Localized bullous drug reaction to cefotaxime leading to wet gangrene in a neonate: A case report

Introduction

Cefotaxime is a third-generation cephalosporin antibiotic widely used in neonatal intensive care units for the treatment and prophylaxis of bacterial infections. While generally well-tolerated, cefotaxime can cause various adverse reactions ranging from mild gastrointestinal symptoms to severe hypersensitivity reactions. ¹ Bullous drug eruptions and subsequent tissue necrosis represent rare but potentially serious complications that can result in significant morbidity.

Fixed drug eruptions (FDE) are characterized by localized skin lesions that recur at the same anatomical site upon re-exposure to the causative drug. ² While several antibiotics have been implicated in FDE, reports of cefotaxime-induced bullous eruptions in neonates are extremely rare. ³ We present a case of cefotaxime-induced bullous drug reaction that progressed to wet gangrene in a term neonate, emphasizing the importance of early recognition and appropriate management.

Patient information

A term male outborn neonate (gestational age 39 weeks, birth weight 3.8 kg) was born via normal vaginal delivery to a 28-year-old primigravida mother. The pregnancy was uncomplicated, with a smooth perinatal transition, and APGAR scores of 8 and 9 at 1 and 5 min of life, respectively. However, on Day 3 of life, the neonate presented to an outside hospital with poor feeding, lethargy, and decreased urine output (oliguria) for 12-hour duration. Physical examination revealed poor state-to-state variability with decreased activity. The neonate presented with a temperature of 37.8°C, while respiratory rate, heart rate, and blood pressure were within normal limits. Systemic examination revealed no additional abnormalities. There were no obvious signs of dehydration or distress. The neonate was initiated on intravenous fluids and cefotaxime for suspected late-onset neonatal sepsis with possible meningitis. .

Clinical course

IV Cefotaxime was given as a slow IV infusion via a peripheral cannula in the left foot (diluted with normal saline as per unit protocol, 50 mg/kg/dose every 8 h). Immediately following the fifth dose of IV cefotaxime administration via left foot cannula anterior to the medial malleolus (same site), multiple translucent bullae with clear fluid content were noted over all five left toes distal to the cannula insertion site (Figure 1(a) and (b)). The lesions showed a localized distribution with intact epidermis and mild surrounding erythema. No vasopressors or other IV medications were administered at that time. Suspecting this as a potential allergic drug reaction, injection pheniramine, and injection dexamethasone were administered immediately. Further doses of cefotaxime were withheld, and oral linezolid and cephalexin were started to prevent secondary infection. The neonate showed clinical improvement without any further fever episodes, improved activity and feeding. The lesions were localized to the toes without proximal extension or systemic compromise. On Day 11 of life, the neonate was discharged at parental request, with a plan for outpatient management that included daily sterile dressings and close clinical monitoring. Parents were counselled regarding warning signs and advised to return for review if progression occurred.OPEN IN VIEWER

After discharge, the parents observed gradual worsening of the lesions, with blackish discoloration first appearing over the left first and fifth toes, accompanied by partial rupture of bullae and an erythematous base (Figure 1(c)). They documented this progression at home, and by Day 15 of life, the discoloration had extended to the remaining toes. At this stage, the parents brought the infant to our tertiary care center for further evaluation and management (Figure 1(d)).

On arrival, the patient appeared well, alert, and active with stable vital signs. The patient was admitted to the neonatal intensive care unit for comprehensive evaluation and management. On admission, complete tissue necrosis of all five left toe tips was observed with sharp demarcation between viable and necrotic tissue, erythematous discoloration extending to the metatarsophalangeal joints, superficial skin peeling, and significant pedal edema without purulent discharge (Figure 1(e)). The left foot remained warm with palpable dorsalis pedis pulses, suggesting preserved vascular supply. Family history was negative for vascular or bleeding disorders. Sepsis screen was negative except for mildly elevated CRP (12 mg/dL). Hematological and coagulation parameters were within normal limits. Bilateral lower limb Doppler study confirmed normal flow with no evidence of deep vein thrombosis. Local wound swab culture was obtained for microbiological analysis. Empirical intravenous piperacillin-tazobactam and vancomycin were initiated. Wound swab culture revealed growth of Acinetobacter baumannii, and antibiotic therapy was adjusted to cefoperazone-sulbactam based on sensitivity patterns.

Plastic surgery consultation was obtained, and daily dressing with mupirocin ointment and paraffin gauze was implemented. Intravenous antibiotics were administered for a total duration of 10 days. Throughout the treatment period, there was no proximal progression of gangrene, indicating treatment efficacy with stabilization of the gangrenous changes. Over time, erythema and edema subsided, well-defined demarcation lines formed, and natural healing became evident (Figure 1(f)). The gangrenous toe tips gradually separated from the viable tissue through a conservative approach, with gentle wound care facilitating the process. By the end of the hospital course, the lesions had improved significantly, with resolution of local inflammation and stabilization achieved through conservative management.

Timeline

Table 1 provides a clear chronological progression of the case from the initial postnatal period through to recovery.

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Table 1.

Chronological progression of the case.

Day	Clinical course
Days 1–2	Normal postnatal course at home with direct breastfeeding
Day 3	Admitted to SNCU for oliguria; started on IV fluids and prophylactic cefotaxime
Day 5	Received 5th dose of cefotaxime via left foot IV cannula; blistering began on toes
Days 7–8	Blackish discoloration of the 1st and 5th toes observed
Day 11	First discharge on oral antibiotics
Day 15	Readmitted due to progression of gangrenous changes involving all five toes
Day 25	Second discharge with clinical improvement and formation of demarcation lines

Diagnostic assessment

Table 2 clearly demonstrates that the patient had normal baseline investigations, ruling out systemic causes for the observed complications. The follow-up investigations show minimal systemic inflammatory response and normal vascular status, supporting a localized drug reaction rather than systemic pathology.

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Table 2.

Diagnostic evaluation.

Investigation	Initial results	Follow-up results (Day 15)
Hb/TLC/Plt (g/dl, cells/microlitre, lakh/microlitre)	17.8/12990/3.22	14/14100/4.17
Serum sodium/potassium (mmol/L)	141/5.09	-
Urea/creatinine (md/dl)	78/1.3	19/0.6
Hematocrit (%)	52.3	41.8
C-reactive protein (mg/L)	1.9	Mildly elevated (12 mg/L)
Procalcitonin (mcg/L)	0.042
Coagulation profile		-
PT/aPTT (seconds)	11.8/31.2
INR	0.87
Fibrinogen (mg/dl)	379 mg/dl
Arterial Doppler study (left lower limb)	Normal flow, no evidence of DVT	Normal flow, no evidence of DVT
Bilateral lower limb Doppler	Normal, no evidence of DVT	Normal, no evidence of DVT
Local wound swab culture	-	Acinetobacter baumannii (sensitive to cefoperazone-sulbactam)

Therapeutic interventions

Follow-up and outcomes

The patient showed gradual improvement with conservative management. Formation of demarcation lines was observed with resolution of erythema and edema. No progression of gangrene occurred during hospitalization. The gangrenous toe tips gradually separated from viable tissue with conservative wound care. At discharge, the lesions had significantly improved with no evidence of active erythema, edema, or discharge. Long-term follow-up is planned to monitor for potential functional limitations.

Discussion

This case represents a rare but severe localized bullous drug reaction progressing to wet gangrene due to cefotaxime administration in a neonate. While cefotaxime is generally considered safe in the neonatal population, severe cutaneous adverse reactions, though uncommon, have been reported. ⁴

In our patient, several factors may have acted in combination to produce this outcome:

(1) Drug concentration: High local concentration due to peripheral IV administration

The sequence of bullous lesions appearing distally in the cannulated foot and later progressing to gangrene raises important diagnostic considerations.

(1) Fixed drug eruption (FDE) versus extravasation injury:

Classically, drug-induced bullous reactions such as FDE are immune-mediated and recur at the same anatomical site upon re-exposure. ² They typically present as round, erythematous plaques on the lips, face, hands, or mucosal surfaces, evolving over several hours after exposure. The absence of previous episodes, lack of re-exposure, and unusual distal distribution without proximal involvement make a classical FDE less likely in this neonate. Nevertheless, cefotaxime has been reported to cause bullous drug eruptions in older patients,^1–3 and its temporal association in this case suggests a possible but unproven hypersensitivity component. A confirmatory test such as a drug-induced lymphocyte stimulation test (DLST) would have been valuable but was not performed, representing a limitation of this report.

(2) Extravasation or vascular compromise:

An alternative explanation is extravasation injury or localized vascular compromise. Antibiotic extravasation can cause tissue inflammation, blistering, and necrosis, especially in neonates whose skin and vasculature are fragile. ⁵ In our patient, lesions appeared exclusively distal to the IV insertion site without proximal extension, which may reflect retrograde drug leakage into the distal circulation.

The site of cannulation over the dorsum of the left foot, anterior to the medial malleolus, makes inadvertent arterial cannulation less likely, though it was considered as a differential. However, the presence of palpable dorsalis pedis pulses and normal Doppler studies made major arterial thrombosis less likely, but transient vasospasm or microvascular compromise could have contributed to ischemia.

(3) Other differential causes of bullous reaction and gangrene were considered. Congenital epidermolysis bullosa can present with neonatal blistering, but the absence of recurrent lesions, mucocutaneous involvement, or family history argues against this

Other differential diagnosis for neonatal gangrene include various etiologies such as congenital heart disease, hypernatremic dehydration, embolic phenomena, umbilical vessel catheterization complications, polycythemia, disseminated intravascular coagulation, birth trauma, and tight extremity binding.^6,7 In our case, these conditions were systematically excluded through appropriate investigations. The subsequent progression to wet gangrene likely reflects a combination of local tissue injury, impaired microcirculation, and secondary bacterial infection. The growth of Acinetobacter baumannii from the wound culture supports the role of superadded infection in worsening local necrosis.

Given the unusual distal-only distribution, absence of reproducibility, and multiple plausible alternative mechanisms, this case should be interpreted as a possible cefotaxime-associated localized bullous reaction with contributory extravasation or vascular injury. It underscores the need for cautious IV cannulation (with careful distinction between venous and arterial sites, appropriate drug dilution, and close monitoring during peripheral infusion in neonates.

Conservative management proved effective in this case, consistent with established recommendations for drug-induced tissue necrosis. ⁸ The key principles include immediate drug discontinuation, treatment of secondary infection, and allowing natural demarcation of viable tissue.