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.