Osseointegration and antibacterial effect of an antimicrobial peptide releasing mesoporous titania implant.

Medical devices such as orthopedic and dental implants may get infected by bacteria, which results in treatment using antibiotics. Since antibiotic resistance is increasing in society there is a need of finding alternative strategies for infection control. One potential strategy is the use of antimicrobial peptides, AMPs. In this study, we investigated the antibiofilm effect of the AMP, RRP9W4N, using a local drug-delivery system based on mesoporous titania covered titanium implants. Biofilm formation was studied in vitro using a safranine biofilm assay and LIVE/DEAD staining. Moreover, we investigated what effect the AMP had on osseointegration of commercially available titanium implants in vivo, using a rabbit tibia model. The results showed a sustained release of AMP with equal or even better antibiofilm properties than the traditionally used antibiotic Cloxacillin. In addition, no negative effects on osseointegration in vivo was observed. These combined results demonstrate the potential of using mesoporous titania as an AMP delivery system and the potential use of the AMP RRP9W4N for infection control of osseointegrating implants.

Differential interactions of the ß-lactam cloxacillin with human renal organic anion transporters (OATs).

The ß-lactam penicillin antibiotic cloxacillin (CLX) presents wide inter-individual pharmacokinetics variability. To better understand its molecular basis, the precise identification of the detoxifying actors involved in CLX disposition and elimination would be useful, notably with respect to renal secretion known to play a notable role in CLX elimination. The present study was consequently designed to analyze the interactions of CLX with the solute carrier transporters organic anion transporter (OAT) 1 and OAT3, implicated in tubular secretion through mediating drug entry at the basolateral pole of renal proximal cells. CLX was first shown to block OAT1 and OAT3 activity in cultured OAT-overexpressing HEK293 cells. Half maximal inhibitory concentration (IC50 ) value for OAT3 (13 µm) was however much lower than that for OAT1 (560 µm); clinical inhibition of OAT activity and drug-drug interactions may consequently be predicted for OAT3, but not OAT1. OAT3, unlike OAT1, was next shown to mediate CLX uptake in OAT-overexpressing HEK293 cells. Kinetic parameters for this OAT3-mediated transport of CLX (Km  = 10.7 µm) were consistent with a possible in vivo saturation of this process for high CLX plasma concentrations. OAT3 is consequently likely to play a pivotal role in renal CLX secretion and consequently in total renal CLX elimination, owing to the low plasma unbound fraction of the antibiotic. OAT3 genetic polymorphisms as well as co-administered drugs inhibiting in vivo OAT3 activity may therefore be considered as potential sources of CLX pharmacokinetics variability.

The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-Resistant Staphylococcus aureus in a Rabbit Model of Experimental Endocarditis.

We investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to perform in vitro time-kill studies using standard (106) and high (108) inocula. Combined therapy was compared to daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied, and the equivalents of cloxacillin at 2 g/4 h, fosfomycin at 2 g/6 h, and daptomycin at 6 to 10 mg/kg/day were administered intravenously. A combination of daptomycin and either fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 µg/ml) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%, P = 0.046) and the decrease in the density of bacteria within the vegetations (P = 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%, P = 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%, P = 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity.

Determination of cloxacillin residues in dairy cows after intramammary administration.

The aim of this study was to perform a comparative analysis of the characteristics of cloxacillin (CLO) (MRL of withdrawal in bovine milk is 30 ng/g) after a single intramammary (IMM) dose in the dry period (DP) and lactation (LP), and to establish a high-performance liquid chromatography (HPLC) analytical method for CLO detection in milk. The research was conducted on a group of 10 cows in DP and 10 in LP. A single dose of 600 mg of CLO was administrated by the IMM route for a single quarter in DP and 500 mg for a single quarter in LP. CLO concentration was analyzed by HPLC. CLO was monitored at a wavelength of 206 nm. Pharmacokinetic calculations were performed using Phoenix® WinNonlin® 6.4 software. The calibration curve was linear over the range of 13.03-28 019.00 ng/g with the coefficient of determination R2  > 0.999. CLO withdrawal in both the LP and DP group had a biphasic nature. The total CLO elimination in the DP and LP group was reached after 36 and 6.5 days, respectively. A quantitative and confirmatory method for the determination of CLO in fresh milk has been established. We have confirmed that the withdrawal of CLO in the DP group is not a linear process and has a stepwise character.

[Reinstating cloxacilin for empiric antibiotic in late-onset sepsis]. / Reposicionando la cloxacilina como antibioticoterapia empírica inicial de la sepsis tardía neonatal.

Vancomycin has been used for more than 50 years in neonatal intensive care units (NICUs) as the therapy of choice for late-onset sepsis, mainly because Coagulase negative Staphylococci (CoNS) are common and mostly resistant to oxacyllin despitelow virulence and unusual association with fulminant sepsis. CUs due to several factors including its high pharmacokinetic variability, difficulty in reaching therapeutic plasmatic drug concentrations and progressively increasing minimum inhibitory concentrations (MIC). The increase of CoNS with higher MICs as well as the rise of infections caused by resistant gram-negative bacilli and candida should move to reconsider Vancomycin as first line treatment. Infections in neonates have a different behavior than in other populations and we consoder of utmost importance to consider the use of oxacyllin as first line antimicrobial therapy for late-onset sepsis.

Reposicionando la cloxacilina como antibioticoterapia empírica inicial de la sepsis tardía neonatal / Reinstating cloxacilin for empiric antibiotic in late-onset sepsis

Vancomycin has been used for more than 50 years in neonatal intensive care units (NICUs) as the therapy of choice for late-onset sepsis, mainly because Coagulase negative Staphylococci (CoNS) are common and mostly resistant to oxacyllin despitelow virulence and unusual association with fulminant sepsis. CUs due to several factors including its high pharmacokinetic variability, difficulty in reaching therapeutic plasmatic drug concentrations and progressively increasing minimum inhibitory concentrations (MIC). The increase of CoNS with higher MICs as well as the rise of infections caused by resistant gram-negative bacilli and candida should move to reconsider Vancomycin as first line treatment. Infections in neonates have a different behavior than in other populations and we consoder of utmost importance to consider the use of oxacyllin as first line antimicrobial therapy for late-onset sepsis.

Vancomicina se utiliza hace más de 50 años en unidades de cuidados intensivos neonatales (UCIN) como terapia de elección en sospecha de sepsis neonatal tardía; su principal indicación se fundamenta en que Staphylococcus coagulasa negativa (SCN) es el principal microorganismo que ocasiona sepsis tardía y éste es habitualmente resistente a cloxacilina; sin embargo, su virulencia es baja y la sepsis fulminante es inusual. Lamentablemente la prescripción de vancomicina se ha convertido en un grave problema en las UCIN, debido a diversas razones incluyendo: alta variabilidad farmacocinética del fármaco, dificultad en alcanzar concentraciones plasmáticas apropiadas y aumento de la concentración inhibitoria mínima (CIM), implicando además una mayor probabilidad de seleccionar cepas resistentes y aumento de otro tipo de infecciones ocasionadas por bacilos gramnegativos resistentes y candidiasis invasora. Considerando lo anteriormente señalado y a lo publicado en la literatura médica con respecto a las infecciones en neonatología, debido a su comportamiento clínico diferente a hospederos en otras etapas de la vida, resulta de suma importancia replantear el uso de vancomicina basado en fundamentos teóricos que avalen la seguridad de no utilizar este antimicrobiano como primera línea en sepsis neonatal tardía.

Comparative efficacies of cloxacillin-daptomycin and the standard cloxacillin-rifampin therapies against an experimental foreign-body infection by methicillin-susceptible Staphylococcus aureus.

We compared the efficacies of daptomycin (doses equivalent to 8 to 10 mg/kg of body weight/day in humans) and cloxacillin alone with those of cloxacillin-rifampin and cloxacillin-daptomycin combinations, using a tissue cage methicillin-susceptible Staphylococcus aureus (MSSA) infection model. Monotherapies were less effective than combinations (P<0.05), and daptomycin resistance emerged. Cloxacillin-daptomycin proved as effective as cloxacillin-rifampin and prevented the appearance of resistance; this combination may be an alternative anti-MSSA therapy, which may offer greater benefits in the early treatment of prosthetic joint infections (PJI).

Cloxacillin concentrations in serum, subcutaneous fat, and muscle in patients with chronic critical limb ischemia.

BACKGROUND: Patients suffering from critical limb ischemia (CLI) have poor wound healing in the ankle and foot areas. Secondary wound infections are frequent and often treated with prolonged courses of antibiotics. PURPOSE: This study set out to investigate to what extent the unbound fraction of 4 g of cloxacillin i.v. reaches its target organ in poorly vascularized tissues, i.e., the calf and foot of patients suffering from CLI. METHODS: Cloxacillin concentrations were measured by HPLC in serum and in microdialysis samples from skin and muscle of the lower part of the calf and as reference subcutaneously at the pectoral level in eight patients suffering from CLI (four males, four females, mean age 78 years, range 66-85 years) and in three healthy controls (two females, one male, mean age 67, range 66-68 years). RESULTS: In patients suffering from CLI, the tissue penetration of cloxacillin after a single 4 g dose was comparable to that of healthy controls, despite impaired blood circulation. CONCLUSIONS: The reduced blood flow in the peripheral vessels of the CLI patients presented here apparently is not the rate-limiting factor for delivery or tissue penetration of cloxacillin.

Saliva versus plasma pharmacokinetics: theory and application of a salivary excretion classification system.

The aims of this work were to study pharmacokinetics of randomly selected drugs in plasma and saliva samples in healthy human volunteers, and to introduce a Salivary Excretion Classification System. Saliva and plasma samples were collected for 3-5 half-life values of sitagliptin, cinacalcet, metformin, montelukast, tolterodine, hydrochlorothiazide (HCT), lornoxicam, azithromycin, diacerhein, rosuvastatin, cloxacillin, losartan and tamsulosin after oral dosing. Saliva and plasma pharmacokinetic parameters were calculated by noncompartmental analysis using the Kinetica program. Effective intestinal permeability (Peff) values were estimated by the Nelder-Mead algorithm of the Parameter Estimation module using the SimCYP program. Peff values were optimized to predict the actual average plasma profile of each drug. All other physicochemical factors were kept constant during the minimization processes. Sitagliptin, cinacalcet, metformin, tolterodine, HCT, azithromycin, rosuvastatin and cloxacillin had salivary excretion with correlation coefficients of 0.59-0.99 between saliva and plasma concentrations. On the other hand, montelukast, lornoxicam, diacerhein, losartan and tamsulosin showed no salivary excretion. Estimated Peff ranged 0.16-44.16 × 10(-4) cm/s, while reported fraction unbound to plasma proteins (fu) ranged 0.01-0.99 for the drugs under investigation. Saliva/plasma concentrations ratios ranged 0.11-13.4, in agreement with drug protein binding and permeability. A Salivary Excretion Classification System (SECS) was suggested based on drug high (H)/low (L) permeability and high (H)/low (L) fraction unbound to plasma proteins, which classifies drugs into 4 classes. Drugs that fall into class I (H/H), II (L/H) or III (H/L) are subjected to salivary excretion, while those falling into class IV (L/L) are not. Additional data from literature was also analyzed, and all results were in agreement with the suggested SECS. Moreover, a polynomial relationship with correlation coefficient of 0.99 is obtained between S* and C*, where S* and C* are saliva and concentration dimensionless numbers respectively. The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion. Future work is planned to test these initial findings, and demonstrate SECS robustness across a range of carefully selected (based on physicochemical properties) drugs that fall into classes I, II or III.

Assessment of interindividual variability of plasma concentrations after administrazion of high doses of intravenous amoxicillin or cloxacillin in critically ill patients.

The aim of the present retrospective observational clinical study was to assess the interindividual pharmacokinetic variability of plasma concentrations of amoxicillin or cloxacillin administered in high doses intravenously in critically ill patients, related to renal function or administration method.Four hundred and two plasma concentrations were measured at steady-state with a high performance liquid chromatography technique in 162 patients treated with 100 - 300 mg/kg/day of intravenous amoxicillin or cloxacillin.For both drugs and administration methods, plasma concentrations were significantly higher for patients with creatinine clearance below 60 ml/min, even though doses were adapted for renal impairment. the correlations calculated between plasma concentrations and creatinine level, creatinine clearance or doses were all low. There were fewer outlying drug concentrations in patients receiving continuous rather than intermittent regimens.Our results are in favor of adapting dosages of these beta-lactam antibiotics based on plasma concentrations, especially in cases of renal impairment.

Tissue distribution of cloxacillin after intramammary administration in the isolated perfused bovine udder.

BACKGROUND: Various intramammary suspensions containing cloxacillin benzathine are registered for use in cattle as antibiotics for intramammary use at drying off. To ensure antibacterial efficacy, the glandular tissue concentration of an antimicrobial agent must be sufficient. Since the possibilities to measure concentrations in the different areas of the glandular tissue in vivo are very limited, it was the aim of the present study to examine the distribution of cloxacillin in vitro using the isolated perfused bovine udder. METHODS: Mammary glands taken at slaughter from healthy lactating cows were perfused in vitro with warmed and gassed Tyrode solution. 600 mg cloxacillin benzathine were administered as Orbenin Extra Dry Cow by the intramammary route to six front and rear quarters each. Samples of glandular tissue--at different distances from and vertical to the teat right up to the udder base--were gathered from the treated quarters after 6 h. Perfusate was also sampled before and hourly after treatment for 6 h. The cloxacillin content of the tissue samples and perfusate samples was analysed by high performance liquid chromatography. RESULTS: The concentration of cloxacillin in the glandular tissue of front quarters measured 6 h after administration tended to decrease with increasing vertical distance from the teat. The decrease pattern of the concentration was not quite clear in rear quarters. A considerable variation in the tissue concentrations of cloxacillin was obvious, which reflects in vivo conditions. The concentrations measured in the perfusate samples were below the limit of quantification at all time points, indicating limited absorption of the antibiotic from the glandular tissue. CONCLUSION: After intramammary administration of the dry off product containing cloxacillin benzathine concentrations of more than 0.5 µg/g (MIC) were reached in all regions of the front and rear quarters.

Intracellular antimicrobial activity appearing as a relevant factor in antibiotic efficacy against an experimental foreign-body infection caused by Staphylococcus aureus.

OBJECTIVES: The presence of bacterial biofilm, tolerance to antibiotics and dysfunctional activity of phagocytic cells are all related to difficulties in eradicating foreign-body infections. We aimed to quantify the presence of intracellular Staphylococcus aureus and to study the extent to which the intracellular activity of antibiotics might determine their efficacy against an experimental rat tissue-cage model of foreign-body infection. METHODS: Using this model, animals were treated for 7 days with 100 mg/kg/day levofloxacin or 200 mg/kg/12 h cloxacillin, or were left untreated. Antibiotic efficacy was evaluated by means of bacterial counts from tissue-cage fluid (TCF); these counts were derived separately in total, intracellular and extracellular bacteria. The presence of intracellular bacteria was checked by electron microscopy. Population analysis was performed with surviving bacteria recovered at the end of levofloxacin therapy. RESULTS: Among a total number of bacteria (mean log cfu/mL +/- SD) from TCF of 6.86 +/- 0.6, we identified 6.38 +/- 0.8 intracellular bacteria and 5.57 +/- 0.5 extracellular bacteria. Levofloxacin was more efficient than cloxacillin (P < 0.05) against both intracellular and extracellular bacteria. The killing activity of levofloxacin against the intracellular population was higher than against the extracellular bacteria (P = 0.1). The frequency of levofloxacin-resistant mutants among surviving bacteria at the end of levofloxacin therapy was similar to that for the wild-type strain. CONCLUSIONS: Intracellular bacteria accounted for the largest proportion of the total inoculum in this model of foreign-body infection. The intracellular activity of an antibiotic seems to be an additional relevant factor in the antibiotic response to these infections.

Effect of multidrug resistance gene-1 (ABCB1) polymorphisms on the single-dose pharmacokinetics of cloxacillin in healthy adult Chinese men.

BACKGROUND: Plasma concentrations of cloxacillin have been found to vary as much as 20-fold among individuals receiving the same oral dose. There is evidence that cloxacillin may be a substrate for P-glycoprotein, suggesting that polymorphisms in the ABCB1 gene may be a contributing factor to the observed variability in plasma cloxacillin concentrations. OBJECTIVE: This study investigated the effect of ABCB1 polymorphisms on the pharmacokinetic profile of cloxacillin in healthy subjects. METHODS: A single oral dose of cloxacillin 500 mg was administered to healthy Chinese male subjects under fasting conditions. Serial blood and urine samples were collected for up to 6 hours after administration. A high-performance liquid chromatography method was used to determine plasma cloxacillin pharmacokinetics and urinary excretion. A polymerase chain reaction technique was used for genotyping of 3 single nucleotide polymorphisms (SNPs) of the ABCB1 gene: exon 12 C1236T, exon 21 G2677T/A, and exon 26 C3435T. Cloxacillin pharmacokinetic parameters and urinary excretion were then compared according to genotype and haplotype groups. RESULTS: The study included 18 healthy Chinese male subjects who ranged in age from 21 to 26 years, had a mean weight ranging from 55.6 to 70.6 kg, and had normal renal function at baseline (mean [SD] serum creatinine, 93.4 [11.0] micromol/L). Plasma concentrations of cloxacillin were generally lower in the group carrying the 1236CC genotype (n = 3) compared with those carrying the 1236CT genotype (n = 9) or the 1236TT genotype (n = 6). Compared with the other groups, carriers of the 1236CC genotype had a significantly lower mean Cmax (-53%; P = 0.013) and AUC(0-infinity) (-40%; P = 0.044), and a significantly higher mean apparent oral clearance (35%; P = 0.013). They also had significantly lower urinary excretion of cloxacillin over 6 hours (-52%; P = 0.027). There were no significant differences in cloxacillin t(1/2) or renal clearance between the 3 C1236T genotypes, nor was the G2677T or C3435T SNP associated with any significant changes in the cloxacillin pharmacokinetic profile. Among subjects with 1 of the 3 major haplotype pairs, those carrying the CGC/CGC pair had a significantly lower C(max) (P = 0.017), AUC (P = 0.032), and urinary excretion of cloxacillin (P = 0.026) compared with those carrying the CGC/TGC and TTT/TTT pairs. CONCLUSIONS: In this small population of healthy Chinese men, the C1236T variant of ABCB1 appeared to be an important contributor to interindi-vidual differences in plasma cloxacillin exposure, most likely through an effect on oral absorption rather than on disposition. Studies of multiple doses in larger sample sizes are needed to confirm these findings.

In vivo efficacy of moxifloxacin compared with cloxacillin and vancomycin in a Staphylococcus aureus rabbit arthritis experimental model.

We investigated the efficacies of moxifloxacin, cloxacillin, and vancomycin in a rabbit model of Staphylococcus aureus arthritis. No significant difference between therapeutic regimens was observed after a 7-day treatment. Oral moxifloxacin could be a suitable alternative to standard parenteral therapy for S. aureus arthritis.

Efficacy of high doses of levofloxacin in experimental foreign-body infection by methicillin-susceptible Staphylococcus aureus.

Antimicrobial efficacy in orthopedic device infections is diminished because of bacterial biofilms which express tolerance to antibiotics. Recently, the use of high doses of levofloxacin with rifampin has been recommended for staphylococcal infections. In the present study, we evaluated the efficacy of levofloxacin at doses of 50 mg/kg/day and 100 mg/kg/day (mimicking the usual and high human doses of 500 mg/day and 750 to 1,000 mg/day, respectively) and compared it to that of to linezolid, cloxacillin, vancomycin, and rifampin in a rat tissue cage model of experimental foreign-body infection by Staphylococcus aureus. The antimicrobial efficacy in vitro (by MIC, minimum bactericidal concentration, and kill curves) for logarithmic- and stationary-phase bacteria was compared with the in vivo efficacy. In vitro bactericidal activity at clinically relevant concentrations was reached by all drugs except rifampin and linezolid in the log-phase studies but only by levofloxacin in the stationary-phase studies. The bacterial count decreases from in vivo tissue cage fluids (means) for levofloxacin at 50 and 100 mg/kg/day, rifampin, cloxacillin, vancomycin, linezolid, and controls, respectively, were: -1.24, -2.26, -2.1, -1.56, -1.47, -1.15, and 0.33 (all groups versus controls, P < 0.05). Levofloxacin at 100 mg/kg/day (area under the concentration-time curve/MIC ratio, 234) was the most active therapy (P = 0.03 versus linezolid). Overall, in vivo efficacy was better predicted by stationary-phase studies, in which it reached a high correlation coefficient even if the rifampin group was excluded (r = 0.96; P < 0.05). Our results, including in vitro studies with nongrowing bacteria, pharmacodynamic parameters, and antimicrobial efficacy in experimental infection, provide good evidence to support the use of levofloxacin at high doses (750 to 1,000 mg/day), as recently recommended for treating patients with orthopedic prosthesis infections.

Assessment of antimicrobial transfer from treated to untreated mammary gland quarters by use of high-pressure liquid chromatography for detection of cloxacillin in milk samples from nonlactating dairy cows.

OBJECTIVE: To determine whether half-udder intramammary infusion of cloxacillin results in transfer of cloxacillin from treated to untreated mammary gland quarters within nonlactating cows, and, if so, at what concentrations, and to determine whether selection of ipsilateral versus diagonal-contralateral quarters for treatment affects cloxacillin transfer among quarters. ANIMALS: 20 Holstein-Friesian cows from a dairy herd. PROCEDURES: A within-cow half-udder comparison trial was used in which 2 of 4 mammary gland quarters (ipsilaterally or diagonally) received an intramammary infusion of cloxacillin on day 1 of the nonlactating period. Three days later, milk samples were taken from all untreated quarters and high-pressure liquid chromatography was used to detect and quantify milk cloxacillin concentrations. RESULTS: Cloxacillin was detected in 25% of all untreated mammary gland quarters. Mean cloxacillin concentration in untreated quarters was below minimum inhibitory concentrations for targeted mastitis pathogens. No significant difference in cloxacillin concentrations was found in the ipsilateral or diagonal treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: Within-cow half-udder comparison trials are valid for antimicrobial trials in nonlactating cows, although transfer of antimicrobials does occur in trace concentrations. Ipsilateral or diagonal-contralateral treatment designs perform similarly. This type of design is economical for researchers, although care must be taken to account for within-cow clustering of mammary gland quarter data.

Use of high-performance liquid chromatography (HPLC) to monitor beta-lactam plasma concentrations during the treatment of endocarditis.

Guidelines recommend high doses of beta-lactams for the therapy of endocarditis. This report describes a retrospective study of 15 endocarditis patients (median age 64 years), treated according to guidelines, whose beta-lactam trough plasma concentrations were measured with high-performance liquid chromatography because of tolerance or efficacy concerns. For amoxycillin, the mean level was 86.8 mg/L (range: 30-212 mg/L); five (45%) patients had concentrations > 1000 x MIC. For cloxacillin, the mean level was 47.9 mg/L (range: 16.7-104 mg/L). The consequences of high and unpredicted beta-lactam trough plasma concentrations for a prolonged period have not yet been thoroughly evaluated.

Effect of proguanil interaction on bioavailability of cloxacillin.

METHODS: To investigate a potential drug-drug interaction between proguanil (PG) and cloxacillin (Clox). Seven healthy adult volunteers received a single oral dose of Clox plus coadministration of single oral doses of PG and Clox in a simple cross-over manner after a wash-out period of 1 week. Total urine voided was collected at predetermined time intervals over 12 h. Amount of Clox in urine was determined by a reversed-phase high-pressure liquid chromatography method. RESULTS: The mean maximum excretion rate [(dDu/dt)max] of Clox when taken alone was 16.13 +/- 2.92 mg/h at tmax of 1.86 +/- 01.07 hours, whereas in the presence of PG, it was 7.72 +/- 3.24 mg/h at tmax of 2.43 +/- 00.98 hours (P < 0.0001). The total amount of Clox excreted in urine (Du infinity) in 12 h was markedly reduced by coadministration with PG by up to 48% with Du infinity of 49.57 +/- 8.16 mg after Clox alone and 25.81 +/- 8.46 mg in the presence of PG (P < 0.0001). The tmax and t1/2-values obtained from the excretion rate plot were lengthened by 23 and 34%, respectively, in the presence of PG but the differences were not statistically significant (P > 0.05). CONCLUSION: These pharmacokinetic values indicate slowed and diminished absorption (bioavailability) of Clox when concurrently administered with PG. The clinical implication is unknown. However, concomitant administration of the two drugs during antibacterial therapy should be done with caution so as to avoid subtherapeutic levels of Clox, which can lead to treatment failure and facilitate drug resistance.

Drug disposition in cystic fibrosis.

There are many pathological changes in patients with cystic fibrosis (CF) which can lead to alterations in drug disposition. Although, in patients with CF, the extent of drug absorption varies widely and the rate of absorption is slower, bioavailability is not altered. Plasma protein binding for the majority of drugs studied did not differ in patients with CF compared with control groups. The difference in volume of distribution of most drugs between patients with CF and healthy individuals vanished when corrected for lean body mass. Despite hepatic dysfunction, patients with CF have enhanced clearance of many, but not all, drugs. Phase I mixed-function oxidases are selectively affected: cytochrome P450 (CYP) 1A2 and CYP2C8 have enhanced activity, while other CYP isoforms such as CYP2C9 and CYP3A4 are unaffected. Increased phase II activities are also demonstrated: glucuronyl transferase, acetyl transferase (NAT1) and sulfotransferase. The increased hepatic clearance of drugs in the presence of CF may be the consequence of disease-specific changes in both enzyme activity and/or drug transport within the liver. The renal clearance (CLR) of many drugs in patients with CF is enhanced although there has been no pathological abnormality identified which could explain this finding: glomerular filtration rate and tubular secretion appear normal in patients with CF. The precise mechanisms for enhanced drug clearance in patients with CF remain to be elucidated. The optimisation of antibiotic therapy in patients with CF includes increasing the dose of beta-lactams by 20 to 30% and monitoring plasma concentrations of aminoglycosides. The appropriate dosage of quinolones has not been definitively established.