Acute generalised exanthematous pustulosis (AGEP) after cefotaxime use

Abstract

A case of acute generalised exanthematous pustulosis (AGEP) after cefotaxime use confirmed by a positive patch test is reported. A 30-year-old woman received cefotaxime, fosfomycin and ciprofloxacin for sinusitis. At 12 days after drug initiation, she developed an extending pustular erythaema associated with fever. Laboratory investigations showed marked leukocytosis. Her blood chemistry was normal. The histological examination showed parakeratosis, spongiosis and non-follicular intra epidermal pustules consistent with AGEP. All medications were withdrawn. The symptoms resolved within 11 days after cefotaxime discontinuation. Patch tests were positive to cefotaxime after 48 h, while ciprofloxacin and fosfomycin yielded negative findings. Based on the Naranjo algorithm, it is probable that the AGEP reaction was due to cefotaxime. To our knowledge, this is the first reported case of AGEP associated to positive cefotaxime patch testing

BACKGROUND

Acute generalised exanthematous pustulosis (AGEP) is a rare and severe skin eruption, which is drug induced in 90% of cases. We report a case of AGEP induced by cefotaxime, a third generation cephalosporin, confirmed by a positive patch test.

CASE PRESENTATION

A 30-year-old woman with no personal or family history of atopy, skin disease or adverse drug reaction was admitted to the Oto-Rhino-Laryngology department for sinusitis. She was given cefotaxime, fosfomycin and ciprofloxacin. On day 12 after drug initiation, she developed an extending itching erythaema with numerous small non-follicular pustules, most pronounced in the inguinal and axillary areas, but also on the trunk, face and proximal limbs associated to fever (39°C) and erosions of the oral mucous membrane (fig 1). Laboratory investigations showed marked leukocytosis (11 000 per mm³) with a neutrophil count of 4000 per mm³ and an eosinophil count of 1400 per mm³. The histological examination showed parakeratosis associated to spongiosis and non-follicular intraepidermal pustules consistent with AGEP (figs 2 and 3).

Figure 1.

Erythaema with numerous small non-follicular pustules.

Figure 2.

Parakeratosis associated to spongiosis (×1000).

Figure 3.

Polymorphonuclear neutrophil infiltration (×1000).

INVESTIGATIONS

We performed patch tests for cefotaxime, fosfomycin and ciprofloxacin. The patch tests were positive to cefotaxime on 48 h reading, while ciprofloxacin and fosfomycin (used before the eruption onset) yielded negative findings (fig 4).

Figure 4.

Positive patch test to cefotaxime.

OUTCOME AND FOLLOW-UP

The skin eruption resolved after cefotaxime discontinuation. As a follow-up, a skin patch test was performed 6 weeks after eruption disappearance.

DISCUSSION

In our case, the clinical, biological and anatomopathological data are in accordance with AGEP diagnosis criteria. Indeed, Beylot et al¹ introduced the term “acute generalised exanthematous pustulosis” to establish the following criteria: clinically, AGEP is characterised by an acute onset of fever and a widespread small non-follicular sterile pustules arising on an oedematous and itching erythaema that may begin on the face or intertriginous areas and become disseminated within hours. The mucous membranes involvement may occur in 25% of cases. Sometimes the pustules converge, giving a false aspect of positive Nikolsky sign. In 80% of cases, the biological findings involve leukocytosis, which is mostly due to a blood polynuclear neutrophil count above 7000 per mm³. Mild eosinophilia may be present in about a third of the cases. The histological criteria are vasculitis associated to non-follicular subcorneal and/or intra epidermal pustules. Our patient met all the criteria except for the neutrophil count. According to a more sophisticated scoring, presented in 2001,² our case deserves a score of 8 points. Thus, the patient’s scoring was definite (table 1).

Table 1.

The patient’s scoring using the acute generalised exanthematous pustulosis (AGEP) validation score of the European Severe Cutaneous Adverse Reactions (EuroSCAR) study group

Variable		Score
Morphology	Pustules (typical)	2
	Erythaema (typical)	2
	Distribution/pattern (compatible)	1
	Postpustular desquamation (yes)	1
Course	PNN >7000/mm3 (no)	0
Histology	Exocytosis of PNN (yes)	2
Total score		8

⩽0: no AGEP; 1–4: possible; 5–7: probable; 8–12: definite.

PNN, polynuclear neutrophil.

In a retrospective study of 63 AGEP cases, Roujeau et al³ characterised this entity as drug induced. Later, drugs were involved in 90% of cases. The offending agents are mostly β-lactams and macrolides. β-Lactams account for 80% of antibiotics implicated in AGEP. Aminopenicillins are the most frequently implicated in AGEP.^3–5 Some sporadic cases of AGEP related to third generation cephalosporins such as ceftriaxone and ceftazidime were reported in the literature.^6,7 To our knowledge, cefotaxime has never been attributed to AGEP. In our case, a clear temporal relationship was observed between cefotaxime administration and the onset of symptoms (12 days, typically 2 to 3 weeks),⁸ the remission of symptomatological pattern after cefotaxime suspension (11 days, typically less than 15 days),⁸ and a positive patch test to cefotaxime. Based on the Naranjo algorithm,⁹ it is probable that AGEP reaction was due to cefotaxime.

The exact AGEP pathomechanism is currently unknown. Most authors suspect a type IV delayed hypersensitivity reaction.^10–12 In AGEP, the infiltration of neutrophils and some eosinophils as well as CD41 and CD81 lymphocytes is striking. Drug-specific T cell clones from lesional skin as well as from the circulation have been found positive for the neutrophil attracting cytokine interleukin 8.

Patch testing may provoke relapses supporting the idea that the immune system is involved.^13–16 This reactivation seems to be triggered by a T cell “memory”. This is also suggested by the observation that patch tests can mimic the morphological characteristics of the original skin reaction in the patch test site. Few cases of reactions spreading beyond this site are reported in the literature and most of them were attributed to diltiazem hydrochloride, none to cefotaxime.¹⁵ Patch testing is a reliable alternative to reveal the culprit drug in AGEP since oral rechallenge may provoke a generalised eruption. Beylot et al,⁴ Wolkestein et al¹⁷ and Watsky¹⁸ have reported positive patch test results in approximately 50% of AGEP cases suggesting a relatively high sensitivity. However, the diagnostic value of patch tests depends on the offending agent.¹⁹ In our case, the positive patch confirmed cefotaxime involvement in inducing AGEP.

In conclusion, we present a case of AGEP associated to positive cefotaxime patch testing. Clinicians should be aware of this side effect and perform skin tests that may be helpful in identifying the culprit drug.

LEARNING POINTS

• Doctors should be aware of acute generalised exanthematous pustulosis (AGEP) and perform skin tests that may be helpful in identifying the culprit drug.