Pediatric Infectious Disease Journal:
Parenteral Antibiotics for the Treatment of Serious Neonatal Bacterial Infections in Developing Country Settings
Darmstadt, Gary L. MD, MS*; Batra, Maneesh MD, MPH†; Zaidi, Anita K. M. MBBS, SM‡
From the *Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; †Department of Pediatrics, University of Washington School of Medicine, Seattle, WA; and ‡Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.
Supported by Wellcome Trust Burroughs Wellcome Fund, Infectious Disease Initiative 2000.
Address for correspondence: Gary L. Darmstadt, MD, MS, Integrated Health Solutions Development, Bill & Melinda Gates Foundation, P.O. Box 23350, Seattle, WA 98102. E-mail: Gary.Darmstadt@gatesfoundation.org.
Background: A number of special issues must be considered when selecting simple, safe, inexpensive, and effective antimicrobial regimens for treatment of neonatal sepsis in developing country community settings.
Methods: We reviewed available data regarding pharmacologic profiles of parenteral antibiotics with specific attention to properties relevant to their use in the treatment of neonatal infections in developing country communities.
Results: For community-based management of neonatal infections, particularly attractive properties include efficacy and safety of extended-interval, intramuscular dosing regimens. The penicillins and cephalosporins have relatively favorable efficacy and safety profiles. Although the aminoglycosides have narrow therapeutic indices, when used appropriately, they are safe and effective. Although inexpensive and effective, the potential for significant life-threatening toxicity among neonates associated with chloramphenicol makes it the least preferred of the parenteral agents for empiric therapy.
Conclusions: The preferred parenteral regimens for community and first-level facility use are a combination of procaine penicillin G and gentamicin, or ceftriaxone given alone, which are safe and retain efficacy when dosed at extended intervals (≥24 hours) by intramuscular administration.
Choosing simple, safe, inexpensive, and effective antimicrobial regimens for treatment of neonatal sepsis in community settings poses many challenges. Adequate data are lacking on identification of pathogens and antimicrobial susceptibilities, efficacy, pharmacokinetics, and safety in neonates. Antibiotics with good safety profiles may be too expensive or impractical for developing countries to use, and legitimate concerns exist about further promoting the emergence of antibiotic resistance, a growing problem in many developing country health facilities.
In this review, we focus primarily on pharmacologic considerations in selecting parenteral antimicrobial regimens for use in developing country settings. A number of special issues must be taken into account when devising antibiotic treatment strategies for neonatal infections in these settings (Tables 1, 2). 1 In general, these factors mandate that studies be performed specifically in neonates to understand and predict reliably the pharmacokinetics and ultimately the efficacy and potential toxicity of antibiotics given for management of infections. However, data from studies among neonates are not uniformly available for many of the antimicrobials currently in use, or for potentially useful agents in the treatment of serious infections.
Antibiotics Choices for Community Settings in Developing Countries
Antibiotics of potential use in community-based strategies in developing country settings are discussed in detail below.
Ampicillin and Penicillin G
Ampicillin has been widely used in neonatal medicine as empiric therapy for early-onset neonatal sepsis and meningitis, in combination with gentamicin for synergistic activity against Group B Streptococcus (GBS), enterococci, Listeria monocytogenes, and some Enterobacteriaceae (eg, Enterobacter spp., Proteus spp., Escherichia coli).2 Ampicillin and gentamicin (see later in the text) continue to be the first-line, standard-of-care antibiotics for treatment of neonatal sepsis in developing as well as developed countries.2–4 Although ampicillin remains the first-line antibiotic of choice for use in health-facilities, use in community-based settings is not feasible because of the need to administer doses more frequently than once daily. Furthermore, increasing ampicillin resistance among Gram-negative rods has developed worldwide.2,5,6 Klebsiella spp. are intrinsically resistant to ampicillin, and most strains of Staphylococcus aureus are now also resistant.7
The half-life of ampicillin is 5 to 6 hours in neonates <7 days old and 2 hours in older neonates.8 Thus, neonates <1 week old can maintain adequate levels with twice daily dosing, but older neonates should be given 3 to 4 doses per day. The low penetration of ampicillin into cerebrospinal fluid (CSF) increases with meningeal inflammation, but higher doses (eg, 200–300 mg/kg/d) should be used to achieve adequate mean inhibitory concentrations (MICs) against many organisms in the CSF.9
In general, ampicillin is preferred to penicillin G due to activity against some Gram-negative pathogens such as Haemophilus influenzae, E. coli, Proteus spp., Salmonella spp., Shigella spp.; significantly increased activity against Listeria; slightly increased activity against enterococci; and equivalent activity against Neisseria meningitides. However, it should be noted that ampicillin is slightly less active against group A and B streptococci and pneumococci than penicillin G. Penicillin G remains the preferred antimicrobial for treatment of Treponema pallidum and for meningococcal infections. The half-life of aqueous penicillin G is inversely correlated with birthweight and postnatal age, with ranges reported from 1.5 to 10 hours in the first week of life.10 The half-life for infants older than 7 days ranges from 1.5 to 4 hours.10 Even in the setting of inflammation of the meninges, penicillin G does not penetrate the CSF well; however, sufficient CSF concentrations can be attained for treatment of Treponema pallidum.10
There is substantial experience in using longer-acting procaine penicillin G administered intramuscularly (IM) to neonates with sepsis and congenital syphilis.2,11,12 Procaine penicillin provides excellent coverage against GBS, Group A streptococci, meningococci, Treponema pallidum, L. monocytogenes, and most strains of Steptococcus pneumoniae. Procaine penicillin combined with an aminoglycoside, administered IM, is used as empiric first-line treatment of neonatal sepsis in some developing countries, especially in areas where difficulty in establishing venous access precludes use of intravenous (IV) ampicillin. This regimen is also used in neonatal IMCI protocols in some countries. The penicillin agents exhibit synergy with aminoglycosides against GBS as well as S. aureus, enterococci, and Listeria. However, ampicillin is preferred over penicillin when venous access and multiple daily dosing are not problematic because of its wider spectrum of activity with an equivalent safety profile and better CSF penetration.
Procaine penicillin is relatively inexpensive and well tolerated. A dose of 50,000 units/kg IM produces peak levels 4 to 6 hours after administration, mean serum levels of 7 to 9 μg/mL for up to 12 hours, and 1.5 μg/mL at 24 hours after the dose in infants <7 days of age, making once-daily dosing possible.13 Procaine penicillin G administered once-daily IM along with gentamicin once daily has been shown recently to be feasible and effective for treatment of serious neonatal infections in the community in Bangladesh and Pakistan.14,15
Serum levels decrease more rapidly in older neonates because of greater renal system maturity, with levels of 0.4 μg/mL at 24 hours.13 Nevertheless, this is above the MIC for streptococci and most pneumococci, which have MICs for penicillin between 0.005 and 0.1 μg/mL.2 CSF penetration is variable.11,13,16
Procaine penicillin has been used successfully in the management of congenital neurosyphilis, although some have expressed concern that adequate spirocheticidal concentrations may not always be achieved.17 The chief disadvantages of procaine penicillin for treatment of neonatal sepsis are lack of coverage against staphylococci, rising resistance among pneumococci, lack of activity against Gram-negative rods, and uncertain CSF penetration.
The combination of parenteral oxacillin (or nafcillin) and gentamicin is widely recommended for empirical treatment of suspected serious staphylococcal infections, for example when umbilical or skin infection, or a consolidated pneumonia suspicious for S. aureus, is identified as the potential source for invasive disease, in addition to some late-onset neonatal infections.2 These antimicrobials can also be used to treat infections caused by streptococci, including Group B streptococcal and pneumococcal infections; however, the natural penicillins are preferred.10 The antistaphylococcal penicillin alone, however, lack activity against enterococci or Gram-negative bacilli. Nafcillin is preferred for central nervous system (CNS) infections. Antistaphylococcal penicillins are safe and well tolerated in neonates, although occasional cases of nephrotoxicity (due to large doses of methicillin) and hepatotoxicity (due to oxacillin) have been described.2 Moreover, repeated IM dosing of these agents may result in muscle damage. Half-life is prolonged in neonates <7 days old and dosing intervals of 12 hours are adequate.18 Oral cloxacillin is commonly used for the treatment of superficial skin and umbilical cord infections in developing countries; however, there is no experience with using oral cloxacillin in the treatment of invasive neonatal infections. Frequent dosing, lack of CSF penetration, and narrow spectrum of activity (eg, not active against enterococci or Gram-negative bacilli) are limitations for home-based therapy. Methicillin resistant S. aureus is reported as a significant pathogen in hospital-based studies in India and elsewhere in low resource settings6,19,20; however, it is unclear if methicillin resistant S. aureus is a problem in the community, although limited data suggest this may be so (Darmstadt GL, unpublished data).
Chloramphenicol was used extensively in the treatment of neonatal infections worldwide before the advent of the third generation cephalosporins.2 Today, because of safer alternatives, use of chloramphenicol is largely restricted to developing countries where third generation cephalosporins are used infrequently because of their expense. Chloramphenicol is cheap, has broad-spectrum activity, and excellent CNS penetration.2 It is bactericidal against H. influenzae and S. pneumoniae, but bacteriostatic against GBS and most Gram-negative enteric rods.2 Large variability in serum concentrations and half-lives after both oral and IV administration has been reported by many investigators.21–29 Therefore, monitoring of serum levels to guide dosage is necessary to avoid subtherapeutic or potentially toxic levels.2,30,31 Concentrations in CSF are 35% to 90% of those in the serum, regardless of meningeal inflammation.29,32 Oral administration of chloramphenicol in neonates results in much lower serum concentrations than those observed after IV or IM administration, and wide fluctuations in levels have been observed in neonates given the same dosage, perhaps because of immaturity of the neonatal gastrointestinal tract and resultant erratic absorption.21,25,26
Chloramphenicol toxicity, especially in preterm and low birth weight babies is well documented, and is the major limitation to its use.2,25,33 A cardiovascular collapse reaction, “gray baby syndrome,” which presents with vomiting, refusal to suck, respiratory distress, metabolic acidosis, abdominal distention, and diarrhea, has been described in many infants.2,25,33 The syndrome is especially common in preterm babies and is related to high serum levels of chloramphenicol, immaturity of the hepatic glucuronyl transferase system, and diminished renal clearance.2 Thus, chloramphenicol is contraindicated in premature or low birth weight babies and should be used with extreme caution in the neonatal period.
IM or IV administration of chloramphenicol is currently recommended in WHO protocols for neonates beyond the first week of life and young infants hospitalized with very severe pneumonia as a first-line agent, and for sepsis as a second-line agent if no improvement occurs after 48 hours of a penicillin and aminoglycoside.3
There is extensive experience on use of cephalosporins in neonates, as parenteral administration of penicillin/ampicillin with third generation cephalosporins, particularly cefotaxime, is standard therapy, albeit second-line, for neonatal sepsis. The cephalosporins tend to be relatively expensive, however, and there is more concern over emergence of resistance with their use than with the penicillins and aminoglycosides.2,34,35 The first generation cephalosporins (eg, cephalexin, cefazolin) lack sufficient activity against Gram-negative pathogens, whereas the third generation agents provide excellent coverage against Gram-negative organisms but activity against S. aureus and Streptococcus pyogenes may be compromised. For example, cefixime, a third generation cephalosporin, entirely lacks activity against S. aureus.
The second generation cephalosporins, such as cefuroxime, have a very favorable side effect profile and good spectrum of activity against most isolates of the principal agents thought to cause serious bacterial infections in neonates in the community, namely S. aureus, S. pneumoniae, S. pyogenes, E. coli, Salmonella spp., Enterobacter spp., and Klebsiella spp. They are relatively expensive, however, costing approximately $1 for a course of treatment. Intravenous cefuroxime, which has equivalent pharmacokinetics as IM administration, has been used in neonates for the treatment of sepsis, meningitis and pneumonia, as well as for Salmonella infections, including meningitis.36–41 However, with the availability of third generation cephalosporins, IV cefuroxime is no longer used in neonates in industrialized countries, since a delayed sterilization (>24 hours) was reported in 10% of cases of meningitis, particularly due to H. influenzae, treated with cefuroxime.5,42
The parenteral third generation cephalosporins are highly active against the major pathogens of neonates and young infants, including GBS, pneumococci, Gram-negative rods, and H. influenzae. They also have some activity against methicillin-susceptible S. aureus, although less compared with first and second generation cephalosporins. They do not have activity against L. monocytogenes and enterococci, but Listeria has not been described as a major pathogen of neonates in developing countries. The cephalosporins also lack synergism with aminoglycosides, although use in combination with aminoglycosides helps to limit risk for emergence of resistance. Two third generation cephalosporins, cefotaxime and ceftriaxone, have been widely used in the treatment of neonatal infections in developed and developing countries.2,5,43–45 Both drugs have excellent CSF penetration and safety profiles, making them drugs of choice for the treatment of Gram-negative meningitis in neonates and young infants.2,46–48 Cefotaxime has been preferred for neonatal therapy because of concern about aggravation of hyperbilirubinemia with ceftriaxone.2,5 Ceftriaxone has high protein-binding capacity and can cause displacement of bilirubin from albumin, and has significant excretion via the biliary system, which may be immature in neonates and low-birth weight infants.49–54 However, attractive features of ceftriaxone include its long serum half-life, which makes once-daily dosing possible—a significant advantage which has popularized its outpatient use; and wide therapeutic index which obviates the need for monitoring drug levels.2,44 Although ceftriaxone has been used successfully, even in low-birth weight babies without significant worsening of jaundice,2,55,56 more experience is needed in the neonatal period. In a recent community-based, randomized controlled trial, ceftriaxone given once daily IM was equally effective and as safe as once daily procaine penicillin plus gentamicin IM.15 Ceftriaxone should not be used alone to treat meningitis due to enterococci, staphylococci or Pseudomonas spp., due to insufficient activity and risk for emergence of resistant strains. The dosage of ceftrioxone is 50 mg/kg once daily for all newborns except those older than 1 week who weigh more than 2 kg, in whom it is increased to 75 mg/kg once daily.2
Aminoglycosides, including gentamicin, have been widely used as first-line therapy for neonatal infections, primarily because of their excellent spectrum of activity against Gram-negative rods, and because of synergy with penicillin agents against GBS as well as S. aureus, enterococci, and Listeria. S. aureus exhibits in vitro susceptibility but break-through colonies appear within 24 to 48 hours—therefore, gentamicin by itself has little activity against staphylococci and has to be combined synergistically with a beta-lactam agent. Hospital data from developing countries indicate that Gram-negative rods are increasingly resistant to gentamicin, but this needs to be confirmed in community settings.57
Several features of gentamicin make it an attractive antibiotic from the point of view of community-based management of sepsis.58 Gentamicin pharmacokinetics are essentially identical whether administered by IM or IV routes. The drug exhibits a concentration-dependent bactericidal effect in which a linear relationship exists between higher peak:MIC ratio and improved clinical response. Moreover, the postantibiotic effect of gentamicin, or the ability of the drug to continue to suppress bacterial growth even after antibiotic concentrations have fallen below the MIC for the organism, is also concentration-dependent.2,5 These 2 features (concentration-dependent killing and postantibiotic effect) mean that gentamicin exerts a significant antibacterial effect even with extended-interval dosing such as once-daily administration. Multiple studies have shown that once-daily dosing of gentamicin produces higher peak drug concentrations than more frequent dosing intervals, and several studies in neonates have confirmed these findings.59–72 Doses used have ranged from 4 to 5 mg/kg given once daily.59–72
A limitation of aminoglycoside therapy is the relatively narrow therapeutic index, and potential for nephrotoxicity and ototoxicity, particularly with prolonged periods during which trough serum levels exceed 2 μg/mL. Moreover, pharmacokinetics are particularly variable in preterm young neonates because of dynamic changes in renal function and fluid status. The serum half-life may also be prolonged in asphyxiated newborns. Thus, monitoring of serum levels is standard-of-care for treatment of serious neonatal infections. A recent developing country study, however, demonstrated that extended interval gentamicin dosing for neonates based on weight category could be administered safely.73 Thus, when guidelines for serum levels are adhered to, aminoglycosides are safe and effective first-line agents for empiric treatment of early and late onset neonatal sepsis and early-onset meningitis (ie, gentamicin in combination with ampicillin). Gentamicin (or amikacin), in combination with ampicillin and possibly also cefotaxime, is also considered by many experts as first-line therapy for late-onset neonatal meningitis; and gentamicin/amikacin plus ampicillin and clindamycin is standard therapy for sepsis of presumed gastrointestinal tract origin.
No data comparing oral and parenteral antibiotic treatment regimens in the community have been reported, and the incremental benefit of injectable over oral antibiotics is not known. Among parenteral agents, there is considerable experience with the use of penicillins, cephalosporins, aminoglycosides, and chloamphenicol in both developed and developing country health-facility settings for the treatment of neonatal infections. For community-based management of neonatal infections, particularly attractive properties include efficacy and safety of extended-interval, IM dosing regimens. The penicillins and cephalosporins have relatively favorable efficacy and safety profiles. Although the aminoglycosides have narrow therapeutic indices, when used appropriately they are safe and effective. Although inexpensive and effective, the potential for significant life-threatening toxicity among neonates associated with chloramphenicol makes it the least preferred of the parenteral agents for empiric therapy.
The preferred parenteral antibiotic regimen for community and first-level facility use is a combination of procaine penicillin G given once daily and gentamicin given at intervals of ≥24 hours, depending on category of body weight (Table 3).58,73 Both agents can be given IM or IV. Ceftriaxone is much more expensive and promotion of resistance in community settings is a major concern; however, it offers an excellent alternative as a single agent given once daily (Table 3). The complexity of the issues involved in antibiotic selection are summarized in Table 4 and are further considered by Bhutta et al in analyzing community-based antibiotic treatment strategies for serious neonatal infections in developing country settings.74
1.Paap CM, Nahata MC. Clinical pharmacokinetics of antibacterial drugs in neonates. Clin Pharmacokinet
2.Saez-Llorens X, McCracken GH Jr. Clinical phamacology of antimicrobial agents. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant.
5th ed. Philadelphia, PA: WB Saunders; 2001:1419–1466.
3.World Health Organization. Management of the Child With Serious Infection or Severe Malnutrition: Guidelines for Care at the First-Referral Level in Developing Countries.
Geneva, IL: World Health Organization; 2000. WHO/FCH/CAH/00.1.
4.Robillard PY, Perez JM, Hulsey TC, et al. Evaluation of neonatal sepsis screening in a tropical area. Part I: major risk factors for bacterial carriage at birth in Guadeloupe. West Indian Med J
5.Fanos V, Dall'Agnola A. Antibiotics in neonatal infections: a review. Drugs
6.Tallur SS, Kasturi AV, Nadgir SD, et al. Clinico-bacteriological study of neonatal septicemia in Hubli. Indian J Pediatr
7.Burman LG, Berglund B, Huovinen P, et al. Effect of ampicillin versus cefuroxime on the emergence of beta-lactam resistance in faecal Enterobacter cloacae
isolates from neonates. J Antimicrob Chemother
8.Kalenic S, Francetic I, Polak J, et al. Impact of ampicillin and cefuroxime on bacterial colonization and infection in patients on a neonatal intensive care unit. J Hosp Infect
9.Kaplan JM, McCracken GH Jr, Horton LJ, et al. Pharmacologic studies in neonates given large dosages of ampicillin. J Pediatr
10.Saez-Llorens X, McCracken GH. Clinical pharmacology of antibacterial agents. In: Remington JS, Klein JO, Wilson CB, et al, eds. Infectious Diseases of the Fetus and Newborn Infant
. Philadelphia, PA: Elsevier Saunders; 2006:1223–1267.
11.Speer ME, Mason EO, Scharnberg JT. Cerebrospinal fluid concentrations of aqueous procaine penicillin G in the neonate. Pediatrics
12.Paryani SG, Vaughn AJ, Crosby M, et al. Treatment of asymptomatic congenital syphilis: benzathine versus procaine penicillin G therapy. J Pediatr
13.McCracken GH Jr, Ginsberg C, Chrane DF, et al. Clinical pharmacology of penicillin in newborn infants. J Pediatr
14.Baqui AH, Arifeen SE, Darmstadt GL, et al. Effect of a package of community-based newborn care delivered by two strategies in Sylhet district, Bangladesh: a cluster-randomised controlled trial. Lancet
15.Zaidi A, Sundar S, Darmstadt G, et al. Antibiotic therapy for serious bacterial infections in young infants: randomized community-based trial [abstract 2753.5]. Pediatric Academic Societies’ Annual Meeting
. San Francisco, CA, April 29–May 2, 2006.
16.Azimi PH, Janner D, Berne P, et al. Concentrations of procaine and aqueous penicillin in the cerebrospinal fluid of infants treated for congenital syphilis. J Pediatr
17.Azimi PH, Bernard B, Tinsely L, et al. Pharmacokinetics of aqueous penicillins in the cerebrospinal fluids of neonates. Pediatr Res
18.Sarff LD, McCracken GH, Thomas ML, et al. Clinical pharmacology of methicillin in neonates. J Pediatr
19.Mehndiratta PL, Vidhani S, Mathur MD. A study on Staphylococcus aureus strains submitted to a reference laboratory. Indian J Med Res
20.Singh M, Paul VK, Narayan S, et al. National Neonatal-Perinatal Database. Report for the year 2000. India: National Neonatology Forum; 2001.
21.Weber MW, Gatchalian SR, Ogunlesi O, et al. Chloramphenicol pharmacokinetics in infants less than three months of age in the Philippines and The Gambia. Pediatr Infect Dis J
22.Rajchgot P, Prober CG, Soldin S, et al. Chloramphenicol in the newborn infant. Prog Clin Biol Res
23.Rajchgot P, Prober CG, Soldin S, et al. Initiation of chloramphenicol therapy in the newborn infant. J Pediatr
24.Nahata MC, Powell DA. Comparative bioavailability and pharmacokinetics of chloramphenicol after intravenous chloramphenicol succinate in premature infants and older patients. Dev Pharmacol Ther
25.Mulhall A, de Louvois J, Hurley R. Chloramphenicol toxicity in neonates: its incidence and prevention. Br Med J (Clin Res Ed)
26.Mulhall A, de Louvois J, Hurley R. The pharmacokinetics of chloramphenicol in the neonate and young infant. J Antimicrob Chemother
27.Kauffman RE, Miceli JN, Strebel L, et al. Pharmacokinetics of chloramphenicol and chloramphenicol succinate in infants and children. J Pediatr
28.Glazer JP, Danish MA, Plotkin SA, et al. Disposition of chloramphenicol in low birth weight infants. Pediatrics
29.Friedman CA, Lovejoy FC, Smith AL. Chloramphenicol disposition in infants and children. J Pediatr
30.Hodgman JE, Burns LE. Safe and effective chloramphenicol dosages for premature infants. Am J Dis Child
31.Ziegra SR, Storm RR. Dosage of chloramphenicol in premature infants. J Pediatr
32.Dunkle LM. Central nervous system chloramphenicol concentration in premature infants. Antimicrob Agents Chemother
33.Laferriere CI, Marks MI. Chloramphenicol: properties and clinical use. Pediatr Infect Dis
34.Maiorini E, Lopez EL, Morrow AL, et al. Multiply resistant nontyphoidal Salmonella gastroenteritis in children. Pediatr Infect Dis J
35.Bhat KG, Andrade AT, Karadesai SG, et al. Antimicrobial susceptibility of Salmonella typhi
to quinolones and cephalosporins. Indian J Med Res
36.Smith ML, Abramson JS, Hampton KD, et al. Salmonella meningitis. Unusual presentation and successful treatment with cefuroxime. N C Med J
37.Sirinavin S, Chiemchanya S, Visudhipan P, et al. Cefuroxime treatment of bacterial meningitis in infants and children. Antimicrob Agents Chemother
38.Mathur YC, Mathur NC, Lal HM. Clinical efficacy of Cefuroxime axetil in S. typhi
. Indian Pediatr
39.de Louvois J, Mulhall A, Hurley R. Cefuroxime in the treatment of neonates. Arch Dis Child
40.Bahaeldin HK, Elbaroudy R, Omran N. The efficacy of cefuroxime in the treatment of bacterial meningitis in infants and children. Clin Ther
41.Mondal GP, Raghavan M, Bhat BV, et al. Neonatal septicaemia among inborn and outborn babies in a referral hospital. Indian J Pediatr
42.Dajani AS, Pokowski LH. Delayed cerebrospinal fluid sterilization, in vitro
bactericidal activities, and side effects of selected beta-lactams. Scand J Infect Dis Suppl
43.Hall MA, Ducker DA, Lowes JA, et al. A randomised prospective comparison of cefotaxime versus netilmicin/penicillin for treatment of suspected neonatal sepsis. Drugs
. 1988;35(suppl 2):169–177.
44.Van Reempts PJ, Van Overmeire B, Mahieu LM, et al. Clinical experience with ceftriaxone treatment in the neonate. Chemotherapy
45.Odio CM. Cefotaxime for treatment of neonatal sepsis and meningitis. Diagn Microbiol Infect Dis
46.McCracken GH Jr. Use of third-generation cephalosporins for treatment of neonatal infections. Am J Dis Child
47.del Rio MA, Chrane D, Shelton S, et al. Ceftriaxone versus ampicillin and chloramphenicol for treatment of bacterial meningitis in children. Lancet
48.de Louvois J. Acute bacterial meningitis in the newborn. J Antimicrob Chemother.
49.Wadsworth SJ, Suh B. In vitro
displacement of bilirubin by antibiotics and 2-hydroxybenzoylglycine in newborns. Antimicrob Agents Chemother.
50.Schaad UB, Hayton WL, Stoeckel K. Single-dose ceftriaxone kinetics in the newborn. Clin Pharmacol Ther
51.Schaad UB. The cephalosporin compounds in severe neonatal infection. Eur J Pediatr
52.Robertson A, Fink S, Karp W. Effect of cephalosporins on bilirubin-albumin binding. J Pediatr
53.Fink S, Karp W, Robertson A. Ceftriaxone effect on bilirubin-albumin binding. Pediatrics
54.Bradley JS, Ching DL, Wilson TA, et al. Once-daily ceftriaxone to complete therapy of uncomplicated group B streptococcal infection in neonates. A preliminary report. Clin Pediatr (Phila)
55.Wiese G. Treatment of neonatal sepsis with ceftriaxone/gentamicin and with azlocillin/gentamicin: a clinical comparison of efficacy and tolerability. Chemotherapy
56.James J, Mulhall A, de Louvois J. Ceftriaxone–clinical experience in the treatment of neonates. J Infect.
57.Thaver D, Ali SA, Bhutta ZA, et al. Antimicrobial resistance of neonatal pathogens in developing countries. Pediatr Infect Dis J.
58.Darmstadt GL, Miller-Bell M, Batra M, et al. Extended-interval dosing of gentamicin for treatment of neonatal sepsis in developed and developing countries. J Health Popul Nutr
59.Agarwal G, Rastogi A, Pyati S, et al. Comparison of once-daily versus twice-daily gentamicin dosing regimens in infants > or = 2500 g. J Perinatol
60.Chotigeat U, Narongsanti A, Ayudhya DP. Gentamicin in neonatal infection: once versus twice daily dosage. J Med Assoc Thai
61.de Alba Romero C, Gomez Castillo E, Manzanares Secades C, et al. Once daily gentamicin dosing in neonates. Pediatr Infect Dis J
62.Hayani KC, Hatzopoulos FK, Frank AL, et al. Pharmacokinetics of once-daily dosing of gentamicin in neonates. J Pediatr
. 1997;131(1 Pt 1):76–80.
63.Hitt CM, Klepser ME, Nightingale CH, et al. Pharmacoeconomic impact of once-daily aminoglycoside administration. Pharmacotherapy
64.Krishnan L, George SA. Gentamicin therapy in preterms: a comparison of two dosage regimens. Indian Pediatr
65.Langlass TM, Mickle TR. Standard gentamicin dosage regimen in neonates. Am J Health Syst Pharm
66.Logsden BA. Gentamicin 3 mg/kg dosing and monitoring within the first 7 days of life. J Pediatr Pharm Practice
67.Lundergan FS, Glasscock GF, Kim EH, et al. Once-daily gentamicin dosing in newborn infants. Pediatrics
. 1999;103(6 Pt 1):1228–1234.
68.Skopnik H, Wallraf R, Nies B, et al. Pharmacokinetics and antibacterial activity of daily gentamicin. Arch Dis Child
. 1992;67(1 Spec No):57–61.
69.Solomon R, Kuruvilla KA, Job V, et al. Randomized controlled trial of once vs. twice daily gentamicin therapy in newborn. Indian Pediatr
70.Stickland MD, Kirkpatrick CM, Begg EJ, et al. An extended interval dosing method for gentamicin in neonates. J Antimicrob Chemother
71.Thureen PJ, Reiter PD, Gresores A, et al. Once- versus twice-daily gentamicin dosing in neonates >/=34 weeks’ gestation: cost-effectiveness analyses. Pediatrics
72.Vervelde ML, Rademaker CM, Krediet TG, et al. Population pharmacokinetics of gentamicin in preterm neonates: evaluation of a once-daily dosage regimen. Ther Drug Monit
73.Darmstadt GL, Hossain MM, Jana AK, et al. Determination of extended-interval gentamicin dosing for neonatal patients in developing countries. Pediatr Infect Dis J
74.Bhutta ZA, Thaver D, Qazi S, et al. Review of studies on community-based management of neonatal sepsis. Pediatr Infect Dis J.
antibiotic resistance; community; developing country; neonatal sepsis; pharmacokinetics; serious bacterial infections
© 2009 Lippincott Williams & Wilkins, Inc.
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