bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro activity and in vivo efficacy of a new series of 9-deoxo-12-deoxy-9,12-epoxyerythromycin A derivatives
Authors: Hardy D J , Swanson R N , Shipkowitz N L , Freiberg L A , Lartey P A , Clement J J
Published: June 2012

Analogs of 9-deoxo-12-deoxy-9,12-epoxyerythromycin A with an epimeric hydroxy, amino, or ketone substitution at the 11 position of the macrolide ring and an amino or epimeric hydroxy substitution at the 4" position of the cladinose sugar were synthesized in an attempt to produce acid-stable derivatives of erythromycin with improved bioavailability and activity against gram-negative bacteria. These modifications produced compounds with in vitro activities which were generally similar to that of erythromycin. In mice, however, selected analogs were more active than was erythromycin against staphylococci, streptococci, Haemophilus influenzae, and Legionella pneumophila. In mice, the 11-keto (A-63881), 11-epiamino (A-69334), 11-epiamino-4"-amino (A-71671), and 11-epiamino-4"-epiamino (A-73020) analogs achieved peak concentrations in serum and lung, serum half-lives, and/or areas under the serum curve which were greater than those of erythromycin. Improved pharmacokinetics, as compared with those of erythromycin, may explain the increased in vivo antibacterial activities of these compounds.
In vitro activities of sparfloxacin, tosufloxacin, ciprofloxacin, and fleroxacin
Authors: Barry A L , Fuchs P C
Published: June 2012

The in vitro activity of sparfloxacin was compared with those of tosufloxacin, ciprofloxacin, and fleroxacin against 730 bacterial isolates representing 49 different species. Sparfloxacin and ciprofloxacin had similar spectra of activity, but sparfloxacin was less active against Pseudomonas aeruginosa and more active against many gram-positive cocci and anaerobic bacteria. Tosufloxacin MICs were generally 8- to 16-fold lower than those for sparfloxacin or ciprofloxacin. All four fluoroquinolones were active against nalidixic acid-susceptible strains of the family Enterobacteriaceae (MIC for 90% of the isolates [MIC90], less than or equal to 0.25 micrograms/ml) but nalidixic acid-resistant strains were less susceptible (MIC90, greater than or equal to 4.0 micrograms/ml). Against Pseudomonas aeruginosa isolates, MIC90s were 1.0 micrograms/ml for tosufloxacin, 2.0 micrograms/ml for ciprofloxacin, and 4.0 micrograms/ml for sparfloxacin. Against Enterococcus faecalis, sparfloxacin and ciprofloxacin MIC90s were 1.0 and 2.0 micrograms/ml, respectively. MIC90s for ciprofloxacin-susceptible Staphylococcus aureus were 0.016 micrograms/ml for tosufloxacin, 0.06 micrograms/ml for sparfloxacin, and 0.5 micrograms/ml for both ciprofloxacin and fleroxacin. With four species of gram-negative bacilli, mutants resistant to two to four times the sparfloxacin MIC occurred spontaneously at frequencies of 10(-7) to 10(-9): single-step high-level resistance was not observed. In vitro-selected sparfloxacin-resistant mutants displayed cross-resistance to other quinolones, as did clinical isolates of ciprofloxacin-resistant S. aureus. Tosufloxacin MICs with broth microdilution methods were four- to eightfold greater than those obtained with agar dilution methods. The two procedures gave comparable results when sparfloxacin or ciprofloxacin was being tested.
In vitro susceptibilities of clinical isolates of cysteine-requiring Escherichia coli to 12 antimicrobial agents
Authors: McIver C J , Tapsall J W
Published: June 2012

The MICs of 12 antimicrobial agents for 42 cysteine-requiring strains of Escherichia coli showed a high concordance when determined on three different media, one of which was supplemented with cysteine. Differences in the MICs of several agents were detected between 18 prototrophic revertants and their parent auxotrophs. A total of 64.7% of the isolates were fully susceptible to all agents, and no particular resistance pattern was evident.
Prophylactic and therapeutic activities of azithromycin in a mouse model of pneumococcal pneumonia
Authors: Azoulay-Dupuis E , Vallée E , Bedos J P , Muffat-Joly M , Pocidalo J J
Published: June 2012

Azithromycin is a new acid-stable 15-membered-ring macrolide that exhibits an extended half-life and excellent tissue distribution, including distribution in the lung. We compared its in vivo activity with that of erythromycin using two models of Streptococcus pneumoniae pneumonia, namely, a model of acute infection in Swiss mice and a model of subacute infection in C57BL/6j mice. Female mice were infected by oral delivery into the trachea of 10(5) CFU of a virulent serotype 3 strain of S. pneumoniae (P 4241). Prophylactic and therapeutic treatments were given orally (p.o.) or subcutaneously (s.c.) by various regimens. In the model of subacute infection, a single dose of azithromycin, 25 mg/kg, given p.o. 7 h before infection protected 92% of the mice, while erythromycin was completely ineffective. In the model of acute infection, a single dose of azithromycin, 50 mg/kg, given s.c. 24 h prior to challenge protected 80% of the mice, whereas only 35% of the mice survived with erythromycin, 50 mg/kg, 1 h before challenge. Therapy, which was studied exclusively in the model of subacute infection, was initiated 48 h postinfection. Two doses of 12.5 mg/kg given p.o. 12 h apart resulted in 80% survival of mice treated with azithromycin versus 7% survival of mice treated with erythromycin. Pulmonary clearance of bacteria was consistent with the survival rates. Two doses (25 mg/kg) of azithromycin given s.c. at 48 and 65 h after infection led to complete clearance of bacteria from the lungs and blood, whereas erythromycin-treated mice remained bacteremic. The pharmacokinetics of azithromycin account for its superior efficacy against S. pneumoniae pneumonia relative to the efficacy of erythromycin.
Application of mathematical model to multiple-dose experimental chemotherapy for fatal murine pneumonia
Authors: Hishikawa T , Kusunoki T , Tsuchiya K , Uzuka Y , Sakamoto T , Nagatake T , Matsumoto K
Published: June 2012

Two beta-lactam antibiotics, cefazolin and cefmenoxime, were administered for 7 days to mice with pneumonia caused by Klebsiella pneumoniae by using dosage regimens that would simulate multiple dosing in usual clinical treatments at dosing intervals of 8 or 12 h. Viable numbers of the bacteria in the lungs were measured at 12- or 24-h intervals. The mathematical model established in a previous single-dose study was applied in this study to explain the time courses of the changes in bacterial count over 7 days. However, because the error in viable count measurements was larger than that in the previous study, the time course of the changes in mean viable count was not regular and the viable count reduction rate changed during multiple dosing, and therefore it was difficult to explain the time course by repeated application of the mathematical model described previously. This study suggests that the changes in pharmacokinetic and pharmacodynamic parameters during multiple dosing need to be considered.
Drug level monitoring in a double-blind multicenter trial: false-positive zidovudine measurements in AIDS clinical trials group protocol 019
Authors: Krogstad D J , Eveland M R , Lim L L , Volberding P A , Sadler B M
Published: June 2012

Twenty-three different laboratories using four different assay methods reported zidovudine (ZDV; azidothymidine) measurements in a double-blind trial of ZDV for asymptomatic human immunodeficiency virus-infected patients (AIDS Clinical Trials Group Protocol 019). The risk of false-positive ZDV measurements was defined with coded specimens containing no ZDV in a quality control testing program. This testing identified six problem laboratories which reported ZDV levels of greater than or equal to 100 ng/ml for specimens with no ZDV; all of these laboratories used high-performance liquid chromatography. These six laboratories reported a disproportionately high fraction of positive assays for subjects randomized to the placebo group (31% for these 6 laboratories versus 4% for the other 17 laboratories; P less than 0.0001). The high number of false-positive ZDV results reported by these six laboratories suggested that many of the positive results that they reported for patient specimens were also false-positive results. This hypothesis was examined by retesting specimens from patients in the placebo group that had been reported as positive by these laboratories. Ninety percent (19 of 21) of these specimens were negative on retesting at the reference laboratory. These results confirm the hypothesis; they demonstrate the need for quality control testing to avoid the misinterpretation of multicenter trials because of incorrect laboratory data.
Effect of beta-lactamase inhibitors on the activities of various beta-lactam agents against anaerobic bacteria
Authors: Wexler H M , Molitoris E , Finegold S M
Published: June 2012

The in vitro activities of several new beta-lactam-beta-lactamase inhibitor combinations (piperacillin plus tazobactam, ceftizoxime and cefonicid with sulbactam and clavulanic acid, and ampicillin plus 8 micrograms of sulbactam per ml) were tested with anaerobic bacteria and compared with known beta-lactam-beta-lactamase inhibitor combinations and other potent antianaerobe agents. All the combinations tested (except for the cefonicid-inhibitor combinations) were active against almost all strains of the Bacteroides fragilis group. This report indicates that beta-lactamase inhibitors may improve the activity of beta-lactam agents with marginal activity against the B. fragilis group.
Cocaine hydrochloride and benzoylecgonine have no in vitro inhibitory effect against Neisseria gonorrhoeae
Authors: Zenilman J M , Reichart C A , Neumann T M , Hook E W
Published: June 2012

We evaluated 72 clinical Neisseria gonorrhoeae isolates for in vitro susceptibility to cocaine hydrochloride and its metabolite benzoylecgonine and to penicillin, tetracycline, erythromycin, ceftriaxone, and ofloxacin. Although there was a wide range of susceptibilities to the antimicrobial agents, cocaine and its major metabolite, benzoylecgonine, had no demonstrable antigonococcal activity. Cocaine use is frequently associated with outbreaks of sexually transmitted disease. We hypothesized that the dramatically decreasing incidence of gonorrhea over the past 15 years may be in part due to pharmacological effects of cocaine. However, since cocaine and its metabolite have no in vitro antigonococcal activity, this hypothesis is unlikely.
Aminoglycoside resistance and aminoglycoside usage: ten years of experience in one hospital
Authors: Gerding D N , Larson T A , Hughes R A , Weiler M , Shanholtzer C , Peterson L R
Published: June 2012

For 10 years the 700-bed Minneapolis Veterans Affairs Medical Center has conducted a policy of carefully controlled aminoglycoside usage and monitoring of resistance of over 25,000 aerobic and facultative gram-negative bacillary isolates to the aminoglycosides. On two occasions during the 1980s, our experience of introducing amikacin at a high level of usage was associated with a significant reduction in resistance to gentamicin and tobramycin among gram-negative bacilli. Rapid reintroduction of gentamicin usage in 1982 after the first amikacin period was associated with a significant and rapid increase in gentamicin and tobramycin resistance. However, in 1986, gentamicin was again reintroduced to this institution at an initially modest level, and the percentage of usage of gentamicin was gradually increased over a 15-month period without a significant change in resistance to gentamicin, tobramycin, or amikacin while maintaining an overall 68% gentamicin usage and 30% amikacin usage. Aminoglycoside usage (measured as patient days) rose steadily from under 2,000 patient days per quarter in 1980 and 1981 to over 3,000 days per quarter in 1985. Since 1985, usage has declined to under 2,500 patient days per quarter in 1990. This usage rise and fall occurred during a steadily declining daily patient census that was 590 in 1980 and 465 in 1989. A move to a new hospital building in June 1988 was associated with an additional significant decline in resistance to all aminoglycosides (P less than 0.05), continuing a trend that was evident for the year preceding the move. Resistance to aminoglycoside antibiotics is now at the lowest level in 10 years at this institution, with only one gram-negative organism, Pseudomonas aeruginosa, that exhibits more than 5% resistance to gentamicin and no gram-negative species that are more than 5% resistant to amikacin and tobramycin.
Effects of intravitreal dexamethasone on concentration of intravitreal vancomycin in experimental methicillin-resistant Staphylococcus epidermidis endophthalmitis
Authors: Smith M A , Sorenson J A , Smith C , Miller M , Borenstein M
Published: June 2012

Intravitreal corticosteroids in the treatment of bacterial endophthalmitis remain controversial. We utilized an experimental rabbit model of methicillin-resistant Staphylococcus epidermidis endophthalmitis (i) to calculate the intravitreal vancomycin concentration in rabbit eyes receiving intravitreal vancomycin alone or in combination with intravitreal dexamethasone and (ii) to determine whether an intravitreal steroid has any effect on intravitreal vancomycin levels. All right eyes were infected and all left eyes were uninfected. The rabbits were divided into two treatment groups: (i) 32 eyes (group I) were injected with intravitreal vancomycin, 1.0 mg (0.1 ml); (ii) 32 additional eyes (group II) were injected with intravitreal dexamethasone, 400 micrograms (0.1 ml), in addition to vancomycin. Measurement of intravitreal vancomycin concentration was performed following sacrifice, utilizing a microbiologic agar diffusion assay. Analyses of intravitreal vancomycin concentrations were performed by using model-independent parameters, with area under the concentration-time curves derived by trapezoidal approximation. The intravitreal vancomycin concentration was significantly lower in both uninfected and infected group II eyes (P less than 0.002). Analysis of intravitreal vancomycin concentration-time relationships was performed by using a nonlinear least-squares regression program; data best fit a one-compartment model. In addition, no vancomycin-dexamethasone interaction could be demonstrated. The reduced level of intravitreal vancomycin in the presence of intravitreal dexamethasone may have important clinical implications.
Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis
Authors: Denning D W , Stevens D A
Published: June 2012

Cilofungin, amphotericin B, and a combination of the two drugs were compared in a model of aspergillosis in immunocompetent mice in three experiments. Cilofungin was equivalent to amphotericin B in preventing death and eradicating cerebral aspergillosis, but it did not sterilize the kidneys. This is the first demonstration of the in vivo activity of cilofungin against any fungus other than Candida albicans. The mortality with combination therapy was higher than those with amphotericin B alone (P = 0.003) and cilofungin alone (P = 0.054), as was weight loss after infection, indicating antagonism between cilofungin and amphotericin B in this model. The mechanisms of action and antagonism remain to be explained.
Activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine compared with that of clarithromycin against multiplication of Mycobacterium avium complex within human macrophages
Authors: Perronne C , Gikas A , Truffot-Pernot C , Grosset J , Vilde J L , Pocidalo J J
Published: June 2012

The activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine against two virulent strains of the Mycobacterium avium complex isolated from patients with AIDS were evaluated in a model of intracellular infection and were compared with that of clarithromycin. Human monocyte-derived macrophages were infected with the M. avium complex at day 6 of culture. The intracellular CFU was counted 60 min after inoculation. The intracellular and supernatant CFU was counted on days 4 and 7 after inoculation. The concentrations used, which were equal to peak levels in serum, were 10 micrograms of rifapentine per ml (MICs for the two strains, 4 and 16 micrograms/ml), 4 micrograms of clarithromycin per ml (MICs, 8 and 4 micrograms/ml), 1 microgram of azithromycin per ml (MICs, 32 and 16 micrograms/ml), 4 micrograms of temafloxacin per ml (MICs, 2 and 16 micrograms/ml), and 1 microgram of sparfloxacin per ml (MICs, 0.5 and 2 micrograms/ml). Compared with controls on day 7 after inoculation, clarithromycin (P less than 0.001), sparfloxacin (P less than 0.001), and azithromycin (P less than 0.001 for the first strain, P less than 0.02 for the second) slowed intracellular replication. Rifapentine (P less than 0.001) and temafloxacin (P less than 0.001) slowed intracellular replication of the first strain but not of the second strain. Azithromycin plus sparfloxacin was as effective as sparfloxacin alone. In this macrophage model, sparfloxacin or clarithromycin (difference not significant) exhibited a better efficacy than rifapentine, azithromycin, or temafloxacin against intracellular M. avium complex infection.
In vitro activity of YM133, a new semisynthesized macrolide
Authors: Terasawa T , Watanabe M , Okubo T , Mitsuhashi S
Published: June 2012

YM133, the 4"-O-(4-methoxyphenyl)acetyltylosin, is a new macrolide. The in vitro activity of YM133 was compared with those of erythromycin, josamycin, and rokitamycin by an agar dilution method. YM133 inhibited 90% of the tested isolates of Streptococcus pneumoniae, Legionella spp., and anaerobic bacteria at less than or equal to 1.56 micrograms/ml. The drug inhibited 90% of erythromycin-resistant staphylococci and Streptococcus pyogenes at less than or equal to 50 micrograms/ml. YM133 showed activity against erythromycin-, josamycin-, and rokitamycin-resistant (MIC greater than or equal to 100 micrograms/ml) strains of staphylococci, streptococci, Bacteroides spp., and Clostridium spp. Enterococci were less susceptible to other YM133-like macrolides. Unlike other macrolides, YM133 showed killing activity, and the MBC/MIC ratios of YM133 for several strains were 1:32, whereas those of erythromycin were 4:1,024. In a time-kill curve study, the reduction of viable cells started within 2 h after the addition of YM133.
Absorption, disposition, and urinary metabolism of 14C-rifabutin in rats
Authors: Battaglia R , Salgarollo G , Zini G , Montesanti L , Strolin Benedetti M
Published: June 2012

14C-rifabutin was given orally (25 mg/kg) and intravenously (i.v.) (10 mg/kg) to female Sprague-Dawley rats. Radioactivity was eliminated by both the renal and fecal routes, amounting to 44.49 and 43.39% of the dose, respectively, in urine and feces at 96 h after the oral dose and to 47.81 and 40.76% of the dose, respectively, in urine and feces after the i.v. dose. Differences between the two routes of administration were negligible. Tissue distribution of radioactivity after the oral dose was investigated by the combustion technique. At 2 h, the highest concentration of radioactivity was observed in the liver, followed by the lung, abdominal adipose tissue, and spleen, whereas at 72 h, the sequence was abdominal adipose tissue, liver, spleen, bone marrow, and lung. Brain levels of radioactivity were very low. The results of whole-body autoradiography after i.v. administration confirmed the above. Whole-body autoradiography of pregnant rats showed higher concentrations of radioactivity in the uterus than in the placenta and trace levels in the fetuses up to 8 h. Radioactivity was absent in the amniotic fluid. The urinary metabolism was studied by radio-high-pressure liquid chromatography. Rifabutin accounted for 7.4 and 7.2% of the dose in 0- to 48-h urine after oral and i.v. administration, respectively. Metabolites 31-OH rifabutin and 25-O-deacetyl rifabutin amounted to 4.3 and 1.6% of the dose, respectively, after oral administration and to 2.6 and 0.7% of the dose, respectively, after i.v. administration. The remaining urinary radioactivity was mainly due to polar compounds.
Single-dose and three-day regimens of ofloxacin versus trimethoprim-sulfamethoxazole for acute cystitis in women
Authors: Hooton T M , Johnson C , Winter C , Kuwamura L , Rogers M E , Roberts P L , Stamm W E
Published: June 2012

We compared the safety and efficacy of a single 400-mg dose of ofloxacin, ofloxacin (200 mg) once daily for 3 days, and trimethoprim-sulfamethoxazole (160:800 mg) twice daily for 7 days for the treatment of acute uncomplicated cystitis (urinary tract infection [UTI]) in women. At 5 weeks posttreatment, 35 (81%) of 43 patients treated with single-dose ofloxacin, 40 (89%) of 45 treated with 3 days of ofloxacin, and 41 (98%) of 42 treated with trimethoprim-sulfamethoxazole were cured (P = 0.03, single-dose ofloxacin group versus trimethoprim-sulfamethoxazole group). Retreatment for symptomatic recurrent UTI was given to 7 (16%) of 43 patients initially treated with single-dose ofloxacin, 3 (7%) of 45 patients treated with 3 days of ofloxacin, and 0 of 42 patients treated with trimethoprim-sulfamethoxazole (P = 0.01, single-dose ofloxacin group versus trimethoprim-sulfamethoxazole group). There was a trend in each of the three treatment groups toward an association between persistent or recurrent episodes of significant bacteriuria and a history of UTI in the past year and with diaphragm use. Ofloxacin was more effective than trimethoprim-sulfamethoxazole in eradicating Escherichia coli from rectal cultures during or soon after therapy, but there were no differences at later follow-up visits. Adverse effects were equally common among the three treatment groups. We conclude that single-dose ofloxacin was less effective than 7 days of trimethoprim-sulfamethoxazole for treatment of uncomplicated cystitis in women, while the 3-day ofloxacin regimen and the trimethoprim-sulfamethoxazole regimen were not significantly different in efficacy.
Effects of enzyme supplementation on oral absorption of ciprofloxacin in patients with cystic fibrosis
Authors: Mack G , Cooper P J , Buchanan N
Published: June 2012

The effect of pancreatic enzyme supplementation on the absorption of an oral dose of 250 mg of ciprofloxacin was studied in six patients with cystic fibrosis in a crossover design. The time to achieve maximum serum concentration was slightly reduced upon coadministration of pancreatic enzymes. There were no significant differences in peak concentration, elimination half-life, and area under the concentration-time curve.
Pharmacokinetics of single-dose intravenous, oral, and intraperitoneal pefloxacin in patients on chronic ambulatory peritoneal dialysis
Authors: Schmit J L , Hary L , Bou P , Renaud H , Westeel P F , Andrejak M , Fournier A
Published: June 2012

Comparison of plasma and dialysate concentrations of pefloxacin after intravenous, oral, or intraperitoneal administration shows excellent bidirectional diffusion of the quinolone through the peritoneal membrane, demonstrating that therapeutical concentrations can be achieved in the dialysate after intravenous or oral administration. In this study, the half-life of the drug was 18.8 +/- 1.4 h, i.e., apparently longer than that reported for normal controls or uremic patients on hemodialysis.
Failure of routine susceptibility tests to detect imipenem resistance among strains of methicillin-resistant Staphylococcus aureus
Authors: Boyce J M , Papa E , Dickenson R , Medeiros A A
Published: June 2012

We tested 75 methicillin-resistant Staphylococcus aureus strains for susceptibility to imipenem by using disk diffusion tests and broth microdilution tests with standard and heavy inocula. Population analysis was performed on isolates that appeared to be susceptible by these methods. All of the strains contained subpopulations of cells that are phenotypically resistant to imipenem.
Susceptibilities of Mycoplasma hominis and Ureaplasma urealyticum to two new quinolones, sparfloxacin and WIN 57273
Authors: Kenny G E , Cartwright F D
Published: June 2012

Mycoplasma hominis was highly susceptible to two new quinolones, with MICs for 90% of isolates tested of 0.004 micrograms/ml for WIN 57273 and 0.063 micrograms/ml for sparfloxacin, which were activities much greater than the 1 microgram/ml found for ofloxacin and tetracycline. Although Ureaplasma urealyticum was less susceptible, the MICs for 90% of isolates tested of 0.25 micrograms/ml for WIN 57273 and 0.5 micrograms/ml for sparfloxacin were four- to eightfold greater than those found for ofloxacin (2 micrograms/ml) and tetracycline (2 micrograms/ml). The finding that U. urealyticum and M. hominis are more susceptible to WIN 57273 and sparfloxacin than they are to other quinolones suggests that these quinolones may be therapeutically useful.
Activity of clarithromycin and its principal human metabolite against Haemophilus influenzae
Authors: Jorgensen J H , Maher L A , Howell A W
Published: June 2012

Clarithromycin is a new macrolide antibiotic which forms a microbiologically active principal in vivo metabolite, 14-OH-clarithromycin. The in vitro activities of clarithromycin and its metabolite were examined separately and in pharmacokinetically relevant fixed combinations of 4:1 and 2:1 against a group of 50 Haemophilus influenzae isolates. Broth microdilution susceptibility tests indicated that clarithromycin was less active than erythromycin against all but highly erythromycin-susceptible strains, while 14-OH-clarithromycin was generally more active than either antibiotic. An enhancement in activity against the majority of strains was demonstrated when clarithromycin and its metabolite were tested in combination.
Persistence mechanisms in Pseudomonas aeruginosa from cystic fibrosis patients undergoing ciprofloxacin therapy
Authors: Diver J M , Schollaardt T , Rabin H R , Thorson C , Bryan L E
Published: June 2012

The mechanisms of persistence to ciprofloxacin in nine sets of Pseudomonas aeruginosa strains isolated during ciprofloxacin therapy of chronic lung infections in cystic fibrosis patients were studied. Low to moderate levels of ciprofloxacin resistance developed in each case. Each set of pretherapy ciprofloxacin-susceptible, during-therapy ciprofloxacin-resistant, and posttherapy ciprofloxacin-susceptible isolates were shown to be genotypically related by using a radiolabeled epidemiological gene probe. All ciprofloxacin-resistant isolates were found to have altered susceptibilities to both nalidixic acid and various chemically unrelated antibiotics. Analysis of possible resistance mechanisms showed that the strains had altered outer membrane protein or lipopolysaccharide profiles. Complementation of possible DNA gyrase mutations with a plasmid-borne, wild-type Escherichia coli gyrA gene indicated that altered DNA gyrase was at least partly responsible for ciprofloxacin resistance in all strains tested. Attempts to generate ciprofloxacin-susceptible revertants in vitro showed that in some strains reversion was rapid in the absence of ciprofloxacin, while in other strains it was not possible to generate revertants. These data indicate that persistence of Pseudomonas aeruginosa to ciprofloxacin involves changes in DNA gyrase and is associated with pleiotropic changes in outer membrane proteins and lipopolysaccharide.
Development of resistance to fleroxacin during therapy of experimental methicillin-susceptible Staphylococcus aureus endocarditis
Authors: Kaatz G W , Seo S M , Barriere S L , Albrecht L M , Rybak M J
Published: June 2012

The efficacy of fleroxacin was compared with that of vancomycin by using the rabbit model of methicillin-susceptible Staphylococcus aureus endocarditis. Animals received intravenous therapy with fleroxacin, 30 mg/kg every 8 h, or vancomycin, 17.5 mg/kg every 6 h, for 4 days. Both antimicrobial agents effectively cleared bacteremia and significantly reduced bacterial counts in vegetations and tissues compared with those in untreated controls. However, resistance to fleroxacin at 5- and 10-fold the MIC arose in the test strain of S. aureus in 73 and 27%, respectively, of animals that received the drug. Resistant isolates were found mainly in vegetations and were composed of up to 7% of the residual population recovered from that site. We conclude that fleroxacin is as effective as vancomycin in this model of a serious systemic S. aureus infection, but resistance to the drug may develop during therapy. If similar results are found with other strains of S. aureus during therapy with this or other fluoroquinolones, such data, when they are combined with the high incidence of fluoroquinolone resistance among S. aureus isolates being reported from selected institutions, would support the contention that these drugs should not be used as first-line therapeutic agents for S. aureus infections.
Nucleotide sequence and phylogeny of a chloramphenicol acetyltransferase encoded by the plasmid pSCS7 from Staphylococcus aureus
Authors: Schwarz S , Cardoso M
Published: June 2012

The nucleotide sequence of the chloramphenicol acetyltransferase gene (cat) and its regulatory region, encoded by the plasmid pSCS7 from Staphylococcus aureus, was determined. The structural cat gene encoded a protein of 209 amino acids, which represented one monomer of the enzyme chloramphenicol acetyltransferase (CAT). Comparisons between the amino acid sequences of the pSCS7-encoded CAT from S. aureus and the previously sequenced CAT variants from S. aureus, Staphylococcus intermedius, Staphylococcus haemolyticus, Bacillus pumilis, Clostridium difficile, Clostridium perfringens, Escherichia coli, Shigella flexneri, and Proteus mirabilis were performed. An alignment of CAT amino acid sequences demonstrated the presence of 34 conserved amino acids among all CAT variants. These conserved residues were considered for their possible roles in the structure and function of CAT. On the basis of the alignment, a phylogenetic tree was constructed. It demonstrated relatively large evolutionary distances between the CAT variants of enteric bacteria, Clostridium, Bacillus, and Staphylococcus species.
Influence of low-level resistance to vancomycin on efficacy of teicoplanin and vancomycin for treatment of experimental endocarditis due to Enterococcus faecium
Authors: Fantin B , Leclercq R , Arthur M , Duval J , Carbon C
Published: June 2012

Emergence of vancomycin-resistant strains among enterococci raises a new clinical challenge. Rabbits with aortic endocarditis were infected with Enterococcus faecium BM4172, a clinical strain resistant to low levels of vancomycin (MIC, 16 micrograms/ml) and susceptible to teicoplanin (MIC, 1 micrograms/ml), and against its susceptible variant E. faecium BM4172S obtained in vitro by insertional mutagenesis (MICs, 2 and 0.5 micrograms/ml, respectively). Control animals retained 8 to 10.5 log10 CFU/g of vegetation. We evaluated in this model the efficacy of vancomycin (30 mg/kg of body weight; mean peak and trough serum levels, 27 and 5 micrograms/ml, respectively), teicoplanin (standard dose, 10 mg/kg; mean peak and trough levels, 23 and 9 micrograms/ml, respectively; and high dose, 20 mg/kg; mean peak and trough levels, 63 and 25 micrograms/ml, respectively), gentamicin (6 mg/kg; mean peak and trough levels, 8.6 and less than 0.1 micrograms/ml, respectively), alone or in combination, given every 12 h intramuscularly for 5 days. Teicoplanin standard dose was as active as vancomycin against both strains. Vancomycin was not effective against E. faecium BM4172 but was highly effective against E. faecium BM4172S (7.5 +/- 1.1 log10 CFU/g of vegetation versus 4.9 +/- 1.0 log10 CFU/g of vegetation for vancomycin against E. faecium BM4172 and E. faecium BM4172S, respectively; P = 0.0012). A high dose of teicoplanin was more effective than vancomycin against E. faecium BM4172 (4.4 +/- 1.8 log10 CFU/g of vegetation versus 7.5 +/- 1.1 log10 CFU/g of vegetation for teicoplanin high dose and vancomycin, respectively; P less than 0.05). Against E. faecium BM4172 glycopeptide-gentamicin combinations were the most effective regimens in vitro and in vivo (2.8 +/- 0.7 and 3.5 +/- 1.3 log10 CFU/g of vegetation for vancomycin plus gentamicin and teicoplanin standard dose plus gentamicin, respectively; P < 0.05 versus single-drug regimens). We concluded that high-dose teicoplanin or the combination of a glycopeptide antibiotic plus gentamicin was effective against experimental infection due to E. faecium with low-level resistance to vancomycin.
Removal of imipenem and cilastatin by hemodialysis in patients with end-stage renal failure
Authors: Konishi K , Suzuki H , Saruta T , Hayashi M , Deguchi N , Tazaki H , Hisaka A
Published: June 2012

The removal of imipenem and cilastatin by hemodialysis was studied in 14 (for imipenem) and 6 (for cilastatin) subjects. Following intravenous infusion of imipenem and cilastatin at a combined concentration of 10 mg/kg of body weight, drug levels in plasma were determined serially during off- and on-hemodialysis periods, which were 2 and 4 h, respectively. The biexponential decay of the drug levels in plasma was evident in each subject for both imipenem and cilastatin. Hemodialysis accelerated the elimination of both imipenem and cilastatin: the mean elimination-phase half-life of imipenem was shortened from 200 to 78 min, and that of cilastatin was shortened from 445 to 115 min. Hemodialysis clearance of imipenem and cilastatin was calculated by five different methods, each with intrinsic assumptions. The mean hemodialysis clearance of imipenem was estimated to be 74.08 +/- 13.29 ml/min, and that of cilastatin was estimated to be 65.0 +/- 8.6 ml/min, after consideration of various methodological limitations. It was estimated that in a hypothetical anephric patient weighing 60 kg, a 4-h hemodialysis treatment would remove 54.8% of the imipenem and 62.9% of the cilastatin present in the body at the start of dialysis.
Effects of antimicrobial agents on survival of Mycobacterium avium complex inside alveolar macrophages obtained from patients with human immunodeficiency virus infection
Authors: Yajko D M , Nassos P S , Sanders C A , Hadley W K
Published: June 2012

Measurements of the activities of antimicrobial agents against the Mycobacterium avium complex (MAC) usually do not take into consideration the intracellular location of the organism. A recent study using mouse macrophage continuous cell line J774 (D. M. Yajko, P.S. Nassos, C. A. Sanders, and W. K. Hadley, Am. Rev. Respir. Dis. 140: 1198-1203, 1989) showed that certain combinations of antimicrobial agents are able to kill MAC inside macrophages and suggested that the J774 cell line could be used as a model for screening of drugs for intracellular activity against MAC. As a test of the validity of this model, alveolar macrophages were isolated from the bronchoalveolar lavages of 36 patients who had AIDS or an AIDS-related condition or were considered to be at risk for AIDS. The macrophages were infected with MAC and then treated with a drug or drug combination for 48 to 72 h. Survival of MAC was measured over time in drug-treated macrophages and untreated control macrophages. No single drug or two-drug combination that was tested was able to cause a decrease in the survival of every one of the MAC strains used in the study. However, several three-drug combinations that had been shown to cause a decrease in survival of all MAC strains inside J774 cells also caused a decrease in survival of all MAC strains inside alveolar macrophages from patients. The good agreement between these results and those obtained previously with J774 cells gives further evidence of the usefulness of the simpler J774 model for screening of drugs for intracellular activity against MAC.
Treatment of acute pelvic inflammatory disease in the ambulatory setting: trial of cefoxitin and doxycycline versus ampicillin-sulbactam
Authors: Kosseim M , Ronald A , Plummer F A , D'Costa L , Brunham R C
Published: June 2012

Ampicillin-sulbactam (750 mg) given orally twice daily for 10 days was evaluated for the treatment of acute pelvic inflammatory disease (PID) in an ambulatory setting in Nairobi, Kenya. The first 26 women received ampicillin-sulbactam in an open-label fashion, and the remaining 75 women were randomly selected to receive either ampicillin-sulbactam (n = 38) or cefoxitin (2 g) intramuscularly and probenecid (1 g) orally, followed by doxycycline (100 mg) orally twice daily for 10 days (n = 37). Women were enrolled in a sexually transmitted disease clinic and were followed for clinical and microbiologic responses at 1 to 2 weeks and 4 to 6 weeks posttreatment. Women had a later follow-up visit to note interim pregnancy or underwent hysterosalpingography for fertility outcome assessment. The short-term clinical response rates were 70% for ampicillin-sulbactam and 72% for cefoxitin-doxycycline (P = 0.47). Among Chlamydia trachomatis-infected women treated with ampicillin-sulbactam, three had microbiologic relapse. The post-PID tubal obstruction rates were similar in the two groups: 18% for ampicillin-sulbactam and 33% for cefoxitin-doxycycline (P = 0.31). Neither regimen was highly effective as a therapy for acute PID. These data strongly argue that primary prevention must be the goal for a reduction of PID morbidity and show that improved therapy for the treatment of PID in the ambulatory setting is needed.
Nucleotide sequences specific for Tn1545-like conjugative transposons in pneumococci and staphylococci resistant to tetracycline
Authors: Poyart-Salmeron C , Trieu-Cuot P , Carlier C , Courvalin P
Published: June 2012

The distributions of tet(M) and conjugative transposons related to Tn1545 were studied by hybridization in 47 clinical isolates of Streptococcus pneumoniae resistant to tetracycline. Resistance to tetracycline was always associated with resistance to minocycline and was due to the presence of the tet(M) gene. Association of tet(M) with int-Tn, the gene encoding the protein required for the movements of Tn1545-like transposons, was found in all but one strain of S. pneumoniae. In contrast, int-Tn was detected in only 2 of 37 strains of Staphylococcus spp. harboring tet(M).
Use of low-dose trimethoprim-sulfamethoxazole thrice weekly for primary and secondary prophylaxis of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients
Authors: Stein D S , Stevens R C , Terry D , Laizure S C , Palte S , Lancaster D J , Weems J J , Williams C L
Published: June 2012

We conducted an open prospective clinical trial to evaluate the efficacy and toxicity of trimethoprim-sulfamethoxazole given as one double-strength tablet thrice weekly for primary and secondary prophylaxis of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus-infected (HIV+) patients. A total of 104 HIV+ patients were evaluated, with 74 being in the primary prophylaxis group and 30 being in the secondary prophylaxis group. All except six patients received concomitant zidovudine; five patients on primary prophylaxis and one patient on secondary prophylaxis refused zidovudine. There were 70 patients evaluated for the efficacy of primary prophylaxis. The mean CD4 count was 124.4 +/- 110.1 cells per microliter. The mean follow-up time was 11.8 +/- 5.8 months (median, 12 months; range, 1 to 32 months). Two noncompliant patients developed PCP after 1 and 3 months of chemoprophylaxis. The failure rate (under the intention to treat principle) was 2 of 70 patients (2.9%; 95% confidence interval, 0.35 to 10%), or 1 per 413 patient-months of observation. There were 27 patients evaluated for the efficacy of secondary prophylaxis. The mean follow-up time was 12.4 +/- 7.2 months (median, 11 months; range, 1 to 29 months). Two patients, one of whom was noncompliant, were treatment failures, developing PCP after 14 and 15 months of chemoprophylaxis; this gave a failure rate of 2 of 27 patients (7.4%; 95% confidence interval, 0.9 to 24.3%), or 1 per 167 patient-months of observation. Adverse reactions sufficient to permanently terminate therapy occurred in 9 of 104 patients (8.7%; 95% confidence interval, 4 to 15.7%) overall. The serum trimethoprim, sulfamethoxazole, and N4-acetyl-sulfamethoxazole concentrations measured by high-pressure liquid chromatography were uniformly low. One double-strength tablet of trimethoprim-sulfamethoxazole taken weekly on Monday, Wednesday, and Friday appeared to be well tolerated and efficacious for the prophylaxis of PCP in HIV+ patients at high risk and deserves further investigation.
Pharmacokinetic analysis of the effects of different foods on absorption of cefaclor
Authors: Oguma T , Yamada H , Sawaki M , Narita N
Published: June 2012

Cefaclor is an oral cephalosporin antibiotic which has a broad antibacterial spectrum. The purpose of this study was to investigate the effect of food on the absorption of cefaclor and to analyze kinetically the absorption process of this drug. Cefaclor was given to eight volunteers at five test times: after overnight fasting, after two rice meals (350 and 700 cal [1 cal = 4.184 J]), and after two bread meals (500 and 1,000 cal). Urinary recoveries of cefaclor and concentrations of the drug in plasma were determined for each administration. Areas under the concentration-time curves and urinary recoveries were not affected by food intake, but the maximum concentration of drug in serum was reduced and the time to maximum concentration of drug in serum was prolonged depending on the type and the quantity of the meal. The larger the quantity of the meal, the more the maximum concentration of drug in serum and the time to maximum concentration of drug in serum were affected. The rice meals affected the absorption process of cefaclor more than the bread meals. The concentrations of cefaclor in plasma following administration after overnight fasting were well fitted to a conventional one-compartment model with a first-order absorption process, but those after the other administrations were not fitted to the model. For the pharmacokinetic analysis of those data, it was necessary to introduce a transfer process from administration site to absorption site to the conventional model. The concentrations in plasma after rice and bread meals were best fitted to the model with a zero-order transfer process than to that with a first-order process. The velocity of the transfer process depended on the type and volume of the meal.
Pharmacokinetics of amikacin and chloramphenicol in the aqueous humor of rabbits
Authors: Mayers M , Rush D , Madu A , Motyl M , Miller M H
Published: June 2012

Composite data describing ocular pharmacokinetics are unreliable because of intersubject variation. To address this problem, an animal model was developed in which multiple aqueous samples from single subjects were obtained. Following direct anterior chamber or intravenous administration of amikacin or chloramphenicol, pharmacokinetic analysis of drug concentrations in the serum and anterior chamber was performed by using a nonlinear least-squares regression program. The number of anterior chamber paracenteses performed did not alter the beta elimination rates or percent penetration into the anterior chamber. The aqueous humor and peripheral-compartment terminal slopes were identical. These data indicate that complete ocular concentration-time curves can be obtained without altering antibiotic pharmacokinetics. Following direct injection into the anterior chamber, the elimination rates for both antibiotics followed a one-compartment model, whereas those following intravenous administration best fit an open, first-order, two-compartment model. Following intravenous administration, the anterior chamber elimination rate constants for both drugs were equal to that of the serum and significantly longer than that following direct injection. The elimination rates of both drugs following direct injection were similar. Systemic administration resulted in drug levels in aqueous humor that persisted longer than those following direct injection. Chloramphenicol, a lipophilic compound, gave higher mean concentrations in aqueous humor than did amikacin. Our model provides a new approach which rigorously examines ocular pharmacokinetics and provides data which suggest that for selected compounds the parenteral route of administration is preferable.
Comparative efficacy of amphotericin B colloidal dispersion and amphotericin B deoxycholate suspension in treatment of murine coccidioidomycosis
Authors: Clemons K V , Stevens D A
Published: June 2012

The efficacy of a novel sterol-complexed preparation of amphotericin B, amphotericin B colloidal dispersion, was compared with that of deoxycholate-complexed amphotericin B in an acute murine model of systemic coccidioidomycosis. Mice (CD-1, female) were infected intravenously with 180 or 200 arthroconidia of Coccidioides immitis, and intravenous therapy was begun 3 days later. Six doses in various regimens of either preparation were given over 14 days, and deaths were tallied for an additional 35 days. All regimens that were not acutely lethal prolonged the survival of mice over that of controls (P less than 0.001). Quantitative determination of residual burdens of C. immitis in the spleen, liver, and lungs of survivors revealed that the colloidal dispersion was not as effective as the deoxycholate suspension on a milligram-per-kilogram basis. Deoxycholate suspension at 1.3 mg/kg cleared the organs in all mice, whereas colloidal dispersion at 5.0 mg/kg was the lowest dose that cleared organisms from all animals. Lower doses cleared organisms from fewer animals or cleared only selected organs. Deoxycholate suspension was more efficacious than colloidal dispersion in clearing C. immitis from the liver or lungs (P less than 0.05 to 0.01, dose and organ dependent) at identical doses. No overt toxicity was observed in mice treated with colloidal dispersion at 10 mg/kg. In contrast, deoxycholate suspension at 2.0 mg/kg was acutely toxic; 50% of the treated mice died after treatment. The two complexes were not equivalent on a milligram-per-kilogram basis; the deoxycholate suspension was three to four times more efficacious and also greater than 5- to greater than or equal to 8-fold more toxic. Thus, the therapeutic index of the colloidal dispersion complex is greater than that of the deoxycholate complex. The amount of amphotericin B per dose could also be increased when given as a colloidal dispersion to an optimally level. Amphotericin B colloidal dispersion shows promise for the therapy of disseminated coccidioidomycosis and should be tested in other animal models and in humans.
In vitro activity of the new difluorinated quinolone sparfloxacin (AT-4140) against Mycobacterium tuberculosis compared with activities of ofloxacin and ciprofloxacin
Authors: Rastogi N , Goh K S
Published: June 2012

MICs of the new fluoroquinolone drugs ofloxacin, ciprofloxacin, and sparfloxacin (AT-4140) for 10 strains of Mycobacterium tuberculosis were determined by using both a BACTEC radiometric method and testing on solid 7H11 agar medium. Radiometric MICs by 7H12 broth testing ranged from 0.5 to 1.0, 0.25 to 0.5, and 0.1 to 0.2 microgram/ml for ofloxacin, ciprofloxacin, and sparfloxacin respectively, whereas MICs in solid medium ranged from 0.5 to 1.0, 0.5 to 1.0, and 0.2 to 0.5 microgram/ml, respectively. The bactericidal action of the quinolones compared with their reported peak concentrations in human serum showed that sparfloxacin is the most bactericidal, followed by ciprofloxacin and ofloxacin. Our results suggest the potential of the new difluorinated quinolone sparfloxacin for use against the tubercle bacillus and indicate that further determination of its antimycobacterial spectrum and intracellular efficacy may be fruitful.