Tissue Distribution of Doxycycline in Animal Models of Tuberculosis.

Doxycycline, an FDA-approved tetracycline, is used in tuberculosis in vivo models for the temporal control of mycobacterial gene expression. In these models, animals are infected with recombinant Mycobacterium tuberculosis carrying genes of interest under transcriptional control of the doxycycline-responsive TetR-tetO unit. To minimize fluctuations of plasma levels, doxycycline is usually administered in the diet. However, tissue penetration studies to identify the minimum doxycycline content in food achieving complete repression of TetR-controlled genes in tuberculosis (TB)-infected organs and lesions have not been conducted. Here, we first determined the tetracycline concentrations required to achieve silencing of M. tuberculosis target genes in vitro Next, we measured doxycycline concentrations in plasma, major organs, and lung lesions in TB-infected mice and rabbits and compared these values to silencing concentrations measured in vitro We found that 2,000 ppm doxycycline supplemented in mouse and rabbit feed is sufficient to reach target concentrations in TB lesions. In rabbit chow, the calcium content had to be reduced 5-fold to minimize chelation of doxycycline and deliver adequate oral bioavailability. Clearance kinetics from major organs and lung lesions revealed that doxycycline levels fall below concentrations that repress tet promoters within 7 to 14 days after doxycycline is removed from the diet. In summary, we have shown that 2,000 ppm doxycycline supplemented in standard mouse diet and in low-calcium rabbit diet delivers concentrations adequate to achieve full repression of tet promoters in infected tissues of mice and rabbits.

Hollow mesoporous carbon nanospheres for imaging-guided light-activated synergistic thermo-chemotherapy.

Carbon-based light-activated materials can absorb optical energy to generate photoacoustic (PA) signals for imaging or transduce optical photons to thermal energy, which holds great promise for biomedical applications. Herein, we synthesize hollow and mesoporous carbon nanospheres (HMCNs) with uniform size on a large scale. The properties of hollow cavity and mesoporous structures make the HMCNs achieve high drug loading (480 mg DOX per g HMCNs). The present intense near infrared (NIR) absorbance achieves excellent photoacoustic imaging ability and photothermal conversion efficacy (32.0%). More interestingly, the encapsulated drugs can have a triggered release under NIR irradiation. The investigations in vitro and in vivo demonstrate that HMCNs have excellent biocompatibility, and accumulate in tumors by the enhanced permeability and retention (EPR) effect. Moreover, under NIR irradiation, in vivo evaluation shows that HMCNs can perform strong PA imaging, and induce great tumor inhibition by the combination of chemotherapy and PTT under the guidance of photoacoustic imaging. The present study provides new insight for design of novel biocompatible light-activated carbons for cancer nanotheranostics.

Pharmacokinetics and tissue depletion of doxycycline administered at high dosage to broiler chickens via the drinking water.

The recommended use of doxycycline (DC) to broiler chicken is 100 mg/L via the drinking water and a 7-day withdrawal time (WDT). However, study of a higher dosage is desirable because of the possible increase of antimicrobial resistance and disease spectrum. Tissue DC residues exceeding the current maximum residue levels (MRL) was our major concern. Therefore, serum concentration and tissue depletion of DC hyclate after administration of 200 mg/L of DC in the drinking water for five consecutive days were studied. The steady-state DC concentration (8.3 ± 0.9 µg/mL) was reached on the third day of medication. The elimination constant (0.05 ± 0.01 1/h), half-life (14.9 ± 1.4 h), area under concentration versus time curve (81.0 ± 9.9 h·µg/mL) and mean residence time (22.7 ± 2.5 h) were obtained using a non-compartmental pharmacokinetic model. It was determined that the current 7-day WDT regulation was still legitimate for the kidney and liver as well as for the breast and leg muscles, which were estimated by linear regression analysis of the 99% upper distribution limit. The unregulated heart and gizzard were considered safe even when the lowest MRL of muscle (100 ng/g) was applied. While at the present time the extra-label use of drugs is only allowed under specific conditions, in the future it may become necessary to increase the general dosage of DC, and the current results suggest a safe range of DC hyclate in chicken; however, skin/fat tissue residues warrant further studies.

Multifunctional poly(ß-amino ester) hydrogel microparticles in periodontal in situ forming drug delivery systems.

In situ forming implants (ISIs) formed from poly(lactic-co-glycolic acid) (PLGA) have been commercialized for local drug delivery to treat periodontitis, but drug release from these bulk materials is typically subject to an initial burst. In addition, PLGA has inferior material properties for the dynamic mechanical environment of gingival tissue. In this work, poly(ß-amino ester) (PBAE) hydrogel microparticles were incorporated into a PLGA matrix to provide several new functions: mechanical support, porosity, space-filling, and controlled co-delivery of antimicrobial and osteogenic drugs. First, the effects of PBAE microparticles on ISI architecture and material properties throughout degradation were investigated. Second, the influence of PBAE microparticles on drug release kinetics was quantified. Over a 15 d period, ISIs containing PBAE microparticles possessed greater porosity, ranging from 42-80%, compared to controls, which ranged from 24-54% (p < 0.001), and these ISIs also developed significantly greater accessible volume to simulated cell-sized spheres after 5 d or more of degradation (p < 0.001). PBAE-containing ISIs possessed a more uniform microarchitecture, which preserved mechanical resilience after cyclical loading (p < 0.001), and the materials swelled to fill the injected space, which significantly increased interfacial strength in an artificial periodontal pocket (p < 0.0001). PBAE microparticles eliminated the burst of freely-mixed simvastatin compared to 36% burst from controls (p < 0.0001), and high-dose doxycycline release was prolonged from 2 d to 7 d by pre-loading drug into the microparticles. PBAE-containing PLGA ISIs are more effective space-filling scaffolds and offer improved release kinetics compared to existing ISIs used to treat periodontitis.

Nanoparticulate delivery of agents for induced elastogenesis in three-dimensional collagenous matrices.

The degradation of elastic matrix in the infrarenal aortic wall is a critical parameter underlying the formation and progression of abdominal aortic aneurysms. It is mediated by the chronic overexpression of matrix metalloprotease (MMP)-2 and MMP-9, leading to a progressive loss of elasticity and weakening of the aortic wall. Delivery of therapeutic agents to inhibit MMPs, while concurrently coaxing cell-based regenerative repair of the elastic matrix represents a potential strategy for slowing or arresting abdominal aortic aneurysm growth. Previous studies have demonstrated elastogenic induction of healthy and aneurysmal aortic smooth muscle cells and inhibition of MMPs, following exogenous delivery of elastogenic factors such as transforming growth factor (TGF)-ß1, as well as MMP-inhibitors such as doxycycline (DOX) in two-dimensional culture. Based on these findings, and others that demonstrated elastogenic benefits of nanoparticulate delivery of these agents in two-dimensional culture, poly(lactide-co-glycolide) nanoparticles were developed for localized, controlled and sustained delivery of DOX and TGF-ß1 to human aortic smooth muscle cells within a three-dimensional gels of type I collagen, which closely simulate the arterial tissue microenvironment. DOX and TGF-ß1 released from these nanoparticles influenced elastogenic outcomes positively within the collagen constructs over 21 days of culture, which were comparable to that induced by exogenous supplementation of DOX and TGF-ß1 within the culture medium. However, this was accomplished at doses ~20-fold lower than the exogenous dosages of the agents, illustrating that their localized, controlled and sustained delivery from nanoparticles embedded within a three-dimensional scaffold is an efficient strategy for directed elastogenesis. Copyright © 2014 John Wiley & Sons, Ltd.

Nanoparticle-Assisted Combinatorial Therapy for Effective Treatment of Endometriosis.

Endometriosis is characterized by the presence of endometrial glands and stroma outside the uterine cavity. Conventional treatment modalities for endometriosis are unsatisfactory; therefore, there is a need to treat the underlying causes and mechanism. Oxidative stress, extracellular matrix degradation, and angiogenesis are associated with the pathogenesis of endometriosis. The anti-angiogenic and antioxidant properties of epigallocatechin gallate and the matrix metalloproteinase inhibitory activity of the antibiotic doxycycline are well established. However, epigallocatechin gallate and doxycycline have several limitations when used in their native forms. This motivated us to synthesize dual drug-loaded (epigallocatechin gallate and doxycycline) nanoparticles and check their therapeutic efficacy in mice with induced endometriosis. The synthesized nanoparticles displayed features of a promising drug-delivery system, such as small size, high encapsulation efficiency, controlled drug release, and low toxicity. The serum of endometriosis-induced mice and controls was assessed for various oxidative stress markers, matrix-degrading enzymes, and angiogenic markers before and after nanoparticle administration. Endometrial glands, stroma, and new microvessels were determined using histochemistry and immunohistochemistry. Treatment with dual drug-loaded nanoparticles markedly decreased oxidative stress, matrix metalloproteinase activity, and angiogenesis, as well as endometrial gland presence and microvessel density. Mitigation of endometriosis-related adverse effects further produced an improvement in the quality of oocytes, which is critical for successful pregnancy outcomes. Our observations suggest that owing to their combinatorial effect, poly(lactic-co-glycolic) acid nanoparticles loaded with epigallocatechin gallate and doxycycline in a single vehicle appear to be promising for the treatment of endometriosis.

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.

Doxycycline-loaded ß-tricalcium phosphate release following EDTA root surface etching improved the clinical outcomes in chronic periodontitis: an in vivo study.

BACKGROUND: The main objective of the present study is to quantify doxycycline (DOX) release from ß-tricalcium phosphate (ß-TCP) after EDTA root surface treatment. METHODS: Thirty systemically healthy patients with ≥1 paired contralateral interproximal intrabony defect ≥4 mm deep along with an interproximal probing depth ≥6 mm and clinical attachment level ≥4 mm were randomized into two groups. Group 1 (G1) consisted of sites treated with open flap debridement followed by placement of DOX blended with ß-TCP (DOX-ß-TCP), whereas group 2 (G2) sites were treated with flap surgery followed by the placement of DOX blended with ß-TCP after EDTA etching of the exposed root surfaces (DOX-ß-TCP + EDTA). Samples of gingival crevicular fluid (GCF) were obtained 1, 3, 7, 14, and 21 days after surgery. Quantitative measurements of DOX were taken with high-performance liquid chromatography. Clinical evaluation and follow-up for 6 months were performed. RESULTS: At 21 days, the DOX-ß-TCP + EDTA-treated group showed a 194.7 µg/mL value. The DOX-ß-TCP + EDTA-treated group retained more DOX during the periods of 3, 7, 10, 14, and 21 days than the DOX-ß-TCP-treated group. Six months after therapy, DOX-ß-TCP + EDTA-treated sites showed more significant clinical improvements compared to DOX-ß-TCP-treated sites (P ≤ 0.05). CONCLUSIONS: EDTA root surface etching enhances DOX availability in the GCF following its release from ß-TCP as a drug carrier.

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.

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.

Use of pradofloxacin to treat experimentally induced Mycoplasma hemofelis infection in cats.

OBJECTIVE: To evaluate the efficacy of the fluoroquinolone pradofloxacin in the treatment of cats experimentally infected with Mycoplasma hemofelis. ANIMALS: 23 young adult specific-pathogen-free cats. PROCEDURES: Cats were inoculated with M hemofelis from a chronically infected donor and assigned to 1 of 4 treatment groups: a doxycycline group, a low-dose-pradofloxacin group, a high-dose-pradofloxacin group, and an untreated control group. Treatment was initiated for 14 days when M hemofelis infection was detected via PCR assay and clinical signs of hemoplasmosis were present. Cats that had negative PCR assay results after treatment were administered a glucocorticoid and monitored via PCR assay for an additional 4 weeks. RESULTS: All cats yielded positive results for M hemofelis via conventional PCR and quantitative PCR assays and developed anemia. The low-dose-pradofloxacin group had significantly lower M hemofelis copy numbers than the doxycycline group. Six cats treated with pradofloxacin yielded negative results during treatment. Of those cats, 4 yielded negative conventional PCR assay results and all yielded negative quantitative PCR assay results for M hemofelis 1 month after administration of high-dose glucocorticoids. CONCLUSIONS AND CLINICAL RELEVANCE: Pradofloxacin had anti-M hemofelis effects similar to those of doxycycline. In addition, pradofloxacin may be more effective at long-term M hemofelis organism clearance than doxycycline.

Administration of doxycycline in drinking water for treatment of spiral bacterial infection in cockatiels.

OBJECTIVE: To determine efficacy of providing drinking water medicated with doxycycline for treatment of spiral bacterial infection in cockatiels. DESIGN: Randomized controlled clinical trial. Animals-18 cockatiels (Nymphicus hollandicus) naturally infected with spiral bacteria. PROCEDURES: Spiral bacterial infection was diagnosed by means of cytologic examination of swab specimens from the choana and oropharynx. Eleven birds (treatment group) were given drinking water to which doxycycline hyclate had been added at a concentration of 400 mg/L for 30 days; the remaining 7 birds (control group) were given unmedicated water. After completion of the study, 6 control birds were treated with drinking water medicated with doxycycline for 21 days. RESULTS: Daily mean plasma doxycycline concentration for birds in the treatment group ranged from 2.26 to 2.86 Mg/mL (overall range, 0.83 to 4.34 Mg/mL). All treated birds were negative for spiral bacteria after treatment for 21 days and remained negative when examined 160 days after treatment ended. Control birds remained positive for spiral bacteria. Control birds treated with doxycycline after completion of the study were negative for spiral bacteria after treatment for 21 days and 30 days after treatment ended. No clinically important adverse effects were associated with treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that providing drinking water to which doxycycline had been added at a concentration of 400 mg/L was effective in eliminating spiral bacterial infections in cockatiels.

Comparison of 2 antibiotics that inhibit protein synthesis for the treatment of infection with Yersinia pestis delivered by aerosol in a mouse model of pneumonic plague.

INTRODUCTION: Intentional release of Yersinia pestis will likely be propagated by aerosol exposure. We explored the effects of neutropenia on the outcome of doxycycline and gentamicin therapy. METHODS: Female BALB/c mice were exposed to 20 LD(50) of Y. pestis CO92 by aerosol. Treatments were saline (negative control), levofloxacin at 15 mg/kg every 12 h (positive control), doxycycline at 40 mg/kg every 6 h, and gentamicin at 12 mg/kg every 6 h, 24 mg/kg every 12 h, and 48 mg/kg every 24 h in cohorts of normal and neutropenic mice for 5 days. RESULTS: Control mice died. Positive control mice (levofloxacin) had 100% survivorship in both neutropenic and nonneutropenic groups. Doxycycline treatment in the presence of granulocytes yielded 90% survivorship; all neutropenic mice died after the termination of treatment (P<<.001). For gentamicin, survivorship of mice receiving drug every 24, 12, and 6 h was, respectively, 80%, 80%, and 90% for normal mice and 80%, 100%, and 70% for neutropenic mice. No significant differences were seen in the neutropenia versus normal mouse comparison or by schedule. CONCLUSIONS: Doxycycline behaves in vivo as a bacteriostatic drug, requiring an intact immune system for clearance of the infection after aerosol challenge with Y. pestis. Gentamicin is bactericidal, even when given on a daily schedule. Neutropenia did not significantly affect survivorship.

Development and evaluation of novel biodegradable microspheres based on poly(d,l-lactide-co-glycolide) and poly(epsilon-caprolactone) for controlled delivery of doxycycline in the treatment of human periodontal pocket: in vitro and in vivo studies.

This study reports on the development of novel biodegradable microspheres prepared by water-in-oil-water (W/O/W) double emulsion technique using the blends of poly(d,l-lactide-co-glycolide) (PLGA) and poly(epsilon-caprolactone) (PCL) in different ratios for the controlled delivery of doxycycline (DXY). Doxycycline encapsulation of up to 24% was achieved within the polymeric microspheres. Blend placebo microspheres, drug-loaded microspheres and pristine DXY were analyzed by Fourier transform infrared spectroscopy (FT-IR), which indicated no interaction between drug and polymers. Differential scanning calorimetry (DSC) on drug-loaded microspheres confirmed the polymorphism of DXY and indicated a molecular level dispersion of DXY in the microspheres. Scanning electron microscopy (SEM) confirmed the spherical nature and smooth surfaces of the microspheres produced. Mean particle size of the microspheres as measured by dynamic laser light scattering method ranged between 90 and 200 mum. In vitro release studies performed in 7.4 pH media indicated the release of DXY from 7 to 11 days, depending upon the blend ratio of the matrix. Up to 11 days, DXY concentrations in the gingival crevicular fluid were higher than the minimum inhibitory concentration of DXY against most of the periodontal pathogens. One of the developed formulations was subjected to in vivo efficacy studies in thirty sites of human periodontal pockets. Significant results were obtained with respect to both microbiological and clinical parameters up to 3 months even as compared to commercial DXY gel. Statistical analyses of the release data and in vivo results were performed using the analysis of variance (ANOVA) method.

Pharmacokinetics of enrofloxacin and its efficacy in comparison with doxycycline in the treatment of Chlamydophila felis infection in cats with conjunctivitis.

The concentrations of enrofloxacin were measured in the tears, saliva and serum of 14 cats with signs of upper respiratory tract infection and eight with no signs, after daily doses of 5 mg/kg. Enrofloxacin concentrations above the minimum inhibitory concentration of Chlamydophila felis were found in the saliva and tears of the cats with and without signs of upper respiratory tract infection. In a prospective randomised clinical trial, the efficacy of enrofloxacin against C. felis infection in cats with conjunctivitis was compared with the efficacy of doxycycline. Twenty-five cats were randomly assigned to treatment with either enrofloxacin or doxycycline for 14 days; 15 of the cats tested positive for C. felis by an immunofluorescent antibody test on conjunctival swabs. The two treatment groups showed equal improvements in the clinical signs of conjunctivitis and C. felis infection status; in each group three cats were still C. felis antigen-positive after the 14-day course of treatment, indicating a persistent infection. No side effects were observed in the cats treated with enrofloxacin.

Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis.

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 microM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.

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.

Review of treatment options for lyme borreliosis.

Lyme borreliosis (Lyme disease) is the most common tick-borne bacterial infection and the incidence is increasing in parts of Europe and the USA. Prompt antimicrobial therapy using oral agents such as doxycycline or amoxicillin is successful among more than 90% of patients. Inadequate penetration of oral agents into the CNS may result in the development of overt neuroborreliosis. The parenteral agent ceftriaxone is the drug of choice for severe acute and chronic infections, due to good penetration into CSF, convenient single daily dosage regimen and proven high efficacy in clinical trials involving a wide variety of disseminated infections. Regardless of therapeutic agent, there appears to a small minority of patients (<10%) who do not respond; such cases may be due to long-term persistence of borrelial cysts and to misdiagnoses based solely on seropositivity. Several adjunct therapies are available, including hyperbaric oxygen therapy and immune system supplements, but clinical trials have yet to be conducted.

Pharmacokinetics of oral doxycycline during combination treatment of severe falciparum malaria.

The pharmacokinetics of oral doxycycline administered at 200 mg every 24 h were investigated in 17 patients recovering from severe Plasmodium falciparum malaria. The data suggest that the doses of doxycycline currently recommended (circa 3.5 mg/kg of body weight daily) may not be optimal.