What are the causes of perforation in premature babies, including the role of fungal pathogens such as Candida species, Mucor, and Rhizopus?

Causes of Perforation in Premature Babies

Primary Infectious Causes

Candida species, particularly Candida albicans, are the most common fungal pathogens causing intestinal perforation in premature infants, while mucormycosis (Mucor and Rhizopus species) represents a rare but devastating cause of perforation with extremely high mortality. 1, 2, 3

Candida-Related Perforation

• Candida albicans is the most frequent fungal species causing invasive candidiasis and subsequent intestinal complications including perforation in neonates, accounting for the majority of cases 1, 4
• Candida parapsilosis is the second most common Candida species causing invasive disease in premature infants and can lead to perforation 1, 4
• Candida tropicalis and other Candida species are seen less commonly, while Candida glabrata and Candida krusei are infrequent causes in the NICU (unlike in adults) 1
• Invasive candidiasis presents with candidemia, urinary tract infection, and involvement of essentially any tissue or structure, including the gastrointestinal tract 1

Mucormycosis-Related Perforation (Mucor and Rhizopus)

• Mucormycosis caused by Rhizopus and Mucor species is uncommon but highly lethal in premature infants, with these organisms having a propensity for angioinvasion that produces tissue necrosis and perforation 1, 3
• Rhizopus oryzae is the most common pathogen identified in mucormycosis cases, followed by other Mucorales including Mucor species 5, 6
• These organisms invade blood vessels causing epidermal and dermal necrosis, which can extend to involve the gastrointestinal tract 1
• Primary cutaneous mucormycosis has been documented in premature infants, often associated with contaminated elastic bandages or other nosocomial sources 6
• Amphotericin B is specifically indicated for treating zygomycosis including mucormycosis due to susceptible species of Mucor and Rhizopus 3

High-Risk Populations

Extremely Premature Infants

• Infants with birth weight <750g have >10% incidence of invasive candidiasis, representing the highest risk group 1, 2
• Infants with birth weight 750-1000g have 5-10% incidence of invasive candidiasis 1, 2
• Infants with gestational age 23-24 weeks have 10-20% incidence, while those 25-27 weeks have 5-10% incidence 1

Timing of Infection

• Invasive candidiasis typically occurs early, with mean onset at day 12 of life in extremely premature infants 7
• The infection generally occurs within the first 6 weeks of life 8
• Early colonization with Candida in the first 2 weeks of life constitutes the first stage of systemic infection in extremely premature infants 7

Major Risk Factors for Fungal Perforation

Medical Interventions

• Central vascular catheterization is a primary risk factor for invasive candidiasis and subsequent perforation 1, 2
• Abdominal surgery significantly increases risk of fungal perforation 1, 2
• Necrotizing enterocolitis (NEC) is strongly associated with fungal perforation risk 1, 2
• Prolonged mechanical ventilation and endotracheal intubation contribute to invasive fungal disease 1, 2

Pharmacologic Exposures

• Broad-spectrum antibacterial agents, particularly third-generation cephalosporins and carbapenems, are major risk factors 1, 2
• Antacid use increases susceptibility to invasive candidiasis 1, 2
• Corticosteroid use predisposes to fungal infections 1, 2

Nutritional Factors

• Parenteral nutrition is a significant risk factor for invasive candidiasis 1, 2
• Delayed enteral feeds contribute to aberrant gut microbiome colonization patterns that favor fungal overgrowth 1

Pathophysiology of Fungal Perforation

Candida Mechanisms

• In extremely premature infants with immature skin and immune systems, colonization and proliferation in skin and/or mucosa constitute the first stage of systemic infection, which can progress to invasive cutaneous-mucosal candidiasis 7
• The premature gastrointestinal tract displays increased intestinal permeability due to reduced expression of tight junction proteins, facilitating fungal translocation 1
• Reduced production of mucus and antimicrobial peptides due to fewer or immature goblet and Paneth cells allows fungal invasion 1
• Higher intestinal pH in preterm infants (due to delayed Bifidobacteriaceae colonization) creates favorable conditions for Candida overgrowth 1

Mucormycosis Mechanisms

• Mucor and Rhizopus organisms have a propensity for angioinvasion, producing painful nodules that rapidly become necrotic and can perforate 1
• These organisms cause epidermal and dermal necrosis because of their tendency to invade blood vessels 1
• Disseminated infections can occur from pulmonary sources with secondary gastrointestinal involvement 1

Clinical Presentation

Candida Perforation

• Presents with nonspecific signs of sepsis in the first 6 weeks of life 8
• A characteristic skin disorder is observed in 83% of cases (10 of 12 patients): erythema with erosion and desquamation, which is atypical for typical candidiasis but indicates early colonization 7
• This invasive cutaneous-mucosal pattern has diagnostic value and indicates the first stage of systemic infection 7

Mucormycosis Perforation

• Skin lesions are usually erythematous, nodular, and tender when present 1
• Local infections may occur from contaminated bandages or other skin trauma 1, 6
• Mortality remains very high even without documented fungal bloodstream infection 1

Diagnostic Approach

For Candida

• Definitive diagnosis relies on growth of Candida in blood culture or cultures from other normally sterile sites, but this identifies fewer than half of cases 8
• Cultures of infected peritoneal fluid are essential 2
• Direct visualization through endoscopy with biopsy for histopathology and culture is recommended 2
• Candida can be isolated from skin and/or mucosal samples in 83% of systemic cases 7

For Mucormycosis

• Blood cultures are almost never positive for Mucor or Rhizopus species, even in disseminated infection 1
• Diagnosis requires tissue biopsy showing characteristic mixture of true hyphae, pseudohyphae, budding yeast, and arthroconidia 1
• Looking for intravascular fungi on histology is pathognomonic for fungal infection 2

Treatment Algorithm

For Candida Perforation

Step 1: Immediate Antifungal Therapy

• Echinocandins (caspofungin, micafungin, or anidulafungin) are the preferred initial treatment for invasive candidiasis with perforation in critically ill neonates 2
• Fluconazole 6 mg/kg daily may be used as alternative only if: no recent azole exposure AND not colonized with azole-resistant Candida species 2
• Amphotericin B lipid formulation (3-5 mg/kg daily) is reserved for patients intolerant to other antifungal agents 2

Step 2: Source Control

• Source control with drainage and/or debridement is essential for successful treatment 2
• Inadequate source control is associated with treatment failure regardless of appropriate antifungal therapy 2

For Mucormycosis (Mucor/Rhizopus) Perforation

Step 1: Immediate Amphotericin B

• Amphotericin B is specifically indicated and the only FDA-approved treatment for mucormycosis due to Mucor and Rhizopus species 3
• Isavuconazole (isavuconazonium sulfate) is an alternative: loading dose of 372 mg IV every 8 hours for 48 hours, then 372 mg once daily 5
• In the mucormycosis trial, median treatment duration was 102 days for primary therapy, with all-cause mortality through Day 42 of 38% 5

Step 2: Aggressive Surgical Debridement

• In all reported cases involving premature infants, elimination of mucormycosis infection involved surgical debridement 6
• One case report documented successful conservative treatment with IV amphotericin B alone in a premature infant with primary cutaneous Rhizopus oryzae infection 6

Prevention Strategies

Antifungal Prophylaxis

• Fluconazole prophylaxis is recommended for infants <1000g birth weight, or <1500g if local incidence of invasive candidiasis exceeds 2% 4
• Nystatin prophylaxis (1 mL suspension, 100,000 U/mL, every 8 hours) results in significant reduction in invasive candidiasis for neonates <1500g 1, 4
• Micafungin must be used for prophylaxis in case of Candida auris colonization or in centers with high prevalence of this pathogen 4

Infection Control Measures

• Avoidance of horizontal transmission in the NICU requires rigorous infection control measures 1
• Treatment of maternal vaginal candidiasis prior to delivery prevents subsequent neonatal colonization 1
• Correct management of central venous catheters and isolation procedures for patients colonized by resistant strains are fundamental 4

Modifiable Risk Factor Reduction

• Rational use of broad-spectrum antibacterial agents, especially third-generation cephalosporins and carbapenems 1, 4
• Reduced use of H2 blockers 4
• Promotion of breast feeding 4
• Discontinuation of central catheters when possible 9

Critical Pitfalls to Avoid

• Delaying antifungal therapy in suspected intra-abdominal fungal infections significantly increases mortality 2
• Using fluconazole empirically in critically ill patients without knowing Candida species susceptibility leads to treatment failure 2
• Failing to recognize the characteristic skin pattern (erythema with erosion and desquamation) in extremely premature infants delays diagnosis of invasive candidiasis 7
• Assuming negative blood cultures rule out mucormycosis—these organisms are almost never recovered from blood despite disseminated infection 1
• Premature discontinuation of therapy before complete resolution 2
• Failure to consider fungal infection in patients with persistent symptoms despite antibacterial therapy 2
• Inadequate source control with failure to perform necessary surgical drainage or debridement 2
• Prophylaxis reduces but cannot completely eliminate invasive candidiasis risk, with parallel risk of selecting antifungal-resistant strains—maintain high clinical suspicion 4