vitro. When preincubated in high-titer antisera, adherence of S. sanguis was reduced compared with controls (adherence ratio mean +/- standard error of the mean, X 10(4): 174 +/- 5 versus 427 +/- 10, P less than 0.001). Preadsorption of immune sera with intact S. sanguis restored adherence to normal values, whereas preadsorption with dextran was partially effective. These studies demonstrate that preformed antibody had a protective role in vivo and suggest that a possible mechanism is blockade of adherence, a crucial early step in the pathogenesis of endocarditis.

Aztreonam (SQ 26,776), a new monocyclic beta-lactam agent, was compared with ampicillin, ampicillin plus chloramphenicol, and gentamicin in rabbits with experimental meningitis induced by, respectively, ampicillin-susceptible Haemophilus influenzae, ampicillin-resistant H. influenzae, and Escherichia coli. Aztreonam was also compared with gentamicin in experimentally induced E. coli cerebritis in rats. Doses of the various agents were delivered that produced near-peak concentrations in serum comparable to those attained in humans on standard parenteral regimens. The percent penetration [( concentration in cerebrospinal fluid/concentration in serum] X 100) of aztreonam into purulent rabbit cerebrospinal fluid was 23% (versus 12, 27, and 21%, respectively, for ampicillin, chloramphenicol, and gentamicin). In experimental meningitis in vivo, aztreonam was more rapidly bactericidal than was ampicillin in ampicillin-susceptible H. influenzae meningitis, ampicillin or chloramphenicol in ampicillin-resistant H. influenzae meningitis, or gentamicin in E. coli meningitis. In the therapy of experimental cerebritis, the early stage of brain abscess formation, aztreonam reduced the numbers of E. coli in rat brain as rapidly as did gentamicin. Aztreonam deserves further evaluation in acute gram-negative bacterial infections of the central nervous system in both experimental animals and in humans.

Acute bacterial meningitis may be associated with increased intracranial pressure, neurological sequelae such as communicating hydrocephalus, and a slow response to antibiotic therapy. Alterations in cerebrospinal hydrodynamics are at least partially responsible for these complications. Constant, low-flow short-duration manometric infusion studies through a hollow-bore pressure monitoring device in direct continuity with the supracortical subarachnoid space were performed in rabbits with experimental meningitis. Maximal resistance to cerebrospinal fluid (CSF) outflow from the subarachnoid to vascular space was markedly increaed in acute pneumococcal meningitis when compared to control, uninfected animals (6.77 +/- 3.52 vs. 0.26 +/- 0.04 mm Hg/microliter per min, P less than 0.001). Similar elevations (8.93 +/- 4.15 mm Hg/microliter per min were found in experimental Escherichia coli meningitis. Despite eradication of viable bacteria from the CSF by penicillin therapy during the acute stage of pneumococcal meningitis, resistance remained elevated (6.07 +/- 4.68 mm Hg/microliter per min) and had not returned to normal up to 15 d later. Administration of methylprednisolone during the early stages of acute pneumococcal meningitis reduced mean peak outflow resistance towards control values (0.59 mm Hg/microliter per min) and no "rebound" effect was apparent 24 h later. These hydrodynamic alterations in experimental meningitis prevent normal CSF absorption and decrease the ability of the bran to compensate for changes in intracranial volume and pressure.

The utility of an experimental animal model is dependent on its ability to simulate the actual clinical situation. With a stereotaxic injection procedure, the susceptibility of rat brain to the spectrum of organisms commonly associated with human brain abscess was determined. Two strains of Escherichia coli were more infective than Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes. Even between the E. coli strains it was possible to document significant differences in degree of infectivity. The E. coli strain with the K-1 capsular polysaccharide was significantly more infective than the E. coli strain without the capsular polysaccharide. The brain was also susceptible to Candida albicans, but at a level higher than any of the aerobic bacteria examined. Brain infection could not be created when microaerophilic or obligately anaerobic organisms alone were injected.

The nonrecirculating isolated perfused rat liver was used to study biliary antibiotic excretion by the liver in a steady-state, controlled environment in which bile flow, bile salt output, and antibiotic delivery were maintained under constant conditions. The effects of piperacillin, ampicillin, and gentamicin on bile flow and bile salt output were analyzed; none altered bile salt output, and only high concentrations of piperacillin (100 micrograms/mL) increased bile flow. The ratio of antibiotic concentration in bile and perfusate depended on the type of antibiotic and perfusate concentration. Piperacillin infusions at perfusate concentrations of 50 or 100 micrograms/mL (in the presence of 60 microM taurocholate) yielded bile to perfusate ratios of 112 +/- 10 versus 49 +/- 3, respectively. Using similar perfusate, the concentration ratios for ampicillin (20 micrograms/mL) and gentamicin (10 micrograms/mL) were only 3.4 +/- 0.5 and 0.5 +/- 0.1, respectively. By altering the perfusate to contain either 60 microM or 240 microM taurocholate, we found variance in bile salt output from 27 +/- 1 to 115 +/- 2 mumol/h, yet this alteration had little effect on the output of ampicillin (perfusate concentration of 20 micrograms/mL), 73 +/- 7 versus 74 +/- 12 micrograms/h, or piperacillin (perfusate concentration 100 micrograms/mL), 10 +/- 1 versus 11 +/- 2 mg/h. Thus, it appears ampicillin and piperacillin are excreted into bile at high concentrations by bile salt-independent pathways. Partial biliary obstruction (6 cm H2O) results in significant decreases in bile volume. Infusion of 50 micrograms/mL of piperacillin resulted in increased biliary flow that approached nonobstructed values. Obstruction resulted in significant decreases in bile piperacillin concentration. Whether the choleretic effect of high concentrations of piperacillin has any clinical significance in nonobstructed or obstructed conditions remains to be established.

Moxalactam, a new beta-lactam antibiotic with a wide in vitro spectrum of activity, was compared with cefazolin after intravenous and intramuscular administration of 1.0 g in a double-blind crossover design in 21 adult male subjects with normal renal function. Serum samples were obtained at 0.5, 1, 2, 3, 4, 6, 8, and 12 h, and urine was collected at 0 to 2, 2 to 4, 4 to 6, 6 to 8, and 8 to 12 h after dosing. Intravenous kinetics were described by a linear two-compartment model. For moxalactam, the drug clearance and volume of distribution were larger (115.2 versus 75.9 ml/min per 70 kg, P = 0.001, and 0.44 versus 0.19 liter/kg, P less than 0.001, respectively), and the t1/2beta was longer (3.47 versus 2.18 h, P = 0.01), with correspondingly smaller area under the curve (151 versus 236 h x mg/ml, P = 0.003) and lower serum concentration at 30 min (62 versus 106 micrograms/ml, P = 0.003) than cefazolin. Intramuscular kinetics were similar and were well described by a single-compartment model. Urinary recovery was essentially identical for both drugs: 55 to 75% in 8 h. Consistent departures from the two-compartment model for moxalactam (not noted for cefazolin) suggested enterohepatic recirculation of moxalactam. Both drugs were well tolerated, and no adverse reactions were noted.

The efficacy of ciprofloxacin (Bay o 9867), a promising new quinolone, was compared with the efficacy of azlocillin plus tobramycin in rabbits with experimentally induced Pseudomonas aeruginosa endocarditis. The MBCs of ciprofloxacin, azlocillin, and tobramycin against the test strain were 0.5, 8, and 4 micrograms/ml respectively. Ciprofloxacin at a concentration of 50 mg/kg or azlocillin at a concentration of 200 mg/kg in combination with tobramycin at a concentration of 5 mg/kg was administered intramuscularly at 8-h intervals for 4 days. Both regimens produced median peak serum bactericidal titers of 1:8. The concentrations of ciprofloxacin, azlocillin, and tobramycin in serum, 1.8 +/- 0.7, 154 +/- 48, and 9.1 +/- 2.4 micrograms/ml (mean +/- standard deviation), respectively, closely approximated concentrations found in humans after accepted dosages. At the end of treatment, the titers of P. aeruginosa were 3.0 +/- 1.6 log10 CFU/g of vegetation (mean +/- standard deviation) for recipients of ciprofloxacin and 3.2 +/- 1.3 log10 CFU/g of vegetation for recipients of azlocillin plus tobramycin. These values compared with control titers of 7.3 +/- 1.6 CFU/g. These data indicate that at the doses used, ciprofloxacin was as effective as azlocillin plus tobramycin in the treatment of P. aeruginosa endocarditis in rabbits. Since the latter drug combination has proven efficacy, ciprofloxacin deserves further evaluation in the therapy of systemic infections in animal models and in humans.

Fulminant bacterial meningitis requires aggressive management in an intensive care unit setting. In this article, the pathophysiology of the various factors contributing to brain tissue injury in this disease are discussed, as well as the management of these complications. The etiological agents of bacterial meningitis, according to age group, are discussed. Recommendations are made for the management of raised intracranial pressure, seizure activity, and empiric antimicrobial therapy.

The pharmacokinetics of cefaclor were characterized in 15 functionally anephric patients on hemodialysis. Each patient received a 500-mg oral dose of cefaclor every 8 h for 10 days. Multiple serum drug levels were measured by bioassay on day 0 (no hemodialysis), day 10 during hemodialysis, and as single determinations 1 h after administration on days 1, 3, and 5. Analysis of cefaclor kinetics in these 15 patients along with kinetics from 24 previously studied patients showed that weight was the best single predictor of volume of distribution. The corrected creatinine clearance (calculated from serum creatinine, age, and sex) proved to be the best predictor of drug half-life (r = 0.969). Thus, a single serum creatinine test provided a better estimated of cefaclor half-life than a 24-h urine collection. Cefaclor was cleared with an average serum half-life of 2.9 h without hemodialysis and 1.5 h during hemodialysis. Cefaclor serum levels measured 1 h after administration on days 0, 1, 3, and 5 showed no evidence of accumulation. Thus, cefaclor may be administered orally in multiple doses without accumulation in functionally anephric patients. In patients on dialysis, dosage interval or quantity should be increased to compensate for doubled drug clearance dialysis.

The in vitro activities of mecillinam, a new β-amidinopenicillin, and ampicillin, alone and in combination, against an Escherichia coli strain and a Klebsiella pneumoniae strain were compared, and these results were correlated with their respective activities in vivo in experimental meningitis. The mecillinam-ampicillin combination was synergistic in vitro against both strains when tested by a modified checkerboard technique (bacteriostatic synergy). However when quantitative bactericidal synergy studies were made, the relative bactericidal rate of the combination was more rapid than that of either drug alone (“bactericidal synergy”) against the Escherichia coli isolate only. In a rabbit model of Enterobacteriaceae meningitis, in vivo bactericidal activity correlated with results obtained in vitro. Both drugs were administered by continuous intravenous infusion for 8 h. Serum and cerebrospinal fluid antibiotic levels were similar to those achieved in humans. Cerebrospinal fluid bacterial concentrations (colony-forming units [CFU] per milliliter) were quantitatively titrated at 2-h intervals. Both drugs, alone or the combination, were ineffective against the K. pneumoniae strain in vivo (change in titer E. coli strain (mean ± standard deviation, decrease of log 10 CFU per milliliter of 3.65 ± 1.02) compared with those of ampicillin alone (decrease of log 10 CFU per milliter of 0.07 ± 0.8) and mecillinam alone (decrease of log 10 CFU per milliliter of 1.6 ± 0.05) ( P < 0.001). When bactericidal synergism can be demonstrated for mecillinam-ampicillin in vitro in a case of gram-negative-bacillary meningitis this combination may be useful in the therapy of the illness.

The role of dextran in the pathogenesis of bacterial endocarditis was investigated by studying the adherence of dextran producing oral streptococci to the constituents of nonbacterial thrombotic endocarditis (NBTE) in vitro and in vivo. The adherence of Streptococcus sanguis to fibrin and platelets was determined in an in vitro assay system simulating nonbacterial thrombotic endocarditis. Adherence was increased when the organisms were grown in sucrose-supplemented media (adherence ratio X 10(4), 177 +/- 6 in 5% sucrose vs. 140 +/- 7 in 0.5% sucrose, P less than 0.001), and decreased by incubating the organisms in dextranase (adherence ratio X 10(4), 117 +/- 16, P less than 0.001), an effect which was nullified by heat inactivating this enzyme (adherence ratio X 10(4), 192 +/- 7, P less than 0.001). The amount of dextran produced in broth by three different oral streptococci correlated directly with the adherence observed to fibrin and a fibrin-platelet matrix in vitro (P less than 0.001). These organisms adhered more readily to a fibrin-platelet matrix than to fibrin alone (adherence ratio X 10(4), 455 +/- 30 vs. 177 +/- 6, respectively, P less than 0.001). The role of dextran formation was also examined in vivo in rabbits with preexisting NBTE. After injection of 10(7) S. sanguis, 12 of 17 animals developed endocarditis. In contrast, when the organisms were pretreated with dextranase (an enzyme that removes dextran from the bacterial cell surface), the same inoculum resulted in endocarditis in only 5 of 19 animals (P less than 0.05). In addition, a fresh strain of S. sanguis that produced high levels of dextran (1,220 +/- 50 microgram/ml) and adhered avidly to fibrin (adherence ratio X 10(4), 220 +/- 11) produced endocarditis in 12 of 18 rabbits after injection of 10(7) organisms. Another isolate of the same strain that had been passed repeatedly in the laboratory produced less dextran (400 +/- 30 microgram/ml), adhered poorly to fibrin (adherence ratio X 10(4), 140 +/- 7), and produced endocarditis in only 3 of 14 rabbits under identical conditions (P less than 0.05). This study demonstrates that dextran production is important in the adherence of oral streptococci to the constituents of NBTE and may play a role in the pathogenesis of bacterial endocarditis by oral streptococci.

The efficacy of clindamycin in the treatment of experimental endocarditis in rabbits was compared with that of nafcillin. Both drugs were administered intramuscularly three times daily for 5 days, clindamycin at doses of 6.25, 12.5, 25, or 50 mg/kg and nafcillin at a dose of 200 mg/kg. The minimum inhibitory and bactericidal concentrations (0.125 microgram/ml) of clindamycin for the test strain of Staphylococcus aureus were very similar to the corresponding concentrations (0.25 microgram/ml) of nafcillin. The effectiveness of clindamycin against the experimental endocarditis was dose dependent. The therapeutic accomplishments of the two highest clindamycin doses were equivalent to those attained with 200 mg of nafcillin per kg. The rates of sterilization of vegetations were equal when the serum bactericidal titers of these drugs were greater than or equal to 1:8. In special situations the administration of clindamycin in high doses could prove useful in the treatment of S. aureus endocarditis.

Cyclacillin, a new aminosalicylic semisynthetic penicillin, was compared with amoxicillin for the therapy of acute bacterial maxillary sinusitis in 80 patients (ages, 12 to 70 years) in a prospective, double-blind, randomized clinical trial. Direct sinus aspirations for quantitative culture were done for all patients before and after 10 days of therapy. Both drugs were administered at a dosage of 500 mg orally three times daily. Among culture-positive patients, clinical cure was achieved in 23 of 26 patients and 25 of 27 patients treated with cyclacillin and amoxicillin, respectively, for an overall cure rate of 91%. Bacteriologic failure occurred in 9% (4 of 44 patients); 3 of the 4 failures were in the cyclacillin group. There was no correlation between clinical or bacteriologic cure and the results of sinus transillumination (clear, dark) at follow-up. Initial direct sinus aspirates were positive in 57 of 80 cases (70%): 25 (44%) of these were the result of Streptococcus pneumoniae and 23 (40%) were the result of Haemophilus influenzae. All of these isolates were susceptible (MIC, less than or equal to 0.5 microgram/ml) to both study drugs; no ampicillin-resistant H. influenzae was recovered. On day 10 of therapy, mean concentrations of both drugs in serum were 2.5 to 2.7 micrograms/ml, but no antibiotic was detectable in 20 of 21 simultaneous sinus aspirates. Adverse effects (rash, diarrhea) were infrequent and similar in both groups. Cyclacillin appears equivalent to amoxicillin in the therapy of acute maxillary sinusitis.

• Cefuroxime axetil, a new β–lactamase-stable cephalosporin, was compared with cefaclor for the treatment of acute bacterial maxillary sinusitis in 106 adult patients. Direct sinus aspirations for quantitative bacterial culture were done for all patients before treatment; aspiration was repeated for most patients after treatment. Pretreatment sinus aspirates were positive for 63 of 134 sampled sinuses. Of specimens yielding at least 104 CFU/mL, Haemophilus Influenzae (38%) and Streptococcus pneumoniae (37%) were the most common pathogens. Ten (42%) of 24 strains of Hinfluenzae , 2 (40%) of 5 Haemophilus parainfluenzae , and all 3 isolates (60%) of Branhamella catarrhalis produced β-lactamase. Cefuroxime axetil, 250 mg twice a day, was compared with cefaclor, 500 mg three times a day. Among culture-positive sinuses, bacteriologic cure was achieved in 36 (95%) of 38 sinuses and 15 (71%) of 21 sinuses treated with cefuroxime axetil and cefaclor, respectively. The overall frequencies of adverse events were similar between drugs, although cefuroxime axetil was associated with more frequent diarrhea. Cefuroxime axetil was an effective therapy for the treatment of acute bacterial maxillary sinusitis in adults. ( Arch Otolaryngol Head Neck Surg. 1989;115:1430-1433)

Although meningitis is the most common form of central nervous system (CNS) blastomycosis, solitary mass lesions are not an infrequent presentation. Four of our patients presented with focal neurological deficits as a result of single intracranial mass lesions. Only 1 had clearcut evidence of extraneural blastomycosis. One was a coal miner, another worked with soil samples, and one was an engineer for a wood pulp company. All were previously healthy and 2 had diabetes. Complement fixation and immunodiffusion tests were negative in all 4 patients, and white blood cell counts and erythrocyte sedimentation rates were normal. Wet mount of tissue obtained intraoperatively by aspiration demonstrated the organism in 2 cases, culture from a lung lesion made the diagnosis in 1 case, and stain and culture of ventricular fluid revealed the organisms in the fourth case. Multiple cultures of cerebrospinal fluid from lumbar puncture were negative. All 4 patients survived. Amphotericin B alone was curative in 2 cases; surgical removal alone was curative in 1. All 4 computerized tomographic scans revealed isodense or slightly hyperdense single mass lesions with homogeneous contrast enhancement and surrounding edema, and tumor was the preoperative diagnosis in 2 cases. Such scans should suggest CNS blastomycoma in patients from the endemic area, despite the lack of other systemic manifestations. Diagnosis nevertheless rests on the characteristic histopathologic appearance in tissues and/or culture. Solitary intracranial blastomycomas may be less rare than previously thought; at our institution, we observed 4 cases in 4 years.

Haemophilus influenzae type b (Hib) lipopolysaccharide (LPS) may be present in the cerebrospinal fluid largely as part of outer membrane vesicles (OMV), which could possibly alter its activity. Similar to inoculation of purified Hib LPS, intracisternal inoculation of Hib OMV into adult rats resulted in dose- and time-dependent increases in blood-brain barrier permeability. Polymyxin B, but not an oligosaccharide-specific monoclonal antibody, significantly inhibited the activity of Hib OMV. No change in blood-brain barrier permeability occurred in leukopenic rats inoculated with Hib OMV. Hib OMV was as active as purified Hib LPS on a weight basis and therefore appears to be a relevant vehicle for the delivery of LPS during meningitis.

The rationale for use of quinolones in the treatment of central nervous system (CNS) infections is reviewed. Quinolones exert potent activity in vitro against many gram-negative meningeal pathogens. Given the concentrations attained in cerebrospinal fluid (CSF), however, activity against gram-positive organisms is marginal. As a group, the quinolones enter (penetrate) the CSF better than do any other class of antimicrobial agents. The percentage penetration into CSF is remarkably similar in animal models and in humans with meningitis receiving concurrent therapy. The relative rank order for CSF penetration is as follows: enoxacin and pefloxacin (approximately 50%) greater than ciprofloxacin and ofloxacin (approximately 20%-30%). Certain quinolones have proven to be equivalent to conventional agents (e.g., third-generation cephalosporins) in the rate with which they eradicate bacterial gram-negative organisms from the CSF in experimental animal models of meningitis, but the serum concentrations have usually been higher than those achieved in humans. Despite these advantages, the concentrations in CSF remain low (e.g., ciprofloxacin, approximately 0.25-0.5 mg/L; pefloxacin, 4-8 mg/L) in humans because of the relatively low concentrations attained in serum. Thus, quinolones will continue to be most useful in the treatment of infections due to problem pathogens or to multiresistant pathogens (e.g., Pseudomonas species). Although quinolones appear to enter brain tissue readily, it is unlikely that they can be used as single agents for the treatment of brain abscess because of poor activity against anaerobes and streptococci, and no animal or human studies have been reported. A single dose of ciprofloxacin administered orally appears promising for use in eradication of the meningococcal carrier state.

The relevance of a postantibiotic effect in the treatment of pneumococcal meningitis was evaluated in a rabbit model. After administration of a single intravenous bolus of ampicillin at various dosages, such an effect was observed in all animals. The duration of this effect in vivo (2.5-18 hr) was consistently longer than that in vitro (1-4.3 hr); however, in rabbits the postantibiotic effect was eliminated by the administration of intravenous plus intracisternal beta-lactamase. In an assessment of the potential therapeutic benefit of the postantibiotic effect, the efficacy to two regimens of treatment with different intervals between doses was compared. One group of animals received ampicillin every 4 hr and another every 12 hr. With sufficiently high doses, drug concentrations in cerebrospinal fluid exceeded the minimal bactericidal concentration for most of the 4-hr interval but for only about one-third of the 12-hr interval. The rate of cure was similar for the two regimens and approximated 100% when peak drug concentrations in cerebrospinal fluid exceeded the minimal bactericidal concentration by at least 10-fold.

Animal models have proven to be invaluable in bridging the gap between in vitro susceptibility testing of an antibiotic and anticipating results obtained in clinical studies. Variables such as antibiotic concentration, inoculum of organism, and pharmacokinetic parameters of the drug can be carefully controlled to provide information about the principles of treating infectious diseases as well as an evaluation of specific antimicrobial agents. End points of treatment can be precisely defined (that is, CSF sterility in meningitis, vegetation counts of bacteria in endocarditis) to allow a quantitative evaluation of a new antibiotic. However, it is important to realize that there may be differences in disease pathogenesis and antibiotic pharmacokinetics between experimental infections in animal models and infections in humans. Therefore, results in animal models should be interpreted with caution and compared with results obtained with antimicrobial regimens in clinical studies. Perhaps one of the most useful features of animal models is suggesting which antimicrobials would not be expected to be of therapeutic benefit in man.

We have studied the pharmacokinetics of 1-g intravenous doses of aztreonam in four groups of six volunteers each, distinguished by their creatinine clearances (greater than 80, 30 to 80, 10 to 29, and less than 10 ml/min). Subjects received 1 g of aztreonam intravenously without any complications. Aztreonam serum and urine levels were measured by microbiological methods and by high-pressure liquid chromatography, and unbound serum aztreonam was determined by ultrafiltration. Serum levels were well described by a two-compartment infusion model. From this model we determined steady-state volume of distribution, alpha distribution phase half-life, beta elimination phase half-life, and total clearance of aztreonam. The mean of beta elimination phase half-life ranged from 2 h in normal subjects to 6 h in anephric patients. The total clearance of aztreonam correlated closely with corrected creatinine clearance calculated from serum creatinine, age, and sex (r = 0.97, P less than 0.001) and ranged from a mean value of 107 ml/min in normal subjects to 29 ml/min in functionally anephric patients. Some 75% of aztreonam excretion was renal. Urinary recovery of aztreonam ranged from 58% of the administered dose in normal subjects to 1.4% in uremic patients. Free aztreonam in serum correlated inversely with creatinine clearance (P less than 0.001). A nomogram was developed as a guide for adjustment of aztreonam dosage according to renal function.

We studied the pharmacokinetics of cefoperazone 2 g i.v. every 12 h for 7 days in 12 patients on hemodialysis with normal hepatic function. The half-life of indocyanine green was determined in each patient via ear oximetry. Serum levels of cefoperazone during dialysis were well described by a two-compartment multidose infusion model. From this model we determined the steady state volume of distribution (Vdss), elimination phase half-life during dialysis T1/2D) and off hemodialysis (T1/2), and the corresponding elimination rate constants (KeD and Ke). Multiple correlations between pharmacokinetic parameters, liver function, and physical characteristics of the patients were evaluated. The T1/2 of cefoperazone was 2.9 h off compared to 2.3 h during hemodialysis. The corresponding elimination rate constants were Ke = 0.45/h versus KeD = 0.80/h. Cefoperazone clearances were 78 ml/min off dialysis compared to 140 ml/min during hemodialysis. Vdss was 0.20 liters/kg. The indocyanine green half-life ranged from 1.8 to 4.6 min with a mean of 2.7 min. The ages of the patients correlated with the beta phase half-life (r = 0.68, p = 0.015). We found no significant correlations among the other parameters including hepatic enzymes and indocyanine green half-life. Thus, hemodialysis approximately doubles the elimination rate constant (clearance), but, assuming drug redistribution kinetics remain unchanged, only shortens half-life by about 20%. Scheduling of a 12-hour dosing regimen to coincide with the end of hemodialysis should obviate any need for alteration of dose. Cefoperazone is thus unique among cephalosporins, since the half-life does not change appreciably with end-stage renal disease or dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-antibody sandwich enzyme-linked immunosorbent assay was developed for the detection of circulating Candida albicans antigen during the course of experimental C. albicans endocarditis. The enzyme-linked immunosorbent assay was positive in 75% of rabbits with polyethylene catheter-induced experimental aortic valve C. albicans endocarditis but was negative in all controls, including catheterized animals that received intravenous Candida or catheterized but uninfected animals, and in rabbits with experimental fungal or bacterial endocarditis of other etiologies. The enzyme-linked immunosorbent assay was much more sensitive than blood culturing or fever determinations in experimental C. albicans endocarditis. This assay is more sensitive than currently available serological techniques, is highly specific, and deserves further study in the diagnosis of invasive, disseminated C. albicans infections, including endocarditis.

The in vitro activity of cefaclor and cephalexin against clinical isolates of four bacterial genera was compared. Both agents had a similar range of activity, but cefaclor was significantly more active by weight than cephalexin for most isolates tested.

Fulminant meningitis requires aggressive management in an intensive care unit setting. The pathophysiology of the various factors that damage the central nervous system in this disease have been reviewed, as well as the management of the many complications of this serious, often devastating, infection. The etiologic agents according to age group have been discussed, and recommendations for empiric therapy have been made.

Bacterial meningitis represents an infection in an area of impaired host defence. Optimal therapy of meningitis requires attaining bactericidal activity within cerebrospinal fluid (CSF). Studies in experimental animal models of meningitis suggest that maximal rates of bacterial killing in vivo and optimal cure rates are achieved when CSF antibiotic concentrations exceed the MBC of the test strain by greater than or equal to ten-fold. The results of clinical trials support this conclusion. In addition, a variable post-antibiotic effect occurs in-vivo after short periods of exposure to antimicrobial activity, thus maintaining therapeutic efficacy with intermittent dosage regimens. These basic principles of therapy are outlined in this review and serve as a basis for rational treatment regimens. For most antibiotics, the optimal dose, dosage interval, and duration of therapy for bacterial meningitis remain to be established.

This review considers the five major principles governing optimal dosing of beta-lactam antibiotics in therapy for bacterial meningitis: off the entry of passage of antibiotics into CSF, (2) the antimicrobial activity of beta-lactams within the purulent CSF in vivo, (3) the bactericidal activity within the CSF, (4) the route and mode of drug administration together with the postantibiotic effect, and (5) the duration of therapy. Special attention is paid to the third principle, bactericidal activity within the CSF, employing the model of the newer, third-generation cephalosporins used in the treatment of meningitis caused by gram-negative aerobic bacilli.

Although increased intracranial pressure and hydrocephalus frequently accompany bacterial meningitis, the pathophysiology of these complications is not understood. To quantify intracranial volume-pressure regulation in meningitis, we performed manometric infusions in rabbits with experimental bacterial meningitis.

Ceftriaxone is a promising antimicrobial agent in the therapy of bacterial meningitis. The rationale for the clinical evaluation of ceftriaxone in patients with meningitis is based on the following favorable characteristics: ceftriaxone has excellent in vitro activity (MBC90 0.25 microgram/ml or less) against the major meningeal pathogens including meningococci, pneumococci, group B streptococci, Hemophilus influenzae, and Escherichia coli, but it is inactive against Listeria monocytogenes; ceftriaxone is rapidly bactericidal within purulent cerebrospinal fluid in experimental animal models of meningitis induced by pneumococci, group B streptococci, H. influenzae, and E. coli; against most of the major meningeal pathogens, the activity attained in cerebrospinal fluid in human subjects with bacterial meningitis is high (1:512 or greater) and active concentrations of ceftriaxone persist in cerebrospinal fluid for prolonged periods compared with those of other cephalosporins; the results of clinical trials reported to date in patients with meningitis are encouraging. Ceftriaxone deserves further clinical evaluation in the treatment of bacterial meningitis; the optimal dose, frequency of administration, and duration of therapy remain to be determined.

Disease syndromes caused by Salmonella species continue to be important, as evidenced by a major outbreak of infection due to multiresistant Salmonella typhimurium in 1985; this outbreak involved more than 12,000 people in five north-central states of the United States. Salmonella species have become progressively more resistant in recent years to the clinically useful antibiotics (trimethoprim-sulfamethoxazole, ampicillin, and chloramphenicol). The clinical experience accumulated thus far indicates that two new classes of antimicrobial agents, the third-generation cephalosporins and the quinolones, offer significant potential for the treatment of specific problems in salmonellosis: bacteremia and enteric fever, meningitis, osteomyelitis, and the chronic carrier state.

It seems appropriate in a symposium dedicated to the examination of septicemia, that one of the topics for discussion should be the examination of the factors which allow circulating bacteria to adhere to intracardiac or vascular endothelium. In the last 10-12 years our understanding of the pathogenesis of this disease has increased markedly. This can be attributed to a large extent to the development by Dr Freedman and hist colleagues at Yale of reproducible, simple, inexpensive animal model of infective endocarditis. The purpose of this discussion will by to summarize studies aimed at helping to explain why bacteria stick to cardiac valves, what forms the stimulus for vegetation propagation, and some new idea for possible prevention of this event.

A uniformly fatal, reproducible model of experimental meningitis due to Listeria monocytogenes was developed in rabbits for study of the natural progression of the disease and was used to evaluate treatment regimens. Bacterial titers in cerebrospinal fluid and pleocytosis approximated those found in humans. Therapeutic studies in vivo revealed that rifampin was less rapidly bactericidal than ampicillin or penicillin, the agents usually recommended for treatment of meningitis; that penicillin plus rifampin was no more efficacious than penicillin alone; that ampicillin demonstrated greater bactericidal activity in vivo than did penicillin; and that addition of an aminoglycoside (gentamicin) to either penicillin or ampicillin significantly enhanced their bactericidal activity in vivo. Ampicillin plus gentamicin was the most effective combination in vivo and may represent the preferred mode of therapy for listeria meningitis.

The cerebral capillary endothelium is unique and functions as an effective blood-brain barrier (BBB) owing to its intercellular tight junctions and rare pinocytotic vesicles. To assess how bacterial meningitis alters the BBB, rats were inoculated intracisternally with three encapsulated meningeal pathogens (Escherichia coli K1+, Streptococcus pneumoniae type III, Haemophilus influenzae type b) and an unencapsulated mutant strain (H. influenzae Rd). After defined infection durations, the morphologic alterations of the cerebral capillary endothelium were quantitatively assessed by transmission electron microscopy. Results revealed a significant increase in pinocytotic vesicle formation (P less than 0.001) early after meningitis induction (4 h) that was sustained with longer infection durations (10 h, 18 h) for all encapsulated strains tested. In addition, there was a progressive increase in completely separated intercellular junctions with increasing infection duration, (P less than 0.05). 4 h after induction of meningitis with H. influenzae Rd, cerebrospinal fluid (CSF) bacterial concentrations, cerebral capillary morphologic changes, and functional BBB permeability to circulating 125I-albumin were similar to those observed with H. influenzae type b. However, prolonging the H. influenzae Rd infection to 18 h allowed for CSF clearance of the organism, thereby precluding the significant increase in separated junctions or progression of functional BBB permeability seen with the encapsulated H. influenzae type b. These data suggest a uniform morphologic explanation for altered BBB permeability in meningitis with a reproducible temporal sequence. Encapsulation does not appear essential for BBB injury, but may facilitate its progression by allowing the organism to evade host clearance.

The occurrence and importance of secondary bacteremia in the pathogenesis of and response to therapy in meningitis is uncertain. Streptococcus pneumoniae type III was injected into the cerebrospinal fluid of the cisterna magna in anesthetized, curarized dogs, and sequential simultaneous samples were obtained from the superior sagittal sinus, cisterna magna, and peripheral blood. The results show that: (i) bacteria are rapidly transported from the cerebrospinal fluid to blood but only after active multiplication within the cerebrospinal fluid, and (ii) entrance into the blood from the cerebrospinal fluid occurs before the height of the febrile response or cerebrospinal fluid pleocytosis.

Gram-negative osteomyelitis frequently responds poorly to conventional therapy. Ciprofloxacin displays excellent in vitro activity against gram-negative bacilli and offers the potential for outpatient therapy. In this ongoing study, ciprofloxacin therapy is being evaluated for the treatment of gram-negative osteomyelitis. Twenty-three patients (16 men and seven women) have been treated under the protocol (750 mg orally twice daily for 1.5 to six months), and 14 patients have completed therapy. All patients had either growth on bone cultures from an open or percutaneous biopsy, or an arthrocentesis to confirm the diagnosis. Involved sites included ankle or tibia (seven patients), vertebra (four patients), hip (five patients), metatarsal (four patients), phalanx (two patients), and metacarpal (one patient); 16 patients had chronic disease, and seven patients had acute disease. Patients had a total of 28 gram-negative bacilli, 12 gram-positive cocci, and one anaerobic gram-negative rod, for an average of 1.8 pathogens per patient. Eighteen of the 28 gram-negative bacilli were Pseudomonas species. The geometric mean minimal inhibitory concentration for all the gram-negative bacilli was 0.15 microgram/ml. The geometric mean minimal inhibitory concentration for the gram-positive isolates was 0.41 microgram/ml. All patients who completed therapy experienced a cure, with a mean follow-up of 6.1 months. Infections in all patients, except for two who are still taking ciprofloxacin, are resolving, both clinically and radiologically. One patient who was not eligible for the protocol experienced a superinfection with methicillin-resistant Staphylococcus aureus. Side effects have included urticaria, lethargy, nausea, and transient elevations of liver and renal function test results. Overall, ciprofloxacin therapy was well tolerated. This study suggests that ciprofloxacin holds promise for the outpatient treatment of gram-negative osteomyelitis.

Although the incidence of fungal infections is increasing, infections caused by more than one fungus are rare. We have described the clinical, pathologic, and mycologic findings in a leukemic patient with simultaneous pulmonary infection and systemic dissemination caused by Aspergillus fumigatus and Rhizopus sp.