MIC90 Ratios Research Articles

Effect of Age on the Pharmacokinetics of Marbofloxacin Following Intravenous Administration in Calves.

The aim of this study was to compare the pharmacokinetics of marbofloxacin after intravenous (IV) administration of a single dose of 10 mg/kg to calves of different ages. The study was carried on 1- (n = 6), 2- (n = 6), and 4-month-old (n = 6) Montofon calves. Plasma concentrations of marbofloxacin were measured using HPLC, and pharmacokinetic data were calculated by non-compartmental analysis. The elimination half-life (t1/2ʎz), volume of distribution at steady state (Vdss), total clearance (ClT), and area under the concentration-versus time curve (AUC0-∞) values of marbofloxacin in 1-month-old calves were 10.62 h, 1.03 L/kg, 0.08 L/h/kg, and 127.90 h*μg/mL, respectively. While the t1/2ʎz (from 10.62 to 3.36 h) and AUC0-∞ (from 127.90 to 47.35 h*μg/mL) decreased in parallel with the age of the calves, ClT (from 0.08 to 0.21 L/h/kg) increased. The Vdss of marbofloxacin was higher in 1- and 2-month-old calves compared to 4-month-old calves. After IV administration of marbofloxacin at a dose of 10 mg/kg, an ƒAUC0-24/MIC90 ratio of ≥ 125 was obtained for bacteria with MIC90 values of ≤ 0.60, ≤ 0.39 and ≤ 0.27 μg/mL in 1-, 2-, and 4-month-old calves, respectively. These results show that the antibacterial effect of marbofloxacin, which has concentration-dependent activity, decreases due to age-related pharmacokinetic changes and that the 10 mg/kg dose should be reviewed according to the MIC90 value of the bacteria.

Comparative Pharmacokinetics of Intravenous Enrofloxacin in One- Six- And Twelve-Month-Old Sheep.

Enrofloxacin (ENR) is a fluoroquinolone antibiotic approved for use in sheep of all ages. The body composition and metabolic capability change with age. These changes may alter the pharmacokinetics of drugs and thus their effect. Therefore, the pharmacokinetics of drugs need to be established in target- age animals. To determine the pharmacokinetics of ENR and its active metabolite, ciprofloxacin (CIP), following a single intravenous administration of ENR at a dose of 10 mg/kg in different ages of sheep. The study was carried out in the one-, six- and twelve-month age period of the sheep. A single dose of 10 mg/kg ENR was administered intravenously through the jugular vein to sheep in all age periods. ENR and CIP plasma concentrations were determined using HPLC-UV and analyzed using a non-compartmental method. ENR was detected in the plasma until 36 h in one-month-old and up to 24 h in other ages. CIP was detected in the plasma up to 24 h in all age groups. The t1/2ʎz and Vdss were significantly higher in one-month-old sheep than in six and twelve-months old sheep. There was no difference in ClT and AUC values in different age groups. AUC0-∞CIP/AUC0-∞ENR ratios were higher in one-month-old than in six- and twelve-months sheep. The most important pharmacokinetic changes associated with aging in sheep are decreased Vdss and t1/2ʎz of ENR and the low ratio metabolizing of ENR to CIP. Pharmacokinetic/pharmacodynamic data showed that ENR after IV administration of 10 mg/kg dose provided the optimal AUC0-24/MIC90 ratios for E. coli, P. multocida and Mycoplasma spp. (>125) with MIC of 0.37 µg/mL and for S. aureus (>30) with MIC of 0.5 µg/mL in all ages of sheep.

The effects of Mannheimia haemolytica and albendazole on marbofloxacin pharmacokinetics in lambs.

The study aimed to define the effects of M. haemolytica and a single oral dose of albendazole on the single-dose pharmacokinetics of marbofloxacin in lambs. The pharmacokinetic-pharmacodynamic integration of marbofloxacin was applied to describe a 3mg/kg intramuscular dose in lambs. The 6 healthy and 12 naturally infected with M. haemolytica lambs (Akkaraman, males weighing 10-15kg and aged 2-3months) were used in this study. In the marbofloxacin group, 6 healthy lambs received marbofloxacin. In the albendazole group after 2weeks washout period, the same animals received marbofloxacin on 1h after albendazole. In the diseased marbofloxacin group, 6 lambs naturally infected with M. haemolytica received marbofloxacin. In the diseased albendazole group, 6 lambs naturally infected with M. haemolytica received marbofloxacin on 1h after albendazole. The marbofloxacin and albendazole were administered each as a single dose of 3mg/kg intramuscular and 7.5mg/kg oral, respectively, in the respective groups. Plasma concentration of marbofloxacin was measured with HPLC-UV and pharmacokinetic parameters were analyzed by non-compartmental model. Albendazole did not change the pharmacokinetic profiles of marbofloxacin in healthy and diseased lambs. However, M. haemolytica affected the pharmacokinetics of marbofloxacin in diseased lambs, AUC0-24/MIC90 ratio was not found to be higher than 125, but Cmax/MIC90 ratios was found to be higher than 10 for an MIC value of 0.25μg/mL in all groups. The marbofloxacin dose described in this study may not be effective for the treatment of infections due to M. haemolytica in lambs, with MIC ≤ 0.25μg/mL.

Pharmacokinetics of enrofloxacin HCl-2H2 O (ENRO-C), PK/PD, and Monte Carlo modeling vs. Leptospira spp. in cows.

The pharmacokinetics, PK/PD ratios, and Monte Carlo modeling of enrofloxacin HCl-2H2 O (Enro-C) and its reference preparation (Enro-R) were determined in cows. Fifty-four Jersey cows were randomly assigned to six groups receiving a single IM dose of 10, 15, or 20mg/kg of Enro-C (Enro-C10 , Enro-C15 , Enro-C20 ) or Enro-R. Serial serum samples were collected and enrofloxacin concentrations quantified. A composite set of minimum inhibitory concentrations (MIC) of Leptospira spp. was utilized to calculate PK/PD ratios: maximum serum concentration/MIC (Cmax /MIC90 ) and area under the serum vs. time concentration of enrofloxacin/MIC (AUC0-24 /MIC90 ). Monte Carlo simulations targeted Cmax /MIC=10 and AUC0-24 /MIC=125. Mean Cmax obtained were 6.17 and 2.46μg/ml; 8.75 and 3.54μg/ml; and 13.89 and 4.25μg/ml, respectively for Enro-C and Enro-R. Cmax /MIC90 ratios were 6.17 and 2.46, 8.75 and 3.54, and 13.89 and 4.25 for Enro-C and Enro-R, respectively. Monte Carlo simulations based on Cmax /MIC90 =10 indicate that only Enro-C15 and Enro-C20 may be useful to treat leptospirosis in cows, predicting a success rate ≥95% when MIC50 =0.5μg/ml, and ≥80% when MIC90 =1.0μg/ml. Although Enro-C15 and Enro-C20 may be useful to treat leptospirosis in cattle, clinical trials are necessary to confirm this proposal.

Disposición plasmática de danofloxacina al 2.5% en cabras

Se determinaron parámetros farmacocinéticos de danofloxacina al 2.5% tras su aplicación endovenosa e intramuscular en hembras caprinas adultas. Los niveles plasmáticos se cuantificaron por HPLC con detector de fluororescencia establecido a 295 nm de excitación y 490 nm de emisión utilizando fase móvil compuesta por agua, acetonitrilo y trietilamina (79:19:1 v/v/v) ajustada a pH 3.0. En cada vía de aplicación, utilizando los datos de concentraciones plasmáticas versus tiempo en cada animal se determinaron parámetros farmacocinéticos con el software PK Solution 2.0. El límite de cuantificación del ensayo fue de 0.0048 μg/ml. El perfil cinético exhibido por danofloxacina en caprinos es similar al conjunto de fluoroquinolonas en animales domésticos. La aplicación intramuscular provee rápida absorción, genera una Cmáx de 0.36 ± 0.13 μg/ml a los 55.1 ± 13.8 minutos y exhibe amplia distribución en el organismo y biodisponibilidad (F) del 109.7 ± 19.8%. Danofloxacina mostró discreta permanencia en el organismo, según expresan los valores conseguidos en el t½â= 4.35 horas (EV), 4.32 horas (IM) y en el TMR= 5.9 horas (EV), 6.7 horas (IM). La aplicación intramuscular es equiparable para la vía endovenosa, pero el uso racional requiere el ajuste posológico para asegurar el éxito clínico-terapéutico debido que las relaciones plasmáticas de Cmáx y ABC respecto la CIM90 de M. haemolytica de 9 y 41, respectivamente, son insuficientes para asegurar eficacia clínica-microbiológica.

Conjunctival Concentrations of a New Ophthalmic Solution Formulation of Moxifloxacin 0.5% in Cataract Surgery Patients

To compare the conjunctival concentrations of moxifloxacin after instillation of a single drop of moxifloxacin ophthalmic solution, 0.5% (Moxi) or a new 0.5% ophthalmic solution formulation (MAF) containing a retention-enhancing agent in patients undergoing cataract surgery. This was a randomized, double-masked, parallel-group study. One hundred thirty patients scheduled for routine phacoemulsification and intraocular lens implantation were randomized to both treatment and post-dose sample collection time points. A single topical drop of Moxi or MAF was instilled in the study eye. At the designated time (0.25, 0.5, 1, 3, or 5 h post-dose), 2 conjunctival biopsy samples were obtained (N = 11-13 per treatment condition). Concentrations of moxifloxacin were determined using a validated ultra-performance liquid chromatography method. Moxifloxacin exposure [maximum mean moxifloxacin concentrations (C(max)) and area under the concentration-time curve (AUC)] was estimated from the observed concentration-time data. The conjunctival moxifloxacin C(max), 43.8 μg/g, for MAF was achieved at 0.25 h. This was 1.8-fold higher than the C(max) for Moxi (24.1 μg/g), which was reached at 0.5 h post-dose. MAF AUC(0-3) was significantly greater than the AUC(0-3) of Moxi [50.5 (μg·h)/g vs. 27.1 (μg·h)/g; P < 0.05]. The conjunctival moxifloxacin C(max) for MAF was 337- to 730-fold greater than the reported minimum inhibitory concentration (MIC(90)) values for Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. The C(max):MIC(90) ratios for Moxi ranged from 185 to 402. Conjunctival AUC(0-24):MIC(90) ratios ranged from 777 to 1,683 for MAF and from 625 to 1,355 for Moxi. The new MAF ophthalmic formulation of moxifloxacin provided higher peak levels of moxifloxacin in the conjunctiva tissue, and larger total tissue exposure than the current, commercially available formulation. The superior penetration of MAF observed in this study could translate into greater eradication of bacteria.

Susceptibility of rapidly growing mycobacteria isolated from cats and dogs, to ciprofloxacin, enrofloxacin and moxifloxacin

Rapidly growing mycobacteria (RGM) cause infections in cats and dogs which require prolonged antibacterial medication for resolution. In Australia, pathogens from the Mycobacterium fortuitum and Mycobacterium smegmatis clusters are responsible for most of the RGM infections in cats and dogs. As fluoroquinolones are often recommended for treating such infections, 14 M. fortuitum isolates, 51 isolates from the M. smegmatis cluster and 2 M. mageritense isolates, collected from feline and canine patients, underwent susceptibility testing to the second generation fluoroquinolones ciprofloxacin and enrofloxacin and the newer generation fluoroquinolone moxifloxacin. Using microbroth dilution, the MIC90 of ciprofloxacin, enrofloxacin, and moxifloxacin that inhibited growth of M. fortuitum isolates were 0.500, 0.250 and 0.063μg/mL respectively. For the M. smegmatis cluster isolates the corresponding MIC90 was 0.500, 0.250 and 0.125μg/mL respectively. E-test results showed similar trends but MICs were lower than those determined by microbroth dilution. Additionally, moxifloxacin was administered to 10 clinically normal cats (50mg per cat, once daily for 4 days). The plasma moxifloxacin concentration 2h after the last dose was determined by liquid chromatography as 2.2±0.6μg/mL. The plasma concentration at 2h:MIC90 ratios for moxifloxacin for M. fortuitum and M. smegmatis cluster was 34.9 and 17.6 respectively which exceeded the recommended threshold of 10, indicating that moxifloxacin has good theoretical efficacy for treatment of those M. fortuitum and M. smegmatis infections in cats and dogs that have become refractory to other antibacterial drug classes.

Ocular Pharmacokinetics of Besifloxacin Following Topical Administration to Rabbits, Monkeys, and Humans

Studies were conducted to evaluate the ocular penetration and systemic exposure to besifloxacin, a fluoroquinolone antibiotic, following topical ocular administration to animals and humans. Besifloxacin ophthalmic suspension (0.6%) was administered as a topical ocular instillation to pigmented rabbits, cynomolgus monkeys, and human subjects. At predetermined intervals after dosing, samples of ocular tissues and plasma were collected and analyzed for besifloxacin levels using HPLC/MS/MS methods. Besifloxacin demonstrated good ocular penetration in rabbits and monkeys, with rapid absorption and sustained concentrations observed in anterior ocular tissues through 24 h after a single administration. Maximum besifloxacin concentrations in conjunctiva, cornea, and aqueous humor of monkeys were 6.43 microg/g, 2.10 microg/g, and 0.796 microg/mL, respectively, after a single topical dose, and concentrations declined in these tissues with an apparent half-life of 5-14 h. Following a single topical ocular administration to humans, the maximum besifloxacin concentration in tears was 610 microg/g with concentrations decreasing to approximately 1.6 microg/g at 24 h. The resulting pharmacokinetic parameters for besifloxacin in human tears were evaluated relative to the MIC(90) values (microg/mL) for besifloxacin against Streptococcus pneumoniae (0.125), Staphylococcus aureus (0.25), Staphylococcus epidermidis (0.5), and Haemophilus influenzae (0.06). Following a single topical administration, the C(max)/MIC(90) ratios for besifloxacin in human tears were > or =1,220, and the AUC((0-24))/MIC(90) ratios were > or =2,500 for these relevant ocular pathogens. Following repeated 3-times daily (TID) topical ocular administration to human subjects with clinically diagnosed bacterial conjunctivitis, maximum besifloxacin concentrations in plasma were less than 0.5 ng/mL, on average. Taken together, the results of the current investigation provide a PK/PD-based rationale that supports the use of besifloxacin for the safe and effective treatment of ocular infections.

Utilización de antimicrobianos en las infecciones odontogénicas en niños y adolescentes: análisis farmacocinético/farmacodinámico (PK/PD)

The objective of this study was to evaluate the efficacy of the most commonly used antimicrobial treatments in odontogenic infections in children and adolescents on the basis of pharmacokinetic/ pharmacodynamic (PK/PD) criteria. Unbound drug plasma concentration-time curves were simulated with mean population pharmacokinetic parameters of amoxicillin, co-amoxiclav, cefuroxime axetil, spiramycin, clindamycin, azithromycin, and metronidazole. For drugs showing time-dependent antibacterial killing, the time above MIC90 of the pathogens studied was calculated (T>MIC). For drugs with concentration-dependent bactericidal activity, the area under the concentration-time curve (AUC)/MIC90 ratio was calculated. Adequate efficacy indexes (T>MIC>40%) against all the microorganisms examined with the exception of Veillonella spp. were obtained with co-amoxiclav (80 mg/kg/day). Clindamycin (40 mg/kg/day) obtained adequate PK/PD indexes except for Lactobacillus, Actinobacillus actinomycetemcomitans, penicillin-resistant Peptostreptococcus, and Eikenella corrodens. High-dose amoxicillin yielded unsatisfactory results against many bacterial species. Azithromycin and metronidazole showed inadequate efficacy indexes against the majority of pathogens studied (AUC/MIC90<25). When antibiotic therapy is needed for odontogenic infections in children and adolescents, the most active empirical therapeutic choice is co-amoxiclav with high doses of amoxicillin. Clindamycin can be used as an alternative option. These results should be confirmed in clinical trials, in which the PK/PD approach could be useful for the design and assessment of results.

Pharmacodynamic target attainment potential of azithromycin, clarithromycin, and telithromycin in serum and epithelial lining fluid of community-acquired pneumonia patients with penicillin-susceptible, intermediate, and resistant Streptococcus pneumoniae

To compare the probability of target attainment (PTA) for macrolides and ketolides against penicillin-susceptible, intermediate, and resistant Streptococcus pneumoniae in both serum and epithelial lining fluid (ELF) of patients with community-acquired pneumonia (CAP). Monte Carlo simulations were used to assess the attainment of the bacterial eradication-linked pharmacodynamic index of the free drug area under the concentration-time curve over 24 hours to minimum inhibitory concentration (fAUC(0-24)/MIC90) by azithromycin, clarithromycin, and telithromycin, at therapeutic doses, against penicillin-susceptible, intermediate, and resistant S. pneumoniae. In serum, azithromycin and clarithromycin were found to have a probability of attaining the recommended fAUC(0-24)/MIC90 ratio of 30 in 50.2% and 74.6%, respectively, of CAP patients with penicillin-intermediate strains, and a probability of 36.9% and 60.7%, respectively, in cases of penicillin-resistant strains. Telithromycin maintained a probability of reaching the fAUC(0-24)/MIC90 ratio of 30 in serum and ELF in 89.1% of CAP patients, regardless of the penicillin resistance of the strain. Clarithromycin results in a higher PTA than azithromycin in the treatment of penicillin-susceptible S. pneumoniae, but both of these agents exhibit a decreasing efficacy as S. pneumoniae penicillin resistance increases. When compared to clarithromycin and azithromycin, telithromycin maintains higher PTA in CAP patients with penicillin-resistant strains of S. pneumoniae.

Calculation of AQCmax: comparison of five ophthalmic fluoroquinolone solutions

ABSTRACTObjective: Ocular tissue penetration of five different ophthalmic fluoroquinolone solutions in the rabbit eye was measured and evaluated by an index of the maximum aqueous concentration (AQCmax).Methods: Moxifloxacin 0.5% (MFLX), levofloxacin 0.5% (LVFX), gatifloxacin 0.3% (GFLX), ofloxacin 0.3% (OFLX), or tosufloxacin tosilate 0.3% (TFLX) were instilled into the eyes of white rabbits every 15 min for a total of three doses. Aqueous humor, cornea, iris/ciliary body and vitreous body were collected 10 to 240 min after instillation and drug concentrations were measured by high-performance liquid chromatography.Results: The concentration of MFLX was the highest in each tissue, with maximum concentrations of MFLX in the aqueous humor (10.16 ± 1.59 µg/mL) at 30 min after instillation, cornea (156.07 ± 95.97 µg/g) and iris/ciliary body (11.92 ± 4.00 µg/g) at 10 min after instillation, and vitreous body (0.099 ± 0.033 µg/mL) at 30 min after instillation. The concentration of TFLX was the lowest in each tissue, with LVFX, GFLX, and OFLX sharing the mid-ranks. AQCmax : MIC90 ratio for S. aureus was 150.67 for MFLX, 10.6 for LVFX, 9.69 for GFLX, 3.48 for OFLX, and could not be determined for TFLX.Conclusion: AQCmax is a useful pharmacokinetic parameter for determining the therapeutic efficacy of an ophthalmic antibiotic, especially when combined with MIC90 values for intraocular pathogens. Cmax of MFLX ophthalmic solution was superior in all tissues (cornea, aqueous humor, iris/ciliary body and vitreous body) among the five ophthalmic solutions studied, exceeding the MIC90 of S. aureus in all tissues, and MIC90s of S. epidermidis, B. cereus, and P. acnes in aqueous humor, cornea, and iris/ciliary body. AQCmax was approximately proportional to Cmax in iris/ciliary body and vitreous, and may be used in combination with MIC90s as an index to predict the most appropriate dose and frequency of ophthalmic antibiotics in conjunction with other PK/PD parameters. This study may provide the groundwork for calculation of AQCmax in humans.

Disposition Kinetics of Difloxacin After Intravenous, Intramuscular and Subcutaneous Administration in Calves

The pharmacokinetics of difloxacin (Dicural) was studied in a crossover study using three groups (n = 4) of male and female Friesian calves after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administrations of 5 mg/kg body weight. Drug concentration in plasma was determined by high-performance liquid chromatography using fluorescence detection. The plasma concentration-time data following i.v. administration were best fitted to a two-compartment open model and those following i.m. and s.c. routes were best fitted using one-compartment open model. The collected data were subjected to a computerized kinetic analysis. The mean i.v., i.m. and s.c. elimination half-lives (t(1/2beta)) were 5.56 +/- 0.33 h, 6.12 +/- 0.42 h and 7.26 +/- 0.6 h, respectively. The steady-state volume of distribution (V(dss)) was 1.12 +/- 0.09 L/kg and total body clearance (Cl(B)) was 2.19 +/- 0.1 ml/(min x kg). The absorption half lives (t(1/2ab)) were 0.38 +/- 0.027 h and 2.1 +/- 0.09 h, with systemic bioavailabilities (F) of 96.5% +/- 6.4% and 84% +/- 5.5% after i.m. and s.c. administration, respectively. After i.m. and s.c. dosing, peak plasma concentrations (C(max)) of 3.38 +/- 0.13 microg/ml and 2.18 +/- 0.12 microg/ml were attained after (t(max)) 1.22 +/- 0.20 h and 3.7 +/- 0.52 h. The MIC90 of difloxacin for Mannheimia haemolytica was 0.29 +/- 0.04 microg/ml. The AUC/MIC90 and C(max)/MIC90 ratios for difloxacin following i.m. administration were 120 and 11.65, respectively and following s.c. administration were 97.58 and 7.51, respectively. Difloxacin was 31.7-36.8% bound to calf plasma protein. Since fluoroquinolones display concentration-dependent activities, the doses of difloxacin used in this study are likely to involve better pharmacodynamic characteristics that are associated with greater clinical efficacy following i.m. administration than following s.c. administration.

Linezolid disposition after standard dosages in critically ill patients undergoing continuous venovenous hemofiltration: A report of 2 cases

Linezolid is a new oxazolidinone antibiotic active against most Gram-positive microorganisms the renal elimination of which accounts for about 30% to 35% of all the clearance. Its pharmacokinetic ability was assessed during continuous venovenous hemofiltration (CVVH) in 2 anuric patients with severe postsurgical intraabdominal infections who were receiving standard dosages (600 mg intravenously twice a day). Blood samples for quantification of linezolid in plasma and in filtrate were collected after more than 4 days of therapy before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9, and 11 hours after the morning 1-hour intravenous infusion, and concentrations were determined by means of high-performance liquid chromatography. Linezolid was partially cleared by CVVH in both the patients (hemofiltration clearance [CL CVVH ] = 0.38 and 0.35 mL/min/kg), with high sieving coefficient values (0.76 to 0.92). Efficacious plasma exposure for time-dependent antibacterial activity of linezolid, either in terms of trough levels above minimum inhibitory concentration (MIC) at which 90% of the isolates are inhibited (Cmin >MIC90 ) or of area under the plasma concentration time curve to MIC90 ratio (AUC/MIC90 ) >100 hours, was ensured during CVVH in both patients. However, despite similar CL CVVH , significant interindividual pharmacokinetic variability was found in the 2 patients (AUC during the observational period [AUC 0-tau ] 334.71 versus 109.34 mg/L x h), mainly owing to substantial differences in non-CVVH-related clearance of linezolid (total CL, 0.55 versus 1.21 mL/min/kg). Our findings indicate that linezolid, although partially removed, does not warrant dosage modification during the first 48 hours when CVVH (with polysulfide hemofilter) at standard 2,000 mL/h substitution flow rate in predilution is applied to anuric patients. Thereafter, this choice is a reasonable one with the exception of those patients who have other features of linezolid toxicity and in which non-CVVH-related clearance might be impaired, although further evaluations are warranted.

An Evaluation of Gentamicin, Tobramycin, and Amikacin Pharmacokinetic/Pharmacodynamic Parameters in HIV-Infected Children

The purpose of the study was to calculate gentamicin, tobramycin, and amikacin pharmacokinetic parameters in HIV-infected children and compare conventional multiple daily aminoglycoside dosing to once-daily aminoglycoside (ODA) dosing in attaining peak serum aminoglycoside concentrations (SACs) to minimum inhibitory concentration for 90% of isolates (MIC(90)) ratios ≥8 against selected pathogens. Patients (<13yrs) receiving an aminoglycoside (15 patients/drug) in the treatment of gram-negative infection were studied. Intravenous gentamicin/ tobramycin were administered at a dose of 6-7.5 mg/kg/day and amikacin at 20-30 mg/kg/d divided every 8 hrs. Peak and trough serum concentrations were obtained and pharmacokinetic parameters were calculated utilizing a one-compartment steady-state model. SACs for gentamicin/tobramycin dosed at 7.5 mg/kg and amikacin at 22.5 mg/kg once daily were simulated using the calculated pharmacokinetic parameters. Peak SAC:MIC(90) ratios were calculated for each dosing method. Mean pharmacokinetic parameters were within 1 standard deviation of reported literature values. Mean peak:MIC(90) ratio of ≥8 was attained only for Klebsiella species (MIC90 1 μg/mL) using conventional gentamicin/tobramycin dosing whereas mean amikacin peak:MIC(90) ratios ≥8 were reached for Klebsiella, Enterobacter, and Citrobacter species (MIC(90) 4 μg/mL). ODA simulations predicted gentamicin/tobramycin peak:MIC(90) ratios ≥8 in 100% of patients with an organism-MIC(90) of 1 μcg/mL and in 80% of patients with an organism-MIC(90) of 2 μg/mL. Amikacin peak:MIC(90) ratio ≥8 was predicted for 93% of patients with an organism-MIC(90) of 4 μg/mL but in only 27% if the MIC(90) was 8 μg / mL. Optimal peak SAC:MIC90 ratios using conventional aminoglycoside dosing were predicted only for organisms with low MIC(90) values. ODA dosing represents an option for improving pharmacodynamic outcomes.

A remarkable reduction in the susceptibility of Neisseria gonorrhoeae isolates to cephems and the selection of antibiotic regimens for the single-dose treatment of gonococcal infection in Japan.

We compared the susceptibilities of 100 Neisseria gonorrhoeae isolates obtained from January to June 2000 to a variety of antimicrobial agents, including various cephems, with the susceptibilities of 55 isolates obtained from May to December 1995. In 11 of the 15 cephems tested, the MIC50 (minimum inhibitory concentration for 50% of isolates) ratios, calculated by dividing the MIC50 for isolates from 2000 by that for isolates from 1995, showed 4-fold to 16-fold differences. The MIC90 ratios of cefodizime and cefditoren showed only a 1-fold and 2-fold difference, respectively. However, the MIC90 ratios of the remaining 13 cephems showed 4-fold to 64-fold differences. We selected the most favorable antibiotic regimens for the single-dose treatment of gonorrhea in Japan according to the antigonococcal activity and pharmacokinetics, based on the criterion (therapeutic time) proposed by Moran and Levine i.e., the regimen should produce a concentration in the serum or plasma at least four times that of the MIC90 value for at least 10 h. Of the 20 single-dose regimens evaluated, only ceftriaxone 1 g intravenously and cefodizime 1 g intravenously were found to have a therapeutic time of more than 10 h for the isolates from 2000. Our results indicated that the susceptibilities of the isolates from 2000 to all the cephems tested, except for cefditoren and cefodizime, decreased remarkably in comparison with the susceptibilities of the isolates from 1995, while parenteral ceftriaxone 1 g and cefodizime 1 g appeared to be the most favorable single-dose regimens for the treatment of gonococcal infections in Japan.