The use of antimicrobials during pregnancy and lactation should balance benefit to the mother with the risk of fetal and infant toxicity (including anatomic anomalies with fetal exposure). A number of factors determine the degree of transfer of antibiotics across the placenta: lipid solubility, degree of ionization, molecular weight, protein binding, placental maturation, and placental and fetal blood flow. The previous FDA labeling of 5 categories of risk will be phased out, replaced by narrative summaries of risks associated with the use of a drug during pregnancy and lactation for the mother, the fetus, and the breastfeeding child. The risk categories from A to X were felt to be too simplistic and are to be phased out by 2020. Risks are now all clearly noted, and for drugs with high fetal risk, black box warnings are included (eg, ribavirin).115
Fetal serum antibiotic concentrations (or cord blood concentrations) following maternal administration have not been systematically studied, but new pharmacokinetic models of transplacental drug transfer and fetal metabolism have recently been developed to provide some insight into fetal drug exposure.116–118 The following commonly used drugs appear to achieve fetal concentrations that are equal to or only slightly less than those in the mother: penicillin G, amoxicillin, ampicillin, sulfonamides, trimethoprim, tetracy- clines, and oseltamivir. The aminoglycoside concentrations in fetal serum are 20% to 50%
of those in maternal serum. Cephalosporins, carbapenems, nafcillin, oxacillin, clindamy- cin, and vancomycin penetrate poorly (10%–30%), and fetal concentrations of erythro- mycin and azithromycin are less than 10% of those in the mother.
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Antimicrobial Therapy for Newborns 5 bials and other agents in human milk can be found at the National Library of Medicine LactMed Web site (http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm; accessed Septem- ber 27, 2018).119
In general, neonatal exposure to antimicrobials in human milk is minimal or insignifi- cant. Aminoglycosides, beta-lactams, ciprofloxacin, clindamycin, macrolides, fluconazole, and agents for tuberculosis are considered safe for the mother to take during breastfeed- ing.120,121 The most common reported neonatal side effect of maternal antimicrobial use during breastfeeding is increased stool output.122 Clinicians should recommend mothers alert their pediatric health care professional if stool output changes occur. Maternal treat- ment with sulfa-containing antibiotics should be approached with caution in the breastfed infant who is jaundiced or ill.
Antimicrobial Therapy According to Clinical Syndromes 6 NOTES
• This chapter should be considered a rough guidance for a typical patient. Dosage recommendations are for patients with relatively normal hydration, renal function, and hepatic function. Because the dose required is based on the exposure of the anti- biotic to the pathogen at the site of infection, higher dosages may be necessary if the antibiotic does not penetrate well into the infected tissue (eg, meningitis) or if the child eliminates the antibiotic from the body more quickly than average. Higher dos- ages/longer courses may also be needed if the child is immunocompromised and the immune system cannot help resolve the infection, as it is becoming clearer that the host contributes significantly to microbiologic and clinical cure above and beyond the antimicrobial-attributable effect.
• Duration of treatment should be individualized. Those recommended are based on the literature, common practice, and general experience. Critical evaluations of duration of therapy have been carried out in very few infectious diseases. In general, a longer duration of therapy should be used (1) for tissues in which antibiotic concentrations may be relatively low (eg, undrained abscess, central nervous system [CNS] infection);
(2) for tissues in which repair following infection-mediated damage is slow (eg, bone);
(3) when the organisms are less susceptible; (4) when a relapse of infection is unac- ceptable (eg, CNS infections); or (5) when the host is immunocompromised in some way. An assessment after therapy will ensure that your selection of antibiotic, dose, and duration of therapy were appropriate. Until prospective, comparative studies are per- formed for different durations, we cannot assign a specific increased risk of failure for shorter courses. We support the need for these studies in a controlled clinical research setting, either outpatient or inpatient.
• Our approach to therapy is continuing to move away from the concept that “one dose fits all,” as noted previously. In addition to the dose that provides antibiotic exposure and host immune competence, the concept of target attainment is being better defined.
The severity of illness and the willingness of the practitioner to accept a certain rate of failure needs to be considered. Hence the use of broad-spectrum, high-dose treat- ment for a child in florid septic shock (where you need to be right virtually 100% of the time), compared with the child with impetigo where a treatment that is approximately 80% effective is acceptable, as you can just see the child back in the office in a few days and alter therapy as necessary.
• Diseases in this chapter are arranged by body systems. Please consult the index for the alphabetized listing of diseases and chapters 7 through 10 for the alphabetized listing of pathogens and for uncommon organisms not included in this chapter.
• A more detailed description of treatment options for methicillin-resistant Staphy- lococcus aureus (MRSA) infections and multidrug-resistant Gram-negative bacilli infections, including a stepwise approach to increasingly broad-spectrum agents, is
Antimicrobial Therapy According to Clinical Syndromes 6
renal function and serum drug concentrations. Its use in organisms with a minimal inhibitory concentration of 2 or greater may not provide adequate exposure for a cure with realistic pediatric doses. Alternatives now approved by the US Food and Drug Administration for children, particularly ceftaroline, are likely to be as effective, but are more likely to be safer, and should be considered.
• Therapy of Pseudomonas aeruginosa systemic infections has evolved from intravenous (IV) ceftazidime plus tobramycin to single-drug IV therapy with cefepime for most infections in immune-competent children, due to the relative stability of cefepime to beta-lactamases, compared with ceftazidime. Oral therapy with ciprofloxacin has replaced IV therapy in children who are compliant and able to take oral therapy, par- ticularly for “step-down” therapy of invasive infections.
• Abbreviations: AAP, American Academy of Pediatrics; ACOG, American College of Obstetricians and Gynecologists; ADH, antidiuretic hormone; AFB, acid-fast bacilli;
AHA, American Heart Association; ALT, alanine transaminase; AmB, amphotericin B;
amox/clav, amoxicillin/clavulanate; AOM, acute otitis media; ARF, acute rheumatic fever; AST, aspartate transaminase; AUC:MIC, area under the serum concentra- tion vs time curve: minimum inhibitory concentration; bid, twice daily; CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus; cap, capsule;
CDC, Centers for Disease Control and Prevention; CMV, cytomegalovirus; CNS, central nervous system; CRP, C-reactive protein; CSD, cat-scratch disease; CSF, cere- brospinal fluid; CT, computed tomography; DAT, diphtheria antitoxin; div, divided;
DOT, directly observed therapy; EBV, Epstein-Barr virus; ESBL, extended spectrum beta-lactamase; ESR, erythrocyte sedimentation rate; ETEC, enterotoxin-producing Escherichia coli; FDA, US Food and Drug Administration; GI, gastrointestinal;
HACEK, Haemophilus aphrophilus, Aggregatibacter (formerly Actinobacillus) actino- mycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella spp; HIV, human immunodeficiency virus; HSV, herpes simplex virus; HUS, hemolytic uremic syndrome; I&D, incision and drainage; IDSA, Infectious Diseases Society of America;
IM, intramuscular; INH, isoniazid; IV, intravenous; IVIG, intravenous immune globu- lin; KPC, Klebsiella pneumoniae carbapenemase; L-AmB, liposomal amphotericin B;
LFT, liver function test; LP, lumbar puncture; MDR, multidrug resistant; MRI, mag- netic resonance imaging; MRSA, methicillin-resistant S aureus; MRSE, methicillin- resistant Staphylococcus epidermidis; MSSA, methicillin-susceptible S aureus; MSSE, methicillin-sensitive S epidermidis; ophth, ophthalmic; PCR, polymerase chain reac- tion; PCV13, Prevnar 13-valent pneumococcal conjugate vaccine; pen-R, penicillin- resistant; pen-S, penicillin-susceptible; PIDS, Pediatric Infectious Diseases Society; pip/
tazo, piperacillin/tazobactam; PMA, post-menstrual age; PO, oral; PPD, purified pro- tein derivative; PZA, pyrazinamide; qd, once daily; qid, 4 times daily; qod, every other day; RIVUR, Randomized Intervention for Children with Vesicoureteral Reflux; RSV,
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Antimicrobial Therapy According to Clinical Syndromes 6 spp, species; STEC, Shiga toxin-producing E coli; STI, sexually transmitted infection;
tab, tablet; TB, tuberculosis; Td, tetanus, diphtheria; Tdap, tetanus, diphtheria, acellular pertussis; tid, 3 times daily; TIG, tetanus immune globulin; TMP/SMX, trimethoprim/
sulfamethoxazole; ULN, upper limit of normal; UTI, urinary tract infection; VDRL, Venereal Disease Research Laboratories; WBC, white blood cell.
er 6. Antimicrobial Therapy According to Clinical Syndromes