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The National Epidemiology of Mycoses Survey (NEMIS) involves six academic centers studying fungal infections in surgical and neonatal intensive care unit (ICU) patients. We studied variation in species and strain distribution and anti-fungal susceptibility of 408 isolates of Candida spp. Candida spp. were isolated from blood, other normally sterile site cultures, abscesses, wounds, catheters, and tissue biopsies of 141 patients hospitalized in the surgical (107 patients) and neonatal (34 patients) ICUs of medical centers located in Oregon, Iowa, California, Texas, Georgia, and New York. Isolates were also obtained from selected colonized patients (16 patients) and the hands of health care workers (27 individuals). DNA typing was performed using pulsed field gel electrophoresis, and antifungal susceptibility to amphotericin B, 5-fluorocytosine, fluconazole, and itraconazole was determined using National Committee for Clinical Laboratory Standards (NCCLS) methods. Important variation in susceptibility to itraconazole and fluconazole was noted: MICs of itraconazole ranged from 0.25 microgram/mL (MIC90) in Texas to 2.0 micrograms/mL (MIC90) in New York. Similarly, the MIC90 for fluconazole was higher for isolates from New York (64 micrograms/mL) compared to the other sites (8-16 micrograms/mL). In general, DNA typing revealed patient-unique strains; however, there were 13 instances of possible cross-infection noted in 5 of the medical centers. Notably, 9 of the 13 clusters involved species of Candida other than C. albicans. Potential transmission from patient-to-patient (C. albicans, C. glabrata, C. tropicalis, C. parapsilosis) and health care worker-to-patient (C. albicans, C. parapsilosis, C. krusei) was noted in both surgical ICU and neonatal ICU settings. These data provide further insight into the epidemiology of nosocomial candidiasis in the ICU setting.

Objective: To assess the efficacy of an infection control program as measured by tuberculin skin-test (TST) conversion rates in medical house staff., Design: Observational study., Setting: University-based hospital in New York City serving a large indigent population., Participants: Medical house staff., Interventions: TST conversions were measured every 6 months in medical house staff from June 1992 to June 1994. Compliance with the isolation policy was measured by identifying room locations 24 hours after admission of patients who had Mycobacterium tuberculosis recovered from respiratory specimens., Results: The TST conversion rate decreased from 5.8 to 0, 2.3, and 0 per 100 person years of exposure in successive 6-month periods. The estimated annual TST conversion rate among interns fell from 7 per 100 person years in June 1992 to 0 per 100 person years in June 1993 and 0 per 100 person years in June 1994 (P < .029). The proportion of patients with pulmonary tuberculosis who were isolated in negative-pressure rooms increased from 38% to 75% over the study period (P < .01)., Conclusion: Development of a multifaceted infection control program can decrease the risk of nosocomial tuberculosis infection in medical house staff.

Chronic lung disease caused by antibiotic-resistant Pseudomonas aeruginosa in patients with cystic fibrosis (CF) is difficult to treat, especially in those who are lung transplantation candidates. Analysis of antibiotic susceptibility and synergy studies of 1,296 isolates revealed that 172 (13.3%) were multiply resistant (i.e., resistant to two or more classes of anti-Pseudomonas agents). beta-Lactam agents (including imipenem and aztreonam) or aminoglycosides inhibited only 11% of the multiply resistant strains, while ciprofloxacin inhibited 34%. High concentrations of tobramycin and gentamicin (200 micrograms/mL), achievable by aerosol administration, inhibited 95% of isolates and overwhelmed permeability-resistance mechanisms. Antimicrobial pairs tested in checkerboard dilutions of clinically achievable drug concentrations inhibited 75% of the multiply resistant strains. On average, three additive and 2.4 synergistic pairs of antimicrobial agents had activity per strain. Transplantation candidates were older than nontransplantation candidates (P = .034), and isolates from transplantation candidates were less likely to be inhibited by antibiotic combinations (P < .001). Administration of aerosolized aminoglycosides and synergy testing of antimicrobial combinations may represent viable therapeutic options for patients with CF.

The purpose of this study was to compare the safety profile of cefepime, a new extended-spectrum, fourth-generation cephalosporin used to treat mild-to-severe bacterial infections, with that of ceftazidime. A total of 2,032 patients enrolled in North American and European cefepime trials were analyzed. The study population spanned adolescence to the elderly (15-100 years); the median age was 62 years. Cefepime was compared with ceftazidime (1,456 patients), a third-generation cephalosporin. Cefepime dosing was 1-4 g/day (0.5-2.0 g twice daily) for adults; ceftazidime dosing was 1-6 g/day (0.5 g every 12 hours to 2.0 g every 8 hours). A limited number of cefepime-treated patients received 2 g every 8 hours. The median length of dosing for both cefepime and ceftazidime was 7 days. In randomized trials in which cefepime (2,032 patients) was compared with ceftazidime (1,456 patients), analysis of comparative data indicated that adverse events of probable or unknown relation to study drugs were observed in 13.8% of cefepime patients and 15.6% of ceftazidime patients. The most commonly observed adverse event for cefepime was headache (2.4%), followed by nausea (1.8%), rash (1.8%), and diarrhea (1.7%). For ceftazidime, the most commonly observed adverse event was diarrhea (3.2%), followed by headache (2.5%), nausea (2.1%), rash (1.9%), and constipation (1.5%). The incidence of positive Coombs' test was higher in high-dose cefepime recipients than in ceftazidime recipients (14.5% vs 8.7%; p = 0.043), although there was no evidence of hemolysis in either treatment group. Coadministration of analgesics, diuretics, and anticoagulants did not increase incidence of adverse events associated with study-drug therapy. Adverse renal and hematologic events, as well as anaphylaxis and death, were rare in both groups. In the comparative trials with cefepime, anaphylaxis was reported in no patients receiving cefepime and in one patient receiving ceftazidime. None of the three seizures reported in patients receiving cefepime and one of six seizures in patients receiving ceftazidime were of probable or possible relationship to the study drugs. None of the 12 cases of gastrointestinal hemorrhage reported in cefepime patients or five cases reported in ceftazidime patients were judged to be related to treatment drug. Tolerance for intravenous administration in both treatment groups was similar. Cefepime did not effect any significant or unusual allergic, hematologic, gastrointestinal, neurologic, or renal toxicity when administered to patients with mild-to-severe infections, including those receiving concomitant medications. The safety profile of cefepime is excellent and comparable to that of ceftazidime and those reported for other cephalosporins.

Ceftibuten, a new orally absorbed cephalosporin with a novel side chain, has broad in vitro activity against most of the important respiratory pathogens including Streptococcus pneumoniae and both beta-lactamase-negative and beta-lactamase-positive Haemophilus influenzae and Moraxella (Branhamella) catarrhalis. Furthermore it has high activity against Enterobacteriaceae, which contain classic TEM-1 beta-lactamases and those containing the new extended spectrum beta-lactamases, which hydrolyze parenteral third generation cephalosporins. Studies have shown that ceftibuten has a postantibiotic effect comparable to that of other beta-lactams against S. pneumoniae, H. influenzae and M. catarrhalis. Blood levels achieved after a single 400-mg dose given once daily or 9 mg/kg/day taken once daily for children yield blood levels and postantibiotic inhibition for the majority of a dosing period. The in vitro and pharmacokinetic data can be correlated to provide reasonable dosing programs for the new oral cephalosporins.

The postantibiotic effect (PAE) of ceftibuten, a novel beta-lactamase-stable cephem, was determined for Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. The ceftibuten PAE after a 2-hour exposure to 2 micrograms/ml (4 x minimum inhibitory concentration) for S. pyogenes was 2.7 to > 10 hours. The PAE for S. pneumoniae after a 2-hour exposure to 15 micrograms/ml, concentrations that are achieved in man after usual therapeutic doses, was 1.1 to 3.4 hours and the PAE for H. influenzae was 1 to 1.1 hours. M. catarrhalis had a PAE of 1.5 to 1.8 hours after exposure to 15 micrograms/ml of ceftibuten. The ceftibuten PAE was not affected by serum. The ceftibuten PAE was prolonged by exposure to a sub-minimum inhibitory concentration concentration of ceftibuten as would occur in the clinical situation. The PAE of ceftibuten was not affected by the copresence of erythromycin as would occur when treating infections in which atypical organisms are suspected. There was no correlation between bacterial reduction in colony-forming units and the duration of PAE. A level of 6 micrograms/ml of ceftibuten had a similar bacterial killing activity compared with a 6-hour exposure to 15 micrograms/ml of ceftibuten against S. pneumoniae, H. influenzae and M. catarrhalis. This study suggests that ceftibuten can be administered orally, once daily in an adult dose of 400 mg or a pediatric dose of 9 mg/kg, to treat respiratory infections caused by the most common pathogens.

Antimicrobial resistance is commonplace among bacteria involved in surgical infections, including Staphylococcus aureus, enterococci, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Bacteroides species. Resistance traits can be encoded on chromosomes or transmissible plasmids. The basic mechanisms of resistance are alteration of drug target, prevention of drug access to target, and drug inactivation. Examples include alteration of penicillin-binding proteins in resistance to penicillinase-resistant penicillins, ribosomal binding site protection in tetracycline resistance, and beta-lactamase destruction of beta-lactam compounds. Resistance due to the many types of beta-lactamases that have thus far been identified is wide-spread among common pathogens; use of beta-lactam/beta-lactamase inhibitor combinations has proved effective as one means of counteracting such resistance. Contending with resistance involves appropriate use of available antimicrobials, development of novel agents or modification of existing agents, and measures to forestall emergence and spread of resistant organisms.

The in vitro activity of SCE-2787, 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3- yl)-2-methoxyiminoacetamido]-3-(1-imidazo[1,2-b]pyridazinium)methy l-3- cephem-4-carboxylate, was compared with those of ceftazidime, ceftriaxone, and imipenem against recent clinical isolates. SCE-2787 inhibited 50% of tested isolates of the family Enterobacteriaceae at < or = 0.25 micrograms/ml. SCE-2787 was equally active as or more active than ceftazidime and ceftriaxone against members of the Enterobacteriaceae, with the exception of Proteus vulgaris. The MIC of SCE-2787 at which 90% of the isolates of Pseudomonas aeruginosa were inhibited was 2 micrograms/ml, two- to fourfold lower than those of imipenem and ceftazidime, respectively. SCE-2787, like ceftazidime and imipenem, did not inhibit the majority of strains of Pseudomonas cepacia and Xanthomonas maltophilia. SCE-2787 inhibited beta-hemolytic streptococci at < or = 0.12 micrograms/ml, but it did not inhibit Enterococcus faecalis, Listeria monocytogenes, or the anaerobic species tested. Methicillin-resistant staphylococci required SCE-2787 MICs of > or = 16 micrograms/ml, whereas methicillin-susceptible staphylococci were inhibited by 2 micrograms/ml. No difference between the MICs and MBCs was noted, except for P. aeruginosa, for which there was a fourfold difference. SCE-2787 was active over a pH range of 6 to 8. The inoculum size of 10(5) to 10(7) CFU caused only a twofold change in the MIC for Escherichia coli and Staphylococcus aureus but a 4- to 16-fold change in Enterobacter cloacae and P. aeruginosa. beta-Lactamases from Bush groups 1, 2a, and 2b did not hydrolyze SCE-2787. There was significant hydrolysis of SCE-2787 by the beta-lactamases designated 2b', i.e., TEM-3, TEM-5, TEM-7, and TEM-9, and by the group 2d beta-lactamases. SCE-2787 had poor affinity for group 1 and group 2b enzymes and constitutively produced chromosomal beta-lactamases such as P-99 of Enterobacter cloacae and plasmid-mediated TEM-1 of E. coli. SCE-2787 has in vitro activity comparable to that of current parenteral cephalosporin and is more active against P. aeruginosa and S. aureus.

The in vitro activity of the new fluoroquinolone CP-99,219 [7-(3-azabicyclo[3.1.0]hexyl)naphthyridone] was compared with those of four other quinolones against 541 gram-negative, 283 gram-positive, and 70 anaerobic bacterial isolates. CP-99,219 inhibited 90% of many isolates in the family Enterobacteriaceae at a concentration of < or = 0.25 micrograms/ml (range, < 0.008 to 1 microgram/ml), an activity comparable to those of tosufloxacin and sparfloxacin and two times greater than that of temafloxacin. Ninety percent of the Proteus vulgaris, Providencia rettgeri, Providencia stuartii, and Serratia marcescens isolates were inhibited by 0.5 to 2 micrograms of CP-99,219 per ml. CP-99,219 inhibited 90% of the Pseudomonas aeruginosa and Haemophilus influenzae isolates at 1 and 0.015 micrograms/ml, respectively. The compound inhibited methicillin-susceptible Staphylococcus aureus at 0.06 micrograms/ml, whereas a ciprofloxacin concentration of 1 microgram/ml was required to inhibit these organisms. CP-99,219 inhibited 90% of methicillin-resistant S. aureus isolates at a concentration of < or = 4 micrograms/ml, while ciprofloxacin and temafloxacin had MICs against these isolates of > 16 micrograms/ml. Streptococci were inhibited by < or = 0.25 micrograms/ml, an activity comparable to that of tosufloxacin. CP-99,219 was eight times more active than ciprofloxacin against Streptococcus pneumoniae. Bacteroides species were inhibited by CP-99,219 at a concentration of 2 micrograms/ml, whereas inhibition of these species required 4- and 16-microgram/ml concentrations of tosufloxacin and ciprofloxacin, respectively. The MBCs of CP-99,219 ranged from two to four times the MICs, and inoculum size had a minimal effect on MIC. CP-99,219 was active against P. aeruginosa at pH 5.5, with only a fourfold increase in MIC compared with values obtained at pH 7.5. The addition of up to 9 mM Mg(2+) increased the MIC range from 0.03 to 0.06 microgram/ml to 0.12 to 0.5 microgram/ml. In view of its excellent in vitro activity against both gram-positive and gram-negative bacteria, CP-99,219 merits further study to determine it's clinical pharmacologic properties and potential for therapeutic use.

During the past decade there have been major changes in the susceptibility of bacteria that cause surgical infections. Resistance to common bacteria is worldwide, both in developed and developing countries. Almost all species of bacteria can develop resistance to antimicrobial agents, and resistance can readily be transferred among bacteria by transmissible elements called plasmids. One of the most important forms of resistance has been the inactivation of antibiotics, particularly penicillins and cephalosporins. The organisms involved in surgical infections include staphylococci, streptococci, enterococci, members of the Enterobacteriaceae, Pseudomonads, and anaerobes. Today virtually all Staphylococcus aureus are resistant to penicillins. Coagulase-negative staphylococci are also increasingly important causes of infection, particularly in cardiovascular surgery, where they may cause serious postoperative complications. Like S aureus, coagulase-negative staphylococci, primarily S epidermidis, also produce beta-lactamases and can be resistant to all beta-lactam antibiotics because of altered penicillin-binding proteins. New beta-lactamases, which destroy extended-spectrum beta-lactam antibiotics, have developed in Enterobacteriaceae, and all Pseudomonas spp. possess beta-lactamases. Various techniques have been used to overcome resistance, one of which is the development of beta-lactamase inhibitors. Currently there are three compounds that are effective inhibitors of many beta-lactamases: clavulanate, sulbactam, and tazobactam. The problem of resistance in surgical infections will not disappear. Increasingly complex operations will be done on more debilitated patients. The development of beta-lactamase inhibitors combined with highly active beta-lactam antibiotics has provided a way of overcoming this form of resistance.

Purpose: To report on a vitreous specimen in a 53-year-old patient with unilateral choroiditis and vitritis of unknown cause., Methods: Cytologic examination of a vitreous aspirate stained by the Papanicolaou method., Results: Intravitreal spirochetes consistent with Borrelia burgdorferi were found in this seronegative patient., Conclusion: Vitreous specimens of patients with choroiditis and vitritis of unknown cause should be examined cytologically, particularly when serologic results do not corroborate the clinical findings of Lyme disease.

Background: Clarithromycin is a new acid-stable, 14-membered macrolide active against many of the organisms responsible for lower respiratory tract infections. It has been administered to over 5,000 patients worldwide and has been shown to be a safe and effective treatment for acute bacterial exacerbations of chronic bronchitis and bacterial pneumonia when given twice daily (250 to 500 mg). Cefixime is an amino-thiazolyl cephalosporin with an extended spectrum of antibacterial activity inhibiting beta-lactamase-producing respiratory pathogens. It has a long half-life, allowing once-daily administration., Methods: This randomized, double-blind multicenter study compared clarithromycin and cefixime as treatment for patients with community-acquired lower respiratory tract infections (n = 213). Patients had bacterial pneumonia (clarithromycin, 19 percent; cefixime, 21 percent) or acute bacterial exacerbation of chronic bronchitis or asthmatic bronchitis (clarithromycin, 81 percent; cefixime, 79 percent). Patients received 500 mg of clarithromycin twice daily (n = 103) or 400 mg of cefixime once daily (n = 110) for 7 to 14 days., Results: Clinical cure or improvement occurred in 86 percent of the clarithromycin-treated patients and 88 percent of the cefixime-treated patients. When only patients with identified infections with Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae were considered, clinical success rates were 97 percent for clarithromycin and 96 percent for cefixime; the rate of bacteriologic eradication was 91 percent for clarithromycin and 90 percent for cefixime. Adverse events occurred in 29 percent of the clarithromycin-treated patients and 23 percent of the cefixime-treated patients., Conclusions: This study demonstrates that clarithromycin and cefixime are effective treatments for pneumonia and acute bacterial exacerbations of bronchitis of mild to moderate severity caused by the most common infecting organisms.

Six double-blind, independently randomized studies evaluated the efficacy and safety of calcium mupirocin ointment in eliminating nasal carriage of Staphylococcus aureus among health care workers. Healthy volunteers with stable nasal carriage of S. aureus (n = 339) received either calcium mupirocin ointment (n = 170) or an identical placebo ointment (n = 169) intranasally for 5 days. Nasal carriage was eliminated 48-96 hours after completion of treatment in 130 (91%) of 143 evaluable volunteers receiving mupirocin but in only 8 (6%) of 142 evaluable volunteers receiving placebo. The 85% crude difference represents a 90% pooled (adjusted) estimate of the risk difference (95% confidence interval, 0.86-0.95) and a risk ratio of 16 (P < .0001). This effect of treatment with mupirocin was observed consistently (risk ratio, 8-32) in all six centers. In addition, 96 of the 130 mupirocin-treated volunteers and 1 of the 8 placebo-treated volunteers who were culture-negative at the end of therapy remained free of S. aureus 4 weeks after treatment. Adverse events in each treatment arm were mild and equally frequent. These data, consistent across six institutions, demonstrate that calcium mupirocin ointment administered intranasally for 5 days is safe and effective in eliminating stable nasal carriage of S. aureus.

Macrophages possess organic anion transporters that carry membrane-impermeant fluorescent dyes, such as lucifer yellow (LY) and carboxy-fluorescein, from the cytoplasm into endosomes and out of the cells. Probenecid, an organic anion transport inhibitor, blocks these processes. Prolonged incubation of J774 cells in medium containing 2.5 mM probenecid eventually kills most of these cells. To identify J774 variants that express increased organic anion transport activity, we selected probenecid-resistant (PBR) J774 cells by growing them in medium containing increasing concentrations of probenecid. When PBR and unselected J774 cells were loaded with LY by ATP4- permeabilization, the amount of LY accumulated by the PBR cells was about half that in the unselected cells. This difference was abolished by adding 10 mM probenecid to the medium in which the cells were loaded, suggesting that the diminished LY accumulation in PBR cells was due to enhanced LY secretion and that the PBR cells expressed increased organic anion transport activity. Direct comparison of LY efflux from J774 and PBR J774 cells showed a faster initial rate of secretion of LY from PBR J774 cells than from unselected J774 cells. To determine whether LY efflux is mediated by P-glycoprotein, we compared LY efflux in unselected J774 cells, PBR J774 cells, and multidrug-resistant J774 cells (J7.C1). LY efflux from J7.C1 cells was not sensitive to verapamil, which inhibits multidrug-resistance transporters, and reverses the multidrug-resistant phenotype of J7.C1 cells. The rates of LY efflux from unselected J774 and J7.C1 cells were virtually identical.(ABSTRACT TRUNCATED AT 250 WORDS)

A review of the published literature detailing the clinical use of amoxycillin/clavulanic acid spanning the period 1979 to 1992 was undertaken to assess the clinical efficacy of the product and to determine whether any changes had occurred during this time. In the 415 publications meeting the selection criteria a total of over 38,500 patients were treated with amoxycillin/clavulanic acid. Analysis of the data confirms the efficacy of amoxycillin/clavulanic acid over a wide range of clinical indications and annual and triennial groupings of publications suggests that there has been little change in the clinical effectiveness of amoxycillin/clavulanic acid. Clinical efficacy rates (cure or improved) with amoxycillin/clavulanic acid were 88% and 92% in comparative and uncontrolled trials, respectively. Gastro-intestinal side effects are the most common adverse event but have been relatively infrequent. Amoxycillin/clavulanic acid should continue to be a useful antibiotic for upper and lower respiratory tract infections, skin structure infections, dental, head and neck infections, and selected urinary tract infections.

The trifluoroquinolone fleroxacin inhibits the majority of Enterobacteriaceae at concentrations < or = 1 micrograms/mL and most Pseudomonas aeruginosa and staphylococci at < or = 2 micrograms/mL. The purpose of this study was to determine the effect of the combination of fleroxacin with other antimicrobial agents. Previous studies that used checkerboard assay, fixed concentrations, and killing curves were reviewed, and these methods were used to evaluate the combination of fleroxacin and agents that had not been previously studied. The combination of fleroxacin with such aminoglycosides as gentamicin, amikacin, and tobramycin is indifferent against most Enterobacteriaceae, as is the combination of fleroxacin with penicillins, cephalosporins, rifampin, clindamycin, and metronidazole. Combinations of fleroxacin with penicillins, cephalosporins, imipenem, aminoglycosides, clindamycin, metronidazole, and rifampin are indifferent against P. aeruginosa. Fosfomycin and fleroxacin acted synergistically against P. aeruginosa. Against staphylococci, combinations of fleroxacin with oxacillin, rifampin, or fosfomycin had synergistic or additive effects, whereas combinations of fleroxacin with vancomycin, gentamicin, or metronidazole have shown indifference. No synergy or antagonism has been found for combinations of fleroxacin with penicillin, vancomycin, erythromycin, clindamycin, or rifampin against streptococci or enterococci. The combination of fleroxacin and metronidazole has proved synergistic against various Bacteroides species. In general, combinations of fleroxacin with other antimicrobial agents display indifference and rarely synergy. Thus, fleroxacin can be combined with other antibiotics to enlarge the spectrum of activity.

The in vitro activity of FK-037, 5-amino-2-[[(6R, 7R)-7-[[(Z)-2-(2-amino-4-thiazolyl)-2- methoxyimino) acetyl] amino]-2-carboxy-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-(2-hydroxyethyl)-1H-pyrazoli um hydroxide, inner salt, sulfate (1:1), a new parenteral cephem, was compared with those of cefepime, ceftazidime, imipenem, and ciprofloxacin. FK-037 inhibited methicillin-susceptible staphylocci at < or = 4 micrograms/ml. Of 98 isolates of homogenous methicillin-resistant Staphylococcus aureus, 55 (56.1%) were inhibited by 8 micrograms of FK-037 per ml, compared to 3.1% for cefepime. Imipenem was the most active beta-lactam tested against staphylococci. The MIC of FK-037 for 90% of the strains tested (MIC90) was 0.06 micrograms/ml for hemolytic streptococci, Streptococcus pneumoniae, viridans group streptococci, and Streptococcus bovis. The MIC90 for many of the members of the family Enterobacteriaceae was 1 microgram/ml, similar to that of cefepime and lower than those of ceftazidime and imipenem. The MIC90 for Klebsiella pneumoniae and Enterobacter cloacae was 8 micrograms/ml, similar to that for cefepime, but all isolates were inhibited by 2 micrograms of imipenem per ml. K. pneumoniae isolates with cefotaxime and ceftazidime MICs of > 32 micrograms/ml with Bush type 2b' beta-lactamases were inhibited by 4 micrograms of FK-037 per ml. E. cloacae, Citrobacter freundii, and S. aureus stably resistant to FK-037 could be selected by repeated transfer in the presence of FK-037. The FK-037 MIC90 for Pseudomonas aeruginosa was 4 microgram/ml, compared to 32 microgram/ml for cefepime and ceftazidime and 8 microgram/ml for imipenem. Xanthomonas maltophilia, Pseudomonas cepacia, Acinetobacter anitratus, and Bacteroides species were resistant to FK-037 (MIC, more than or equal 32 microgram/ml). MBCs were identical to or within twofold of the MICs except for a 32-fold greater MBC for P. aeruginosa. Inoculum size and acid environment did not lower the activity of FK-037. FK-037 was not appreciably hydrolyzed by Bush group 1, 2a, 2b, and 2e beta-lactamases but was hydrolyzed by 2b' and 2d enzymes at rates comparable to that of ceftazidime. Nonetheless, FK-037 inhibited bacteria possessing TEM-3, -5, and -7 and SHV -5 at less than or equal 8 microgram/ml. Overall, FK-037 has lower MICs against staphylococci and P. aeruginosa than the currently available iminomethoxy aminothiazolyl cephalosporins and has activity against members of the family Enterobacteriaceae comparable to that of cefepime.

There is and has been continued change in organisms causing infection in the hospital. In the past few years, although Gram-negative bacteria have remained a major cause of mortality, Gram-positive bacteria and fungi have become increasingly important. This has caused organisms such as methicillin-resistant staphylococci, enterococci, Xanthomonas maltophilia and multiply resistant Pseudomonas aeruginosa to be common pathogens. Can this difficult state of affairs be changed by better antimicrobial prescribing practices? Yes and no. Virtually any agent will select MRSA and MRSE since the chromosomal location of the resistance of multiple-antibiotics makes such selection common and explains the rapid rate of the fluoroquinolones as therapy of MRSA. Restriction of oral vancomycin will markedly reduce the pressure to select Enterococcus faecium and thus limit the spread of the organisms and delay transmission of glycopeptide resistance to S. aureus. Judicious use of antibiotics in the intensive care environment will be major factor in "saving" antibiotics for other patients since the ICU patient goes to other parts of the hospital carrying with him/her the baggage of resistant Staphylococcus haemolyticus, klebsiella, P. aeruginosa, acinetobacter, enterobacter, xanthomonas and Pseudomonas cepacia. All of these organisms have the potential to become resistant to the agents heretofore used to treat them and are common in ICU patients.

In an attempt to overcome some of the gaps in their antibacterial spectrum, e.g. some Gram-positive bacteria (notably streptococci and Streptococcus pneumoniae) and anaerobes, the fluoroquinolones have been combined with other bactericidal and bacteriostatic agents. In general, the fluoroquinolones rarely show either synergy or antagonism when used in combination with other antimicrobial agents against most bacteria. Therefore, in infections where the fluoroquinolones do not provide cover against all potential organisms, combined treatment with an appropriate agent may be considered. Current data suggest that the fluoroquinolones are not antagonistic with beta-lactams, macrolides, clindamycin and the imidazoles. Aminoglycosides in combination with the fluoroquinolones do not show synergy. Antipseudomonal penicillins, ceftazidime or imipenem in combination with the fluoroquinolones are synergistic and may be useful for treating infections in immunocompromised patients. Rifampicin in combination with a fluoroquinolone for the treatment of staphylococcal endocarditis or osteomyelitis may be useful, although in vitro and in vivo results do not always coincide.

J774 macrophage-like cells express organic anion transporters that promote the efflux of fluoroquinolone antibiotics such as norfloxacin (NFX) from these cells. Gemfibrozil (GFZ) blocks organic anion transport in J774 cells, thereby facilitating the intracellular accumulation of NFX (Cao, C., H.C. Neu, and S.C. Silverstein. 1991. J. Cell Biol. 115:467a [Abstr.]). To determine whether GFZ enhances the efficacy of fluoroquinolone antibiotics against intracellular bacterial pathogens, J774 cells were infected with Listeria monocytogenes and incubated in medium containing a fluoroquinolone antibiotic in the presence or absence of GFZ. Intracellular growth of L. monocytogenes was evaluated by lysing J774 cells and assaying for colony-forming units of Listeria. GFZ intensified the bacteriostatic effect of 4 micrograms/ml NFX and rendered 8 micrograms/ml bactericidal for L. monocytogenes. GFZ had a similar potentiating effect when used in combination with 2 micrograms/ml ciprofloxacin (CFX). CFX plus GFZ was bactericidal for intracellular L. monocytogenes. Treatment of J774 cells with NFX plus GFZ markedly reduced the cytotoxic effect of the bacteria on these cells. Over 55% of cells treated with 8 micrograms/ml NFX alone were dead 16 h after infection, whereas only 5% of cells treated with 8 micrograms/ml NFX plus GFZ were dead at 16 h. Similarly, GFZ potentiated the ability of 2 micrograms/ml to protect J774 cells against the cytocidal effect of Listeria. NFX in combination with GFZ limited cell-to-cell spread of L. monocytogenes. In antibiotic-free medium, > 99% of J774 cells contained intracellular L. monocytogenes at 14 h after infection. NFX alone in the medium did not change this outcome. However, 4 micrograms/ml NFX plus GFZ decreased bacterial spread by approximately 40% at 24 h postinfection, and 8 micrograms/ml NFX plus GFZ prevented all spread beyond the initially infected cell population. These results suggest that GFZ could be used clinically to enhance the efficacy of fluoroquinolone and of other anionic antibiotics against bacteria that grow and/or reside within macrophages and/or other cells.

The plasma bactericidal activity of a new C-5 methyl fluoroquinolone, OPC-17116, was determined after once-daily oral ingestion of 400 mg and 800 mg in normal, healthy volunteers. OPC-17116 at a 400-mg dose produced plasma bactericidal titers greater than or equal to 1:16 at 12 hours against Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Haemophilus influenzae, and Moraxella catarrhalis. OPC-17116 bactericidal titers against Pseudomonas aeruginosa were 1:2 or 1:4 at 6 and 12 hours. The plasma bactericidal titers against Streptococcus pyogenes and Streptococcus pneumoniae were 1:4 or greater, but bactericidal titers against Staphylococcus aureus were 1:2 at 12 hours and less than 1:2 at 24 hours. The 800-mg dose of OPC-17116 produced bactericidal titers of at least 1:32 at 12 hours for the Enterobacteriaceae, Haemophilus, and Moraxella, and 1:4 for S. pyogenes and S. pneumoniae, but bactericidal titers against S. aureus were 1:2. These data would suggest that an 800-mg dose of OPC-17116 taken orally once daily would provide adequate concentrations to treat infections due to the pathogens examined in this study.

CP-74,667, a 6-fluoro-7-bridged piperazinyl-1-cyclopropyl-4 quinolone, inhibited 90% of staphylococci, beta-hemolytic streptococci, enterococci, Enterobacteriaceae, and Pseudomonas aeruginosa at less than or equal to 2 micrograms/ml. Ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus had minimum inhibitory concentration (MIC50) of 4 micrograms/ml and an MIC90 of 8 micrograms/ml. CP-74,667 was fourfold more active than ciprofloxacin against Streptococcus pneumoniae and St. pyogenes, but equal or less active than tosufloxacin against Gram-positive species. The MIC90 for P. aeruginosa was 5 micrograms/ml similar to temafloxacin. The CP-74,667 MIC90 for Bacteroides fragilis was 2 micrograms/ml, equal to tosufloxacin and temafloxacin. Activity was eight- to 16-fold less at pH 5.5 compared with pH 7.4 and also eight- to 16-fold less in urine. Magnesium ions markedly increased the CP-74,667 minimum bactericidal concentrations (MBCs). The development of resistance to CP-74,667 was similar to that found for other fluoroquinolones.

The synthesis of large numbers of antibiotics over the past three decades has caused complacency about the threat of bacterial resistance. Bacteria have become resistant to antimicrobial agents as a result of chromosomal changes or the exchange of the exchange of genetic material via plasmids and transposons. Streptococcus pneumoniae, Streptococcus pyogenes, and staphylococci, organisms that cause respiratory and cutaneous infections, and members of the Enterobacteriaceae and Pseudomonas families, organisms that cause diarrhea, urinary infection, and sepsis, are now resistant to virtually all of the older antibiotics. The extensive use of antibiotics in the community and hospitals has fueled this crisis. Mechanisms such as antibiotic control programs, better hygiene, and synthesis of agents with improved antimicrobial activity need to be adopted in order to limit bacterial resistance.

We evaluated the antimicrobial activity of two metal compounds, JM-1397 (OsO2[xylyl]2) and JM-2469 (AuCl[S2CPEt3]). Both inhibited methicillin-susceptible and methicillin-resistant Staphylococcus aureus at concentrations of 0.5-2 micrograms/ml, with a minimum inhibitory concentration (MIC90) of 1 microgram/ml for JM-1397 and 0.5 microgram/ml for JM-2469. Similar concentrations inhibited methicillin-susceptible and -resistant coagulase-negative staphylococci (S. epidermidis, S. haemolyticus, and S. saprophyticus). JM-2469 inhibited group A, B, C, F, and G beta-hemolytic streptococci and viridans group streptococci at 1-8 micrograms/ml (MIC90 4 micrograms/ml) but Enterococcus faecalis and E. faecium had MICs of 8-16 micrograms/ml. JM-1397 had MICs for these organisms of greater than 64 micrograms/ml. Bacteroides fragilis, other Bacteroides, and Clostridium species were inhibited by less than or equal to 0.12-4 micrograms/ml (MIC90, 0.5 microgram/ml). MICs of both compounds for Enterobacteriaceae and Pseudomonas spp. were greater than 64 micrograms/ml. These studies show that osmium and gold compounds have potential as topical agents against Gram-positive and anaerobic species.

The in vitro activity of MC-352, 3,4'-dideoxy-5-O-mycaminosyltylonolide, was compared with those of erythromycin, clarithromycin, and rokitamycin. The MC-352 MIC90 (MIC for 90% of isolates) for erythromycin-susceptible Staphylococcus aureus and Staphylococcus epidermidis was less than or equal to 1 microgram/ml, similar to those of the other agents. The MC-352 MIC50 for erythromycin-resistant S. aureus was 2 micrograms/ml, similar to that of rokitamycin. The MC-352 MIC90 (0.12 micrograms/ml) for Streptococcus pyogenes was similar to those of erythromycin and clarithromycin and superior to that of rokitamycin, and the MC-352 MIC90 for group B, C, and G streptococci was 0.25 microgram/ml. MC-352 and clarithromycin had an MIC90 of 0.12 microgram/ml for Streptococcus pneumoniae. Erythromycin-susceptible Enterococcus faecalis was inhibited by MC-352 at 1 microgram/ml, but the MIC for constitutively erythromycin-resistant isolates was greater than 16 micrograms/ml. Legionella pneumophila was inhibited by less than or equal to 0.25 microgram/ml. MC-352 was the most active agent against Bacteroides fragilis, with an MIC90 of 8 micrograms/ml, and was more active than the other agents against Haemophilus influenzae, with an MIC90 of 4 micrograms/ml. Moraxella spp. were inhibited by MC-352 at less than or equal to 0.25 microgram/ml. The MIC90 for Escherichia coli, Klebsiella pneumoniae, and Salmonella, Shigella, Yersinia, Enterobacter, Citrobacter, and Serratia spp. was greater than or equal to 32 micrograms/ml. MC-352 was bactericidal for S. pyogenes and S. pneumoniae, and its activity was not altered by human serum.

The antimicrobial activity of vermisporin, a new antibiotic produced by fermentation of the fungus Ophiobolus vermisporis, was tested in vitro. Vermisporin inhibited 90% of Bacteroides fragilis and other Bacteroides spp. at 1 microgram/ml (range 0.25-1 micrograms/ml). Clostridium perfringens were inhibited by 1 microgram/ml (range 0.25-2 micrograms/ml). Vermisporin inhibited 90% of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, at 0.5 micrograms/ml (range 0.12-0.5 micrograms/ml). Vermisporin MICs for group A, B, C, F and G streptococci were < 1 microgram/ml when tested in Haemophilus Test Medium but > or = 8 micrograms/ml in the presence of blood. Vermisporin MICs for Enterobacteriaceae, Pseudomonas aeruginosa and Haemophilus influenzae exceeded 64 micrograms/ml. Inhibited organisms had MBCs 16- to 32-fold above the MICs.

Fluoroquinolone antimicrobial agents inhibit most Enterobacteriaceae at extremely low concentrations, less than or equal to 0.5 microgram/mL. The half-lives of the agents range from 4 to 18 hours. Most of the available fluoroquinolones can be administered once daily to treat urinary tract and diarrheal infections. Newer agents with long half-lives that inhibit gram positive organisms at lower concentrations than the older fluoroquinolones, less than or equal to 1 microgram/mL, and have a long post-antibiotic effect have the potential to be used once daily as treatment of respiratory, skin-structure and selected bone infections as well. Careful clinical studies are needed to establish the efficacy of once daily use of fluoroquinolones, to determine that clinical efficacy is equivalent to multiple doses, and that once-daily dosing does not select more resistant bacteria. Single-dose therapy with quinolones would be an improvement in cost and patient compliance.

HR 916B is a new orally absorbed cephalosporin. In tests its active metabolite, RU29246, inhibited Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus pneumoniae at less than or equal to 0.12 micrograms/ml, which is similar to the antibacterial activity of cefuroxime, and was more active than cefaclor. It was also more active (MIC 2 micrograms/ml) than cefixime, cefuroxime, cefaclor and cefotaxime against staphylococci. RU29246 inhibited Escherichia coli, Klebsiella pneumoniae, Citrobacter diversus, Klebsiella oxytoca, Proteus mirabilis, Providencia stuartii and Salmonella spp. at less than or equal to 1 microgram/ml, thus being more active than cefuroxime and cefaclor, but was less active than cefixime and cefotaxime. It did not inhibit Pseudomonas aeruginosa and other Pseudomonas spp., Enterobacter spp., Serratia marcescens or Bacteroides fragilis. RU29246 was not hydrolyzed by TEM-1, Staphylococcus aureus TEM-2 or Moraxella catarrhalis beta-lactamases, but was hydrolyzed by TEM-3 and the chromosomal beta-lactamases of Proteus vulgaris and Morganella morganii. Plasmid and chromosomal beta-lactamases were inhibited by RU29246.

RP 59500 is a 30:70 mixture of RP 57669 and RP 54476. The activity of RP 59500 and its two components against Gram-positive and Gram-negative organisms was compared with that of clarithromycin, roxithromycin, azithromycin and rokitamycin. RP 59500 inhibited 90% of erythromycin-susceptible and resistant Staphylococcus aureus and coagulase-negative staphylococci at less than or equal to 1 mg/L (range 0.06-2 mg/L). Both inducibly and constitutively-resistant strains of S. aureus, as well as strains resistant to rifampicin, gentamicin and ciprofloxacin, were inhibited. Streptococcus pyogenes, including erythromycin-resistant isolates, and group C and G streptococci were inhibited by 0.5 mg/L. Streptococcus pneumoniae and viridans group streptococci were inhibited by 1 mg/L. The MIC90 was 4 mg/L for Haemophilus influenzae and 1 mg/L for Moraxella catarrhalis. RP 59500 did not inhibit Enterobacteriaceae or Pseudomonas aeruginosa. The activity of RP 59500 against streptococci was less than that of the four other macrolides. Clostridium perfringens strains were highly susceptible, as were Bacteroides spp. RP 59500, when combined with ciprofloxacin, cefotaxime or gentamicin, did not have altered activity against susceptible species or alter the activity of the other component of the combination against susceptible species. MBCs in serum were increased two- to four-fold for S. pyogenes, S. pneumoniae and S. aureus, compared with MBCs in broth, but RP 59500 was as active at pH 6 as at pH 7, and there was not an appreciable inoculum effect. RP 59500 has potential use as an agent against inducibly and constitutively erythromycin-resistant isolates of Gram-positive species and selected anaerobic organisms.

The post-antibiotic effect (PAE) of RP 59500, a new streptogramin antibiotic, was determined for Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Streptococcus pneumoniae, and Streptococcus pyogenes. A 30 min exposure of Staphylococcus aureus to 5 micrograms/ml of RP 59500 produced a PAE of 1.9-6.9 h, and a 60 min exposure of 2.5 micrograms/ml produced a PAE of 3.2-8 h. A 30 min exposure of 5 micrograms/ml of RP 59500 of coagulase-negative staphylococci produced a PAE of 2.5-7.5 h. PAEs of constitutively erythromycin-resistant staphylococcal isolates were shorter than were the PAEs of highly susceptible isolates. A 30 min exposure to 5 micrograms/ml of RP 59500 produced a PAE of 7.5-9.5 h for Streptococcus pneumoniae and a PAE of greater than 18 h for Streptococcus pyogenes. RP 59500 produced a longer PAE with Staphylococcus aureus than did vancomycin, oxacillin or erythromycin. These results suggest that RP 59500 may be administered less frequently than would be suggested by its half-life.

The in vitro activity of LJC 10,627, a new carbapenem, was compared with those of imipenem, cefotaxime, ceftazidime, and gentamicin. LJC 10,627 inhibited 90% of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Hafnia alvei, Citrobacter freundii, Citrobacter diversus, Proteus mirabilis, Morganella morganii, Proteus rettgeri, Serratia marcescens, Pseudomonas cepacia, salmonellae, shigellae, aeromonas, and yersiniae at less than or equal to 2 micrograms/ml. Haemophilus influenzae was inhibited by 0.5 microgram/ml, and moraxellae were inhibited by 0.12 microgram/ml. LJC 10,627 was twofold more active than imipenem against aerobic gram-negative organisms and inhibited ceftazidime-, cefotaxime-, and gentamicin-resistant members of the genera Klebsiella, Enterobacter, Citrobacter, and Serratia at less than or equal to 2 micrograms/ml. Xanthomonas maltophilia strains were resistant to the drug. Imipenem was two- to fourfold more active than LJC 10,627 against Staphylococcus aureus and Staphylococcus epidermidis. LJC 10,627 did not inhibit most methicillin-resistant Staphylococcus aureus or methicillin-resistant Staphylococcus epidermidis strains. LJC 10,627 inhibited Streptococcus pyogenes and Streptococcus pneumoniae at 0.06 and 0.12 microgram/ml, respectively. Bacteroides fragilis and other Bacteroides spp. were inhibited by 0.5 microgram of LJC 10,627 per ml. Serum (50%) did not affect the MICs. LJC 10,627 was not hydrolyzed by plasmid-mediated beta-lactamases of Bush types 2b, 2b', TEM-1, TEM-2, TEM-3, TEM-5, TEM-7, TEM-9, and SHV-1; the chromosomal beta-lactamases of Bush type 1; P-99; a Morganella enzyme; or a Citrobacter freundii enzyme. The Bush type 2c and 2d enzymes OXA-1, OXA-2, PSE-1, PSE-2, and PSE-4 did not hydrolyze LJC 10,627, nor did the beta-lactamases of Staphylococcus aureus, Moraxella spp., Bacteroides fragilis, and Proteus vulgaris. The beta-lactamase of Xanthomonas hydrolyzed LJC 10,627, albeit at approximately one-third the rate that imipenem was hydrolyzed.

The in vitro activity of OPC-17116, a new C-5 methyl fluoroquinolone, was compared with the activities of other fluoroquinolones. OPC-17116 inhibited 50% of the members of the family Enterobacteriaceae tested and 90% of Haemophilus influenzae, Neisseria species, and Moraxella catarrhalis isolates at less than or equal to 0.25 microgram/ml. At less than or equal to 2 micrograms/ml, 90% of the Enterobacteriaceae were inhibited, which was comparable to or better than the activities of fleroxacin, ofloxacin, and lomefloxacin but less than the activity of ciprofloxacin. OPC-17116 inhibited 90% of the staphylococci tested at less than or equal to 0.25 micrograms/ml, but it did not inhibit methicillin-resistant, ciprofloxacin-resistant Staphylococcus aureus or Staphylococcus epidermidis. Group A, B, C, F, and G streptococci and Streptococcus pneumoniae were inhibited by less than or equal to 0.5 microgram/ml, being four-fold more active than ciprofloxacin and ofloxacin. Tosufloxacin was the most active agent tested against gram-positive cocci. OPC-17116 inhibited Bacteroides fragilis at 4 micrograms/ml. There was a minimal effect of inoculum size on MIC, and the MBCs were within 1 dilution of the MICs. The activity of OPC-17116 was decreased at pH 6 and in the presence of high Mg2+ concentrations, but it was unaffected by human serum. OPC-17116 showed a postantibiotic effect against Pseudomonas aeruginosa and Staphylococcus aureus similar to the postantibiotic effects reported for other fluoroquinolones. The frequency of spontaneous single-step resistance was low (less than 10(-9)), but repeated passage of organisms in the presence of OPC-17116 resulted in the selection of resistant isolates.

The in vitro activity of S-1006, the active component of a new orally absorbed cephalosporin, S-1108, inhibited 90% of Staphylococcus aureus isolates at less than or equal to 2 micrograms/ml, 90% of group A, B, C, F, and G streptococci and Streptococcus pneumoniae isolates at less than or equal to 0.12 microgram/ml, and all Haemophilus influenzae isolates at less than or equal to 0.06 microgram/ml. Although 50% of the members of the family Enterobacteriaceae were inhibited by less than or equal to 2 micrograms of S-1006 per ml, Enterobacter spp. and Citrobacter freundii resistant to ceftriaxone were resistant to S-1006. The MICs of S-1006 for approximately 20% of Providencia, Proteus vulgaris, and Serratia isolates were 4 micrograms/ml. S-1006 was hydrolyzed by the plasmid TEM-3, TEM-5, PSE-1, and PSE-4 beta-lactamases and by the chromosomal beta-lactamase of Enterobacter and Morganella spp. and P. vulgaris.

The in vitro activity of cefquinome, a new aminothiazolyl cephalosporin with a C-3 bicyclic pyridinium group, was compared with ceftazidime, cefpirome, and cefepime. Cefquinome inhibited members of the Enterobacteriaceae at less than or equal to 0.5 microgram/ml for Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Citrobacter diversus, Salmonella Shigella, Proteus mirabilis, Morganella, and Providencia. Although most Citrobacter freundii and Enterobacter cloacae were inhibited by less than 2 micrograms/ml, some strains resistant to ceftazidime were resistant, [minimum inhibitory concentration (MIC) greater than 16 micrograms/ml]. Serratia marcescens were inhibited by less than 1 microgram/ml and Pseudomonas aeruginosa by 8 micrograms/ml similar to the activity of cefepime. The majority of Haemophilus influenzae and Neisseria gonorrhoeae were inhibited by less than 0.25 microgram/ml. Most enterococci had cefquinome MICs of 4-8 micrograms/ml. Cefquinome was extremely active against group-A streptococci and Streptococcus pneumoniae with MICs less than 0.12 microgram/ml. 90% of methicillin-susceptible Staphylococcus aureus 90% were inhibited by 2 micrograms/ml. Overall, the in vitro activity of cefquinome was comparable with aminothiazolyl cephalosporins. It inhibited some Enterobacter and Citrobacter freundii resistant to ceftazidime as did cefpirome and cefepime. Cefquinome was not destroyed by the common plasmid beta-lactamases TEM-1, TEM-2, SHV-1, or by the chromosomal beta-lactamases of Klebsiella, Branhamella, and Pseudomonas, but it was hydrolyzed by TEM-3, TEM-5, and TEM-9. Its activity was not adversely decreased in different medium or protein, and minimum bactericidal concentrations (MBCs) for most species except for Enterobacter were within a dilution of MICs.

The activity of decaplanin, a new glycopeptide, was compared to that of vancomycin, teicoplanin and daptomycin. Decaplanin was two- to four-fold less active than vancomycin, telcoplanin and daptomycin against Staphylococcus aureus and Staphylococcus epidermidis, with an MIC90 of 2 micrograms/ml for methicillin-susceptible and 4 micrograms/ml for methicillin-resistant isolates. Decaplanin had activity similar to that of vancomycin against Streptococcus pyogenes, Streptococcus agalactiae, group C and G streptococci, with an MIC90 of 0.12 micrograms/ml. It was less active than the other agents against the viridans group streptococci (MIC90 4 micrograms/ml). The activity of decaplanin against enterococci (MIC90 4 micrograms/ml) was similar to that of vancomycin. Clostridium spp. were inhibited by 0.5 micrograms/ml, peptostreptococci and peptococci by 0.25 microgram/ml. Decaplanin was active from pH 5.5 to 7.5. Inoculum size had a minimal effect on MICs, and increased concentrations of Ca2+ and Mg2+ and 50% serum did not alter MICs or MBCs.

The populations at risk for urinary tract infection include the newborn, particularly the premature, prepubertal girls, young boys, sexually active young women, elderly males, and elderly females. Risk factors that contribute to lower tract infection in women include sexual intercourse, diaphragm-spermicide use, and voiding behavior. Host factors, more than bacterial virulence, are probably the most important contributors to infection. The genetic factors that are important contributors are secretor status and P blood group phenotype. Which patients to culture, when to culture, and the number of organisms required to define infection have changed in the past decade. A concentration of 10(2) colony forming units/mL can cause an acute urinary tract infection in the healthy woman. The presence of leukocytes in the urine is of increasing diagnostic importance. Complicated urinary tract infections occur in neonates with such congenital anomalies of the urinary tract as urethral valves or in patients with neurologic disease resulting in urinary stasis. In older men or women, complicated urinary tract infections occur with obstruction, instrumentation, surgery, anatomic abnormalities, or stones. Single-dose therapy of uncomplicated urinary tract infection is useful in only a small subset of patients, specifically in patients less than 45 years of age who have short duration of symptoms. The majority of patients with uncomplicated infections should receive treatment for 3-5 days. Response to therapy and long-term cure rates in complicated urinary tract infection are related both to the type of underlying abnormality and to the species of the infecting organism. Complicated urinary tract infections should be treated for 7-14 days.

Correlation of pharmacokinetic and pharmacodynamic properties of antimicrobial agents with in vitro activity is critical to proper use of antibiotics. Knowledge of minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) is essential for life-threatening infections and has increased relevance with regard to development of resistance when treating selected urinary tract and wound infections. Factors that decrease absorption of oral agents profoundly affect clinical efficacy. The dose and frequency of dosing programs of the new oral fluoroquinolones should be correlated with the body site of infection, the organism being treated, and the propensity of the organism to become resistant. The long elimination half-life and high urine concentrations of newer fluoroquinolones permit once-daily therapy in many infections.

When dealing with infections of the central nervous system (CNS), the clinician is often faced with a daunting diagnostic and therapeutic challenge. The clinical presentation can vary from an insidious course that allows time for a full diagnostic examination to fulminant catastrophic events that require immediate therapeutic intervention. Fortunately, a thorough clinical evaluation combined with current laboratory and imaging techniques often allows for a prompt provisional diagnosis of infection. Clinical experience and scientific investigation have laid the basis for rational empiric antimicrobial therapy of CNS infection. The role of antibiotics in the treatment of CNS infections is reviewed and updated, emphasizing current rationale for empiric therapy as well as the proper use of specific antibiotics for specific pathogens.

The effectiveness and safety of mupirocin calcium ointment applied to the anterior part of the nares for 5 days in the eradication of nasal carriage of Staphylococcus aureus was investigated in a placebo-controlled, double-blind study. Subjects were healthy medical center staff who had two positive cultures of the anterior nares for S aureus. Antimicrobial susceptibility, phage typing, and restriction endonuclease analysis of plasmid DNA were used to monitor the identity of relapsing and persisting strains. Mupirocin eliminated 74% of S aureus at early follow-up and 91% of original strains. At 4 weeks, 78% of the original strains were eradicated, whereas all of the placebo group remained colonized. Recolonization with mupirocin-resistant strains occurred in six patients, but these were of different phage and plasmid types from the original isolates. None of the subjects had serious adverse effects. Applied intranasally for 5 days, a calcium preparation of mupirocin in a paraffin base is effective in eliminating S aureus nasal carriage and is well tolerated.

Mouse macrophages and J774 macrophage-like cells express probenecid-inhibitable organic anion transporters that remove anionic dyes from the cells' cytoplasmic matrix and secrete these dyes into the extracellular medium. The present studies show that these transporters also secrete antibiotics from J774 macrophages. Penicillin G permeates J774 cells poorly, but after it was introduced into the cell cytoplasm, it was secreted in a probenecid-inhibitable fashion. The quinolone norfloxacin enters macrophages readily. Probenecid retarded the secretion of intracellular norfloxacin by J774 cells and enhanced norfloxacin accumulation three- to fourfold. Thus the intracellular accumulation of norfloxacin is regulated in part by organic anion transporters that secrete norfloxacin (and penicillin G) from J774 cells. This transport process may have clinical significance, as fluoroquinolones inhibit growth of intracellular pathogens such as mycobacteria and Brucella organisms in vitro but fail to arrest infections with these organisms in vivo.

The objectives of this United States Consensus Panel meeting were to evaluate the effectiveness of current surveillance systems for the detection of bacterial resistance as well as to formulate recommendations that can assist hospitals in determining actions that should be taken when a resistance problem is detected. These recommendations may be particularly helpful in controlling the emergence and spread of type-I beta-lactamase resistance. Numerous case reports of antimicrobial resistance among Enterobacter species, Pseudomonas aeruginosa, and other Gram-negative nosocomial pathogens known to produce type-I beta-lactamases have appeared in the literature since the introduction of the newer "third-generation" cephalosporins. The widespread use of these newer antimicrobial agents, often selected as standard therapy for serious hospital-acquired infections, has been associated with a corresponding increase in resistance to them. The failure of hospitalwide surveillance methods to describe the scope of this problem, especially among the most critically ill patients, may have resulted in a false sense of security among some infectious disease specialists and clinicians prescribing these antimicrobials as empiric therapy. High-level resistance in individual hospital units may be masked in hospitalwide antibiograms. A variety of conclusions and recommendations were formulated based on the collective experiences of the Consensus Panel members. Microbiology laboratories must make it a high priority to identify markers that will assist in rapidly identifying resistant organisms. Cooperative efforts are needed among users of commercial and automated microbiology test instruments to standardize results and to improve quality control, thereby making the data more directly comparable between laboratories.(ABSTRACT TRUNCATED AT 250 WORDS)

This chapter reviews the chemistry, microbiology, pharmacology, and clinical use of the fluoroquinolone antimicrobial agents. The molecular and clinical problems of bacterial resistance are reviewed. The clinical areas in which fluoroquinolones have been investigated are detailed, with particular attention to areas of appropriate and inappropriate use.