APPENDIX 6

Dosing in Preterm and Term Neonates 32 to 44 Weeks' Postmenstrual Age (Gestational Age Plus Chronologic Age)

THESE ANTIMICROBIALS AND DOSAGES HAVE NOT BEEN REVIEWED OR APPROVED BY THE FDA FOR USE IN NEWBORN INFANTS, UNLESS SPECIFICALLY NOTED. THESE DOSES ARE PROVIDED ONLY AS GUIDANCE DURING AN EMERGENCY BIOLOGICAL WEAPON EVENT, ON THE BASIS OF AVAILABLE LITERATURE OR EXTRAPOLATION FROM PHARMACOKINETIC DATA FROM OLDER CHILDREN, WITH KNOWLEDGE OF MATURATION OF NEONATAL CLEARANCE MECHANISMS.
Dosing guidance for anthrax in newborn infants has not been proposed earlier because of the paucity of pharmacologic data describing kinetics, safety, and efficacy and the broad range of developmental changes that will affect therapy in this immature population. This guidance accommodates not only term newborn infants but also neonates who may be born at 32 wk postmenstrual age (PMA). For neonates of earlier gestational age, please consult with a neonatologist, pharmacologist, or infectious diseases physician for appropriate dosing. Doses are provided for newborns with developmentally appropriate renal and hepatic function. Doses may vary for those with some degree of organ failure.
By convention, the neonatal period ends 28 d (4 wk) after birth, but at 4 wk of age, the physiologic maturity of a preterm infant lags significantly behind a term infant. Preterm infants continue to undergo developmental changes through 44 wk PMA that affect pharmacokinetics, with maturation of mechanisms of renal elimination and hepatic enzymatic drug inactivation that occur at different rates for different antimicrobial agents, some closely linked to PMA or chronologic age, but most demonstrate aspects of both. Hence, we provide guidance for all newborn infants through 44 wk PMA while recognizing that many physiologic processes mature during this developmental period and that new dosing recommendations are likely to follow as additional data become available. Should these medications be required for treatment or prophylaxis, it will be especially important to plan prospectively to monitor serum/plasma concentrations in a systematic fashion to acquire good data that relate dose of drug to concentration, efficacy, and occurrence of adverse effects.
Antimicrobial-related adverse effects are always possible; however, the benefit of antimicrobial therapy for life-threatening infection justifies assuming greater risk during therapy. In general, the frequency and severity of adverse events seem to be less, rather than more, in neonates.
A. Triple therapy for severe anthraxa (anthrax meningitis or disseminated infection and meningitis cannot be ruled outb)
Duration of therapy: For ≥2–3 wk, until clinical criteria for stability are met (see text). Will require prophylaxis to complete an antibiotic course of up to 60 days from onset of illness (see Appendix 6E).
Antimicrobial8432–34 wk Gestational Age34–37 wk Gestational AgeTerm Newborn Infant
0–1 wk of Age1–4 wk of Age0–1 wk of Age1–4 wk of Age0–1 wk of Age1–4 wk of Age
1. A bactericidal antimicrobial (fluoroquinolone)
Ciprofloxacin IV858720 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h30 mg/kg/day, divided q12h30 mg/kg/day, divided q12h
OR
Levofloxacin IV88
OR
Moxifloxacin IV89,905 mg/kg/day, q24h5 mg/kg/day, q24h5 mg/kg/day, q24h5 mg/kg/day, q24h10 mg/kg/day, q24h10 mg/kg/day, q24h
PLUS
2. A bactericidal antimicrobial (β-lactam)
a. For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
Meropenem IV919360 mg/kg/day, divided q8h90 mg/kg/day, divided q8h60 mg/kg/day, divided q8h90 mg/kg/day, divided q8h60 mg/kg/day, divided q8h90 mg/kg/day, divided q8h
OR
Imipenemc IV949650 mg/kg/day, divided q12h75 mg/kg/day, divided q8h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h
OR
Doripenemd IV20 mg/kg/day, divided q12h30 mg/kg/day, divided q8h20 mg/kg/day, divided q12h30 mg/kg/day, divided q8h20 mg/kg/day, divided q12h30 mg/kg/day, divided q8h
OR
b. Alternatives for penicillin-susceptible strains
Penicillin G97,98200 000 Units/kg/day, divided q12h300 000 Units/kg/day, divided q8h300 000 Units/kg/day, divided q8h400 000 Units/kg/day, divided q6h300 000 Units/kg/day, divided q8h400 000 Units/kg/day, divided q6h
OR
Ampicillin100 mg/kg/day, divided q12h150 mg/kg/day, divided q8h150 mg/kg/day, divided q8h200 mg/kg/day, divided q6h150 mg/kg/day, divided q8h200 mg/kg/day, divided q6h
PLUS
3. A protein synthesis inhibitor
Linezolide 9910220 mg/kg/day, divided q12h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h
OR
Clindamycin10 mg/kg/day, divided q12h15 mg/kg/day, divided q8h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h
OR
Rifampinf 10310510 mg/kg/day, divided q12h10 mg/kg/day, divided q12h10 mg/kg/day, divided q12h10 mg/kg/day, divided q12h10 mg/kg/day, divided q12h20 mg/kg/day, divided q12h
OR
Chloramphenicolg25 mg/kg/day, q24h50 mg/kg/day, q12h25 mg/kg/day, q24h50 mg/kg/day, q12h25 mg/kg/day, q24h50 mg/kg/day, q12h
B. Therapy for severea anthrax when meningitis can be ruled outb
Duration of therapy: For ≥2–3 wk, until clinical criteria for stability are met (see text). Will require prophylaxis to complete an antimicrobial course of up to 60 days from onset of illness (see Appendix 6E).
1. A bactericidal antimicrobial
a. For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
32–34 wk Gestational Age34–37 wk Gestational AgeTerm Newborn Infant
0–1 wk of Age1–4 wk of Age0–1 wk of Age1–4 wk of Age0–1 wk of Age1–4 wk of Age
Ciprofloxacin IV20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h30 mg/kg/day, divided q12h30 mg/kg/day, divided q12h
OR
Meropenem IV40 mg/kg/day, divided q8h60 mg/kg/day, divided q8h60 mg/kg/day, divided q8h60 mg/kg/day, divided q8h60 mg/kg/day, divided q8h60 mg/kg/day, divided q8h
OR
Levofloxacin IV
OR
Imipenemc IV40 mg/kg/day, divided q12h50 mg/kg/day, divided q12h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h
OR
Vancomycin IV (dosing based on serum creatinine for infants ≥32 wk gestational age). Follow vancomycin serum concentrations to modify dose.Serum creatinine <0.715 mg/kg/doseq12h
Serum creatinine 0.7 -0.920 mg/kg/doseq24h
Serum creatinine 1–1.215 mg/kg/doseq24h
Serum creatinine 1.3–1.610 mg/kg/doseq24h
Serum creatinine >1.615 mg/kg/doseq48h
Begin treatment with a 20-mg/kg loading dose
OR
b. Alternatives for penicillin-susceptible strains
Penicillin G IV200 000 U/kg/day, divided q12h300 000 U/kg/day, divided q8h300 000 U/kg/day, divided q8h400 000 U/kg/day, divided q6h300 000 U/kg/day, divided q8h400 000 U/kg/day, divided q6h
OR
Ampicillin IV100 mg/kg/day, divided q12h150 mg/kg/day, divided q8h150 mg/kg/day, divided q8h200 mg/kg/day, divided q6h150 mg/kg/day, divided q8h200 mg/kg/day, divided q6h
PLUS
2. A protein synthesis inhibitor
Clindamycin IV10 mg/kg/day, divided q12h15 mg/kg/day, divided q8h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h
OR
Linezolid IVe20 mg/kg/day, divided q12h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h
OR
Doxycycline IV (loading dose 4.4 mg/kg)106,1074.4 mg/kg/day, divided q12h4.4 mg/kg/day, divided q12h
OR
Rifampin IVf10 mg/kg/day, q24h10 mg/kg/day, q24h10 mg/kg/day, q24h10 mg/kg/day, q24h10 mg/kg/day, q24h10 mg/kg/day, q24h
C. Oral follow-up combination therapy for severea anthrax
Duration of therapy: to complete a treatment course of 10–14 days or greater. May require prophylaxis to complete an antimicrobial course of up to 60 days from onset of illness (see Appendix 6E, Postexposure Prophylaxis).
1. A bactericidal antimicrobial
a. For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
32–34 wk Gestational Age34–37 wk Gestational AgeTerm Newborn Infant
0–1 wk of Age1–4 wk of Age0–1 wk of Age1–4 wk of Age0–1 wk of Age1–4 wk of Age
Ciprofloxacinh PO20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h30 mg/kg/day, divided q12h30 mg/kg/day, divided q12h
OR
Levofloxacin PO
OR
b. Alternatives for penicillin-susceptible strains
Amoxicillin PO10811150 mg/kg/day, divided q12h75 mg/kg/day, divided q8h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h75 mg/kg/day, divided q8h75 mg/kg/day, divided q8h
OR
Penicillin VK PO50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h75 mg/kg/day, divided q8h75 mg/kg/day, divided q6–8h
PLUS
2. A protein synthesis inhibitor
Clindamycini PO10 mg/kg/day, divided q12h15 mg/kg/day, divided q8h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h
OR
Doxycyclinej PO (loading dose 4.4 mg/kg)4.4 mg/kg/day, divided q12h4.4 mg/kg/day, divided q12h
OR
Linezolid POe20 mg/kg/day, divided q12h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h30 mg/kg/day, divided q8h
OR
D. Treatment of cutaneous anthrax without systemic involvement
Duration of therapy:
For naturally acquired infection: 7–10 days
For a biological weapon–related event, may require additional prophylaxis for inhaled spores to complete an antimicrobial course of up to 60 days from onset of illness (see Appendix 6E).
1. For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
32–34 wk Gestational Age34–37 wk Gestational AgeTerm Newborn Infant
0–1 wk of Age1–4 wk of Age0–1 wk of Age1–4 wk of Age1–4 wk of Age0–1 wk of Age
Ciprofloxacinh PO20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h30 mg/kg/day, divided q12h30 mg/kg/day, divided q12h
OR
Doxycyclinej PO (Loading dose 4.4 mg/kg)4.4 mg/kg/day, divided q12h4.4 mg/kg/day, divided q12h
OR
Clindamycinh PO10 mg/kg/day, divided q12h15 mg/kg/day, divided q8h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h
OR
Levofloxacinh PO
OR
2. Alternatives for penicillin-susceptible strains
Amoxicillink PO50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h75 mg/kg/day, divided q8h75 mg/kg/day, divided q8h
OR
Penicillin Vk PO50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h75 mg/kg/day, divided q8h75 mg/kg/day, divided q6–8h
E. Postexposure prophylaxis for Bacillus anthracis
Duration of therapy: 60 days from exposure
1. For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
32–34 wk Gestational Age34–37 wk Gestational AgeTerm Newborn Infant
0–1 wk of Age1–4 wk of Age0–1 wk of Age1–4 wk of Age0–1 wk of Age1–4 wk of Age
Ciprofloxacinh PO20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h20 mg/kg/day, divided q12h30 mg/kg/day, divided q12h30 mg/kg/day, divided q12h
OR
Clindamycin PO10 mg/kg/day, divided q12h15 mg/kg/day, divided q8h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h15 mg/kg/day, divided q8h20 mg/kg/day, divided q6h
OR
Doxycyclinej PO (loading dose 4.4 mg/kg)4.4 mg/kg/day, divided q12h4.4 mg/kg/day, divided q12h
OR
Levofloxacinh PO
OR
2. Alternatives for penicillin-susceptible strains
Amoxicillink PO50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h75 mg/kg/day, divided q8h75 mg/kg/day, divided q8h
OR
Penicillin Vk PO50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h50 mg/kg/day, divided q12h75 mg/kg/day, divided q8h75 mg/kg/day, divided q8h75 mg/kg/day, divided q6–8h
  • div, XXX; q, every.

  • Bold font: preferred antimicrobial agent.

  • Normal font: alternative selections are listed in order of preference for therapy for patients who cannot tolerate first-line therapy, or if first-line therapy is unavailable.

  • a Severe anthrax includes anthrax meningitis; inhalation anthrax; or injection, gastrointestinal, or cutaneous anthrax with systemic involvement; extensive edema; or lesions of the head or neck.

  • b Neonates with irritability, vital sign instability, bulging fontanel, or focal neurologic deficits should be considered to have CNS infection if CSF examination is not possible. Normal CSF may not completely exclude deep brain hemorrhage/abscess.

  • c Increased risk of seizures associated with imipenem/cilastatin therapy.

  • d Doripenem is approved in Japan at this dose for the treatment of community-acquired bacterial meningitis in older children.

  • e Linezolid should be used with caution in newborn infants with thrombocytopenia, as it may exacerbate it. Linezolid use for >14 days may be associated with additional hematopoietic toxicity.

  • f Rifampin is not a protein synthesis inhibitor; it also may be used in combination therapy based on in vitro synergy.

  • g Should be used only if other options are not available because of toxicity concerns; obtain chloramphenicol serum concentrations, if possible.

  • h Safety data are unavailable for fluoroquinolones for duration of therapy >30 days. Tendinopathy and arthralgia have been reported with fluoroquinolone antimicrobial agents in ambulating animals and humans. These problems appear to be much less, if they occur at all, in pediatric patients, especially in newborn infants.54,112,113

  • i On the basis of in vitro susceptibility data rather than studies of clinical efficacy.

  • j A single 10- to 14-day course of doxycycline is not routinely associated with tooth staining in older children but may stain developing teeth in neonates.40,41,114

  • k Be aware of the possibility of emergence of penicillin-resistance during monotherapy with amoxicillin or penicillin.