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The pharmacokinetic and antibacterial properties of cefotaxime were determined in normal adult volunteers. Single doses of 250, 500, 1,000 and 2,000 mg were evaluated following 5- and 20-min intravenous (i.v.) infusions and intramuscular (i.m.) administration. Cefotaxime was well tolerated and mean peak serum levels exceeded the minimum inhibition concentration (MIC) values for a wide spectrum of potential bacterial pathogens. Approximately 48% of the i.v. doses was excreted renally; average volume of distribution was 30% of body weight and the t 1/2 was about 1 h. Cefotaxime was rapidly absorbed following i.m. injection with maximum serum concentrations occurring at approximately 0.6 h. Serum and urine antibacterial activity reflected the concentration of cefotaxime and MIC of the bacterial pathogens tested.

A microdilution technique using commercially available media and materials was developed and used to determine the minimal inhibitory concentrations (MICs) of clindamycin, chloramphenicol, tetracycline, minocycline, ampicillin, carbenicillin, cephalothin, and gentamicin for 101 anaerobic isolates. Representative strains of Bacteroides, Clostridium, Fusobacterium, Peptococcus, and Peptostreptococcus were tested. The use of Schaedler broth at pH 7.2, an inoculum of 10(5) to 10(7) colony-forming units per ml, and incubation at 35 C in an anaerobic glove box with an atmosphere of 80% nitrogen, 10% hydrogen, and 10% carbon dioxide resulted in good growth and easily interpretable results. After 48 h of incubation, 97% of strains tested were inhibited by 3.1 mug or less of clindamycin per ml and 98% were inhibited by 12.5 mug or less of chloramphenicol per ml. Tetracycline and minocycline inhibited 81 and 88% of strains tested in concentrations of 1.6 mug or less per ml and 1.6 mug or less per ml, respectively. Ampicillin inhibited all strains other than B. fragilis in concentrations of 3.1 mug or less per ml. Excluding certain strains of Bacteroides and Clostridium, carbenicillin in concentrations of 12.5 mug or less per ml and cephalothin in concentrations of 6.2 mug or less per ml inhibited all strains tested. Gentamicin was inactive although some strains of anaerobic cocci and Bacteroides were inhibited by 3.1 mug or less per ml. After 18 to 24 h of incubation, eight of the 101 strains had not grown sufficiently for MICs to be determined; for the 93 strains which had grown sufficiently, 93% of 744 MICs were the same or one concentration lower than the 48-h MICs.

A rabbit chamber model was developed and inoculated with 10(9) colony-forming units (cfu) of viable Neisseria gonorrhoeae to determine whether the lipopolysaccharide-derived Gc2 polysaccharide cell wall antigens could be detected by counterimmunoelectrophoresis (CIE). Four hours after inoculation, a polymorphonuclear leukocyte response was noted in the chambers; this response was followed by progressive phagocytosis of the organisms and a fall in number of cfu/ml. All visible bacteria were intracellular, and chamber fluids were sterile 6 hr after inoculation. Use of sero specific antisera permitted detection by CIE of the Gc2 polysaccharide antigen in sera of all rabbits within 48 hr after inoculation of the chambers, whereas blood cultures remained sterile throughout the experiment. At 2-6 hr after inoculation, the Gc2 polysaccharide antigen was also detected as a single precipitin band in the chamber fluid of inoculated rabbits. At 24 hr the precipitin band was not observed; rather, a halo above the antigen well was noted. The halo was found to be a nonspecific complex containing the Gc2 polysaccharide antigen and no antibody. In the rabbit model studied, CIE was sufficiently sensitive to detect concentrations of the Gc2 polysaccharide antigen of greater than or equal to 0.97 microgram/ml in serum and chamber fluid.

Male New Zealand white rabbits with subcutaneous polyethylene chambers in place for at least 3 months were inoculated by one of the following three methods: (i) "intra-chamber" (IC) inoculation with "normal" chamber fluid: (ii) intratesticular inoculation with Treponema pallidum; or (iii) IC inoculation with T. pallidum. Rabbits given dexamethasone only, oxisuran only, both drugs, or no drug were observed serially after inoculation. T. pallidum survived and temporarily multiplied to significant numbers within subucutaneous chambers after IC inoculation in rabbits given dexamethasone. In rabbits not treated with dexamethasone, T. pallidum counts in chamber fluid decreased rapidly and remained at low levels for 30 days after IC inoculation. Oxisuran appeared to have little or no effect on T. pallidum multiplication. All rabbits studied had a nonreactive serum and chamber fluid serological test for syphilis before inoculation. All rabbits inoculated with T. pallidum eventually developed reactive serum and chamber fluid serological tests. The IC route of inoculation was associated with a delay in the development of serum serological reactivity and with earlier chamber fluid reactivity as compared with the intratesticular route of inoculation. An immediate but transent influx of polymorphonuclear leukocytes was associated with IC inoculation of T. pallidum. Chamber fluid total protein content declined very slightly in all groups of rabbits during the month after inoculations. Successful cultivation of T. pallidum in an in vivo setting suggests that this animal model may be useful in further studies of the biology of the organism of the pathogenesis, immunology, and treatment of syphilis.

Cefamandole resistance in five patients was studied. Microorganisms emerged resistant to cefamandole during therapy with the drug in three patients with complicated infections. This resistance was associated with an enhanced production of beta-lactamase and/or with a change in the substrates and the isoelectric focusing patterns of the enzymes. Cross-resistance to other beta-lactam antibiotics developed concurrently in isolates from these patients. Disk diffusion tests did not detect resistance to cefamandole in the pretreatment isolate from the fourth patient; this isolate produced inactivating enzymes, and resistance was detected only in broth dilution tests. In the fifth patient, infection with a cefamandole-resistant Enterobacter developed during postoperative therapy with the drug. Resistance to cefamandole in the isolate from this patient was unstable and was associated with inducible beta-lactamase activity. These examples emphasize the need for close monitoring of patients who are given cefamandole and for thorough in vitro evaluation of isolates from the patients both before and after treatment.

A case of pleuropulmonary infection caused by Clostridium sordellii is reported for the first time. The clinical presentation with acute onset resembling pulmonary infarction, the absence of toxicity, hemolysis and shock, and response to penicillin and drainage was similar to that of patients with pleuropulmonary infection caused by C. perfringens.

Cefaclor, a new orally administered cephalosporin, was evaluated by a randomized trial for effectiveness in the treatment of uncomplicated urethritis due to Neisseria gonorrhoeae in men. Regimens included 2,3, and 4 g of cefaclor, with or without 1 g of orally administered probenecid, as single daily doses for three days. The diagnoses were confirmed by isolation of N. gonorrhoeae; cures or therapeutic failures were determined by follow-up cultures on day 7 after completion of therapy. Sixty-six (73%) of 90 treated patients were evaluable for efficacy. The bacteriologic cure rate was 98% (65/66); one patient treated with 2 g of cefaclor plus probenecid had a positive culture for N. gonorrhoeae on follow-up examination. Adverse reactions consisted of mild nausea in five patients (7%) and vomiting in one patient (1%) who received 3- or 4-g doses. No treatment was discontinued, and no abnormality of screening hematologic tests or enzymes was observed. Thus, cefaclor, given in multiple doses, was highly efficacious for treatment of uncomplicated gonococcal urethritis in men.

Endocarditis caused by Cardiobacterium hominis was observed in a penicillin-allergic patient with a prosthetic cardiac valve who had received prophylactic therapy with erythromycin for dental extractions. The organism was resistant to erythromycin and vancomycin, with minimal inhibitory concentrations of 12.5 microgram/ml and 25 microgram/ml, respectively, but was sensitive to penicillin G, tetracycline, cephalexin, and cefaclor. This case suggests that currently recommended antibiotic prophylactic therapy for endocarditis, especially in penicillin-allergic patients, may be inadequate for unusual pathogens such as C hominis.

Four patients with Bacteroides fragilis bacteremia, one patient with a brain abscess due to Bacteroides species, Fusobacterium naviforme, and Peptostreptococcus species, and an infant with Bacteroides species ventriculitis and meningitis were treated with metronidazole. In all cases the anaerobic pathogens were eradicated. Five of the six patients recovered. One patient with leukemia in whom B fragilis bacteremia was eradicated by metronidazole treatment subsequently died of Pseudomonas aeruginosa bacteremia. Ventricular fluid and serum concentrations of metronidazole were determined in the case of meningitis and are reported.

In an evaluation of the limulus lysate assay (LLA) as a method for detecting gonococcal endotoxin in cervical exudates diluted 1:800, positive LLA results were obtained from 17 of 18 patients (94%) with culture-proved gonococcal cervicitis, and negative results were obtained from 22 of 22 patients (100%) with culture-negative specimens. In vitro tests comparing the sensitivity of the LLA for Neisseria gonorrhoeae and other gram-negative organisms showed the LLA to be more sensitive in detecting N. gonorrhoeae (minimum sensitivity, 10(4) organisms per milliliter) than other commonly encountered urogenital gram-negative bacteria (minimum sensitivity, greater than 10(5) organisms per milliliter). Thus, in preliminary studies involving otherwise healthy women, the LLA appeared to correlate with bacteriologic methods for diagnosing gonococcal cervicitis and may aid in identifying nongonococcal cervicitis. In addition, the LLA was easy to perform, with test results available within an hour after the patient's initial examination.

The minimal inhibitory concentrations of gentamicin and minocycline alone and in combination were determined by a broth microdilution method for 100 aerobic, facultative, and anaerobic isolates representative of pathogens recovered from patients with intra-abdominal sepsis. Gentamicin inhibited all strains of Klebsiella, Enterobacter, and Pseudomonas aeruginosa in concentrations of 0.4 to 3.1 mug/ml and all strains of Escherichia coli and Proteus mirabilis in concentrations of 0.8 to 12.5 mug/ml. Whereas minocycline did not consistently inhibit these organisms in concentrations of 1.6 mug or less/ml, it did act synergistically with gentamicin against 43% of the Enterobacteriaceae tested in clinically achievable concentrations; significant synergy was most common with E. coli (60%). Minocycline inhibited 62% of Bacteroides fragilis, 71% of Clostridium, 40% of anaerobic cocci, and 40% of enterococci tested in concentrations of 1.6 mug or less/ml. Whereas gentamicin rarely inhibited these organisms in concentrations of 6.2 mug or less/ml, it did act synergistically with minocycline against 20% of B. fragilis, 67% of Clostridium, 22% of anaerobic cocci, and 22% of enterococci (which had minimal inhibitory concentrations of minocycline within the range tested) at clinically achievable concentrations. Although only four (13%) of the 30 isolates resistant to both gentamicin and minocycline alone were inhibited by clinically achievable concentrations of the combination, the observed synergy, particularly against strains of E. coli, was considered to be of potential clinical usefulness. Antagonism between gentamicin and minocycline was not observed at the concentrations tested.

Patients undergoing elective intraabdominal operations received a three-dose prophylactic regimen of either moxalactam (83 patients) or cefazolin (98 patients) in a blinded, randomized fashion. There was a 9% overall infection rate with 6% for those in the cefazolin group (6/98), and 12% for those treated with moxalactam (10/83) (p = 0.26). Infection rates stratified by types of surgery were similar for both regimens. The drugs were well tolerated, with minimal side effects. Patients at highest risk of infection were those with obstruction of upper gastrointestinal tract and those with pancreatitis. We concluded that moxalactam was no more effective than cefazolin in preventing postoperative infections in this study population.

In a single-blind study, 50 men who had acute gonococcal urethritis were treated with a single oral dose of either 720 mg trimethoprim (TMP) plus 3,600 mg sulfamethoxazole (SMZ) or 3.5 g ampicillin plus 1 g probenecid. Isolates of Neisseria gonorrhoeae were tested for in-vitro susceptibility to the chemotherapeutic agents administered by agar-dilution and disk-diffusion methods, and results were correlated with cure or failure to cure as determined bacteriologically. Among patients returning for follow up, the cure rate after TMP/SMZ was 69%. Cure was predictable when the isolates of N. gonorrhoeae were inhibited by < or = 0.63/11.87 micrograms/ml of TMP/SMZ (fixed ratio, 1:19) or when the zones of inhibition were > or = 23 mm; failure was predictable when > or = 1.25/23.75 micrograms/ml of TMP/SMZ was necessary for inhibition and when zones of inhibition were < or = 21 mm (P < 0.02). The cure rate after therapy with ampicillin was 100%, a rate significantly higher than that found after TMP/SMZ (P < 0.02); all isolates were inhibited by < or = 0.16 microgram/ml of ampicillin. Adverse reactions were not seen after either TMP/SMZ or ampicillin.

In an evaluation of the limulus assay as a method for detecting endotoxin in urethral exudates, positive results of urethral samples at a 1/200 dilution were obtained from 73 out of 73 patients with culture-positive gonococcal urethritis while negative results were obtained from 26 out of 27 patients with cuture-negative urethral specimens. A specimen from one patient, which gave negative results on Gram stain and culture, gave positive results to the limulus test. The overall accuracy of the limulus test for predicting culture results was 99% (p less than 0.001). Thus, in preliminary studies of otherwise healthy men, the results of the limulus assay correlated with those of biological methods for diagnosing urethral gonorrhoea; the test may, therefore, be of use in identifying cases of nongonococcal urethritis.

A standardized disk diffusion test was developed and used to test the susceptibility of 102 strains of Neisseria gonorrhoeae to combinations of trimethoprim and sulfamethoxazole (TMP/SMX) by relating zone diameters of inhibition to minimal inhibitory concentrations (MIC's). MIC's for TMP/SMX in ratios of 1:20 ranged from 0.08/1.52 to 2.5/47.5 mug/ml and zones of inhibition ranged from 34 to 10 mm. The coefficient of correlation (r) was -0.75. For comparison, a regression line was similarly calculated for ampicillin. MIC's ranged from 0.02 to 0.32 mug/ml and zones of inhibition ranged from 50 to 31 mm; r was -0.71. With establishment of MIC breakpoints to define the categories, susceptible, intermediate, and resistant, the disk duffusion test would be as reliable for estimating susceptibility of gonococci to TMP/SMX as for estimating susceptiblity to ampicillin.

The efficacy of cefotaxime sodium for treatment of patients with lower respiratory infections was evaluated by three protocols in multicenter trials. The first trial studied cefotaxime alone; the second and third trials compared cefotaxime with cefazolin in observer-blind and single-blind randomized controlled studies, respectively. A total of 656 patients were entered in the three trials; 527 received cefotaxime. Overall rates of bacteriologic and clinical cure, analyzed by pathogen, for the cefotaxime treated patients were 89.9% and 93.9%, respectively. In the two comparative trials, overall rates of bacteriologic and clinical cure with cefotaxime, by pathogen, were greater than 94% and numerically exceeded those for cefazolin in each instance. The efficacies in the comparative studies, when analyzed by total patient responses, were significantly different only for clinical responses to cefotaxime in the single-blind randomized trial (P = 0.03). Favorable cure rates with cefotaxime were obtained in patients with infections due to Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Staphylococcus aureus, and Escherichia coli, and nearly comparable responses were obtained for infections due to Proteus, Enterobacter, and Klebsiella species. Cefotaxime was clinically effective in some of the infections due to Serratia marcescens and Pseudomonas aeruginosa, but bacteriologic failures occurred in 67% and 61% of cases, respectively. All Serratia strains were highly susceptible in vitro to cefotaxime, but the range of minimal inhibitory concentrations of cefotaxime for Pseudomonas isolates was wide.

Clinical evaluation of intramuscular tobramycin was accomplished in 30 patients with respiratory, soft tissue, urinary tract, bone or septicemic infections due to gram negative bacilli. Median sensitivity to tobramycin of Pseudomonas aeruginosa isolates (19 strains) was 0.62 mug/ml and range 0.31-2.5 mug/ml; less activity was observed for Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae and Enterobacter species isolates but median minimum inhibitory concentrations were less than or equal to 2.5 mug/ml. Therapy resulted in clinical and bacteriologic cures in 16 patients (53 per cent) including 13 of 16 (181 per cent) with urinary tract infections; 9 of the 14 patients who did not obtain bacteriologic cure had satisfactory clinical responses. Tobramycin was effective for selected gram negative bacillary infections and particularly for P. aeruginosa.

Cefmenoxime was evaluated in an open trial consisting of 41 patients. Forty infections in 36 patients could be evaluated. Thirteen patients had pyelonephritis due to Escherichia coli (two bacteremic), Pseudomonas aeruginosa, Klebsiella pneumoniae, or Streptococcus faecalis; all improved and 12 of 13 were clinically cured, but one relapse (S. faecalis) occurred at two weeks. Six patients with cystitis due to E. coli, Citrobacter freundii, Serratia marcescens, P. aeruginosa, or S. faecalis all improved, but relapse or reinfection, or both, occurred in five due to P. aeruginosa, S. faecalis, C. fruendii, or E. coli. Neurogenic bladder or other complications were present in five of 13 patients with pyelonephritis and five of six with cystitis. Ten patients with pneumonia and one with tracheobronchitis due to Hemophilus influenzae, S. pneumoniae, S. agalactiae, or Neisseria meningitidis all improved and seven had resolution without relapse, but P. aeruginosa emerged in two patients, one of whom died. Eight soft tissue infections due to Staphylococcus aureus, Peptococcus prevotti, Streptococcus species, or infections of mixed origin resolved in six. Sterility of blood cultures was obtained in one patient with endocarditis due to S. anginosus, but other therapy was substituted. Clinical resolution of the toxic shock syndrome and subsequent negative endocervical cultures for S. aureus occurred in one. Granulocytopenia of unverified cause in four (with less than 1,500 mm3) and two (with less than 2,000 mm3) was reversible. Headache during treatment occurred in six patients and a possible disulfiram-like effect in three. Elevations of serum glutamic oxalacetic transaminase and alkaline phosphatase occurred in five, Coombs' positivity in two, and diarrhea in three. Clinical efficacy of cefmenoxime was significant. Possible side effects require further study.

Chemical and cellular characteristics of fluid within subcutaneously implanted polyethylene chambers in rabbits were studied over a 3-month period. The fluid attained a relatively stable protein and cellular composition which was consistent with a mononuclear exudate. After a single dose of intramuscular penicillin G, the antibacterial activity of chamber fluid was found to be dynamic and similar to the serum antibacterial activity. This animal model may be useful for in vivo studies of the interaction of microorganisms with antimicrobial agents.

Twenty-seven patients with skin and soft tissue infections, including three with contiguous osteomyelitis, were given cefoxitin intravenously or intramuscularly; the infections of 25 (93%) were resolved with cefoxitin therapy. Etiologic agents included staphylococci, streptococci, Enterobacteriaceae, and anaerobes. Susceptible pathogens were inhibited by less than or equal to 8 micrograms of cefoxitin/ml. This level of drug was surpassed by mean peak serum concentrations eight- to 12-fold after intravenous infusions and two- to threefold after intramuscular injections and resulted in eradication of susceptible organisms from lesions during treatment. Intravenously administered cefoxitin was well tolerated, although eosinophilia, phlebitis, elevation of levels of hepatic enzymes, and a positive direct Coombs' test were observed. Intramuscular injections of cefoxitin in 0.5% lidocaine caused pain and induration and thus were poorly tolerated.

Eighteen of 349 cases (5.2 per cent) of bacterial meningitis seen between 1949 and 1973 were hospital-associated (developed after admission to the hospital). The patients were adults, usually males, and developed symptoms and signs of meningitis from 2 to 23 days (mean, 10.1 days) after hospital admission. The diagnosis of bacterial meningitis was made from less than 1 day to 15 days (mean, 4.8 days) after the onset of symptoms. Fourteen of the 18 patients had received antibiotics during the week prior to developing meningitis. Nine (50 per cent) had a chronic, noninfection, underlying illness. Diagnostic or surgical procedures involving the neuraxis or adjacent structures preceded the development of meningitis in 10 of the 18 patients (56 per cent). Only 6 of the 18 patients survived their infection. Prompt recognition, diagnosis, and therapy of hospital-associated meningitis in high-risk patients may reduce the significant mortality.

Three-hundred and forty-nine cases of acute bacterial meningitis treated during a 25-year period (1949 through 1973) were reviewed to determine the prognostic significance of initial historical, physical and laboratory findings. A poor prognosis was associated with age greater than or equal to 40 years (p less than 0.01), presence of predisposing illness (p less than 0.01), associated illness (p less than 0.01), absence of nuchal ridity (p less than 0.05), and derangement of cerebral function (p less than 0.01). The effects of predisposing illness and moderate cerebral dysfunction were dependent upon age. In contrast, the effects of associated illness, mild or severe cerebral dysfunction, and absent nuchal rigidity were independent of age. Laboratory studies associated with a poor prognosis included an elevated cerebrospinal fluid (CSF) protein (p less than 0.05), a positive CSF smear (p less than 0.05), or culture (p less than 0.01), or bacteremia (p less than 0.01). No prognostic significance could be attributed to race (p greater than 0.05), sex (p greater than 0.05), prior antibiotic therapy (p greater than 0.05), duration of illness before institution of adequate therapy (p greater than 0.05), CSF leukocyte count (p greater than 0.05), frequency of polymorphonuclear leukocytes in CSF (p greater than 0.05), CSF sugar less than or equal to 40 mg/100 ml (p greater than 0.05), or a CSF sugar-simultaneous blood sugar ratio less than or equal to 0.40 (p greater than 0.05).

Dorsoventral thoracic radiographs of 9 dogs were taken from 0 degree to 20 degrees to the right and to the left of a vertical line from mid-sternum to the mid-thoracic vertebrae. Certain measurements indicated that angles greater than 5 degrees from the vertical introduced significant distortions of the heart shadow and thoracic wall in some instances. A method is proposed for determining from a DV thoracic radiograph when improper positioning has produced an angulation greater than 5 degrees.

To evaluate the potential usefulness of a single large oral dose of trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment of uncomplicated genitourinary gonorrhea, the pharmacokinetics of a 12-tablet dose containing 960 mg of TMP and 4,800 mg of SMZ were studied in 15 male volunteers, and the tolerance of this regimen was compared to that of a placebo in a double-blind crossover study. Both TMP and SMZ were rapidly absorbed. Peak mean serum concentrations (+/- standard deviation) of TMP, total SMZ, and free SMZ were 9.2 +/- 2.2, 259.4 +/- 40.9, and 233.7 +/- 33.6 mug/ml, respectively. Elimination half-lives were 16.7, 14.6, and 12.9 h, respectively. When results were compared to data from similar studies after smaller doses, peak mean serum concentrations were proportional to dose, but elimination half-lives were longer after larger doses. Urinary concentrations of TMP, total SMZ, and free SMZ were many-fold higher than serum concentrations. Percents recovery (+/- standard deviation) in urine were 60.6 +/- 10.6, 80.2 +/- 7.8, and 37.4 +/- 6.5%, respectively, during the 48 h after administration. The incidence of severe headache and of objective transient oliguria was significantly higher after TMP-SMZ than after placebo. Although the observed serum concentrations of TMP and SMZ surpassed concentrations necessary to inhibit clinical isolates of Neisseria gonorrhoeae in vitro for longer than 24 h, the adverse reactions associated with a 12-tablet dose of TMP-SMZ would preclude the clinical usefulness of such a therapeutic regimen.

Cephacetrile, a new derivative of 7-aminocephalosporanic acid, was evaluated in 27 patients. Soft tissue infections due primarily to gram-positive cocci were treated in 16 patients; 12 had bacteriological and clinical cure, and 4 improved but the lesions resolved incompletely or cultures remained positive. Seven of eight patients with respiratory tract infections were cured, including three with pneumococcal pneumonia; the eighth proved to have a noninfectious process and failed to respond. Two patients with acute urinary tract infections due to Escherichia coli had prompt clinical and bacteriological improvement, but follow-up was incomplete. One patient with sepsis due to Staphylococcus aureus expired. Laboratory abnormalities observed during cephacetrile therapy included mild eosinophilia in four patients, thrombocytosis in nine, direct Coombs' test positivity in four, and an elevated serum glutamic pyruvic transaminase in eight patients. No evidence of nephrotoxicity was detected. Severe superinfection due to Enterobacter species was observed in one patient. Mean peak serum concentrations of cephacetrile were 22, 69, and 104 mug/ml after 1 g intramuscularly, 1 g intravenously, and 1.5 g intravenously, respectively. Thus, in early studies cephacetrile was efficacious for selected bacterial infections, but determination of its comparative value within the cephalosporin group of antibiotics requires further clinical investigation.