Case report :

AMOXYCILLIN AND CLAVULANIC ACID INDUCED

STEVENS-JOHNSON SYNDROME: A CASE REPORT

ABSTRACT
Stevens-Johnson syndrome (SJS) is an immune mediated hypersensitivity reaction. Significant involvement of
oral, nasal, eye, vaginal, urethral, GI and lower respiratory tract mucous membrane may develop. It is usually a
reaction due to a medication or due to an infection. In 95 % of case reports, drugs were found to be an important
cause for the development of SJS. In this case report, a 32 year old female reported chief complaint of itch skin
eruptions all over the body along with erosive lesions on tongue, lips, buccal mucosa and genital mucosa. The
reaction occurred after administration of augmentin (containing amoxycillin and clavulanic acid). She was
treated
with antimicrobials, antiallergics and conservative management. The patient improved and was discharged from
the hospital. Causality assessment using Naranjo Adverse Drug Reaction Probability Scale revealed that
amoxycillin and clavulanic acid combination was a possible cause for the adverse reaction with a score of 4.

Keywords: Stevens-Johnson syndrome, amoxycillin and clavulanic acid, hypersensitivity, lesions, Naranjo
Adverse Drug Reaction Probability scale

INTRODUCTION
Stevens-Johnson syndrome (SJS) is a rare but very serious disorder of skin and mucous
membranes. It is usually a reaction due to a medication or due to an infection. It is considered
as an acute life-threatening condition and a medical emergency and requires hospitalization.
In SJS recovery takes weeks to
months, depending on the severity of the patient’s condition (Mayo Clinic, 2014). The
proportion of females has been estimated to be 33-62 %. The largest series reports 39.9 % of
females in a group of 315 patients with Stevens-Johnson syndrome.
In a large cohort, the mean age of patients with Stevens-Johnson syndrome was 25
years. In a smaller series, the mean age of patients with Stevens-Johnson syndrome was
reported as 47 years. However, cases have been reported in children as young as 3 months
and adults as old as 78 years (Foster, 2016). SJS may present as a nonspecific febrile illness
leading to malaise, headache, cough, rhinorrhea with polymorphic lesions of the skin and
mucous membrane characterized by acute blisters and erosions (French, 2006). Various
etiologic factors have been implicated
as causes of Stevens-Johnson syndrome. Drugs most commonly are blamed.
The four etiologic categories are infectious, drug induced, malignancy-related and idiopathic.
Stevens-Johnson syndrome is idiopathic in 25-50 % of cases. Drugs and malignancies are
most often implicated as the etiology in adults and elderly persons. Pediatric cases are related
more often to infections (Foster, 2016). As per case reports and studies, more than 100 drugs
have been identified as causes of
SJS (Schöpf et al., 1991; Roujeau and Stern, 1994). The drugs that cause SJS commonly are
antibacterials (sulfonamides), anticonvulsants (phenytoin, phenobarbital, and
carbamazepine), nonsteroidal anti-inflammatory drugs (oxicam derivatives), and oxide
inhibitors (allopurinol) (Deore et al., 2014).
CASE REPORT
A 32 year old female came to our hospital in emergency department with itchy skin
eruptions all over the body. She gave a history of sore throat for which she was administered
augmentin (containing amoxycillin and clavulanic acid). The eruptions were seen after taking
first dose which she took at night. The eruptions were erythematous, hyper pigmented, target-
like, round lesions. The eruptions were 2-3 cm in diameter and present throughout the body,
more concentrated on the upper and lower limbs, upper chest, abdomen, face, palms and
soles. On examination,
erosive lesions were present on the lips, buccal mucosa and the tongue. Painful erosions were
also seen on the genital mucosa. Redness of eyes and blurring of vision was also noted. A
diagnosis of Stevens-Johnson syndrome was made. Subsequently, multiple vesicles and
bullae with antral necrosis developed in the area of the lesions. Blistering of the lesions was
noted. Swelling of the face and lips were noted. A slough and whitish plaques were observed
over the tongue. The lesions later crusted on the skin and the oral cavity. Bleeding time and
clotting time were
in the normal limits. Absolute eosinophil count was normal. Blood urea and serum creatinine
levels were normal. Liver function tests were normal. Neutrophils were increased.

The following drugs were administered :

 Injection piperacillin/tazobactam 4.5 g i.v. three times a day
 Injection linezolid 600 mg i.v. two times a day
 Injection albumin 50 ml i.v. once a day for three days
 Injection pheniramine 8 mg i.v. twice a day
 Tablet fluconazole 150 mg once weekly
 Tablet loratidine 10 mg at bed time daily
 Tablet folic acid 5 mg once daily
 Syrup paracetamol two teaspoons full three times a day
 Syrup K-lyte (potassium bicarbonate potassium citrate) two teaspoon full three
 times a day
 Potassium permanganate mouth wash
 Polymyxin B ointment
 Fusidic cream
 Nystatin drops
 Saline wash.

During her stay in ward swelling was noted in her both legs and diagnosis of DVT
was made through color Doppler. Following drugs were given for DVT:
- Tablet Rivaroxaban 15 mg twice a day used for seven days, then shifted to Tablet
warfarin 10 mg once a day
- Injection Enoxaparin sodium 60 mg subcutaneously twice a day.

The patient improved with the above treatment and was subsequently discharged
from the hospital with the advice not to be administered beta-lactam antimicrobials in the
future.
DISCUSSION
In 1922, Stevens and Johnson described 2 male patients of 7 and 8 years old, who developed
extraordinary generalized eruption with fever and inflamed buccal mucosa (Barvaliya et al.,
2011; Stevens and Johnson, 1922). SJS can be differentiated from other skin conditions on
three clinical criteria, (i) the pattern of individual skin lesions, (ii) distribution of lesions, and
(iii) extent of epidermal detachment. The characteristic findings in SJS are widespread
erythematous or purpuric macules which form flat atypical target lesions as the disease
progresses to cause full thickness epithelial necrosis (French, 2006). In the oral cavity, SJS
causes widespread ulcerative lesions. A prodrome occurs in about 30 % of cases and may
begin within 1 to 3 weeks of starting a new drug and lasts 1 to 2 weeks before the onset of
mucocutaneous manifestations, presenting with flu-like symptoms, sore throat, headache,
arthralgias, myalgias, fever, bullous and other rashes, pneumonia, nephritis or myocarditis
(Farthing et al., 2005). Balanitis, urethritis and vulval ulcers may occur. Our patient did not
report any prodrome, but skin, mouth and genital ulcerations were present. Drug-induced SJS
is characterized by mucosal erosions
plus widespread distribution of atypical targets or purpuric macules and epithelial detachment
involving less than 10 % BSA on the trunk, face and extremities (Ayangco and Rogers,
2003). SJS has to be clinically differentiated from viral stomatitides, pemphigus, EM, TEN
and the sub-epithelial immune blistering
disorders like pemphigoid. There are no specific diagnostic tests for SJS (Farthing
et al., 2005). Our case showed ulceration of oral cavity, involvement of eye with redness,
ulceration of genital region along with numerous healed lesions on chest, abdomen and limbs
which showed typical appearance of “target lesions”. The lesions were widespread as
compared to EM, which is localized. Adverse drug reactions (ADRs) are one of the leading
causes of death among hospitalized
patients and occur in 0.3 to 7 per cent of all hospital admissions. These may vary from mild
rashes to severe reactions such as Stevens-Johnson syndrome (Doshi et al., 2012). Hällgren et
al. (2003) stated that antibiotics are the most common cause of Stevens-Johnson syndrome,
followed by analgesics, cough and cold medication, NSAIDs, psychoepileptics and antigout
drugs. Of antibiotics, penicillins and sulfa drugs are prominent; ciprofloxacin has also been
reported (Hällgren et al., 2003). Patel et al. (2012) reported in their study that antimicrobials
were the most commonly
suspected drugs (45 %) causing SJS as has also been reported in Australia (Sanmarkan et al.,
2011). In a study conducted on 225 references in India, 10 references were included as per
selection criteria. The major causative drugs were antimicrobials (37.27 %), anti-epileptics
(35.73 %) and nonsteroidal anti-inflammatory drugs (15.93 %), Carbamazepine (18.25 %),
phenytoin (13.37 %), fluoroquinolones (8.48 %) and paracetamol (6.17 %) (Patel et al.,
2013). Coamoxiclav is a generally well tolerated antimicrobial. Its most frequently reported
adverse effects are gastrointestinal adverse reactions and hepatotoxicity (Salvo et al., 2007).
It has been reported in few publications as etiology of SJS in adults (Abou-Elhamd, 2009).
Our patient did not report any of these. Amoxycillin and clavulanic acid combination therapy
was identified as the causative agent because of the temporal relationship between the
administration of the combination and the beginning of the eruptions. There have also been
several other previous reports
linking amoxycillin and clavulanic acid to Stevens-Johnson syndrome. According to Naranjo
Adverse Drug Reaction Probability Scale, amoxycillin and clavulanic acid induced SJS was
possible in our patient (a score of 4). The first step in the management was an immediate
withdrawal of the offending agent followed by supportive care. Garcia-Doval et al. (2000)
report that earlier the drug is withdrawn,
better the prognosis while exposure to drugs with longer half-lives increases the risk
of death. Supportive care must include the management of fluid and electrolyte requirements
(Garcia-Doval et al., 2000). Adjuvant treatments such as corticosteroids and
immunosuppressants may also be used in severe
cases of SJS (Gerull et al., 2011).

Financial interests
None declared.

Conflicts of interest
The authors declare that they have no conflict of interest.

CONCLUSION
This case report reports the fact that severe hypersensitivity reactions can occur with
amoxycillin and clavulanic acid, which can be possibly dangerous and life-threatening.
Therefore, clinicians must be more cautious while prescribing this drug. Affected patients and
their first-degree relatives should be educated regarding the adverse effects of beta lactam
antimicrobials and instructed to avoid them in future.