What are the Philippine Society of Newborn Medicine guidelines for empiric antimicrobial therapy and overall management of suspected neonatal sepsis in neonates (≤28 days of life)?

Management of Suspected Neonatal Sepsis

While specific Philippine Society of Newborn Medicine guidelines are not available in the provided evidence, the management of suspected neonatal sepsis should follow international best practices with empiric ampicillin plus gentamicin as first-line therapy, initiated within 1 hour for septic shock and within 3 hours for sepsis without shock, with mandatory reassessment at 48 hours for de-escalation or discontinuation based on culture results and clinical improvement.

Immediate Recognition and Antibiotic Initiation

Timing of Antibiotic Administration

• For neonates with septic shock, start antimicrobial therapy within 1 hour of recognition 1
• For neonates with sepsis-associated organ dysfunction but without shock, initiate antimicrobials within 3 hours after appropriate evaluation 1
• Obtain blood cultures before administering antibiotics whenever possible, but never delay antibiotic administration to obtain cultures 1

Empiric Antibiotic Selection

Early-Onset Sepsis (≤72 hours of life):

• Ampicillin (or penicillin) plus gentamicin is the recommended first-line regimen 2, 3, 4
• This combination covers Group B Streptococcus, Escherichia coli, and Listeria monocytogenes—the primary pathogens in early-onset neonatal sepsis 3, 4
• Ampicillin dosing: 50-100 mg/kg/dose IV every 12 hours (adjust based on gestational age and postnatal age) 3
• Gentamicin dosing: 4-5 mg/kg/dose IV every 24-48 hours (adjust based on gestational age and renal function) 3

Late-Onset Sepsis (>72 hours of life):

• Continue ampicillin plus gentamicin as initial empiric therapy, as this covers both early-onset pathogens and hospital-acquired organisms 3, 4
• If there is high risk for staphylococcal infection (presence of vascular catheter, skin lesions), consider adding or substituting with vancomycin 3
• For suspected Pseudomonas infection (typical skin lesions, prolonged hospitalization), consider anti-Pseudomonas agents such as ceftazidime or piperacillin 3
• In settings with high aminoglycoside resistance, consider netilmicin or amikacin instead of gentamicin 3

Critical Caveat on Third-Generation Cephalosporins

• Avoid routine use of third-generation cephalosporins (ceftriaxone, cefotaxime) as initial empiric therapy unless there is documented high local resistance to ampicillin-gentamicin 3
• Extensive use of cephalosporins leads to rapid emergence of drug-resistant organisms 3
• Antagonistic interactions can occur when penicillins are combined with cephalosporins 3
• Reserve third-generation cephalosporins for documented gram-negative meningitis or when cultures identify resistant organisms 3

Systematic Screening and Risk Stratification

• Implement systematic screening protocols for timely recognition of septic shock and sepsis-associated organ dysfunction in all acutely unwell neonates 1
• Screening should be tailored to institutional resources and patient population 1
• Establish institutional protocols/guidelines for standardized management of neonatal sepsis 1

Critical 48-Hour Reassessment Protocol

This is the most important decision point to prevent unnecessary antibiotic exposure:

If Blood Cultures Are Negative at 48 Hours:

• Discontinue antibiotics immediately if the neonate is clinically well and the probability of sepsis is low 2, 4
• Clinical improvement indicators include: normalized vital signs, improved feeding, normal activity level, and resolution of any organ dysfunction 2
• Prolonged empiric antibiotic therapy (≥5 days) in preterm infants is associated with increased risks of late-onset sepsis, necrotizing enterocolitis, and mortality 4

If Blood Cultures Are Positive:

• Narrow antimicrobial therapy to targeted treatment based on pathogen identification and sensitivities 1
• Perform daily clinical and laboratory assessment for ongoing de-escalation opportunities 1
• Use optimized dosing strategies based on pharmacokinetic/pharmacodynamic principles, accounting for altered drug clearance in septic neonates 1

If Cultures Are Negative But Clinical Suspicion Remains High:

• Continue antibiotics if the neonate has pneumonia or clear clinical sepsis despite negative cultures 3
• Narrow or stop empiric therapy based on clinical presentation, site of infection, host risk factors, and adequacy of clinical improvement in consultation with infectious disease specialists 1

Duration of Antimicrobial Therapy

• For culture-proven sepsis with minimal or absent focal infection: 10-14 days of appropriate antibiotics 3
• Duration depends on the site of infection, microbial etiology, response to treatment, and ability to achieve source control 1
• For meningitis: minimum 14-21 days depending on organism 5
• For bacteremia without focal infection: 7-10 days if clinical improvement is rapid 5

Pathogen-Specific Treatment Modifications

Group B Streptococcal Sepsis:

• Consider combination therapy with ampicillin plus gentamicin for synergy, even though routine combination therapy is not recommended for other pathogens 1
• This is one of the specific situations where empiric multiple antimicrobials directed against the same pathogen may be indicated 1

Staphylococcal Infections:

• Use penicillinase-resistant penicillins (oxacillin, nafcillin) for methicillin-sensitive Staphylococcus aureus 3
• Use vancomycin for methicillin-resistant strains or coagulase-negative staphylococci 3
• Consider adding clindamycin for suspected toxic shock syndrome with refractory hypotension 1, 6

Enterococcal Infections:

• Treat with ampicillin (or penicillin) plus gentamicin for synergy 3
• Use vancomycin plus gentamicin for ampicillin-resistant strains 3

Gram-Negative Infections:

• Ampicillin (or extended-spectrum penicillin) plus aminoglycoside is effective for most Enterobacteriaceae 3
• For Pseudomonas aeruginosa: use piperacillin or ceftazidime plus an aminoglycoside 3
• Ceftazidime has superior in vitro activity against Pseudomonas compared to cefoperazone or piperacillin 3
• Emerging resistance in Enterobacteriaceae (particularly Klebsiella and E. coli) to ampicillin, gentamicin, and third-generation cephalosporins is a growing concern, necessitating local antibiogram review 7

Source Control

• Identify and address the source of infection as early and aggressively as possible 1
• Perform thorough physical examination for focal infection sites: umbilicus, skin, respiratory tract, urinary tract 2
• Remove infected indwelling vascular access devices after establishing alternative access 1
• Drain abscesses or infected fluid collections emergently 6
• Perform surgical debridement for necrotizing infections (necrotizing fasciitis, gangrenous myonecrosis) 1

Supportive Care During Resuscitation

Fluid Resuscitation:

• Administer isotonic crystalloids or albumin in 20 mL/kg boluses over 5-10 minutes 1, 6
• Continue boluses up to 40-60 mL/kg or more during the first hour if needed to restore perfusion 1, 6
• Stop fluid boluses immediately if hepatomegaly or rales develop, indicating fluid overload requiring inotropic support 1, 6
• Monitor for adequate perfusion: normalized heart rate, capillary refill <2 seconds, warm extremities, urine output >1 mL/kg/hr, improved mental status 6

Metabolic Corrections:

• Correct hypoglycemia and hypocalcemia immediately 1
• Provide glucose infusion to prevent hypoglycemia, especially in preterm neonates 6

Vasoactive Support for Fluid-Refractory Shock:

• Begin peripheral inotropic support (epinephrine or dopamine) if hypotension or poor perfusion persists after initial fluid resuscitation 1, 6
• Establish central venous access for continuous inotrope infusion 1, 6
• For cold shock with normal blood pressure: titrate epinephrine and consider adding vasodilators (milrinone, nitroprusside) 1
• For cold shock with low blood pressure: titrate epinephrine 1
• For warm shock with low blood pressure: titrate norepinephrine 1

Adjunctive Therapies:

• Consider hydrocortisone 50 mg/m²/24 hours as continuous infusion for catecholamine-resistant shock if absolute adrenal insufficiency is suspected 1, 6
• Target hemoglobin ≥10 g/dL during resuscitation when ScvO₂ <70% 1, 6
• Consider IVIG for refractory toxic shock syndrome, though evidence is limited 1

Common Pitfalls and How to Avoid Them

Pitfall 1: Continuing Antibiotics Beyond 48 Hours Without Clear Indication

• This is the most common error in neonatal sepsis management 4
• Always reassess at 48 hours and discontinue if cultures are negative and clinical improvement is evident 2, 4
• Document specific reasons if continuing antibiotics beyond 48 hours with negative cultures 4

Pitfall 2: Routine Use of Third-Generation Cephalosporins

• Reserve cephalosporins for specific indications (meningitis, documented resistant organisms) 3
• Overuse drives resistance and may have antagonistic effects with penicillins 3

Pitfall 3: Inadequate Source Control

• Failure to remove infected devices or drain abscesses is associated with increased mortality in a synergistic manner with inadequate antibiotics 1
• Always evaluate for removable sources of infection 1

Pitfall 4: Delayed Antibiotic Administration

• Vascular access can be difficult in neonates—consider intramuscular or oral routes (if tolerated) until IV access is established 1
• Never delay antibiotics to obtain cultures if vascular access is difficult 1

Pitfall 5: Ignoring Local Resistance Patterns

• Antibiotic choice must be guided by local antibiograms, as resistance patterns vary significantly between institutions and regions 7
• In areas with high aminoglycoside resistance, consider alternative aminoglycosides (netilmicin, amikacin) or combination with third-generation cephalosporins 3