G. Petrikkos

Pharmacokinetics of three newer quinolones in pregnant and lactating women

Sixty pregnant women with fetuses affected by beta-thalassemia major underwent termination of gestation induced by amniocentesis and intrauterine instillation of prostaglandin F2 alpha between 19 and 25 weeks. Pharmacokinetics of ciprofloxacin in maternal blood and amniotic fluid were studied after two doses of ciprofloxacin (200 mg intravenously every 12 hours), after two doses of pefloxacin (400 mg intravenously every 12 hours), and after two doses of ofloxacin (400 mg intravenously every 12 hours). Twenty patients were studied in each group. The ranges of mean maternal serum and amniotic fluid levels were as follows: ciprofloxacin in maternal serum 0.01 to 0.28 micrograms/ml, in amniotic fluid 0.1 to 0.13 micrograms/ml; pefloxacin in maternal serum 2.65 to 4.31 micrograms/ml, in amniotic fluid 1.97 to 2.74 micrograms/ml; and ofloxacin in maternal serum 0.07 to 0.68 micrograms/ml, in amniotic fluid 0.13 to 0.25 micrograms/ml. Three groups of lactating women (10 women in each), were given three doses of 750 mg ciprofloxacin orally, 400 mg pefloxacin orally, and 400 mg ofloxacin orally. Serum and milk samples were obtained simultaneously at two, four, six, nine, 12, and 24 hours after dosage administration. The mean breast milk levels of ciprofloxacin at the corresponding time intervals were 3.79, 2.26, 0.86, 0.51, 0.20, and 0.02 micrograms/ml. The mean breast milk levels of pefloxacin were 3.54, 3.43, 2.93, 2.24, 1.79, and 0.88 micrograms/ml, and of ofloxacin, 2.41, 1.91, 1.25, 0.64, 0.29, and 0.05 micrograms/ml. It is concluded that all studied quinolones penetrate the placenta and are found in amniotic fluid at low concentrations and at much higher levels in breast milk. Because of the potential for quinolones to cause arthropathy in juvenile animals, their use should be avoided in pregnant and lactating women.

Activity of Plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece

Abstract The in vitro activity of plazomicin was evaluated against 300 multidrug resistant (MDR) (carbapenemase and/or ESBL-producing) isolates from four hospitals in Athens, an area where carbapenemase-producing organisms are endemic. Most of the isolates were also resistant to the legacy aminoglycosides with the MIC50/MIC90 to tobramycin, amikacin and gentamicin being 32/>32, 32/>32 and 4/>8 μg/ml, respectively. ACHN-490 retained activity (MICs⩽4 μg/ml) against all isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. tested with MIC50 and MIC90 of 1 and 2 μg/ml, respectively, irrespective of their MDR phenotype and it represents a promising alternative for the treatment of the most problematic Gram-negative pathogens.

Colistin/daptomycin: an unconventional antimicrobial combination synergistic in vitro against multidrug-resistant Acinetobacter baumannii.

The in vitro activity of the combination colistin/daptomycin was evaluated against multidrug-resistant Acinetobacter baumannii clinical isolates. Clonal relationships were assessed by pulsed-field gel electrophoresis. The following synergy studies were undertaken: (i) daptomycin MICs were determined by E-test on Mueller-Hinton agar plates supplemented with a subinhibitory concentration of colistin; and (ii) time-kill methodology using tubes containing an inoculum of 5×10(5)CFU/mL and subinhibitory concentrations of each antibiotic alone or in combination subcultured at 0, 5 and 24h for colony counting. Synergy was defined as ≥2log10CFU/mL decrease of viable colonies compared with colistin alone. Ten colistin-susceptible and four colistin-resistant A. baumannii isolates were tested. Isolates were assigned to nine different clonal types. Enhanced in vitro activity of the combination was detected only against colistin-susceptible isolates; using plates supplemented with colistin, the daptomycin MIC was reduced by 4- to 128-fold. From a total of 30 isolate-concentration combinations in time-kill studies, a synergistic interaction was detected in 16 (53.3%). The combination exhibited synergy against 8 and 12 of these combinations at 5h and 24h, respectively. No antagonism was detected. Colistin alone was bactericidal against two colistin-susceptible isolates at 24h, whereas the combination was bactericidal against 9 colistin-susceptible isolates at 24h. Against all colistin-resistant isolates, the combination exhibited a static effect and indifference in time-kill studies. Potent in vitro synergistic interactions between colistin and daptomycin provide evidence that this unorthodox combination may be beneficial in the treatment of colistin-susceptible multidrug-resistant A. baumannii.

Antimicrobial activity of copper surfaces against carbapenemase-producing contemporary Gram-negative clinical isolates

OBJECTIVES The antimicrobial activity of copper surfaces against a variety of contemporary carbapenemase-producing Gram-negative bacteria representative of the most problematic nosocomial pathogens worldwide was evaluated. METHODS Twenty-four clinical isolates, comprising four of Escherichia coli, two of Enterobacter spp., eight of Klebsiella pneumoniae and five each of Pseudomonas aeruginosa and Acinetobacter baumannii producing either VIM-1 and/or KPC-2 or VIM-2 or OXA-type carbapenemases, were studied. The antimicrobial activity of 99% copper (Cu99%) and a 63% alloy (Cu63%) was evaluated in comparison with that of stainless steel (SS) and polyvinylchloride (PVC) by incubating ∼10(6) cfu/cm(2) of the tested strains on each surface at room temperature. RESULTS Copper demonstrated antimicrobial activity against all studied isolates. This effect was observed earlier and was more pronounced for Cu99% than for Cu63%. Cu99% showed a bactericidal effect after <2 h for A. baumannii, 3 h for Enterobacter spp., 5 h for K. pneumoniae and 6 h for P. aeruginosa and E. coli. No viable colonies were recovered from five (20.8%) isolates after 3 h and from nine (37.5%) isolates after 5 h of incubation on Cu99%. CONCLUSIONS Copper has significant antimicrobial activity against multidrug-resistant nosocomial Gram-negative pathogens. This supports the hypothesis that replacement of high-contact materials with copper could reduce the high burden of environmental contamination around high-risk patients. However, this strategy should be seen as an adjunctive measure to established cleaning protocols and to good hygiene practices for prevention of hospital-acquired infections.

Norfloxacin versus cotrimoxazole in the treatment of lower urinary tract infections

In a randomised prospective study 61 patients with lower urinary tract infection received either 200 mg norfloxacin (33 patients) or 480 mg cotrimoxazole (28 patients) twice daily for ten days. Pathogens includedEscherichia coli in 48 patients,Proteus mirabilis in ten patients, andEnterobacter cloacae, Klebsiella pneumoniae, Citrobacter freundii andStaphylococcus saprophyticus in one patient each. The MICs of norfloxacin and cotrimoxazole were ⩽ 0.03 mg/l and ⩽ 1 mg/l respectively. On the tenth day of treatment 94 % of the patients receiving norfloxacin and 89 % of the patients receiving cotrimoxazole were clinically cured, and the pathogens were eradicated in 94 % and 96 % of the patients respectively. At six week follow-up one patient given cotrimoxazole and two given norfloxacin had a reinfection. No side-effects or toxicity were observed with the exception of a diffuse rash in one patient receiving cotrimoxazole in whom treatment was discontinued. It is concluded that norfloxacin is safe and as effective as cotrimoxazole in the treatment of lower UTI and should have an important role to play whenever multiresistant organisms are implicated.

Comparative pharmacokinetics of ciprofloxacin, ofloxacin and pefloxacin in human aqueous humour

Eighty-five patients undergoing cataract surgery were given for prophylaxis of intraocular infection two intravenous doses each of 200 mg, 300 mg or 400 mg ciprofloxacin (35 patients), 400 mg or 800 mg pefloxacin (30 patients), or 400 mg ofloxacin (20 patients). Ciprofloxacin levels in aqueous humour ranged from 0.02 to 0.50 µg/ml, pefloxacin levels from 1.04 to 7.80 µg/ml, and ofloxacin levels from 0.44 to 2.27 µg/ml with ratios of aqueous humour to serum levels ranging from 3.8 % to 25 %, 21 % to 48.1 % and 44 % to 88.4 %, respectively. It is concluded that the quinolones studied might be suitable for surgical prophylaxis or treatment of anterior chamber infections due toEnterobacteriaceae, while ciprofloxacin at high doses is preferable forPseudomonas aeruginosa infections.

A study of cefoxitin, moxalactam, and ceftazidime kinetics in pregnancy

In 27 women with fetuses affected by beta-thalassemia major, termination of gestation between 19 and 21 weeks was induced by amniocentesis and intrauterine instillation of prostaglandin F2 alpha. Pharmacokinetics in maternal blood and amniotic fluid were studied after at least three doses of one of the following antibiotics and before prostaglandin F2 alpha infusion: (1) cefoxitin, 2 gm, intravenously, 1/2-hour infusion, three times per day; (2) moxalactam, 2 gm, intravenously, 1/2-hour infusion, three times per day; and (3) ceftazidime, 1 gm, intramuscularly, three times per day. Successful amniotic fluid levels effective against various pathogens implicated in maternal-fetal infections appeared at least 3 hours beyond administration of the drug and ranged between 2.3 and 6.7 micrograms/ml, 1.56 and 15 micrograms/ml, and 1.5 and 5 micrograms/ml for cefoxitin, moxalactam, and ceftazidime, respectively. Beyond the third-hour after infusion a percentage ratio of amniotic fluid to simultaneous maternal serum level of almost greater than or equal to 50 was constantly observed for all studied antibiotics. Cefoxitin serum levels were about the same as those in nonpregnant women, while moxalactam and ceftazidime serum levels were 50% lower than the expected level in normal individuals.

Asymptomatic Bacteriuria in Freely Voiding Elderly Subjects

SummaryThe aim of this open, randomised study was the comparison of 3-month continuous (group A, n = 34) vs pulse oral ofloxacin therapy (group B, n = 33) in eliminating asymptomatic bacteriuria over 3 further months in 64 freely voiding, ambulant, very old subjects (mean age 83 years). A positive (group C, n = 29) and a negative control (group D, n = 40) were run simultaneously; two subjects in group A were withdrawn because of adverse effects. During therapy 86.7% of 30 cultures, 84.4% of 32 cultures and 24.1 % of 29 cultures in groups A, B and C, respectively, had sterile urine (A + B vs C: p < 0.001), whereas 12.8% of 39 cultures (group D) developed positive urine. At 3 months post-therapy 57.2%, 53.1%, 25.9% and 84.2% of 28, 32, 27 and 38 cultures, respectively, of the above groups remained free of infection (A + B vs C: p < 0.012); >50% of positive cultures in groups A+ B were due to new microorganisms, resistant to ofloxacin. Mild decreases in serum creatinine occurred in the treated subjects; haematocrit, serum bilirubin, blood urea, and SGPT were not affected. No deterioration in mobility occurred in any group, and the overall mortality (5 deaths) not connected with underlying urinary tract infection was low. It was concluded that: (a) ofloxacin pulse therapy was about equal to a continuous regimen in eliminating bacteriuria (>80% sterile urine) for 3 months, with negative cultures at a 3-month follow-up in ≥50%; (b) recurrences were caused chiefly by ofloxacin-resistant organisms; (c) serum creatinine indicated a trend towards lower values in the treated groups; (d) compliance was better and costs were much less in the pulse therapy group. Thus, if required, 3-month pulse therapy can be safely used to keep the urinary tract free of infecting microorganisms.

Penetration of pefloxacin into maxillary sinus cavity and nasal secretions

The ability of oral pefloxacin to penetrate into maxillary sinus cavity and nasal secretions was studied in 39 patients suffering from an exacerbation of chronic maxillary sinusitis. The mean levels of pefloxacin in sinus aspirate fluid 0, 3, 6, 9 and 12 h after the second oral dose of 400 mg were 2.30, 6.92, 3.74, 3.47 and 2.82 mg/l respectively. In sinus cystic fluid (macroscopically non-purulent) the mean pefloxacin levels were 2.30, 7.15, 4.20 and 4.15 mg/l respectively, and in nasal secretion 1.90, 9.05, 3.71, 3.20 and 2.85 mg/l respectively. The mean pefloxacin levels in serum obtained simultaneously were 1.50, 5.00, 3.10, 2.70 and 2.20 mg/l respectively. It is concluded that pefloxacin accumulates in inflamed sinus fluid at concentrations exceeding blood levels.

Survival of Elderly Bacteriuric Subjects Following Long-Term Quinolone Therapy

Abstract This study aimed to determine whether long-term oral fluoroquinolone administration exerts a significant positive effect on mobility and mortality in elderly subjects with asymptomatic bacteriuria. 132 institutionalized patients were divided into 4 groups: groups A and B were treated with ofloxacin while groups C and D were positive and negative control groups. At 3 months following treatment discontinuation 57%, 53% and 26% of patients in groups A, B and C respectively had negative urine cultures and all subjects were alive. After 3 years, positive cultures were 41.7%, 54.5% and 42.9% respectively for uncatheterized subjects per group vs. 13.3% for group D. In groups A, B, and C 20%, 15% and 29% of survivors respectively had permanent bladder catheters vs. 11.5% of survivors of group D. Survival in groups A, B and C, combined or per group did not differ significantly from group D, although it was shorter. “Pulse” antibiotic administration tended to perform better, in terms of clearing infection and maintaining continence. At 3 years, bacteriuria recurred and the need for bladder catheterization was doubled. Mortality increased independently of treatment. More elderly bacteriuric subjects should be studied to evaluate mobility and mortality issues.