Adult male Crl:CD1 (ICR) mice were fed chow containing Candida albicans to induce sustained gastrointestinal colonization by the yeast. Groups of mice were rendered neutropenic with cyclophosphamide and subsequently received ceftriaxone, while other groups received normal saline and served as controls. Stool cultures were obtained immediately before and at the end of treatment. The administration of cyclophosphamide substantially increased the C. albicans counts in the stools of mice. The addition of ceftriaxone to the cyclophosphamide regimen did not significantly increase the level of gastrointestinal colonization by C. albicans. There was no evidence of Candida dissemination to internal organs.

Slime-producing staphylococci frequently colonize catheters, and when they are embedded in biofilm, they become resistant to various antibiotics. In the study that is described, the comparative efficacies of vancomycin, clindamycin, novobiocin, and minocycline, alone or in combination with rifampin, were tested in an in vitro model of colonization. The model consisted of the modified Robbins device with antibiotic-impregnated cement filling the lumen of catheter segments. The synergistic combination of minocycline and rifampin was the most efficacious in preventing bacterial colonization of slime-producing strains of Staphylococcus epidermidis and Staphylococcus aureus to catheter surfaces. A similar trend was observed when the inhibitory activities of polyurethane catheters coated with minocycline and rifampin were compared with the inhibitory activities of catheters coated with other antimicrobial agents. The inhibitory activities of catheters coated with minocycline and rifampin against S. epidermidis, S. aureus, and Enterococcus faecalis strains, for example, were significantly better than those of catheters coated with vancomycin (P < 0.05). The inhibitory activities of catheters coated with minocycline and rifampin against gram-negative bacilli and Candida albicans were comparable to those of catheters coated with ceftazidime and amphotericin B, respectively. We found that the combination of minocycline and rifampin is unique and highly effective in preventing the colonization of catheters with slime-producing staphylococci and that it also displays a broad-spectrum inhibitory activity against gram-negative bacteria and yeast cells.

The antibacterial activity of levofloxacin was compared with those of ofloxacin and ciprofloxacin against bacterial isolates from patients with cancer. In general, levofloxacin was as active or was twofold more active than ofloxacin and was two- to fourfold less active than ciprofloxacin against most gram-negative pathogens. Against Pseudomonas aeruginosa, ciprofloxacin was the most active agent tested (MIC for 90% of isolates tested, 1.0 microgram/ml). Overall, all three agents had similar activities against gram-positive organisms and were moderately active against methicillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci, Streptococcus species, and Enterococcus species.

Three-month-old, male, Crl:CD1 (ICR) BR mice were fed chow containing Candida albicans or regular chow. Subsequently, both groups were given either antibiotics or normal saline for 10 days. Stool cultures were performed immediately before administration, at the end of antibiotic administration, and 1 week after the discontinuation of antibiotics, to determine the effect on the concentration of C. albicans in the stools. The stools of mice fed C. albicans and given antibiotics had substantially higher Candida counts than those of control mice fed C. albicans and given saline. Significantly higher candidal concentrations were observed in the stools of mice given chloramphenicol compared with those of mice given ciprofloxacin, sulfamethoxazole-trimethoprim, and ampicillin. No mice developed histopathological evidence of local gastrointestinal invasion or disseminated candidiasis. In this mouse model, Candida colonization increases substantially after the administration of antimicrobial agents with broad spectra and anaerobic activities.

The in vitro antimicrobial susceptibilities of 42 isolates of rapidly growing mycobacteria (Mycobacterium fortuitum, M. chelonae, and Mycobacterium species [other than M. fortuitum and M. chelonae]) to nine quinolones, including newer agents, two new aminoglycosides, and an aminocyclitol (trospectomycin) were determined by a broth microdilution method. The new quinolones, PD 117596, PD 127391, and PD 117558, showed excellent in vitro activities against M. fortuitum (MICs for 90% of isolates [MIC90s], 0.06, 0.06, and 0.12 microgram/ml, respectively). The MIC90 of ciprofloxacin for M. fortuitum was 0.5 microgram/ml. Only 14 to 28% of isolates of M. chelonae were susceptible to various quinolones. Most isolates of all three species were susceptible to the new aminoglycosides SCH 21420 and SCH 22591. The MIC90s of trospectomycin were 8 micrograms/ml for M. chelonae, 32 micrograms/ml for Mycobacterium species, and > 64 micrograms/ml for M. fortuitum.

We evaluated the in vitro activities of 21 different antimicrobial agents against nine clinical isolates of Flavimonas oryzihabitans obtained from patients with cancer. The organisms were susceptible to most agents commonly used for the empiric therapy (aminoglycosides, ureidopenicillins, extended-spectrum cephalosporins, monobactams, and carbapenems) and prevention of infections (quinolones and trimethoprim-sulfamethoxazole) in this patient population.

The efficacies of cilofungin (Ly121019), a semisynthetic lipopeptide antifungal agent, and amphotericin B in the treatment of disseminated candidiasis in normal and neutropenic mice were compared. In mice infected with 2 x 10(6) CFU of Candida albicans, treatment with cilofungin in twice-daily doses of 25 or 35 mg/kg of body weight by intraperitoneal injection for 10 days gave survival rates of 83 and 90%. In contrast, there was 97% mortality in infected controls receiving 2 x 10(6) CFU intravenously and 93% survival in mice treated with 1 mg of amphotericin B per kg once a day. Mice rendered granulocytopenic by the administration of cyclophosphamide showed survival rates of 83 and 80% when treated with 25 or 35 mg of cilofungin per kg for 10 days compared with 43% survival rate in mice treated with 1 mg of amphotericin B per kg (P = 0.0030 and P = 0.0080, respectively). Similar results were obtained when the two antifungal agents were administered for a period of 30 days. Administration of 25 or 35 mg of cilofungin per kg twice a day to granulocytopenic mice receiving 10(6) CFU of C. albicans gave survival rates of 93% and 93% compared with 53% survival with amphotericin B. With 15 mg of cilofungin per kg twice a day for 10 days, a survival rate of 43 to 50% was observed in both normal and granulocytopenic mice compared with 56 and 60%, respectively, when this dosage was continued for 30 days. Cilofungin eradicated C. albicans from the kidneys, spleens, and livers of surviving animals. No toxic effects were observed with any of the dosage regimens used. The clearance of C. albicans from the kidneys, spleens, livers, and brains in normal mice was studied following infection with 5 x 10(5) and 1 x 10(5) intravenously. The mice in the treatment groups received 25 mg of cilofungin per kg twice a day for 10 days. In 8 to 12 days, this treatment was able to clear the organisms from the kidneys, spleens, and livers of mice infected with 5 x 10(5) C. albicans. Mice infected with 10(5) C. albicans and treated with cilofungin (25 mg/kg) twice a day for 10 days had no organisms in the kidney, spleen, and liver at days 8, 2, and 8, respectively. There was 1-log-unit reduction in C. albicans counts in brain tissue from mice of one of the treated groups between 2 h and 2 days postinfection, after which the numbers of organisms remained the same until day 12. These data demonstrate the efficacy of cilofungin in the treatment of disseminated C. albicans infections in normal and granulocytopenic mice. The treatment regimen used in this study was able to clear C. albicans from the kidneys, spleen, and liver but not from brain tissue.

This study evaluated the effects of broad-spectrum antibiotics on the gastrointestinal (G.I.) yeast flora of humans and correlated the findings with those obtained from a mouse model of G.I. colonization by Candida albicans. We prospectively studied 46 adult cancer patients who received one of five broad-spectrum antibiotics (ceftriaxone, ceftazidime, ticarcillin-clavulanic acid, imipenem-cilastatin, and aztreonam) as therapy for infections. Quantitative examination of yeast colonization of stools was conducted at the baseline, at the end of antibiotic treatment, and 1 week after discontinuation of therapy. Antibiotics with anaerobic activity (ticarcillin-clavulanic acid) or high G.I. concentrations (ceftriaxone) caused a higher and more sustained increase in G.I. colonization by yeasts than did antibiotics with poor anaerobic activity (ceftazidime and aztreonam) or a low G.I. concentration (imipenem-cilastatin). These results were similar to those obtained with a mouse model of G.I. colonization by C. albicans that involved the same antibiotics. Hence, the mouse model may be useful for evaluation of yeast colonization of the human G.I. tract.

The in vitro activity of Ro 23-9424 against bacterial isolates from patients with cancer was compared with those of fleroxacin, ciprofloxacin, cefoperazone, and ceftazidime. Ro 23-9424 inhibited the majority of the members of the family Enterobacteriaceae and all Aeromonas isolates at a concentration of less than or equal to 1.0 micrograms/ml. It was also active against Acinetobacter spp. and Haemophilus influenzae, including beta-lactamase-producing strains. The MIC for 90% of isolates (MIC90) of Pseudomonas aeruginosa was 16.0 micrograms/ml. All group A and B streptococci were inhibited by less than or equal to 0.25 micrograms/ml, and 90% of group G streptococci and Streptococcus pneumoniae were inhibited by 1.0 micrograms/ml. All methicillin-susceptible strains of Staphylococcus aureus and 60% of methicillin-resistant strains were susceptible to 2.0 micrograms of Ro 23-9424 per ml, whereas the MIC90 for Staphylococcus epidermidis and Staphylococcus hominis isolates was 4.0 micrograms/ml. Staphylococcus haemolyticus and Enterococcus spp. were less susceptible; MIC90s for them were 16.0 and 32.0 micrograms/ml. Ro 23-9424 has a broad antibacterial spectrum and potential utility for therapy of infections in cancer patients.

In vitro antifungal susceptibility testing generally remains unstandardized and unreliable for directing therapy. When azoles are tested, this problem is further compounded by the lack of definite reading end points. We determined the in vitro susceptibility of 50 Candida albicans isolates (including 10 reference strains) to fluconazole by using a microbroth dilution method in which microtiter plates were agitated immediately before reading. Six fungal inoculum sizes (ranging from 2 x 10(2) to 4 x 10(5) CFU/ml), three different times of reading (24, 48, and 72 h), and two temperatures (30 and 35 degrees C) were tested. We also compared visual and spectrophotometric determinations of MIC end points. This agitation method resulted in clear-cut visual end points that were reproducible for different observers within the same laboratory, that were independent of inoculum size, temperature of incubation, and time of reading, and that correlated well with the degree of fungal inhibition as determined by spectrophotometry. Median MICs also correlated with usually achievable levels of fluconazole in serum and tissue of humans and experimental animals.

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Male Crl:CD1 (ICR) BR mice, 3 months old, were fed regular chow or chow containing Candida albicans. Subsequently, both groups were treated with either antibiotics or normal saline for 10 days. Stool cultures were obtained to determine the extent of C. albicans colonization immediately before treatment, at the end of treatment, and 1 week after the discontinuation of treatment. Animals in the antibiotic-treated groups had substantially higher Candida counts than control animals fed C. albicans, especially if they received ceftriaxone, cefoperazone, or ticarcillin-clavulanic acid. There was no evidence of Candida dissemination to internal organs.

The in vitro activity of sparfloxacin, a new quinolone, was compared with those of ciprofloxacin and fleroxacin against gram-positive and gram-negative bacteria, greater than 90% of which were isolated from blood culture specimens of cancer patients. Sparfloxacin was extremely active against Acinetobacter species, Aeromonas hydrophila, Citrobacter diversus, Enterobacter species, Escherichia coli, Klebsiella species, Proteus vulgaris, and Serratia marcescens (inhibiting greater than 90% of these isolates at a concentration of 0.5 microgram/ml) and moderately active against Pseudomonas species, other Proteus species, and Citrobacter freundii. Sparfloxacin inhibited greater than 90% of staphylococci (including methicillin-resistant and coagulase-negative strains) at a concentration of 0.12 microgram/ml and greater than 90% of streptococci (including Streptococcus pneumoniae) at a concentration of 1.0 microgram/ml. It was also active against Bacillus cereus, Enterococcus species, and Corynebacterium jeikeium, organisms that have become fairly common in cancer patients.

The susceptibilities of 45 clinical and 3 environmental isolates of Xanthomonas maltophilia to 14 antimicrobial agents was determined by broth microdilution. The newer quinolones PD117596, PD117558, PD127391, A-56620, amifloxacin, and fleroxacin were the most active agents tested, with 70 to 99% of isolates being susceptible to these agents. All isolates were resistant to trospectomycin. The new aminoglycosides SCH24120 and SCH22591 were active against 12 and 1% of isolates, respectively.

The MICs and minimum fungicidal concentrations of amphotericin B, natamycin, miconazole, itraconazole, and flucytosine against 17 isolates of Fusarium solani, 14 isolates of Fusarium moniliforme, 10 isolates of Fusarium oxysporum, and 3 isolates of Fusarium semitectum were determined by a broth microdilution method. Amphotericin B and natamycin were the most active agents tested and failed to show any inoculum size effect. In contrast, miconazole and itraconazole showed poor inhibitory and fungicidal activities, and the inoculum size had a major effect on the results. Flucytosine had no activity against any of the isolates tested.

Thirty-four clinical isolates of the family Enterobacteriaceae from the University of Texas M. D. Anderson Cancer Center appeared resistant to ticarcillin-potassium clavulanate in agar dilution and broth macrodilution tests. Among those isolates producing a single non-class I beta-lactamase, resistance was due to production of high levels of TEM-1, SHV-1, or class IV enzymes. In five Escherichia coli isolates, production of low levels of PSE-1 was responsible for resistance which seemed due to rapid hydrolysis of ticarcillin rather than diminished susceptibility of PSE-1 to inhibition by potassium clavulanate. Comparisons of dilution and disk diffusion tests revealed major discrepancies, with 65% false susceptibility in the disk test. Revision of the interpretive criteria used for disk diffusion tests from less than or equal to 11 to less than or equal to 18 mm for resistance is proposed to resolve these discrepancies until clinical data are obtained which can be used to determine which in vitro test is most predictive of therapeutic outcome. These new criteria would diminish false susceptibility without introducing false resistance.

The in vitro activities of 16 antimicrobial agents against 14 clinical isolates of Citrobacter diversus and 27 isolates of Citrobacter freundii were studied. C. freundii isolates were more resistant, being susceptible only to amikacin, netilmicin, gentamicin, imipenem, ciprofloxacin, and enoxacin. C. diversus isolates were susceptible to many more of the agents tested.

The in vitro activity of paldimycin, a novel antimicrobial agent, was compared with that of vancomycin against 306 gram-positive isolates (representing 12 bacterial species) obtained from patients with cancer. Paldimycin had lower MICs for 90% of isolates than vancomycin did against most isolates tested. Its activity, however, was medium and pH dependent, being greatest in Nutrient broth at a pH of 6.8.

The in vitro activity of S-25930 and S-25932, two new 4-quinolones, against 450 aerobic gram-negative organisms isolated from cancer patients was evaluated and compared with the activity of ciprofloxacin, enoxacin, difloxacin (A-56619), and A-56620. Both agents inhibited most members of the family Enterobacteriaceae at concentrations of less than or equal to 2.0 micrograms/ml, but their activity against Pseudomonas aeruginosa was inferior to that of other quinolones. Although considerably less active than ciprofloxacin and A-56620, S-25930 was frequently two- to eightfold more active than S-25932 and was comparable to difloxacin and enoxacin against most isolates.

Fungal infections in neutropenic cancer patients have increased in frequency and constitute an important cause of morbidity and mortality. Empiric antifungal therapy is often administered to those patients who have failed to respond to antibacterial antibiotics. We conducted a prospective, randomized trial of amphotericin B and ketoconazole for 172 neutropenic cancer patients with presumed or proven fungal infections. Overall, amphotericin B and ketoconazole were equally effective. Amphotericin B may have been more effective than ketoconazole for the treatment of pneumonia. Also, five of eight Candida tropicalis infections treated with amphotericin B responded, whereas all eight infections treated with ketoconazole failed to respond (P = 0.03). Response rates for localized fungal infections were similar with both drugs. Ketoconazole should not be used as empiric antifungal therapy at institutions where there is a high frequency of infections caused by Aspergillus spp. or C. tropicalis because this agent lacks activity in vitro against these species.

The in vitro activity of 18 antimicrobial agents against 40 clinical isolates each of Acinetobacter calcoaceticus subsp. anitratum and Acinetobacter lwoffi was studied. Most of the newer 4-quinolone derivatives were extremely active against these organisms. Newer beta-lactam agents, such as cefpirome, BMY 28142, and BRL 36650, were also extremely active, inhibiting all strains at clinically achievable levels. Most agents were two- to fourfold more active against A. lwoffi.

Imipenem-cilastatin was used to treat 79 febrile episodes in 71 cancer patients, most of whom had neutropenia. The overall response rate was 67%, and 76% of the 45 documented infections responded. The response rates for septicemias and pneumonias were 79 and 62%, respectively. Only 1 of the 17 infections caused by gram-negative bacilli failed to respond to this therapy. The most common side effects were skin rash, nausea, and diarrhea. Eight superinfections were detected during therapy.

BRL 36650 [sodium 6 beta-(D-2-[(4-ethyl-2, 3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-dihydroxyphenyl) acetamido)-6 alpha-formamido-penicillinate] is a new semisynthetic penicillin. It was tested in vitro for activity against 884 organisms cultured from blood specimens of cancer patients. BRL 36650 had broad-spectrum activity against the gram-negative bacilli tested but had no gram-positive activity. The MIC against 90% of the Pseudomonas aeruginosa isolates was 3.12 micrograms/ml. The activity of BRL 36650 was superior to that of piperacillin, comparable or slightly inferior to that of aztreonam and ceftazidime, and lower than that of imipenem and amifloxacin. BRL 36650 should prove useful for the management of gram-negative bacillary infections, including those caused by P. aeruginosa.

BMY-28142 was compared with other broad-spectrum antibiotics against gram-positive cocci and gram-negative bacilli. BMY-28142 was highly active against all gram-negative bacilli and especially against Enterobacter cloacae, Serratia marcescens, and Morganella morganii. Its in vitro activity suggests that BMY-28142 should prove to be useful for the treatment of gram-negative bacillary infections.

Eighteen patients with hematological malignancies received aztreonam in one of two dosing regimens, 1 or 2 g every 8 h for a total of 7 to 9 days. Throat and stool cultures were obtained before and during treatment with aztreonam. Aztreonam had little effect on the predominant throat flora. In contrast, facultatively anaerobic gram-negative bacilli were markedly decreased in stools during the administration of aztreonam. Strict anaerobes in the stool were variably affected by aztreonam.

The pharmacokinetics of aztreonam were studied in 25 adult patients with hematological malignancies. Two groups of nine patients each received aztreonam (1 or 2 g every 8 h) prophylactically, and seven infected patients received a therapeutic regimen of aztreonam (1.5 g every 4 h). The mean peak serum concentration after a 1-g dose of aztreonam (given over 0.5 h on day 1) was 75.5 micrograms/ml; after a 2-g dose it was 177.2 micrograms/ml. The mean peak serum concentration after a 1.5-g dose of aztreonam (given over 2 h on day 1) was 68.5 micrograms/ml. The serum half-life ranged between 1.7 and 2.0 h for all regimens studied. The urinary concentration of the metabolite of aztreonam, SQ 26,992, increased during 1 week of administration of the drug; however, serum levels of the metabolite were barely detectable.