PENDALUHUAN

A fixed drug eruption (FDE) is an unusual and common adverse cutaneous reaction to an ingested
drug. Lesions usually develop 1-2 weeks after the first exposure. But with subsequent exposures,
they appear within 24 hours. FDE is characterised by the formation of one or a few, round, sharply
demarcated erythematous and oedematous plaques, bulla, or erosions. The lesions usually occur on
the lips, face, hands, feet and genitalia. If the patient is re-challenged with the offending drug, the
FDE occurs repeatedly at the identical skin site (i.e. fixed). They fade over several days, leaving a
residual post-inflammatory hyper-pigmentation. The most important characteristic feature of FDE is
recurrence of skin lesions at the same site of a previous involvement whenever the offending drug is
taken.

Ornidazole is a synthetic newer 5-nitroimidazole derivative and is commonly prescribed for amoebic
dysentery in developing countries as it has excellent activity against protozoa and anaerobic
microorganisms.Only Metronidazole and Tinidazole have been reported to cause FDEs with cross
sensitivity to each other (Kanwar et al., 1990 and Thami et al., 1998). On the other hand,
Ofloxacin is a synthetic antibiotic and belongs to the secondgeneration Fluoroquinolone and is used
to treat various bacterial infections. According to Food and Drug Association (FDA), the combination
of Ofloxacin and Ornidazole is irrational but is still prescribed and used extensively for treatment of
acute gastrointestinal infections. Both Ornidazole and Ofloxacin are known to cause FDE individually
as well as in combination. We report a case of FDE with fixed dose combination of Ofloxacin and
Ornidazole, with cross sensitivity to Metronidazole.

JURNAL 05

DEFENISI

Fixed drug eruptions (erythema fixum) are adistinctive variant of drug induced dermatosis with
characteristic recurrence at the same skin and/or mucosal sites after repeated administration of the
same drug. Sites of predilection include: lips, extremi-ties and genitalia; lesions are sharply
demarcated,round to oval measuring several centimeters in diam-eter. Erythema fixum presents as
solitary or multiplepatches, usually localized, however repeated episodesmight have increased the
number and size of thelesions, as described in the case presented herein.Pruritus and burning
sensation may well be associat-ed symptoms.

JURNAL 04

EPIDEMIOLOGI

Archive

The age range of the patients was 17 to 60 years with a mean age standard deviation of 36.110.9
years. The time interval between drug exposure and the development of genital FDE ranged from 1
day to 7 days with an average of 2.852.1 days. Eleven patients (30.6%) had a history of the same
lesions in the past. Eighteen patients (50%) had erythema in the genital area and 18 patients (50%)
had erythema and erosion in the genital area. The most common causative drug was co-trimoxazole
in 33 patients (91.7%), followed by aspirin, norfloxacin, and erythromycin, each used by 1 patient
(2.8%). In the genital area, the most frequent involved site was the glans penis in 22 patients
(61.1%), followed by the penis shaft in 11 patients (30.6 %) and the scrotum in 2 patients (5.6%).
One patient (2.8 %) had lesions on the penis shaft and scrotum at the same time. Considering the
involvement of other skin areas together with genital lesions, 27 patients (75%) had no lesions
elsewhere, 5 patients (13.9%) had lesions on the upper extremity, 2 patients (5.6%) had lesions on
the lower extremity, and one patient (2.8%) had lesions on the lip at the same time.

JURNAL 10

ETIOLOGI

which are almost exclu-sively prescription or proprietary medications. On rare occasions foods are
implicated,producing a fixed food reaction. The list of offending agents is extensive. The following
list includes the more common offenders, but is not all-inclusive. Medications:

PATOFISIOLOGI

Intraepidermal CD8 Tcells resident in the FDE lesions clearly have amajor contributory role in the
development of localized tissue damage. Resting FDE lesions long after clinical resolution are
characterized by signi-cant numbers of CD8 T cells with an effectormemory phenotype aligning
along the epidermal side of the dermoepidermal junction. These T cells are composed of a
phenotypically homogeneous population that expresses TCR-ab, CD3, CD8, CD45RA, and CD11b but
not CD27 and CD56 . This phenotype of T cells most closely resembles that of effector memory T
cells. These T cells are also found in intact epidermis at an exceedingly low level and are
phenotypically more heterogeneous in nature. Such accumulation of T cells with an effector
memory pheno- type has also been found at the site of repeated pathogen entry, such as the lung,
suggesting that these T cellsmay confer protective immunity. These T cells are also consistently
found at signicantly higher levels following infection in such tissues. In support of their protective
immune effector function, T cells with an effectormemory phenotype preferentially migrate into
the sites of infection, such as mucosal sites, and persist for long periods of time following infection, a
nding consistent with FDE lesions initially appearing at sites of previously traumatized skin, such as
burn scars and insect bites. Thus, the immune functions of intraepidermal CD8 T cells found in the

FDE lesions may be protective in nature and not alwaysdestructive. These ndings reinforce the
notion that intraepidermal CD8 T cells resident in the FDE lesions are critical in the initiation of
destructive immune responses while protecting the epidermis from repeated infections. In this
regard, we have recently noted that the vast majority of patients with FDE are asymptomatic HSV-
seropositive individuals without a previous history of clinical herpetic lesions [28]. In view of the
nding that anti-HSV IgG titers were much higher in these FDE patients than those with a history of
HSV recurrences, these intraepidermal CD8 T cells resident in the FDE lesions may represent
effectormemory T cells that are originally recruited from the circulation into the site of repeated
infections to mediate protective immunity. Intraepidermal CD8 T cells are not constitutively cyto-

lytic but, once activated via the CD3TCR complex, display a cytolytic activity against natural killer
(NK)- sensitive or NK-resistant tumor cells and cultured kera-tinocytes. They produce large amounts
of IFNg without proliferation, when activated in vivo and in vitro. The lack of an antigen-induced
proliferative response by these T cells makes it difcult to demon-strate their antigen specicity,
although some of these T cells may be self-reactive. Although our quanti-tative PCR analysis of
intraepidermal CD8 T cells isolated from resting FDE lesions demonstrated that they utilized a very
limited range of TCR Va and Vb gene families as compared with peripheral blood T cells obtained
from the same patients, neither has the antigen specicity of these CD8 T cells nor has the nature
of the self-antigens unmasked after drug intake has been determined. Tissue damage results when
intraepidermal CD8 T cells are activated to directly kill surrounding keratino-cytes and release large
amounts of cytokines such as IFNg into the localmicroenvironment. The main effector function of
intraepidermal CD8 T cells is mediated by IFNg, although the effector function also involves direct
cytolysis by perforin or Fas L. Probably, activation of intraepidermal T cells is sufcient for trig-gering
the lesion but not sufcient to cause extensive tissue damage observed in fully evolved lesions. Cyto-
kine or adhesion molecule-mediated nonspecic recruit-ment of CD4, CD8 Tcells and neutrophils
to a specic tissue site without recognition of their cognate antigen would serve to enhance tissue
damage, thereby contri-buting to the late stages of development of FDE lesions.

These intraepidermal CD8 T cells that have partici-pated in the early phase of the inammatory
cascade may have been diluted by the inux of such nonspecic recruitment of CD4 and CD8 T
cells. Thus, it is difcult to differentiate the effects of intraepidermal T cells fromthose secondarily
recruited fromthe circulation in a biopsy specimen obtained at a given time.

Although a severe form of FDE clinically and histologi- cally mimics TEN, subsequent evolution of the
two diseases is quite different. The former resolves spon- taneously upon discontinuation of the
causative drug,whereas the latter often results in a potentially fatal outcome even after withdrawal
of the drug. Our recent studies have important implications for populations that serve to prevent
disease progression to TEN; CD4FoxP3 regulatory T (Treg) cells were abundantly detected in the
fully evolved FDE lesions (24 h-oldlesions), which eventually resolved. The inux into the epidermis
of CD4 T cells, in particular Treg cells, during the evolution of drug reactions could reect an
appropriate response that may contribute to homeostatic control of potentially harmful immune
reactions mediated by intraepidermal CD8 T cells. These ndings suggest that FDE is a form of
classic delayed-type hypersensitivity (DTH) mediated by CD8 T cells. However, FDE lesions usually
appear within 2 h of clinical challenge with the causative drug, inconsistent with typical DTH
reactions. In this regard, we previously demonstrated that mast cells localized in the vicinity of the
epidermis in FDE lesions could be readily activated upon skin exposure to the causative drug. During
the initial phase of FDE reactions, mast cells are thought to contribute to the activation of

intraepidermal CD8 T cells through the induction of cell adhesion molecules on keratinocytes.
Furthermore, studies on in-vitro models showed that mast cells, which accumulate at sites of
previous FDE lesions, could accomplish this task by producing TNFa. Our sequential studies of
developing FDE lesions have demonstrated that the immediate wheal-and-are-like reaction is
followed by activation of intraepidermal CD8 Tcells.

Jurnal 01
MANIFESTASI KLINIK

FDE usually appears as a solitary or a small number of pruritic, well circumscribed, erythematous
macules that evolve into edematous plaques; these lesions typically re-solve after discontinuation of
the offending drug, leaving hyperpigmentation at the site of lesions (gure 1A). They recur in exactly
the same sites when rechallenged with each administration of the offending drug (gure 1B). The
appearance of these lesions is often preceded and accompa-nied by sensations of burning. Although
FDE may occur anywhere on the skin or mucous membrane, the most common locations are the lip,
palms, soles, glans penis, and groin areas. Discrete lesions often appear in the same bilaterally
symmetrical regions of the skin, particularly in the abdominal and the inner aspect of the arms and
legs.

Most FDE lesions occur with orally administered rather than injected drugs. In some patients,
however, FDE lesions can be caused after sexual intercourse with their partners taking the offending
drug.Although drugs causing FDE differ in countries depending on the availability of the various
drugs, themost frequent drugs associatedwith FDE are sulphonamides, tetracyclines, mefenamic
acid, and ter-binane. Although the incidence of FDE is generally thought to be decreasing,
particularly in the western world with the much lower usage of medications frequently asso- ciated
with the classic form, the unusual forms described below appear to be increasing rather than
decreasing in frequency, probably due to unawareness of the unusual presentations.

The diagnosis of FDE is not difcult for dermatologists even after clinical resolution, when there are
single or several round or oval, demarcated hyperpigmentations (gure 1A). The number of involved
sites and the size of the lesions often increase with repeated exposures. Systemic provocation is safe
and is still the most reliable method for establishing the etiologic agent in FDE; however, convincing
results can be also achieved with topical provo-cation of certain drugs when applied to sites of
previous FDE lesions. Positive reactions are usually obtained at the sites of previous FDE but no
reaction occurs on sites of previously unaffected skin. However, false negative results have been
reported, and have been attributed to either inadequate transepidermal penetration of the drug or
the requirement of metabolites of the drug not present in the testmaterial: vehicles and drugs that
can be used for topical provocation are still quite limited. Thus, a negative skin reaction gives no
reliable information.

Although a single drug is usually responsible for FDE, in some patients FDE lesions develop following
the ingestion of multiple drugs. This usually occurs when the offending drugs have common
chemical structures; however, in some cases, drugs or other agents with totally different chemical
structures can cause exacerbations precisely similar to those caused by the inducing drug, a
phenomenon known as polysensitivity . This phenomenon is much more frequent than is actually
reported and may have been over-looked in the past, because the lesions ared by these agents
could not generally be recognized as FDE and as a consequence, these cases would be
underdiagnosed. Indeed, evidence is accumulating to indicate that FDE lesions can be ared not only
by the original offending drug but also by nonspecic stimuli, including a particular food and stroking
with a pencil. Following each exacerbation, some patients with FDE demonstrate a refractory period,
during which the offending drug fails to activate the lesions. The duration of this period is variable,
lasting from a few weeks to several months. The eruption seems to wonder when sites involved
during one are are not involved during a subsequent are because of a prolonged refractory
period. Interestingly, despite the continued administration of the offending drug some lesions may
show a gradual decrease in the intensity of are and may even disappear.A similar desensitization
procedure may be successfully applied in the case of patients who cannot avoid the offending drug
for treatment. Thus, the diagnosis of FDE is made more complex by the recognition that
exacerbations precisely similar to those caused by the inducing drug can occur at the same sites not
only by drugs or agents of totally

different chemical structures but also by other nonspecic stimuli such as a combination of
cytokines. In some patients, the eruption can only be reproduced when multiple drugs are
administered in combination but not separately. This indicates that false negative results may be
seen when systemic provocation tests are per- formed separately with each constituent to identify
the chemical structure responsible for FDE, instead of the combined preparation, and suggests that
combinatorial interactions of each constituent with unique immunomodulatory properties might be
needed for full expression of the disease. Several less common clinical types of FDE have been
reported and will be described in the following sections.

Jurnal 09

DIAGNOSIS

The diagnosis of FDE is generally thought to be easy for many dermatologists even after clinical
resolution. How- ever, because the clinical spectrum is quite varied, the diagnosis of FDE is not as
straightforward as generally thought. FDE often presents with a wide spectrum of clinical
manifestations indistinguishable from those of other skin diseases, such as erythema multiforme, SJS
or TEN, cellulitis, paronychia, neutrophilic dermatosis, lichen planus, and parapsoriasis en pla-ques.
Such unusual forms of FDE may be easily overlooked unless clinicians take special care to recog- nize
the presence of such variants. As blister for-mation often occurs at an advanced stage of FDE reac-
tions in association with systemic symptoms such asfever, clinicians often nd a great deal of
difculty in distinguishing between a multiple, bullous variant of FDE and TEN, particularly when
bullous lesions become more widespread with systemic manifestations.

In addition, this variant does not leave typical hyperpig-mentation after clinical resolution as is
typically seen in nonpigmenting FDE [21], thus often leading to misdiag-nosis as TEN or bullous
pemphigoid. Careful history taking about drug intake and a prior history of recurrent lesions in the
same sites are essential for the precise diagnosis of FDE

JURNAL 01

Dermatologic Physical Exam

Primary Lesions

1. A sharply demarcated macule or plaque, color initially pink but rapidly becoming dusky violet or
violet-brown.

2. Surface vesicles or bullae. Bullae may be so large as to obscure the underlying inflammatory
macule or plaque.

Secondary Lesions
1. Moist erosions as bullae separate.

2. Deep dusky brown or gray-brown hyperpigmentation that persists.

Distribution

Microdistribution: None.

Macrodistribution: FDE may occur at any site on skin or mucous membranes. More common sites
include periorbital and perioral regions of the face, genitalia, and perianal areas.

Configuration

Plaques are usually round or oval

PENATALAKSANAAN

The first line treatment for FDE is prevention of attacks and recurrences, which is done simply by
avoiding the offended drug if possible. Discontinuation of the drug itself is usually the only necessary
treatment; in addition, topical corticosteroids might as well be effective in lesion regression.

Jurnal 04

The main goal

After a diagnosis of FDE, 54 patients (40.3%) did not receive any treatment, and 58 patients (43.3%)
used a topical steroid. A local treatment other than topical steroid was prescribed for 26 patients
(19.4%) and antihistamines were prescribed for 19 patients (14.2%). A systemic steroid equivalent to
prednisolone (26.019.2 mg) was prescribed for 15 patients (11.2%) for an average of 11.59.7
days. Patients with acute lesions were prescribed systemic steroids in 23.1% cases. Systemic steroid
use was not related to any causative drugs or to a multiplicity of FDE lesions. (aac)

KOMPLIKASI

Hyperpigmentation is the most likely complication of a fixed drug erution. The potential for infection
exists in the setting of multiple, eroded lesion. Generalized eruption have been reported following
topical and oral provocation testing.

PROGNOSIS

The prognosis is very good and an uneventful recovery should be expected. No deaths due to fixed
drug eruption have been reported. Residual hyperpigmentation is very common, but this is less likely
with the nonpigmenting variant.

Widespread lesions may initially mimic toxic epidermal necrolysis, but they have benign clinical
course. Again, localized hyperpigmentation is common complication, but pain, infectionand rarely.

PENCEGAHAN
Patients should be counseled on medication avoidance and possible cross-reactions of similiar
medications. Patients should notify their physicians of all drug allergies they have experienced.