Discussion
Drug-induced skin reactions are one of the most commonly observed adverse effects of drugs. Skin reactions could be induced by almost any type of drug, but some drugs including antiepileptics, antibiotics, and non-steroidal anti-inflammatory drugs (NSAIDs) are more frequently reported to be associated with these reactions. Cutaneous drug reactions could be mild and self-limiting or severe and life-threatening, including photosensitivity, pigmentary disorders, alopecia, fixed drug eruptions, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), vasculitis, etc [5, 6]. Fluoroquinolones are a widely used group of antibiotics. The third generation of quinolones like levofloxacin act against gram-positive, gram-negative, and atypical agents, and is one of the second-line treatments of TB. Fluoroquinolones have an acceptable safety profile. Gastrointestinal and neurologic complications are among the most common adverse effects. In contrast, cutaneous adverse reactions are relatively rare. TEN, hypersensitivity reactions, drug reaction with eosinophilia and systemic symptoms (DRESS), leukocytoclastic vasculitis, and fixed drug eruption have been associated with levofloxacin exposure [7, 8].
Lorente et al [9] reported a 71-year-old male who developed blue-gray pigmentation on limbs and trunk after two months of exposure to levofloxacin Skin biopsy was taken and showed hemosiderin-like deposits in macrophages and myoepithelial cells and fibroblasts in the superficial and deep dermis. Redondo et al [10] reported a 72-year-old man who had been receiving levofloxacin for several months and dark discoloration of the legs appeared a few weeks after exposure to the drug. Skin biopsy revealed brown granular cytoplasm in macrophages and confirmed the diagnosis. Connors et al [11] introduced a 58-year-old male with brown-gray hyperpigmentation 20 days after initiation of levofloxacin. In contrast to the previous reports, skin discoloration was in a photosensitive distribution. Similarly, pefloxacin, another member of the fluoroquinolone Family, was reported to be associated with skin hyperpigmentation in the legs [12].
In our case, the resolution of skin changes after discontinuation of the culprit drug and the timing association between levofloxacin exposure and the onset of the skin changes confirmed the causality of levofloxacin. Therefore, we did not take a skin biopsy from our patient. The specific feature of our patient was developing alopecia. As far as we know no previous article reported alopecia in association with levofloxacin or other quinolones. Three well-known types of drug-related alopecia are anagen effluvium (caused by cytotoxic chemotherapy drugs), telogen effluvium, and idiopathic androgenic alopecia (caused by drugs with androgen activity) [13]. In our patient, we detected alopecia areata with ophiasis pattern which did not fit any of the mentioned types.
The approach to resistance to isoniazid for TB treatment depends on the time of detection of resistance. Isoniazid-resistant TB (Hr-TB) treatment is expected to be started if either of the following circumstances applies [14]:
1) Hr-TB is confirmed and rifampicin resistance ruled out before TB treatment is started – in such cases, the 6-month course of (H)REZ-Lfx regimen is started immediately. If the diagnosis is strongly presumed (e.g. close contacts of a confirmed Hr-TB source case) but results of DST are still pending, the regimen may be introduced. Should DST results taken at the start eventually show susceptibility to isoniazid, then levofloxacin is stopped and the patient continues treatment in order to complete a 2HREZ/4HR regimen.
2) Hr-TB is discovered after the start of treatment with the 2HREZ/4HR regimen (this includes patients who had undiagnosed isoniazid resistance at the start or who developed isoniazid resistance while on first-line treatment) – in such cases, rapid molecular testing for rifampicin resistance must be done (or repeated). Once rifampicin resistance has been excluded, a full 6-month course of (H)REZ-Lfx is given. The duration is driven by the need to give levofloxacin for 6 months.
All medicines in this regimen are to be used daily for 6 months. When fixed-dose combination formulations are used, isoniazid is included but is not obligatory for the regimen. If levofloxacin cannot be used because there is fluoroquinolone resistance or intolerance or other contraindications to the use of fluoroquinolone, then 6(H)REZ may be prescribed daily for 6 months.
In the present case, considering the existing conditions and the lack of knowledge of resistance to rifampin at the beginning of the treatment, the challenge was the possibility of developing resistance to rifampin during the period of time that isoniazid was used. So he was asked on two occasions for a gene expert experiment, which confirmed the sensitivity to rifampin. Since during the hospitalization following the discontinuation of the drugs, the edema of the limbs and scaling disappeared, and the hyperpigmentation became less, these symptoms were attributed to drug side effects, and since these symptoms occurred after the initiation of levofloxacin, this drug is the first defendant that was abandoned from the treatment regimen.
We conclude that skin discoloration could be a potential adverse effect of levofloxacin which resolves gradually after discontinuation of the drug. Clinicians should be aware of this potential complication for appropriate diagnosis and treatment.