Doxycycline

Placebo-controlled studies

Doxycycline 100 mg/day alone or in combination with diethylcarbamazine + albendazole has been used in a 6-week, double-blind, randomized, placebo-controlled field trial in patients with Brugia malayi infection [ ]. After 4 months of treatment with doxycycline (n = 119) or placebo (n = 42), the patients were given diethylcarbamazine 6 mg/kg + albendazole 400 mg or a matching placebo. The adverse effects of doxycycline were mild and included myalgia (n = 6), nausea (n = 4), dizziness (n = 5), headache (n = 3), insomnia (n = 2), abdominal pain (n = 2), itching (n = 2), diarrhea (n = 1), rash (n = 1), malaise (n = 1), and drowsiness (n = 1); none of the patients had to stop taking doxycycline because of adverse reactions. There were no reports of photosensitivity reactions. Adverse events in the placebo group (n = 42), were myalgia (n = 2), nausea (n = 1), dizziness (n = 2), insomnia (n = 1), and itching (n = 1). Adverse reactions were least common in those who took doxycycline + placebo and most common in those who took placebo and diethylcarbamazine + albendazole. There were significantly fewer patients with high fever and severe adverse reactions in those who took doxycycline and diethylcarbamazine + albendazole.

In a randomized, placebo-controlled trial in Ghana, 67 patients with onchocerciasis took doxycycline 200 mg/day for 4 or 6 weeks, followed by ivermectin 0.15 mg/kg after 6 months [ ]. After 6, 20, and 27 months, efficacy was evaluated by onchocercoma histology, PCR, and determination of microfilariae. Doxycycline resulted in endobacteria depletion and female worm sterilization; the 6-week regimen was macrofilaricidal, and over 60% of the female worms were found dead, despite the presence of new Wolbachia -containing worms acquired after the administration of doxycycline. Doxycycline could be developed as a second-line drug for onchocerciasis, to be administered in areas without transmission, in foci with ivermectin resistance, and in areas with Loa loa co-infections. Treatment with doxycycline was associated with bloody diarrhoea in one patient; it resolved after withdrawal and treatment with metronidazole, although day 3 may have been too early for antibiotic-associated colitis. Other adverse events were mild, did not last longer than 3 days, and did not occur more often after administration of doxycycline. No serious adverse events were observed.

In a randomized, placebo-controlled study in 150 patients with chronic meibomian gland dysfunction, doxycycline 20 or 200 mg bd both increased tear production and reduced symptoms [ ]. However, the high-dose group reported adverse effects more often than the low-dose group (18 versus 8, 39% versus 17%).

Doxycycline is currently used in the treatment of filariasis to deplete Wolbachia endosymbionts, which leads to inhibition of worm development, embryogenesis, fertility, and viability in onchocerciasis. In a double-blind, placebo-controlled trial of doxycycline 200 mg/day for 3 weeks, followed by standard antifilarial treatment (albendazole 400 mg + ivermectin 150 micrograms/kg) at month 4 in 44 individuals from the western region of Ghana with Wuchereria bancrofti infections adverse reactions to standard antifilarial treatment were similar in frequency between doxycycline and placebo [ ]. Moderate adverse reactions (increased body temperature and/or chills, papular rash, itching, and headache) occurred only with placebo followed by standard antifilarial treatment and were recorded in three of 17 patients. The severity of the adverse reactions was associated with microfilaremia, Wolbachia bacteria in the plasma, and proinflammatory cytokines in the plasma, in line with previous observations that suggest that adverse events after antifilarial treatment are related to the release of parasite-related antigens into the circulation.

Nervous system

Peripheral neuropathy from doxycycline has been reported [ ].

• A 61-year-old doctor with recurrent bronchopneumonia took two courses of doxycycline. During the first course he had persistent numbness in his feet. During the second course, a few months later, he noticed after only 2 or 3 days that the numbness accelerated markedly and was associated with a low threshold for muscle cramps in the feet. He stopped taking doxycycline and during the following weeks noticed slight improvement. However, some symptoms persisted and he had neurological investigations. A wide range of clinical and laboratory tests showed no cause for his neuropathy.

A search for an association between doxycycline and polyneuropathy failed to identify any documented cases. An inquiry to the Swedish Adverse Drug Reactions Advisory Committee elicited information about three cases of “paresthesia,” two cases of “sensitivity disturbance,” and one case of “neuropathy.” The last was a man who had had pain and paresthesia in the feet, arms, and face after taking doxycycline 100 mg/day for 2 weeks for prostatitis. The symptoms began to wane 1 week after treatment was stopped, and disappeared completely 1 week later.

Pseudotumor cerebri, or benign intracranial hypertension, is a diagnosis of exclusion made by the following criteria:

• signs and symptoms of increased intracranial pressure such as papilledema;

• normal cerebral anatomy as shown on imaging;

• increased intracranial pressure demonstrated on lumbar puncture;

• normal cerebrospinal fluid (CSF) composition.

It can occur either as a primary condition or secondary to medications, and minocycline has long been known to cause it [ , ]. Doxycycline has rarely been implicated [ , ], but another case has been reported [ ].

• A 23-year-old woman took oral doxycycline 100 mg bd for acne and after 5–8 weeks developed worsening headaches associated with occasional nausea and blurred vision. Physical examination was normal except for bilateral papilledema. A lumbar puncture showed a mildly raised pressure with no cerebrospinal fluid abnormalities. She felt substantially better soon after the lumbar puncture. An MRI scan of the brain was unremarkable and ruled out dural sinus thrombosis. Pseudotumor cerebri was suspected and doxycycline was withdrawn. Her headache, nausea, and blurred vision resolved after 1 week and the papilledema after 3 months.

Pseudotumor cerebri typically occurs in obese women in their 30s and 40s, and has been described in two patients taking doxycycline [ ].

• A slightly overweight 21-year-old woman presented with headaches and blurred vision after taking doxycycline 100 mg/day for malaria prophylaxis during a 3-week vacation. She had severe papilledema with hemorrhages and cotton wool spots. Lumbar puncture showed an increased opening pressure of 52 cm of fluid, and intracranial hypertension was diagnosed. Doxycycline was withdrawn, and her symptoms gradually resolved.

• A slightly overweight 19-year-old woman presented with vomiting, headache, and blurred vision after taking doxycycline 100 mg/day for malaria prophylaxis over about 4 months. Her vision was severely reduced and her visual fields constricted. She had papilledema with hemorrhages and cotton wool spots. Lumbar puncture showed an increased cerebrospinal fluid pressure of over 40 cm of fluid. Intracranial hypertension was diagnosed and doxycycline was withdrawn. Her symptoms stabilized and the disc swelling resolved, but optic atrophy developed. Color vision and visual fields remained poor, with an estimated 70% loss of vision.

The authors concluded that doxycycline should be prescribed with caution to overweight women of childbearing age or with a history of idiopathic intracranial hypertension and that awareness of this adverse drug reaction in travellers should be increased to allow prompt withdrawal of the causing drug and appropriate medical therapy in affected individuals.

Metabolism

Doxycycline can cause hypoglycemia.

• A 70-year-old man with type 2 diabetes mellitus presented with sudden confusion, which rapidly progressed to loss of consciousness [ ]. The only drug he had taken during the previous 2 months was doxycycline (100 mg/day), which he had taken for 5 days for an upper respiratory tract infection. Urine tests for sulfonylureas were negative. Routine hematological and biochemical tests and an electrocardiogram were normal. He improved with intravenous glucose and withdrawal of doxycycline and had no further episodes of hypoglycemia over the next 3 months.

Plasma insulin was not measured in this case, so the mechanism of hypoglycemia was unclear.

Hypoglycemia has also been attributed to doxycycline in a non-diabetic patient [ ].

Teeth

Four patients with brucellosis developed yellow-brown discoloration of permanent teeth after taking doxycycline 200 mg/day for 30–45 days [ ]. In all cases, the staining completely resolved and the teeth recovered their original color after abrasive dental cleaning. The authors suggested that staining of the permanent dentition associated with doxycycline may be much commoner than reported, especially if the drug is taken during the summer months, and that strict avoidance of sunlight exposure during high-dose, long-term doxycycline therapy may prevent this complication.