Scrub typhus meningoencephalitis occurring during doxycycline therapy for Orientia tsutsugamushi.

We report on a scrub typhus patient who contracted meningoencephalitis during doxycycline administration. This is the first case of scrub typhus in which doxycycline concentrations were measured in serum and cerebrospinal fluid. Clinicians should be alerted to the possibility that meningoencephalitis can occur because of inadequate maintenance of serum doxycycline level caused by antacids administered along with doxycycline.

Oral doxycycline for treatment of neurosyphilis in two patients infected with human immunodeficiency virus.

The frequency of syphilis has been increasing during the past 5 years primarily among men who have sex with men, many of whom are infected with the human immunodeficiency virus (HIV). Data on treatment options other than intravenous or intramuscular penicillin for syphilis are very limited. We describe two HIV-infected patients with asymptomatic neurosyphilis who were successfully treated with oral doxycycline. The first patient was a 45-year-old Hispanic man with well-suppressed HIV RNA who had a positive Venereal Disease Research Laboratory (VDRL) titer of 1:128. His cerebral spinal fluid (CSF) revealed a positive VDRL titer of 1:16, and an elevated white blood cell count of 96 cells/mm(3) and protein level of 89 mg/dl. He received high-dose doxycycline 200 mg twice/day for 28 days. Two months later, his CSF VDRL titer, white blood cell count, and protein level decreased to 1:4, 5 cells/mm(3), and 60 mg/dl, respectively. The second patient was a 37-year-old Caucasian man with complications from acquired immunodeficiency disease. A routine VDRL titer was found to be 1:64. Although the CSF VDRL was nonreactive, both his white blood cell count and protein level were elevated at 29 cells/mm(3) and 46 mg/dl, respectively. High-dose doxycycline 200 mg twice/day was prescribed for 28 days. Three months later, the patient's VDRL titer decreased to 1:2; his CSF white blood cell count decreased significantly to 1 cell/mm(3), and his protein level was within normal limits. Clinicians should be aware that an extended course of high-dose, oral doxycycline may be an effective and safe alternative regimen to intravenous or intramuscular penicillin, without requiring hospitalization or home health care, for the treatment of neurosyphilis in HIV-infected patients. Prospective trials are needed to assess the long-term efficacy oral doxycycline for neurosyphilis.

A sensitive cell-based assay to measure the doxycycline concentration in biological samples.

Doxycycline (DOX) is widely used as a pharmacological agent and as an effector molecule in inducible gene expression systems. For most applications, it is important to determine whether the DOX concentration reaches the level required for optimal efficacy. We developed a sensitive bioassay for measuring the DOX concentration in biological samples. We used a modified HeLa cell line with the luciferase reporter gene under the control of the DOX-inducible Tet-On system for regulation of gene expression. These HeLaDOX cells constitutively express a novel variant of the rtTA transcriptional activator protein that is highly DOX-sensitive. Incubation of the cells with a DOX-containing biological sample triggers luciferase expression, which can be quantitated by standard methods. This bioassay is sensitive, with a DOX detection limit of 22 ng/ml in plasma. The assay was used to determine the DOX concentration in plasma derived from DOX-treated rhesus macaques and mice. Furthermore, we found that the DOX concentration in murine cerebrospinal fluid is 31-fold lower than the concurrent plasma DOX level. This bioassay for the quantification of DOX concentration in biological samples has several advantages over high-performance liquid chromatography-based and microbiological assays: (1) multiple samples can be assayed in a single experiment; (2) only small sample volumes are required; (3) the assay has a low detection limit; and (4) the assay can be performed in any cell culture laboratory.

Study of intragastric administration of doxycycline: pharmacokinetics including body fluid, endometrial and minimum inhibitory concentrations.

The objectives of this study were to determine the pharmacokinetics and tissue concentrations of doxycycline after repeated intragastric administration, and to determine the minimum inhibitory concentrations (MIC) for equine pathogenic bacteria. In experiment 1, 2 mares received a single intragastric dose of doxycycline hyclate (3 mg/kg bwt). Mean peak serum concentration was 0.22 microg/ml 1 h postadministration. In experiment 2, 5 doses of doxycycline hyclate (10 mg/kg bwt), dissolved in water, were administered to each of 6 mares via nasogastric tube at 12 h intervals. The mean +/- s.e. peak serum doxycycline concentration was 0.32+/-0.16 microg/ml 1 h after the first dose and 0.42+/-0.05 microg/ml 2 h after the fifth dose. The mean trough serum concentrations were > 0.16 microg/ml. Highest mean synovial concentration was 0.46+/-0.13 microg/ml and highest mean peritoneal concentration was 0.43+/-0.07 microg/ml, both 2 h after the fifth dose. Highest urine concentration was mean +/- s.e. 145+/-25.4 microg/ml 2 h after the last dose. Highest endometrial concentration was mean +/- s.e. 1.30+/-0.36 microg/ml 3 h after the fifth dose. Doxycycline was not detected in any of the CSF samples. Mean +/- s.e. Vd(area) was 25.3+/-5.0 l/kg and mean t1/2 was 8.7+/-1.6 h. In experiment 3, minimum inhibitory concentrations of doxycycline were determined for 168 equine bacterial culture specimens. The MIC90 was < or = 1.0 microg/ml for Streptococcus zooepidemicus and 0.25 microg/ml for Staphylococcus aureus. Based on drug concentrations achieved in the serum, synovial and peritoneal fluids and endometrial tissues and MIC values determined in the present study, doxycycline at a dose of 10 mg/kg bwt per os every 12 h may be appropriate for the treatment of infections caused by susceptible (MIC < 0.25 microg/ml) gram-positive organisms in horses.

Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis.

Concentrations of doxycycline and penicillin G in serum and cerebrospinal fluid (CSF) were analyzed in 46 patients during treatment for neuroborreliosis. Twenty patients were treated intravenously with penicillin G at 3 g every 6 h (q6h), and 26 patients were treated orally with doxycycline at 200 mg q24h. All samples were collected on day 13 of treatment. The median concentrations of penicillin G in serum were 0.5, 37, and 5.6 micrograms/ml before and 1 and 3 h after drug administration, and that in CSF was 0.5 (range, 0.3 to 1.6) microgram/ml after 2 to 3 h. The median concentrations of doxycycline in serum were 2.1, 6.1, and 4.7 micrograms/ml before and 2 and 6 h after drug administration, and that in CSF was 0.6 (range, 0.4 to 2.5) microgram/ml after 4 h. All patients had concentrations of penicillin G or doxycycline in CSF above the lowest reported MICs of penicillin G (0.003 microgram/ml) and doxycycline (0.12 microgram/ml) for Borrelia burgdorferi. However, no patients had a drug concentration in CSF above the highest reported MIC of penicillin G (8 micrograms/ml), and only one had a drug concentration in CSF above the highest reported MIC of doxycycline (2 micrograms/ml), despite good clinical response to treatment. No treatment failure or relapse was observed during a 1-year follow-up, although one patient treated with penicillin G and one treated with doxycycline were retreated because of residual pain. The chosen dosages of penicillin G and doxycycline seem to give sufficient concentrations in serum and CSF for the treatment of neuroborreliosis.

Penetration of doxycycline into cerebrospinal fluid in patients treated for suspected Lyme neuroborreliosis.

Twelve patients were treated orally with 100 mg of doxycycline twice a day (b.i.d.) and 10 patients were treated with 200 mg b.i.d. for suspected tick-borne neuroborreliosis (Lyme borreliosis). At 5 to 8 days after the start of therapy, the mean concentrations in serum were 4.7 micrograms/ml for the doxycycline dose of 100 mg b.i.d. and 7.5 micrograms/ml for 200 mg b.i.d., 2 to 3 h after the last drug administration. The corresponding levels for cerebrospinal fluid were 0.6 and 1.1 micrograms/ml. Since a doxycycline concentration in cerebrospinal fluid above the estimated MIC for Borrelia burgdorferi (0.6 to 0.7 microgram/ml) is wanted in patients treated for severe neuroborreliosis, the higher dose is preferable.

Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent or neurosyphilis.

Five patients with laboratory evidence of latent or neurosyphilis were treated orally with doxycycline (200 mg) twice a day for 21 days. After the seventh dose, the mean level of doxycycline in serum was 5.8 micrograms/ml, with a mean drug level in cerebrospinal fluid of 1.3 micrograms/ml. The mean penetration into cerebrospinal fluid was 26%. These preliminary findings suggest that doxycycline, administered orally at a dose of 200 mg twice a day, reaches a sufficient concentration in cerebrospinal fluid to be worthy of further evaluation as an alternative regimen to penicillin therapy for latent or neurosyphilis.

Interference with human memory by an antibiotic.

Thirty-two volunteers learned a sentence after awakening from early in the first REM period of sleep and recalled it after awakening from the third REM period, under experimental conditions that controlled for state dependency. The tetracycline antibiotic doxycycline (200 mg), taken at bedtime, impaired recall possibly through a putative inhibitory action on brain protein synthesis.

The penetration of doxycycline into CSF.

After single oral or intravenous doses of doxycycline the concentrations found in the spinal fluid did not exceed 0.1 mcg/ml. Daily oral administration for 2-10 days gave a level in the spinal fluid of 0.1-0.76 mcg/ml. The mean value, 0.37 mcg/ml, corresponded to 14% of the concentrations found in serum. Further studies of the penetration of doxycycline in patients with a damaged blood-brain barrier should be performed before doxycycline can be recommended for the treatment of CNS-infections.

[The pharmacokinetics of doxycycline in kidney insufficiency in geriatric patients compared to younger adults]. / Die Pharmakokinetik von Doxycyclin bei Niereninsuffizienz und geriatrischen Patienten im Vergleich zu jüngeren Erwachsenen

In young adults i.v. injection of 200 mg doxycycline was followed by a rapid fall in serum levels in the first 30 minutes and than a slow decrease (serum concentration after 24 h on average 1.0 mug/ml). Biological half-life was 11.9 h, final distribution volume 50.0 litres and urine recovery 70%. After oral administration of 200 mg doxycycline the serum peaks measured were 3.4 mug/ml (2 1/2 h later). With repeated doses of 100 mg every 24 h serum peaks were 2.8 mug/ml and serum concentrations after 24 h 0.8-0.9 mug/ml (urine recovery 43%). The area under the curve was 25.5% less than after i.v. injection. In 7 adults with chronic renal failure the half-life of doxycycline varied between 10 and 24 h. With repeated oral administration of doxycycline (100 mg every 24 h) there was no accumulation of the drug in blood. During hemodialysis (Stuttgart kidneys, Rhône-Poulenc plates) doxycycline injected i.v. was eliminated as rapidly as before. In renal failure doxycycline may be given in the same dosage as where renal function is normal. In 12 geriatric patients without renal disease, serum levels of doxycycline after i.v. injection of 200 mg were not significantly different from those of young adults (distribution volume 46.2 +/- 16.2 litres). It can therefore be assumed that tissue penetration of the drug is similar in the elderly and in young adults.