Population pharmacokinetics of doxycycline in the tears and plasma of northern elephant seals (Mirounga angustirostris) following oral drug administration.

OBJECTIVE: To assess tear and plasma concentrations of doxycycline following oral administration to northern elephant seals (Mirounga angustirostris). DESIGN: Pharmacokinetic study. ANIMALS: 18 juvenile northern elephant seals without signs of ocular disease. PROCEDURES: Study seals were receiving no medications other than a multivitamin and were free from signs of ocular disease as assessed by an ophthalmic examination. Doxycycline (10 or 20 mg/kg [4.5 or 9.1 mg/lb]) was administered orally every 24 hours for 4 days. Tear and plasma samples were collected at fixed time points, and doxycycline concentration was assessed by means of liquid chromatography-tandem mass spectrometry. Concentration-time data were calculated via noncompartmental analysis. RESULTS: Following administration of doxycycline (10 mg/kg/d, PO), maximum plasma doxycycline concentration was 2.2 µg/mL at 6.1 hours on day 1 and was 1.5 µg/mL at 4.0 hours on day 4. Administration of doxycycline (20 mg/kg/d, PO) produced a maximum plasma doxycycline concentration of 2.4 µg/mL at 2.3 hours on day 1 and 1.9 µg/mL at 5.8 hours on day 4. Doxycycline elimination half-life on day 4 in animals receiving doxycycline at a dosage of 10 or 20 mg/kg/d was 6.7 or 5.6 hours, respectively. Mean plasma-to-tear doxycycline concentration ratios over all days were not significantly different between the low-dose (9.85) and high-dose (9.83) groups. For both groups, doxycycline was detectable in tears for at least 6 days following cessation of dosing. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of doxycycline at the doses tested in the present study resulted in concentrations in the plasma and tears of northern elephant seals likely to be clinically effective for treatment of selected cases of systemic infectious disease, bacterial ulcerative keratitis, and ocular surface inflammation. This route of administration should be considered for treatment of corneal disease in northern elephant seals and possibly other related pinniped species.

Experimental determination of a subantimicrobial dosage of doxycycline hyclate for treatment of periodontitis in Beagles.

OBJECTIVE: To identify a subantimicrobial dose of doxycycline hyclate (SDD) and for the treatment of periodontitis in dogs. ANIMALS: 20 healthy Beagles for measurement of serum doxycycline concentration and 15 Beagles with periodontitis for evaluation of the efficacy of the SDD. PROCEDURES: 5 dogs each received doxycycline hyclate PO at a dose of 1, 2, 3, or 5 mg/kg. Blood samples were collected before and after administration, and serum concentrations of doxycycline were measured via high-performance liquid chromatography. Mean serum doxycycline concentrations were calculated, and SDDs were identified. In a separate trial, the identified SDDs (1 or 2 mg/kg) were administered PO once a day for 1 month to dogs with periodontitis (n = 5/group) and a control group (5) was fed vehicle only during the same period. Degree of gingival attachment and bleeding on probing (present or absent) were recorded. Gingival samples were collected before and after the 1-month period from the same anatomic sites. Degree of matrix metalloproteinase inhibition in gingival samples was determined via gelatin zymography and compared among treatment groups. RESULTS: Mean serum doxycycline concentrations in healthy dogs that received 1 or 2 mg of doxycycline/kg were consistently significantly lower than the minimal inhibitory doxycycline concentration for treatment of periodontitis throughout the 24-hour posttreatment period. Zymographic intensities were lower in dogs given 1 and 2 mg/kg than in the control dogs, and the degree of gingival attachment and bleeding significantly improved in dogs given 2 mg/kg, compared with in the control dogs and dogs given 1 mg of doxycycline/kg. CONCLUSIONS AND CLINICAL RELEVANCE: A doxycycline dosage of 2 mg/kg daily appeared to be an appropriate subantimicrobial regimen for dogs with periodontitis. Furthermore, this dosage may be suitable for long-term treatment of gelatinolytic inflammatory diseases such as periodontitis in this species.

Serum and tissue concentrations of doxycycline in broilers after the sub-cutaneous injection of a long-acting formulation.

1. The antibacterial agent doxycycline hyclate (Dox) is usually administered to broilers in drinking water or as a feed supplement. Parenteral injection is not the usual route for administration, so a long-acting formulation (Dox-LA) was tested to evaluate if serum concentrations can achieve the pharmacokinetic/pharmacodynamic (PK/PD) ratios regarded as adequate for the drug. 2. A poloxamer-based matrix was used to provide Dox-LA. Serum and tissue concentrations of Dox vs time were determined in two day-old broilers after subcutaneous (SC) injection of Dox-LA or oral administration of a single bolus of aqueous Dox (Dox-PO), at a dose of 20 mg/kg. Weight gain, feed conversion rate, haematological variables, aspartate aminotransferase and alanine aminotransferase activities, blood urea and creatinine were determined and compared for Dox-LA with Dox-PO and non-medicated controls. 3. Dox-LA had a high relative bioavailability (1200%). Maximum serum concentrations were not statistically different (5·1 ± 1·1 µg/ml for Dox-LA and 6·1 ± 1.4 µg/ml for Dox-PO), but half-life of Dox-LA was much greater than the value obtained for Dox-PO (73·0 ± 0·9 h and 2·0 ± 0·02 h, respectively). Tissue concentrations were higher, and stayed higher for longer periods in the Dox-LA group. 4. In conclusion, considering the minimum effective serum concentration against Mycoplasma spp is 0·5 µg/ml, a dose-interval of 180 h can be achieved with Dox-LA, but only for 24 h after Dox-PO. Better PK/PD ratios for Dox-LA should result in improved clinical outcomes compared with Dox-PO.

Doxycycline stabilizes vulnerable plaque via inhibiting matrix metalloproteinases and attenuating inflammation in rabbits.

Enhanced matrix metalloproteinases (MMPs) activity is implicated in the process of atherosclerotic plaque instability. We hypothesized that doxycycline, a broad MMPs inhibitor, was as effective as simvastatin in reducing the incidence of plaque disruption. Thirty rabbits underwent aortic balloon injury and were fed a high-fat diet for 20 weeks. At the end of week 8, the rabbits were divided into three groups for 12-week treatment: a doxycycline-treated group that received oral doxycycline at a dose of 10 mg/kg/d, a simvastatin-treated group that received oral simvastatin at a dose of 5 mg/kg/d, and a control group that received no treatment. At the end of week 20, pharmacological triggering was performed to induce plaque rupture. Biochemical, ultrasonographic, pathologic, immunohistochemical and mRNA expression studies were performed. The results showed that oral administration of doxycycline resulted in a significant increase in the thickness of the fibrous cap of the aortic plaque whereas there was a substantial reduction of MMPs expression, local and systemic inflammation, and aortic plaque vulnerability. The incidence of plaque rupture with either treatment (0% for both) was significantly lower than that for controls (56.0%, P<0.05). There was no significant difference between doxycycline-treated group and simvastatin-treated group in any serological, ultrasonographic, pathologic, immunohistochemical and mRNA expression measurement except for the serum lipid levels that were higher with doxycycline than with simvastatin treatment. In conclusion, doxycycline at a common antimicrobial dose stabilizes atherosclerotic lesions via inhibiting matrix metalloproteinases and attenuating inflammation in a rabbit model of vulnerable plaque. These effects were similar to a large dose of simvastatin and independent of serum lipid levels.

Influence of mycotoxins and a mycotoxin adsorbing agent on the oral bioavailability of commonly used antibiotics in pigs.

It is recognized that mycotoxins can cause a variety of adverse health effects in animals, including altered gastrointestinal barrier function. It is the aim of the present study to determine whether mycotoxin-contaminated diets can alter the oral bioavailability of the antibiotics doxycycline and paromomycin in pigs, and whether a mycotoxin adsorbing agent included into diets interacts with those antibiotics. Experiments were conducted with pigs utilizing diets that contained blank feed, mycotoxin-contaminated feed (T-2 toxin or deoxynivalenol), mycotoxin-contaminated feed supplemented with a glucomannan mycotoxin binder, or blank feed supplemented with mycotoxin binder. Diets with T-2 toxin and binder or deoxynivalenol and binder induced increased plasma concentrations of doxycycline administered as single bolus in pigs compared to diets containing blank feed. These results suggest that complex interactions may occur between mycotoxins, mycotoxin binders, and antibiotics which could alter antibiotic bioavailability. This could have consequences for animal toxicity, withdrawal time for oral antibiotics, or public health.

PK and PK/PD of doxycycline in drinking water after therapeutic use in pigs.

A commercial doxycycline formulation was administered in drinking water to 12 pigs at the recommended dose of 10 mg/kg daily for 5 days. The mean plasma concentration at steady-state was 1.37 +/- 1.21 microg/mL, which was reached at 68 +/- 27.2 h postadministration. Absorption and elimination half-life values were 7.20 +/- 2.42 and 7.01 +/- 2.10 h, respectively. Most plasma concentrations during dosing were higher than the minimum inhibitory concentrations (MICs) described for the main porcine bacterial pathogens of the respiratory tract (Pasteurella multocida, Actinobacillus pleuropneumoniae, Bordetella bronchiseptica and Mycoplasma hyopneumoniae). It is concluded that when pigs were treated with doxycycline in drinking water at the recommended rate, therapeutically effective concentrations were achieved throughout the treatment period, supporting the clinical use of this tetracycline in the control of respiratory infections. However, inter-animal differences were marked.

Correlation between ratio of serum doxycycline concentration to MIC and rapid decline of antibody levels during treatment of Q fever endocarditis.

Endocarditis is the major clinical manifestation of chronic Q fever. Although doxycycline along with hydroxychloroquine remains the mainstay of medical therapy for Q fever endocarditis, there are wide variations in the rapidity of the patient's decline of antibody levels during such therapy. We undertook a retrospective examination of whether there was any correlation between the ratio of serum concentration to MIC of doxycycline and response to treatment in patients with Q fever endocarditis. Included herein are 16 patients from whom Coxiella burnetii was isolated from cardiac valve materials. Serology and measurement of doxycycline and hydroxychloroquine serum levels were performed and recorded after 1 year of treatment. The MIC of doxycycline for C. burnetii isolates was determined using the shell vial assay in a real-time quantitative PCR assay. At the completion of a year-long therapy with doxycycline-hydroxychloroquine, all those that showed a low decline of antibody levels (n = 6) (i.e., <2-fold decrease in antibody titer to phase I C. burnetii antigen) had a ratio of serum doxycycline concentration to MIC between 0.5 and 1. In contrast, those having a ratio of > or =1 showed a rapid decline of phase I antibody levels (n = 9; P < 0.05). The only patient who died had a serum doxycycline-to-MIC ratio of <0.5, and the isolate of C. burnetii cultured from this patient was resistant to doxycycline (MIC = 8 microg/ml). The ratio of serum doxycycline concentration to MIC should be monitored during the course of therapy in patients with Q fever endocarditis.

Continuous periaortic infusion improves doxycycline efficacy in experimental aortic aneurysms.

OBJECTIVE: We created a novel continuous infusion system to evaluate the efficacy of juxta-aortic doxycycline delivery as a transitional step toward developing hybrid drug/device treatment strategies for abdominal aortic aneurysm (AAA) disease. METHODS: Controlled comparison of treatment outcomes was studied in animal models with molecular and morphologic tissue analysis in a collaboration between university and corporate research laboratories. Rat AAAs were created via porcine pancreatic elastase (PPE) infusion and grouped and analyzed by subsequent treatment status (either doxycycline in vehicle or vehicle alone) and drug delivery method (continuous infusion via periaortic delivery system [PDS] or twice-daily subcutaneous injection). The main outcome measures were AAA diameter via direct measurement, medial elastin lamellar preservation via light microscopy, mural smooth muscle cell (SMC) proliferation and SMC and macrophage density via immunostaining and counting, expression of matrix metalloproteinases 2, 9, and 14 and tissue inhibitors of metalloproteinases 1 and 2 via real-time reverse transcriptase-polymerase chain reaction, and enzymatic activity via substrate zymography. Serum drug levels were analyzed via liquid chromatography/mass spectroscopy. RESULTS: PDS (1.5 mg/kg/day) and subcutaneous (60 mg/kg/day) delivery methods caused comparable reductions in AAA diameter during the period of 14 days after PPE infusion. PDS rats gained more weight during the postoperative period (P <.001), possibly as a result of reduced serum drug levels and systemic toxicity. Doxycycline treatment reduced AAA macrophage infiltration and SMC proliferation significantly. Despite reduced diameter, circumferential elastic lamellar preservation was not apparent in doxycycline-treated AAAs. CONCLUSIONS: Continuous periaortic infusion lowers the effective doxycycline dose for experimental AAA limitation. Alternative biologic inhibition strategies might also be amenable to direct intra-aortic or juxta-aortic delivery. Periaortic infusion might improve the clinical outcome of minimally invasive AAA treatment strategies. Clinical relevance Aneurysm remodeling may continue after successful endovascular AAA exclusion. Continued proteolytic activity within the aneurysm wall potentiates late graft migration and failure. The doxycycline infusion system developed in these experiments may serve as a prototype for adjuvant treatment modalities that complement endovascular AAA exclusion. Local delivery of doxycycline or other agents active in AAA disease, either continuously or at selected intervals after graft implantation, may stabilize the wall and aid in maintaining aneurysm exclusion. Alternative delivery methods could include passive diffusion from either the graft material itself or treatment reservoirs incorporated into endografts. Given the recognized limitations of current technologies, adjuvant biologic therapies have the potential to improve long-term patient outcome significantly after endovascular exclusion.

Pharmacokinetics of doxycycline after administration as a single intravenous bolus and intramuscular doses to non-lactating Egyptian goats.

The pharmacokinetics of doxycycline hydrochloride (DoxHcl) at a dose of 5 mg kg-1 BW was studied after an intravenous (i.v.) bolus and intramuscular (i.m.) injections in non lactating goats. A microbiological assay employing Bacillus subtilis as the test organism was used to measure its concentrations in serum and urine. Following a single i.v. injection, the serum concentration-time curves of doxycycline hydrochloride were best represented by a two-compartment open model. The drug was rapidly distributed and slowly eliminated with half-lives of distribution (t1/2 alpha) and elimination (t1/2 beta) of 0.52 and 4.62 h, respectively. After i.m. injection of the same dose, the peak serum concentration C(max) was 1.60 microg ml-1 attained at 0.86 h (Tmax). Following i.v. and i.m. injections, the concentrations of doxycycline in urine were much higher than that in serum. Urinary drug concentrations decreased gradually till reaching its lowest detectable level 12 and 24h post-injections, respectively. The extent of serum protein binding percent was 32.8% and the systemic bioavailability was 99.40% after i.m. injection of 5 mg kg-1 BW

Efficacy of enrofloxacin or doxycycline for treatment of Bartonella henselae or Bartonella clarridgeiae infection in cats.

Enrofloxacin and doxycycline are antimicrobial agents used to treat bacterial diseases of cats. In vitro susceptibility data indicate that either drug should be effective against Bartonella species. In vivo efficacies of these drugs for eradication of chronic Bartonella henselae or Bartonella clarridgeiae infections were examined in 18 experimentally infected cats and 25 naturally exposed cats treated with enrofloxacin (22.7 mg given orally [PO] every 12 h [q12h] [14 days, n = 10; 28 days, n = 13]) or with doxycycline (25 mg PO q12h [14 days, n = 9; 28 days, n = 8]) or not treated (n = 3). Plasma drug concentrations were determined in experimental cats by high-performance liquid chromatography. Only 23 of 43 cats enrolled ultimately met inclusion criteria. Bacteremia was eliminated for 12 to 25 weeks posttreatment in four of seven cats receiving 14 days of enrofloxacin, five of seven cats receiving 28 days of enrofloxacin, one of six cats receiving 14 days of doxycycline, and one of two cats receiving 28 days of doxycycline. Defining a negative result by blood culture as treatment success may be erroneous; these results may reflect the insensitivity of blood culture or the relapsing nature of Bartonella bacteremia. Our results suggest that MICs obtained with axenic media do not predict antimicrobial activity against intracellular Bartonella, that a long treatment course is required to eliminate infection, and that duration of therapy correlates with pretreatment bacterial load. Given current concern about the development of antimicrobial resistance, we would reserve recommendation for treatment to cats owned by an immunocompromised individual or as an alternative to euthanasia of a pet.

Administration of doxycycline hydrochloride via drinking water to turkeys under laboratory and field conditions.

A series of experiments were carried out in order to determine doxycycline hydrochloride (DoxHCl) plasma levels in 6-wk-old turkeys medicated via drinking water containing DoxHCl at a concentration of 250 mg/L under laboratory and field conditions. Maximal plasma concentration (Cmax) values of 5.7 (+/-1.0) microgram/mL and 4.9 (+/-1.4) micrograms/mL obtained after DoxHCl administration during 2 and 7 d, respectively, were not significantly different. A significant difference was found between the area under the plasma concentration-time profile, calculated between 0 and 168 h (AUC(0-168)), Cmax, and the minimal plasma concentration (Cmin) values obtained after medication with a DoxHCl solution at a concentration of 250 mg/L (431.9 +/- 96.6 micrograms.h/mL, 4.9 +/- 1.4 micrograms/mL and 0.7 +/- 0.3 microgram/mL) and after medication with a DoxHCl solution at a concentration of 750 mg/L (1,176.5 +/- 201.8 micrograms.h/mL, 12.5 +/- 2.7 micrograms/mL and 2.9 +/- 0.4 micrograms/mL), respectively. The increase in body weight was also significantly higher for turkeys medicated with a DoxHCl solution at a concentration of 750 mg/L (83.7 g/d) than for the lower concentration (35.6 g/d). The DoxHCl solution uptake significantly decreased with the increase of DoxHCl concentration. A Cmax value of 1.7 +/- 0.6 micrograms/mL and a Cmin value of 0.5 +/- 0.1 microgram/mL were observed during the field experiment. Water consumption under laboratory conditions was followed for tap water (70 +/- 50 mL/kg.d) and for a DoxHCl solution at a concentration of 250 mg/L supplemented with 1 g anhydrous citric acid/L (119 +/- 6 mL/kg.d) and revealed to be not significantly different. The variability was significantly higher for tap water than for the DoxHCl solution. The stability of the DoxHCl solution containing 1 g citric acid/L over 24 h was 99% expressed as the percentage of the initial concentration.

Randomised controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by Vibrio cholerae 01 or 0139.

BACKGROUND: Effective antimicrobial therapy can reduce the duration and volume of cholera diarrhoea by half. However, such treatment is currently limited by Vibrio cholerae resistance to the drugs commonly prescribed for cholera, and by the difficulties involved in the administration of multi-drug doses under field conditions. Because of its favourable pharmacokinetics we thought it likely that single-dose ciprofloxacin would be effective in the treatment of cholera. METHODS: In this double-blind study treatment was either a single 1 g oral dose of ciprofloxacin plus doxycycline placebo, or a single 300 mg oral dose of doxycycline plus ciprofloxacine placebo. 130 moderately or severely dehydrated men infected with V cholerae 01 and 130 infected with V cholerae 0139 were randomly assigned treatment. Patients stayed in hospital for 5 days. We measured fluid intake and stool volume every 6 h, and a sample of stool for culture was obtained daily. The primary outcome measures were clinical success--the cessation of watery stool within 48 h; and bacteriological success--absence of V cholerae from cultures of stool after study day 2. FINDINGS: Among patients infected with V cholerae 01, treatment was clinically successful in 62 (94%) of 66 patients who received ciprofloxacin and in 47 (73%) of 64 who receive doxycycline (difference 21% [95% Cl 8-33]); the corresponding proportions with bacteriological success were 63 (95%) and 44 (69%) (27% [14-39]). Among patients infected with V cholerae 0139, treatment was clinically successful in 54 (92%) of 59 patients who received ciprofloxacin and in 65 (92%) of 71 who received doxycycline (< 1% [-9 to 9]), and bacteriologically successful in 58 (98%) and 56 (79%), respectively (19% [9-30]). Total volume of watery stool did not differ significantly between ciprofloxacin-group and doxycycline-group patients infected with either V cholerae 01 or 0139. All but one of the V cholerae 01 and all of the 0139 isolates were susceptible in vitro to doxycycline, whereas 48 (37%) of the V cholerae 01 isolates and none of the 0139 isolates were resistant to tetracycline. Treatment clinically failed in 14 (52%) of 27 doxycycline-treated patients infected with a tetracycline-resistant V cholerae 01 strain, compared with three (8%) of 37 patients infected with a tetracycline-susceptible strain (44% [23-65]). INTERPRETATION: Single-dose ciprofloxacin is effective in the treatment of cholera caused by V cholerae 01 or 0139 and is better than single-dose doxycycline in the eradication of V cholerae from stool. Single-dose ciprofloxacin may also be the preferred treatment in areas where tetracycline-resistant V cholerae are common. In V cholerae, in-vitro doxycycline susceptibilities are not a useful indicator of the in-vivo efficacy of the drug.

Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys.

Concentrations of penicillin, doxycycline, and ciprofloxacin were measured by bioassay in sera of rhesus monkeys treated with these drugs for inhalation anthrax. Antibiotic doses were determined on the basis of published serum concentration data from humans and comparative body surface area calculations for humans and rhesus monkeys. The antibiotics were well tolerated. Serum peak and trough concentrations of penicillin, doxycycline, and ciprofloxacin, respectively, averaged 2.7 and 0.8, 1.31 and 0.26, and 1.22 and 0.14 microgram/mL. These were within the range usually observed with standard oral doses in humans, and peak concentrations in all monkeys exceeded the MICs for 90% of Bacillus anthracis strains.

Antibiotic treatment of acute salpingitis. A study of plasma concentrations of two tetracyclines (doxycycline and lymecycline).

A group of 782 patients with a diagnosis of acute salpingitis (a few of the patients because of other infection in the pelvis) were treated with the recommended oral dose of doxycycline (200 mg the first day and 100 mg once daily for at least the following 9-12 days) in combination with 1 g benzyl penicillin and 0.6 g procaine penicillin twice daily intramuscularly for 5-7 days. The plasma concentrations of doxycycline were determined on the third day of treatment before the next dose was given. In 26.5% of the patients the concentrations were below 1 microgram/ml plasma, considered as the minimum therapeutic level. The dose of doxycycline was increased to 200 mg a day in these patients and the plasma concentrations increased accordingly. In another group of 80 patients, 40 were treated with the standard doxycycline dose, and the other 40 patients with the standard lymecycline dose (300 mg twice a day). The plasma concentrations, determined before the dose on the third day, were below 1 microgram/ml in 35% of the patients treated with doxycycline, and in 5% of those treated with lymecycline. Since acute salpingitis in most cases is a serious complication to a lower genital tract infection, often a sexually transmitted disease caused by tetracycline-sensitive organisms, the importance of achieving and determining the therapeutic plasma concentrations of tetracyclines is stressed.