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New dosing strategies for antibacterial agents in the neonate
Seminars in Fetal & Neonatal Medicine (2005) 10, 185e194
www.elsevierhealth.com/journals/siny
New dosing strategies for antibacterial agents in the neonate Matthijs de Hooga,*, Johan W. Moutonb,c, John N. van den Ankera,d,e,f a
Department of Pediatrics, Erasmus MC-Sophia, Sophia Children’s Hospital, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands b Department of Medical Microbiology and Infectious Diseases, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands c Department of Medical Microbiology and infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands d Departments of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue NW, Washington, DC 20010, USA e Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA f Washington Pediatric Pharmacology Research Unit, Washington DC, USA
KEYWORDS Antibiotics; Meningitis; Necrotizing enterocolitis; Neonate; Pharmacodynamics; Review
Summary Dosing of antibiotics in neonates requires finding a delicate balance between maximal efficacy and minimal toxicity. There is a lack of data on efficacy of currently used antibiotics in neonates, and rational dosing therefore needs to be based on gestational- and postnatal-age-dependent pharmacokinetics in combination with surrogate markers. These surrogate markers are: (i) the area-under-the serum concentration time curve to minimum inhibitory concentration ratio (AUC/ MIC); (ii) peak concentration to MIC ratio (Cmax/MIC); and (iii) the time the concentration remains above the MIC (TOMIC). Whereas the efficacy of b-lactam antibiotics (including carbapenems) depends on TOMIC, the efficacy of most other antimicrobials (including aminoglycosides and fluoroquinolones) is related to AUC/ MIC and Cmax/MIC. Most modern dosing regimens are adequate when these concentration effect relationships are taken into account. Dosing adjustments in neonates are suggested, based on these relationships. Several antimicrobial combinations for treatment of meningitis and necrotizing enterocolitis exist. Empiric treatment should be based on efficacy, concerns about resistance as well as information from institutional microbiological surveillance. ª 2004 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: C311 463 6363 pager 39596; fax: C311 463 6796. E-mail address: [email protected] (M. de Hoog). 1744-165X/$ - see front matter ª 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2004.10.004
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Introduction Neonatal sepsis remains one of the main causes of mortality and morbidity of newborn infants admitted to a neonatal intensive care unit (NICU).1 Sepsis in this age group can be divided in early onset, defined as within the first 4 days of life, and late onset, occurring after 4 days.1 Furthermore, invasive infections such as pneumonia, meningitis and necrotizing enterocolitis (NEC) threaten the newborn infant. Group B streptococcus and Gram-negative organisms such as Escherichia coli and Haemophilus influenzae are the most common causative organisms for early-onset sepsis.2 In the United States in particular, an increase of Gram-negative neonatal infections has been noted as a result of prenatal use of antibiotics.3 Late-onset neonatal sepsis is related to the increased use of invasive procedures such as central venous lines and includes major pathogens and Gram-positive organisms from the skin: Staphylococcus epidermidis and S. aureus.4 The spectrum of pathogens in these two different age groups has led to commonly accepted empiric antibiotic strategies. Early-onset sepsis is treated with a combination of a penicillin and either a third-generation cephalosporin or an aminoglycoside. Empiric treatment of late-onset sepsis is often initiated with a combination of flucloxacillin and either a third-generation cephalosporin or an aminoglycoside, with a switch made to vancomycin when culture results and resistance patterns indicate a need for change.4,5 NEC is treated with a combination of either amoxicillin/clavulanic acid and an aminoglycoside or a carbapenem antibiotic, mostly meropenem. These factors imply that the antibiotics most often used in NICUs are penicillins, cephalosporins, aminoglycosides, vancomycin (and alternatively teicoplanin or linezolid) and meropenem. Current insights into rational dosing of these antibiotics in the NICU will be discussed in this chapter. Special attention will be paid to rational treatment of meningitis and NEC.
General considerations The dosing of antibiotics is based on a balance between maximal efficacy and minimal toxicity, as well as induction of resistance. Ideally, efficacy should be studied in the context of specific diseases and pathogens, with several dosing regimens. However, most currently recommended dosing guidelines for antibiotics in neonates are not based on this level of evidence. Although
M. de Hoog et al. pharmacokinetic (PK) information in neonates is available, there is a general lack of high-quality data on the efficacy of these dosing regimens. Monitoring efficacy of antibiotic treatment in neonates is difficult. Culture-proven early-onset sepsis occurs in approximately 2% of very low birthweight infants, but there are limitations to the amount of blood that can be drawn for blood cultures and single blood cultures can give false negative results.2 Furthermore, increasing prenatal treatment of mothers with antibiotics obscures culture results in newborns. This implies that until adequate efficacy data are generated, dosing has to be based on surrogate markers to determine relationships between the serum PK profiles and efficacy. During the last decade, enormous progress has been made in this area to establish relationships between dosing regimens, susceptibility of micro-organisms and efficacy. The three surrogate markers, or pharmacodynamic indices, predominantly used are area-under-the serum concentration time curve to minimum inhibitory concentration ratio (AUC/MIC), peak concentration to MIC ratio (Cmax/MIC) and the time the concentration remains above the MIC (TOMIC).6 In this way, the concentrationeeffect relationships for antibacterial agents against micro-organisms can be adequately described and, combined with PK knowledge in neonates, used to rationalize dosing in this vulnerable age group. In general, antibacterial agents can be divided in two groups. The efficacy of all b-lactam agents is dependent on the time the free, non-protein-bound concentration remains above the MIC of the microorganism. The efficacy of virtually all other antibacterial agents is related to the AUC/MIC ratio and the Cmax/MIC ratio (Table 1). This has important consequences for the design of dosing regimens. It means that, for b-lactam agents, the frequency of dosing is an important factor in determining outcome. Indeed, continuous infusion of b-lactam Table 1 Suggested surrogate markers for efficacy of antibiotics used in neonates. Values relate to the nonprotein bound, free fraction of the drug Antibiotic
Marker
Desired goal
Penicillins Cephalosporins Carbapenems Aminoglycosides
TOMIC TOMIC TOMIC AUC/MIC or Cmax/MIC TOMIC
O40e50% O50e60% O30e40% Cmax/MICO5e10
Glycopeptides
100% for TOMIC
AUC/MIC, area-under-the serum concentration time curve to MIC ratio; Cmax/MIC, peak concentration to MIC ratio; TOMIC, time the concentration remains above the MIC.
New dosing strategies for antibacterial agents in the neonate antibiotics, maintaining the concentration of the antimicrobial agent above the MIC during the whole dosing interval, has become more and more standard practice, especially in ICU units. This is in contrast to the aminoglycosides and the fluoroquinolones, where the total daily dose e as reflected by the AUC or peak concentration e is the most important driver of efficacy; these antibiotics should therefore preferably given once daily. One of the important questions in relation to these relationships is what the value of the pharmacodynamic index should minimally be to ensure a high probability of therapeutic success. In this regard, it is important to realize that premature neonates have to be regarded as immunocompromised patients. Thus, in the case of b-lactam agents, the percentage TOMIC minimally needed is larger than for immunocompetent patients and is reflected by the need of, in general, higher or e preferably e more frequent dosing. It has also to be realized that large individual variations in volume of distribution (Vd) and total body clearance (Cl) exist, and that dosing regimens in this vulnerable age group should cover also those individuals with a relative short half-life (t1/2b); dosing regimes should therefore be conservative to ensure appropriate concentrations in all neonates. The PK of the majority of antibiotics used in neonates as described in this chapter follow general principles. Penicillins, cephalosporins, aminoglycosides and glycopeptides all distribute in extracellular water and are excreted mainly by glomerular filtration and, for the penicillins, tubular excretion Therefore, changes in body water and development of renal function influence the disposition of these drugs. All these antibiotics have a larger Vd and lower Cl in premature neonates, and even more so when compared to adults, and dosing regimens thus have to be adjusted accordingly. Improvement of Cl follows the gestational age (GA) and postnatal age (PNA) dependent increase in glomerular filtration rate (GFR).7 Other factors in the NICU that directly influence Vd or renal function, such as extracorporeal membrane oxygenation (ECMO) or exposure to indomethacin, were shown to significantly alter neonatal PK of these drugs.8e10
Penicillins Penicillins inhibit bacterial cell wall synthesis and are bactericidal. The penicillins most often used in the NICU are small-spectrum, b-lactamaseinsensitive penicillins such as flucloxacillin and broad-spectrum penicillins like amoxicillin and ampicillin.
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Although renally excreted, adjustment of dose the interval is only necessary in neonates with severe renal failure.
PK of penicillins Vd is higher in prematures, being 0.3 l/kg for ampicillin,11 0.45 l/kg for flucloxacillin12 and 0.41e0.68 l/kg for amoxicillin.12,13 The t1/2b of penicillins in neonates ranges from 2 to 9.5 h and is longer in premature neonates.11e15 Oral flucloxacillin is well absorbed in neonates.16 Both the Cl and Vd of penicillins are related to birthweight and neonatal asphyxia.15
Dosing of penicillins Although the therapeutic goal for penicillins in general is related to a TOMIC of 30e40%, neonates have to be regarded as immunocompromised and should at least be in the order of 40e50%, especially with respect to Gram-negatives. Ampicillin and amoxicillin (25e50 mg/kg b.i.d.) are generally combined with an aminoglycoside and are effective in the empiric treatment of neonatal sepsis.17 The efficacy of flucloxacillin has only been described in case series in neonates.18 For amoxicillin, a dose of 25 mg/kg twice daily was effective in preterm infants with a GA of less than 32 weeks.13 Although doseeeffect relations have not been studied well in neonates, currently advised dosing of ampicillin, amoxicillin and flucloxacillin in neonates19 is probably safe given the PK data, which have shown that serum concentrations remain above the MIC for long enough.13,15,18
Cephalosporins Cephalosporins, like penicillins, belong to the group of b-lactam antibiotics. They are bactericidal and interfere with synthesis of the bacterial cell wall. Cephalosporins most often used in neonatology are cefotaxime, ceftriaxone and ceftazidime. Cefotaxime and ceftriaxone have a broad and almost similar spectrum of activity, but both are notably not active against Pseudomonas aeruginosa. Ceftazidime is still the drug of choice for P. aeruginosa but has impaired activity against some of the Gram-positives, notably S. aureus. The use of broad-spectrum cephalosporins on NICUs has been associated with increasing resistance and restriction of use should be born in mind. For the same reason as for penicillins, a TOMIC of at least 50e60% is advisable.
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Cephalosporin PK
Aminoglycosides
Vd in neonates ranges from 0.46e0.69 l/kg for cefotaxime20 and 0.29e0.36 l/kg for ceftazidime8 to 0.45 l/kg for ceftriaxone.21 Vd is mainly dependent on GA and PNA. They are excreted almost exclusively via the urine and dose adjustment is indicated based on the degree of renal insufficiency. Serum half-life is 2e6 h for cefotaxime, 5e9 h for ceftazidime and 16e19 h for ceftriaxone.20,22,23 Like other renally excreted antibiotics, Cl and t1/2b are related to GA and concomitant increase of renal function, although cefotaxime Cl and t1/2b are the same for neonates weighing !1000 and O1000 g.20,24 For ceftazidime, a positive relation between Cl and an increase of GA and renal function has been demonstrated.24 Prenatal exposure to indomethacin decreases renal function and ceftazidime Cl.8 Postnatal age significantly increases the Cl of ceftazidime8 and cefotaxime.23
Aminoglycosides are bactericidal and inhibit protein synthesis and cell wall integrity through binding to ribosomes. Aminoglycosides are mainly used for treating serious Gram-negative infections caused by enteric bacilli. Aminoglycosides are synergistic with cephalosporins and penicillins in the setting of Gram-negative infections and are also used in combination treatment with vancomycin for S. aureus. The susceptibility of most Gramnegative bacteria to gentamicin, tobramycin and netilmicin is similar and, although susceptibility to amikacin is three- to fourfold less than to the other aminoglycosides, this is compensated for by the lower toxicity of amikacin, and therefore higher allowable dose. Given the increase of Gram-negative infections in the NICU, possibly due to the liberal prenatal use of antibiotics, aminoglycosides play an important role in the initial empiric treatment of neonatal sepsis3; after penicillins, they are the most commonly used antibiotic in the NICU.33
Cephalosporin dosing
Aminoglycoside PK Efficacy of cephalosporins is related to TOMIC. Several dosing regimens for cephalosporins have been examined in neonates. For cefotaxime, doses of 100e200 mg/kg/day, divided in 2e4 gifts for sepsis, meningitis or NEC have been investigated, with cure rates varying between 91 and 98.6%.25,26 The metabolite desacetylcefotaxime shows antimicrobial activity, although far less than cefotaxime itself. Studies and simulations have shown that serum concentrations of cefotaxime in neonates remain above the MIC of common neonatal pathogens (E. coli, H. influenzae, S. pneumoniae) when dosing at 50 mg/kg two or three times daily, which is the currently recommended dosing regimen for cefotaxime in neonatal sepsis and meningitis.19,25 Clinical efficacy of ceftazidime as empiric therapy in neonatal sepsis was 79% (monotherapy) and 97% (in combination with ampicillin).27 Ceftazidime is mainly used in the setting of Gram-negative infection. Because Listeria monocytogenes is resistant, ceftazidime cannot be used as monotherapy. Doses of 25 mg/kg twice daily result in adequate trough serum concentrations in term and preterm infants.28,29 Ceftriaxone has a longer serum half-life and therefore the advantage of a once-daily dosing regimen. Ceftriaxone should, however, not be used routinely in neonatal sepsis because displacement of bilirubin from albumin, bile sludging and a high incidence of diarrhoea.30e32
Aminoglycoside Vds range from 0.47 to 0.70 l/kg and are even higher in premature neonates, leading to lower peak serum concentrations in this age group.34 The t1/2b is longer in premature neonates, leading to higher serum trough concentrations in this group.34 Substantial effort has been put into developing equations, mostly based on population PK studies, which will potentially lead to better prediction of serum concentrations in the individual patient. In practice, these equations are not able to adequately predict variability and subsequent serum concentrations in the same patient.34 The usefulness of performing therapeutic drug monitoring (TDM) in infants in the first week of life is therefore not clear. In patients with patent ductus arteriosus (PDA), postnatal exposure to indomethacin and ECMO individualized dosing based on TDM should be made.
Aminoglycoside toxicity The main concerns with aminoglycosides are nephro- and ototoxicity. The incidence of aminoglycoside nephrotoxicity in neonates is not well known but seems to be considerably lower than in adults. Although reversible tubular dysfunction has been shown in many studies involving neonates, persistent glomerular filtration impairment has not been conclusively shown in prospective studies.10 Ototoxicity is an infrequent occurrence in neonatal
New dosing strategies for antibacterial agents in the neonate studies. Recent studies with extended dose intervals have failed to demonstrate aminoglycosideinduced hearing loss and no relation to serum concentrations was found.35,36
Aminoglycoside TDM and dosing Aminoglycoside efficacy is related to both peakserum-concentration to MIC ratio (Peak/MIC) and AUC/MIC in clinical and experimental studies. Peak/MIC ratios of 5e10 are desirable for clinical efficacy.37 Commonly accepted trough concentration goals in adults are !2 mg/l but those were based on a three-times-daily schedule; when dosing once a day, most authors keep !1 mg/l as a safe limit.38e40 Based on the aminoglycoside susceptibility of Gram-negative pathogens involved in neonatal septicemia, a reasonable target range for neonates would therefore be peak serum concentrations of 5e10 mg/l for gentamicin, netilmicin and tobramycin and 15e30 mg/l for amikacin. Trough concentration goals are !2 mg/l when dosing three times daily, !0.5e1.0 mg/l for once-daily dosing in gentamicin, netilmicin and tobramycin and 1.5e3 mg/l for amikacin.10 Aminoglycoside dosing in neonates has changed over the recent past to extended dosing intervals.41,42 Although this has been associated with adequate serum concentrations and a lack of toxicity, an increase of efficacy has not yet been demonstrated.35,41,42 Recent studies have demonstrated that serum concentrations as described above can be reached with doses of 3.5e5 mg/kg (gentamicin, tobramycin, netilmicin) and 7.5e 15 mg/kg (amikacin) even without a loading dose.41e43 Efficacy and toxicity have not been clearly related to peak or trough serum concentrations with extended dose intervals and clinically important nephro- and ototoxicity are rare in neonates treated with courses with a duration of less than 7 days. Furthermore, subsequent serum concentrations cannot be adequately predicted in this age group.34 The importance of routine TDM in the first week of life for efficacy and toxicity reasons has therefore been questioned.34,35 In neonatal patients with renal failure, asphyxia and/or who are exposed to drugs or situations that alter PK behavior (e.g. indomethacin, ECMO), repeated TDM is necessary.
Glycopeptides The bactericidal activity of glycopeptide antibiotics is based on the inhibition of bacterial cell wall synthesis. Glycopeptide antibiotics are the drugs
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of choice for methicillin-resistant staphylococcal infections and are widely used as empiric treatment for central-venous-line-related infections in neonates. These infections are often caused by coagulase-negative staphylococci (CONS).44 Given the concerns about development of resistance by overuse of vancomycin, routine prophylaxis with low-dose vancomycin should not be instituted.9,45
Glycopeptide PK The Vd of glycopeptides changes with the amount of body water and is larger in premature neonates. Vancomycin and teicoplanin Vd range from 0.57e0.69 l/kg in term neonates to as high as 0.97 l/kg in prematures.9 Glycopeptide Cl changes with maturation of renal function in the first weeks of life, with a lower clearance for teicoplanin than vancomycin. Clearance in relation to postconceptional age is the main determinant in the PK profile of vancomycin in neonates.9
Glycopeptide toxicity Toxicity related to glycopeptides has often been reported. Infusion-related adverse events have decreased enormously since removal of impurities from early preparations. Studies on vancomycin in neonates have seldom detected nephrotoxicity; some studies found a reversible rise in serum creatinine.9 Again, no relation to serum concentrations peak O40 mg/l and/or trough serum concentration O10 mg/l) has been detected.46 Studies of teicoplanin use in neonates have not demonstrated significant nephrotoxicity.47,48 Information on glycopeptide ototoxicity in neonates is scarce. Teicoplanin-related ototoxicity has not been described in pediatric patients. Vancomycin-induced hearing loss has not been clearly demonstrated in this age group and could not be related to duration of treatment or abnormal peak/trough serum concentrations.35 The usefulness of routine TDM of vancomycin for toxicity reasons is therefore doubtful.
Glycopeptide TDM and dosing Based on in vitro studies, vancomycin trough concentrations should exceed 4e5 mg/l. This is based on the assumption that MICs of most bacteria for which vancomycin is used is !1e2 mg/l and protein binding !50%.49 Concentrations of vancomycin in cerebrospinal fluid (CSF) of 5e10 mg/l are needed for treatment of central nervous system (CNS) infections.50 Vancomycin, in doses
190 of 20e40 mg/kg/day, was effectively used in neonates and infants of varying GAs.9,51,52 Continuous infusion of vancomycin was effective in 13 documented invasive infections in concentrations ranging from 3 to 37.6 mg/l.53 These studies, with relative few numbers of patients, show that a wide range of vancomycin peak and trough concentrations are effective against Gram-positive infections in neonates and infants. This certainly does not substantiate the currently used therapeutic range of 20e40 mg/l for peak and 5e10 mg/l for trough serum concentrations. For teicoplanin serum trough concentrations above the MIC, and preferably O10 mg/l, are correlated with efficacy in adults.54 No clear relation to teicoplanin serum concentrations has been demonstrated in the neonatal population. The clinical and bacteriological response in neonates given daily doses of 8e10 mg/kg, after a loading dose of 10e20 mg/kg, ranges from 80 to 100% in neonates.55 Neonatal dosing of teicoplanin is advised at 8e10 mg/kg after a loading dose of 15e20 mg/kg.55 Routine TDM of peak vancomycin concentrations can be questioned. As discussed before, neither efficacy nor toxicity are related to peak serum concentrations in neonates. Furthermore, it has been shown in neonates that peak serum concentrations O40 mg/l are seldom seen with trough concentrations below 10e15 mg/l.56,57 Microbiological studies indicate the need for sufficiently high trough serum concentrations, so a case can be made for measuring trough serum concentrations. Several dosing regimens, which have been discussed before e especially those with dose intervals exceeding 8 h in very low birthweight infants e have shown that trough serum concentrations can be lower than 5 mg/l, indicating a need for trough level monitoring.58e60 Trough level monitoring should thus be aimed at ascertaining that serum concentrations remain O5 mg/l. The feasibility of tailoring vancomycin dose in neonates with the help of TDM has been shown.61 These studies indicate that TDM using two serum concentrations can predict subsequent serum concentrations reasonably well.
Linezolid Linezolid inhibits bacterial protein synthesis and is relatively bacteriostatic against staphylococci and bactericidal against streptococci. It is used for treating Gram-positive infections in neonates with drug-resistant S. aureus (MRSA), CONS and penicillin-resistant Streptocococcus pneumoniae.
M. de Hoog et al.
Linezolid PK Linezolid is mainly excreted via non-renal pathways (oxidation and reduction). The Vd ranges from 0.65 to 0.81 l/kg, corresponding to total body water. There is a large increase of Cl in the first week of life in both premature and term neonates.62 Cl of neonates after 1 week is higher than in older children and adults.63 The t1/2b ranges from 1.5 to 6 h, depending on GA and PNA.
Linezolid efficacy and dosing Linezolid efficacy was initially thought to be dependent on TOMIC,64 but recent studies indicate that efficacy is related to AUC/MIC; further studies are needed to further clarify these relationships. A recent study has shown that concentrations based on developmental neonatal PK differences will lead to adequate serum concentrations in most neonates when dosing 10 mg/kg three times daily.62
Carbapenems Carbapenems are a class with one of the broadest spectra of antimicrobial activity available, including P. aeruginosa, and are stable against hydrolysis by extended spectrum b-lactamases (ESBL) and AmpC chromosomal b-lactamases. The most important indications for carbapenems are infections due to Gram-negative micro-organisms resistant to cephalosporins and infections with multiple organisms. Although many species of the Enterobacteriaceae, such as Enterobacter cloacae have always been resistant to most cephalosporins because of the production of chromosomal b-lactamases, the increasing incidence of ESBL-producing E. coli and Klebsiella spp. has stimulated the use of carbapenems.65 Furthermore, because of their broad spectrum e with coverage against both Grampositives as well as anaerobes e carbapenems are ideally suited to treat infections with a multifactorial origin or when it is not entirely clear which organisms cause the infection. An example in neonates is the treatment of NEC. Caution should be exercised with extensive treatment, however. Because of its broad spectrum, the colonization resistance is hampered and this might lead to an increased probability of candidal infections. Meropenem is slightly more active against Gram-negatives than imipenem, whereas the latter is more active against Gram-positives. This could be taken into consideration when applying one of the agents.66
New dosing strategies for antibacterial agents in the neonate Like other b-lactams, carbapenems are bactericidal and their efficacy is related to TOMIC. Both imipenem67 and meropenem68 have been studied in preterm neonates. As with other drugs distributing in extracellular fluid, the volume of distribution is increased. For imipenem, Vd was 0.5 (SD 0.1) l/kg, and for meropenem the Vd was 0.74 (range 0.24e1.2) l/kg. The half-lives were around 2.5 h and 3.4 h, respectively, which is substantially longer than the 1 h in adults.66 In both studies, it is concluded that, because of the increased half-life, a twice-daily dose would suffice: 20 mg/kg for imipenem and 15 mg/kg for meropenem, respectively. It should be noted, however, that the halflife of cilastatin, co-administered with imipenem to prevent its degradation by dehydropeptidase-1 is increased to more than 9 hours in preterms and that cilastatin therefore accumulates over time. The effects of this are not clear.67 Adjustments over time are needed because of increasing renal clearance and decreasing volume of distribution after the first days of life.
Treatment of bacterial meningitis and NEC Bacterial meningitis Empiric treatment of bacterial meninigitis, which is more common in the first month of life than at any other time, should take regional differences in epidemiology of micro-organisms into account. Predominant organisms follow the same pattern as early-onset and late-onset neonatal sepsis. The main causative bacteria is group B streptococcus, followed by other Gram-positive (including L. monocytogenes) and Gram-negative microorganisms (30e40%).69 Hydrophilic antibiotics such as b-lactam antibiotics and vancomycin enter CSF more freely in meningitis, unlike lipophilic antibiotics, the uptake of which in CSF is unchanged by inflammation.70 Efficacy is based on the same general principles as described in the introduction. Percentage uptake into the CSF differs enormously between antibiotics.70 CSF penetration by penicillin and ampicillin is 2.1e8.5% and 11e65% of corresponding serum concentrations, respectively.5 Although cefotaxime has a variable CSF penetration in neonates, with a degree of meningeal inflammation and a dependent CSF/serum ratio of 0e0.63, cure rates are high (94e100%) with sterile cultures 24e96 h after commencement of therapy.25,26,71 CSF penetration of ceftazidime is comparable to cefotaxime; CSF penetration of aminoglycosides in neonates has not been studied.
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In adults, CSF penetration is poor but clinical studies show efficacy with once-daily dosing.72 In case of Gram-negative bacterial meningitis, cefotaxime is often combined with an aminoglycoside.25,26 Due to the variable CSF penetration (7e68%), vancomycin cannot be used as the sole antibiotic in Gram-positive meningitis.9 Carbapenems have an increasing role in treating serious infections in the NICU. They are effective against most organisms causing meningitis but have not been tested in meningitis trials in neonates. CSF penetration is similar to that of other b-lactam antibiotics.73 The emergence of resistant Streptococcus pneumoniae and K. pneumoniae infections warrants judicious use.74,75 Overall, initial empiric choice of antibiotics has to cover both Gram-positive and Gram-negative organisms and the drugs of choice still are ampicillin or amoxicillin combined with a third-generation cephalosporin or an aminoglycoside.
Necrotizing enterocolitis Antibiotic treatment of NEC has to cover possible polymicrobial invasion of Gram-negative, Grampositive and anaerobic micro-organisms, and also has to take fungal sepsis into account. In practice, this leads to a commonly used initial combination of amoxicillin, a third-generation cephalosporin or an aminoglycoside and metronidazole.76,77 Vancomycin is often used instead of amoxicillin because of the increasing prevalence of coagulase-negative staphylococci. Other combinations have been tried, such as amoxicillin/clavulanic acid and an aminoglycoside, but have not been formally tested. An institutional antibiotic regimen should take the dominant flora in the NICU into account. On theoretical grounds, the antibacterial components of this therapy can be supplanted by meropenem monotherapy, although no studies in neonates have been performed as yet. Again, increasing carbapenem resistance, when used as first-line therapy, is of concern.
Conclusions The dosing of antibiotics in neonates should reflect current insights into established relationships between dosing regimens, susceptibility of microorganisms and efficacy. Initial empirical antibacterial treatment should reflect institutional microbiological surveillance data. Important concerns about developing resistance have to be weighed in choices of empiric treatment of neonatal sepsis, meningitis and NEC.
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Practice points Disposition of most antibiotics in neonates is strongly influenced by the developmental stage of the neonate. Dosing of most antibiotics in neonates should be based on weight, GA and PNA. There is a lack of quality data on efficacy of antibiotics in neonates. Dosing of antibiotics in neonates should be based on current insights into the use of surrogate markers, such as TOMIC, Cmax/ MIC and AUC/MIC. Currently used dosing regimens of blactam antibiotics in neonates probably leads to a TOMIC that is long enough. Routine therapeutic drug monitoring of aminoglycosides as well as vancomycin is questionable. Extending the dose interval of vancomycin in very low birthweight infants warrants therapeutic drug monitoring. Routine use of meropenem as first-line treatment should be viewed with caution because of the emergence of resistance. Empiric treatment should be based on efficacy, concerns about resistance and information from institutional microbiological surveillance.
Research directions Prospective efficacy studies of antibiotic treatment in neonates. Validation of pharmacodynamic endpoints in neonates. Determination of evidence-based GArelated dose and intervals of antibiotics in neonates.
Acknowledgement Supported in part by grant 1 U10 HD45993-01 (J.N.A.), National Institute of Child Health and Development, Bethesda, MD.
References 1. Klein JO, Michael Marcy S. Bacterial sepsis and meningitis. In: Remington JS, Klein JO, editors. Infectious Diseases of the Fetus & Newborn Infant. WB Saunders & company; 1995. p. 836.
2. Stoll BJ, Gordon T, Korones SB, et al. Early onset sepsis in very low birth weight neonates: a report from the national institute of child health and human development neonatal research network. J Pediatr 1996;129:72e80. 3. Shah SS, Ehrenkranz RA, Gallagher PG. Increasing incidence of gram-negative rod bacteremia in a newborn intensive care unit. Pediatr Infect Dis J 1999;18: 591e595. 4. Stoll BJ, Gordon T, Korones SB, et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996;129:63e71. 5. Fanos V, Dall’Agnola A. Antibiotics in neonatal infections: a review. Drugs 1999;58:405e27. 6. MacGowan A, Bowker K. Developments in PK/PD: optimising efficacy and prevention of resistance. A critical review of PK/PD in in vitro models. Int J Antimicrob Agents 2002; 19:291e8. 7. Drukker A, Guignard JP. Renal aspects of the term and preterm infant: a selective update. Curr Opin Pediatr 2002;14:175e82. 8. van den Anker JN, Hop WC, Schoemaker RC, van der Heijden BJ, Neijens HJ, de Groot R. Ceftazidime pharmacokinetics in preterm infants: effect of postnatal age and postnatal exposure to indomethacin. Br J Clin Pharmacol 1995;40:439e43. 9. de Hoog M, van den Anker JN, Mouton JW. Vancomycin: pharmacokinetics and administration regimens in neonates. Clin Pharmacokinet 2004;43:417e40. 10. de Hoog M, Mouton JW, van den Anker JN. The use of aminoglycosides in newborn infants. In: Choonara I, Nunn AJ, Kearns G, editors. Introduction to Paediatric and Perinatal Drug Therapy. Nottingham: Nottingham University Press; 2003. p. 117e40. 11. Yoshioka H, Takimoto M, Riley Jr HD. Pharmacokinetics of ampicillin in the newborn infant. J Infect Dis 1974;129: 461e4. 12. Adrianzen Vargas MR, Danton MH, Javaid SM, et al. Pharmacokinetics of intravenous flucloxacillin and amoxicillin in neonatal and infant cardiopulmonary bypass surgery. Eur J Cardiothorac Surg 2004;25:256e60. 13. Huisman-de Boer JJ, van den Anker JN, Vogel M, Goessens WH, Schoemaker RC, de Groot R. Amoxicillin pharmacokinetics in preterm infants with gestational ages of less than 32 weeks. Antimicrob Agents Chemother 1995; 39:431e4. 14. Dahl LB, Melby K, Gutteberg TJ, Storvold G. Serum levels of ampicillin and gentamycin in neonates of varying gestational age. Eur J Pediatr 1986;145:218e21. 15. Charles BG, Preechagoon Y, Lee TC, Steer PA, Flenady VJ, Debuse N. Population pharmacokinetics of intravenous amoxicillin in very low birth weight infants. J Pharm Sci 1997;86:1288e92. 16. Herngren L. Flucloxacillin kinetics in newborn infants. Eur J Clin Pharmacol 1989;36:325. 17. Tessin I, Trollfors B, Thiringer K, Larsson P. Ampicillinaminoglycoside combinations as initial treatment for neonatal septicaemia or meningitis. A retrospective evaluation of 12 years’ experience. Acta Paediatr Scand 1991;80: 911e6. 18. Herngren L, Ehrnebo M, Broberger U. Pharmacokinetics of free and total flucloxacillin in newborn infants. Eur J Clin Pharmacol 1987;32:403e9. 19. Young TE, Mangum B. Neofax: A Manual for Drugs used in Neonatal Care. Raleigh, NC: Acorn Publishing; 2003. 20. Kearns GL, Jacobs RF, Thomas BR, Darville TL, Trang JM. Cefotaxime and desacetylcefotaxime pharmacokinetics in
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very low birth weight neonates. J Pediatr 1989;114: 461e7. Martin E, Koup JR, Paravicini U, Stoeckel K. Pharmacokinetics of ceftriaxone in neonates and infants with meningitis. J Pediatr 1984;105:475e81. Aujard Y, Brion F, Jacqz-Aigrain E, et al. Pharmacokinetics of cefotaxime and desacetylcefotaxime in the newborn. Diagn Microbiol Infect Dis 1989;12:87e91. Kafetzis DA, Brater DC, Kapiki AN, Papas CV, Dellagrammaticas H, Papadatos CJ. Treatment of severe neonatal infections with cefotaxime. Efficacy and pharmacokinetics. J Pediatr 1982;100:483e9. van den Anker JN, Schoemaker RC, Hop WC, et al. Ceftazidime pharmacokinetics in preterm infants: effects of renal function and gestational age. Clin Pharmacol Ther 1995;58:650e9. Kearns GL, Young RA, Jacobs RF. Cefotaxime dosage in infants and children. Pharmacokinetic and clinical rationale for an extended dosage interval. Clin Pharmacokinet 1992;22:284e97. Dellagrammaticas HD, Christodoulou C, Megaloyanni E, Papadimitriou M, Kapetanakis J, Kourakis G. Treatment of gram-negative bacterial meningitis in term neonates with third generation cephalosporins plus amikacin. Biol Neonate 2000;77:139e46. de Louvois J, Dagan R, Tessin I. A comparison of ceftazidime and aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn. European Society for Paediatric Infectious DiseaseseNeonatal Sepsis Study Group. Eur J Pediatr 1992; 151:876e84. van den Anker JN, Schoemaker RC, van der Heijden BJ, Broerse HM, Neijens HJ, de Groot R. Once-daily versus twice-daily administration of ceftazidime in the preterm infant. Antimicrob Agents Chemother 1995;39: 2048e50. Tessin I, Thiringer K, Trollfors B, Brorson JE. Comparison of serum concentrations of ceftazidime and tobramycin in newborn infants. Eur J Pediatr 1988; 147:405e7. Fink S, Karp W, Robertson A. Ceftriaxone effect on bilirubin-albumin binding. Pediatrics 1987;80:873e5. Hoffman JA, Mason EO, Schutze GE, et al. Streptococcus pneumoniae infections in the neonate. Pediatrics 2003; 112:1095e102. Paap CM, Nahata MC. Clinical pharmacokinetics of antibacterial drugs in neonates. Clin Pharmacokinet 1990;19: 280e318. Anonymous. Early neonatal drug utilization in preterm newborns in neonatal intensive care units. Italian Collaborative Group on Preterm Delivery. Dev Pharmacol Ther 1988;11:1e7. de Hoog M, Mouton JW, Schoemaker RC, Verduin CM, van den Anker JN. Extended-interval dosing of tobramycin in neonates: implications for therapeutic drug monitoring. Clin Pharmacol Ther 2002;71:349e58. de Hoog M, van Zanten BA, Hop WC, Overbosch E, WeisglasKuperus N, van den Anker JN. Newborn hearing screening: tobramycin and vancomycin are not risk factors for hearing loss. J Pediatr 2003;142:41e6. Meyer C, Witte J, Hildmann A, et al. Neonatal screening for hearing disorders in infants at risk: incidence, risk factors, and follow-up. Pediatrics 1999;104:900e4. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987;155:93e9.
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38. Semchuk W, Borgmann J, Bowman L. Determination of a gentamicin loading dose in neonates and infants. Ther Drug Monit 1993;15:47e51. 39. Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995;39:650e5. 40. Prins JM, Weverling GJ, de Blok K, van Ketel RJ, Speelman P. Validation and nephrotoxicity of a simplified once-daily aminoglycoside dosing schedule and guidelines for monitoring therapy. Antimicrob Agents Chemother 1996;40:2494e9. 41. de Hoog M, Schoemaker RC, Mouton JW, van den Anker JN. Tobramycin population pharmacokinetics in neonates. Clin Pharmacol Ther 1997;62:392e9. 42. Lundergan FS, Glasscock GF, Kim EH, Cohen RS. Once-daily gentamicin dosing in newborn infants. Pediatrics 1999; 103:1228e34. 43. Kotze A, Bartel PR, Sommers DK. Once versus twice daily amikacin in neonates: prospective study on toxicity. J Paediatr Child Health 1999;35:283e6. 44. Kallman J, Kihlstrom E, Sjoberg L, Schollin J. Increase of staphylococci in neonatal septicaemia: a fourteen-year study. Acta Paediatr 1997;86:533e8. 45. Craft AP, Finer NN, Barrington KJ. Vancomycin for prophylaxis against sepsis in preterm neonates. Cochrane Database Syst Rev 2000:2. 46. Bhatt-Mehta V, Schumacher RE, Faix RG, Leady M, Brenner T. Lack of vancomycin-associated nephrotoxicity in newborn infants: a case- control study. Pediatrics 1999; 103:e48. 47. Degraeuwe PL, Beuman GH, van Tiel FH, Maertzdorf WJ, Blanco CE. Use of teicoplanin in preterm neonates with staphylococcal late-onset neonatal sepsis. Biol Neonate 1998;73:287e94. 48. Reed MD, Yamashita TS, Myers CM, Blumer JL. The pharmacokinetics of teicoplanin in infants and children. J Antimicrob Chemother 1997;39:789e96. 49. Begg EJ, Barclay ML, Kirkpatrick CJ. The therapeutic monitoring of antimicrobial agents. Br J Clin Pharmacol 1999;47:23e30. 50. Nagl M, Neher C, Hager J, Pfausler B, Schmutzhard E, Allerberger F. Bactericidal activity of vancomycin in cerebrospinal fluid. Antimicrob Agents Chemother 1999; 43:1932e4. 51. Schaad UB, Nelson JD, McCracken Jr GH. Pharmacology and efficacy of vancomycin for staphylococcal infections in children. Rev Infect Dis 1981;3:S282e8. 52. Naqvi SH, Keenan WJ, Reichley RM, Fortune KP. Vancomycin pharmacokinetics in small, seriously ill infants. Am J Dis Child 1986;140:107e10. 53. Pawlotsky F, Thomas A, Kergueris MF, Debillon T, Roze JC. Constant rate infusion of vancomycin in premature neonates: a new dosage schedule. Br J Clin Pharmacol 1998; 46:163e7. 54. Wilson AP. Clinical pharmacokinetics of teicoplanin. Clin Pharmacokinet 2000;39:167e83. 55. Fanos V, Kacet N, Mosconi G. A review of teicoplanin in the treatment of serious neonatal infections. Eur J Pediatr 1997;156:423e7. 56. de Hoog M, Mouton JW, van den Anker JN. Why monitor peak vancomycin concentrations? (letter). Lancet 1995; 345:646. 57. Shackley F, Roberts P, Heath P, Bowler I, Saunders N. Trough-only monitoring of serum vancomycin concentrations in neonates. J Antimicrob Chemother 1998;41: 141e2.
194 58. Grimsley C, Thomson AH. Pharmacokinetics and dose requirements of vancomycin in neonates. Arch Dis Child Fetal Neonatal Ed 1999;81:F221e7. 59. McDougal A, Ling EW, Levine M. Vancomycin pharmacokinetics and dosing in premature neonates. Ther Drug Monit 1995;17:319e26. 60. Gous AG, Dance MD, Lipman J, Luyt DK, Mathivha R, Scribante J. Changes in vancomycin pharmacokinetics in critically ill infants. Anaesth Intensive Care 1995;23: 678e82. 61. Rodvold KA, Gentry CA, Plank GS, Kraus DM, Nickel E, Gross JR. Bayesian forecasting of serum vancomycin concentrations in neonates and infants. Ther Drug Monit 1995;17:239e46. 62. Kearns GL, Jungbluth GL, Abdel-Rahman SM, et al. Impact of ontogeny on linezolid disposition in neonates and infants. Clin Pharmacol Ther 2003;74:413e22. 63. Jungbluth GL, Welshman IR, Hopkins NK. Linezolid pharmacokinetics in pediatric patients: an overview. Pediatr Infect Dis J 2003;22:S153e7. 64. Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am 2003;17: 479e501. 65. Paterson DL, Hujer KM, Hujer AM, et al. Extendedspectrum beta-lactamases in Klebsiella pneumoniae bloodstream isolates from seven countries: dominance and widespread prevalence of SHV- and CTX-M-type betalactamases. Antimicrob Agents Chemother 2003;47: 3554e60. 66. Mouton JW, Touzw DJ, Horrevorts AM, Vinks AA. Comparative pharmacokinetics of the carbapenems: clinical implications. Clin Pharmacokinet 2000;39:185e201. 67. Reed MD, Kliegman RM, Yamashita TS, Myers CM, Blumer JL. Clinical pharmacology of imipenem and
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cilastatin in premature infants during the first week of life. Antimicrob Agents Chemother 1990;34: 1172e7. van Enk JG, Touw DJ, Lafeber HN. Pharmacokinetics of meropenem in preterm neonates. Ther Drug Monit 2001; 23:198e201. Pong A, Bradley JS. Bacterial meningitis and the newborn infant. Infect Dis Clin North Am 1999;13:711e33. viii. Lutsar I, McCracken Jr GH, Friedland IR. Antibiotic pharmacodynamics in cerebrospinal fluid. Clin Infect Dis 1998;27:1117e27. quiz 1128e9. Jacobs RF, Kearns GL. Cefotaxime pharmacokinetics and treatment of meningitis in neonates. Infection 1989;17: 338e42. Andes DR, Craig WA. Pharmacokinetics and pharmacodynamics of antibiotics in meningitis. Infect Dis Clin North Am 1999;13:595e618. Nau R, Lassek C, Kinzig-Schippers M, Thiel A, Prange HW, Sorgel F. Disposition and elimination of meropenem in cerebrospinal fluid of hydrocephalic patients with external ventriculostomy. Antimicrob Agents Chemother 1998;42: 2012e6. Boyle RJ, Curtis N, Kelly N, Garland SM, Carapetis JR. Clinical implications of inducible beta-lactamase activity in Gram-negative bacteremia in children. Pediatr Infect Dis J 2002;21:935e40. McMaster P, McIntyre P, Gilmour R, Gilbert L, Kakakios A, Mellis C. The emergence of resistant pneumococcal meningitiseimplications for empiric therapy. Arch Dis Child 2002;87:207e10. Lee JS, Polin RA. Treatment and prevention of necrotizing enterocolitis. Semin Neonatol 2003;8:449e59. Newel SJ. Gastrointestinal disorders. In: Rennie JM, Roberton NRC, editors. Textbook of Neonatology. Edinburgh: Churchill Livingstone; 1999. p. 744e64.
www.elsevierhealth.com/journals/siny
New dosing strategies for antibacterial agents in the neonate Matthijs de Hooga,*, Johan W. Moutonb,c, John N. van den Ankera,d,e,f a
Department of Pediatrics, Erasmus MC-Sophia, Sophia Children’s Hospital, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands b Department of Medical Microbiology and Infectious Diseases, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands c Department of Medical Microbiology and infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands d Departments of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue NW, Washington, DC 20010, USA e Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA f Washington Pediatric Pharmacology Research Unit, Washington DC, USA
KEYWORDS Antibiotics; Meningitis; Necrotizing enterocolitis; Neonate; Pharmacodynamics; Review
Summary Dosing of antibiotics in neonates requires finding a delicate balance between maximal efficacy and minimal toxicity. There is a lack of data on efficacy of currently used antibiotics in neonates, and rational dosing therefore needs to be based on gestational- and postnatal-age-dependent pharmacokinetics in combination with surrogate markers. These surrogate markers are: (i) the area-under-the serum concentration time curve to minimum inhibitory concentration ratio (AUC/ MIC); (ii) peak concentration to MIC ratio (Cmax/MIC); and (iii) the time the concentration remains above the MIC (TOMIC). Whereas the efficacy of b-lactam antibiotics (including carbapenems) depends on TOMIC, the efficacy of most other antimicrobials (including aminoglycosides and fluoroquinolones) is related to AUC/ MIC and Cmax/MIC. Most modern dosing regimens are adequate when these concentration effect relationships are taken into account. Dosing adjustments in neonates are suggested, based on these relationships. Several antimicrobial combinations for treatment of meningitis and necrotizing enterocolitis exist. Empiric treatment should be based on efficacy, concerns about resistance as well as information from institutional microbiological surveillance. ª 2004 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: C311 463 6363 pager 39596; fax: C311 463 6796. E-mail address: [email protected] (M. de Hoog). 1744-165X/$ - see front matter ª 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2004.10.004
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Introduction Neonatal sepsis remains one of the main causes of mortality and morbidity of newborn infants admitted to a neonatal intensive care unit (NICU).1 Sepsis in this age group can be divided in early onset, defined as within the first 4 days of life, and late onset, occurring after 4 days.1 Furthermore, invasive infections such as pneumonia, meningitis and necrotizing enterocolitis (NEC) threaten the newborn infant. Group B streptococcus and Gram-negative organisms such as Escherichia coli and Haemophilus influenzae are the most common causative organisms for early-onset sepsis.2 In the United States in particular, an increase of Gram-negative neonatal infections has been noted as a result of prenatal use of antibiotics.3 Late-onset neonatal sepsis is related to the increased use of invasive procedures such as central venous lines and includes major pathogens and Gram-positive organisms from the skin: Staphylococcus epidermidis and S. aureus.4 The spectrum of pathogens in these two different age groups has led to commonly accepted empiric antibiotic strategies. Early-onset sepsis is treated with a combination of a penicillin and either a third-generation cephalosporin or an aminoglycoside. Empiric treatment of late-onset sepsis is often initiated with a combination of flucloxacillin and either a third-generation cephalosporin or an aminoglycoside, with a switch made to vancomycin when culture results and resistance patterns indicate a need for change.4,5 NEC is treated with a combination of either amoxicillin/clavulanic acid and an aminoglycoside or a carbapenem antibiotic, mostly meropenem. These factors imply that the antibiotics most often used in NICUs are penicillins, cephalosporins, aminoglycosides, vancomycin (and alternatively teicoplanin or linezolid) and meropenem. Current insights into rational dosing of these antibiotics in the NICU will be discussed in this chapter. Special attention will be paid to rational treatment of meningitis and NEC.
General considerations The dosing of antibiotics is based on a balance between maximal efficacy and minimal toxicity, as well as induction of resistance. Ideally, efficacy should be studied in the context of specific diseases and pathogens, with several dosing regimens. However, most currently recommended dosing guidelines for antibiotics in neonates are not based on this level of evidence. Although
M. de Hoog et al. pharmacokinetic (PK) information in neonates is available, there is a general lack of high-quality data on the efficacy of these dosing regimens. Monitoring efficacy of antibiotic treatment in neonates is difficult. Culture-proven early-onset sepsis occurs in approximately 2% of very low birthweight infants, but there are limitations to the amount of blood that can be drawn for blood cultures and single blood cultures can give false negative results.2 Furthermore, increasing prenatal treatment of mothers with antibiotics obscures culture results in newborns. This implies that until adequate efficacy data are generated, dosing has to be based on surrogate markers to determine relationships between the serum PK profiles and efficacy. During the last decade, enormous progress has been made in this area to establish relationships between dosing regimens, susceptibility of micro-organisms and efficacy. The three surrogate markers, or pharmacodynamic indices, predominantly used are area-under-the serum concentration time curve to minimum inhibitory concentration ratio (AUC/MIC), peak concentration to MIC ratio (Cmax/MIC) and the time the concentration remains above the MIC (TOMIC).6 In this way, the concentrationeeffect relationships for antibacterial agents against micro-organisms can be adequately described and, combined with PK knowledge in neonates, used to rationalize dosing in this vulnerable age group. In general, antibacterial agents can be divided in two groups. The efficacy of all b-lactam agents is dependent on the time the free, non-protein-bound concentration remains above the MIC of the microorganism. The efficacy of virtually all other antibacterial agents is related to the AUC/MIC ratio and the Cmax/MIC ratio (Table 1). This has important consequences for the design of dosing regimens. It means that, for b-lactam agents, the frequency of dosing is an important factor in determining outcome. Indeed, continuous infusion of b-lactam Table 1 Suggested surrogate markers for efficacy of antibiotics used in neonates. Values relate to the nonprotein bound, free fraction of the drug Antibiotic
Marker
Desired goal
Penicillins Cephalosporins Carbapenems Aminoglycosides
TOMIC TOMIC TOMIC AUC/MIC or Cmax/MIC TOMIC
O40e50% O50e60% O30e40% Cmax/MICO5e10
Glycopeptides
100% for TOMIC
AUC/MIC, area-under-the serum concentration time curve to MIC ratio; Cmax/MIC, peak concentration to MIC ratio; TOMIC, time the concentration remains above the MIC.
New dosing strategies for antibacterial agents in the neonate antibiotics, maintaining the concentration of the antimicrobial agent above the MIC during the whole dosing interval, has become more and more standard practice, especially in ICU units. This is in contrast to the aminoglycosides and the fluoroquinolones, where the total daily dose e as reflected by the AUC or peak concentration e is the most important driver of efficacy; these antibiotics should therefore preferably given once daily. One of the important questions in relation to these relationships is what the value of the pharmacodynamic index should minimally be to ensure a high probability of therapeutic success. In this regard, it is important to realize that premature neonates have to be regarded as immunocompromised patients. Thus, in the case of b-lactam agents, the percentage TOMIC minimally needed is larger than for immunocompetent patients and is reflected by the need of, in general, higher or e preferably e more frequent dosing. It has also to be realized that large individual variations in volume of distribution (Vd) and total body clearance (Cl) exist, and that dosing regimens in this vulnerable age group should cover also those individuals with a relative short half-life (t1/2b); dosing regimes should therefore be conservative to ensure appropriate concentrations in all neonates. The PK of the majority of antibiotics used in neonates as described in this chapter follow general principles. Penicillins, cephalosporins, aminoglycosides and glycopeptides all distribute in extracellular water and are excreted mainly by glomerular filtration and, for the penicillins, tubular excretion Therefore, changes in body water and development of renal function influence the disposition of these drugs. All these antibiotics have a larger Vd and lower Cl in premature neonates, and even more so when compared to adults, and dosing regimens thus have to be adjusted accordingly. Improvement of Cl follows the gestational age (GA) and postnatal age (PNA) dependent increase in glomerular filtration rate (GFR).7 Other factors in the NICU that directly influence Vd or renal function, such as extracorporeal membrane oxygenation (ECMO) or exposure to indomethacin, were shown to significantly alter neonatal PK of these drugs.8e10
Penicillins Penicillins inhibit bacterial cell wall synthesis and are bactericidal. The penicillins most often used in the NICU are small-spectrum, b-lactamaseinsensitive penicillins such as flucloxacillin and broad-spectrum penicillins like amoxicillin and ampicillin.
187
Although renally excreted, adjustment of dose the interval is only necessary in neonates with severe renal failure.
PK of penicillins Vd is higher in prematures, being 0.3 l/kg for ampicillin,11 0.45 l/kg for flucloxacillin12 and 0.41e0.68 l/kg for amoxicillin.12,13 The t1/2b of penicillins in neonates ranges from 2 to 9.5 h and is longer in premature neonates.11e15 Oral flucloxacillin is well absorbed in neonates.16 Both the Cl and Vd of penicillins are related to birthweight and neonatal asphyxia.15
Dosing of penicillins Although the therapeutic goal for penicillins in general is related to a TOMIC of 30e40%, neonates have to be regarded as immunocompromised and should at least be in the order of 40e50%, especially with respect to Gram-negatives. Ampicillin and amoxicillin (25e50 mg/kg b.i.d.) are generally combined with an aminoglycoside and are effective in the empiric treatment of neonatal sepsis.17 The efficacy of flucloxacillin has only been described in case series in neonates.18 For amoxicillin, a dose of 25 mg/kg twice daily was effective in preterm infants with a GA of less than 32 weeks.13 Although doseeeffect relations have not been studied well in neonates, currently advised dosing of ampicillin, amoxicillin and flucloxacillin in neonates19 is probably safe given the PK data, which have shown that serum concentrations remain above the MIC for long enough.13,15,18
Cephalosporins Cephalosporins, like penicillins, belong to the group of b-lactam antibiotics. They are bactericidal and interfere with synthesis of the bacterial cell wall. Cephalosporins most often used in neonatology are cefotaxime, ceftriaxone and ceftazidime. Cefotaxime and ceftriaxone have a broad and almost similar spectrum of activity, but both are notably not active against Pseudomonas aeruginosa. Ceftazidime is still the drug of choice for P. aeruginosa but has impaired activity against some of the Gram-positives, notably S. aureus. The use of broad-spectrum cephalosporins on NICUs has been associated with increasing resistance and restriction of use should be born in mind. For the same reason as for penicillins, a TOMIC of at least 50e60% is advisable.
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Cephalosporin PK
Aminoglycosides
Vd in neonates ranges from 0.46e0.69 l/kg for cefotaxime20 and 0.29e0.36 l/kg for ceftazidime8 to 0.45 l/kg for ceftriaxone.21 Vd is mainly dependent on GA and PNA. They are excreted almost exclusively via the urine and dose adjustment is indicated based on the degree of renal insufficiency. Serum half-life is 2e6 h for cefotaxime, 5e9 h for ceftazidime and 16e19 h for ceftriaxone.20,22,23 Like other renally excreted antibiotics, Cl and t1/2b are related to GA and concomitant increase of renal function, although cefotaxime Cl and t1/2b are the same for neonates weighing !1000 and O1000 g.20,24 For ceftazidime, a positive relation between Cl and an increase of GA and renal function has been demonstrated.24 Prenatal exposure to indomethacin decreases renal function and ceftazidime Cl.8 Postnatal age significantly increases the Cl of ceftazidime8 and cefotaxime.23
Aminoglycosides are bactericidal and inhibit protein synthesis and cell wall integrity through binding to ribosomes. Aminoglycosides are mainly used for treating serious Gram-negative infections caused by enteric bacilli. Aminoglycosides are synergistic with cephalosporins and penicillins in the setting of Gram-negative infections and are also used in combination treatment with vancomycin for S. aureus. The susceptibility of most Gramnegative bacteria to gentamicin, tobramycin and netilmicin is similar and, although susceptibility to amikacin is three- to fourfold less than to the other aminoglycosides, this is compensated for by the lower toxicity of amikacin, and therefore higher allowable dose. Given the increase of Gram-negative infections in the NICU, possibly due to the liberal prenatal use of antibiotics, aminoglycosides play an important role in the initial empiric treatment of neonatal sepsis3; after penicillins, they are the most commonly used antibiotic in the NICU.33
Cephalosporin dosing
Aminoglycoside PK Efficacy of cephalosporins is related to TOMIC. Several dosing regimens for cephalosporins have been examined in neonates. For cefotaxime, doses of 100e200 mg/kg/day, divided in 2e4 gifts for sepsis, meningitis or NEC have been investigated, with cure rates varying between 91 and 98.6%.25,26 The metabolite desacetylcefotaxime shows antimicrobial activity, although far less than cefotaxime itself. Studies and simulations have shown that serum concentrations of cefotaxime in neonates remain above the MIC of common neonatal pathogens (E. coli, H. influenzae, S. pneumoniae) when dosing at 50 mg/kg two or three times daily, which is the currently recommended dosing regimen for cefotaxime in neonatal sepsis and meningitis.19,25 Clinical efficacy of ceftazidime as empiric therapy in neonatal sepsis was 79% (monotherapy) and 97% (in combination with ampicillin).27 Ceftazidime is mainly used in the setting of Gram-negative infection. Because Listeria monocytogenes is resistant, ceftazidime cannot be used as monotherapy. Doses of 25 mg/kg twice daily result in adequate trough serum concentrations in term and preterm infants.28,29 Ceftriaxone has a longer serum half-life and therefore the advantage of a once-daily dosing regimen. Ceftriaxone should, however, not be used routinely in neonatal sepsis because displacement of bilirubin from albumin, bile sludging and a high incidence of diarrhoea.30e32
Aminoglycoside Vds range from 0.47 to 0.70 l/kg and are even higher in premature neonates, leading to lower peak serum concentrations in this age group.34 The t1/2b is longer in premature neonates, leading to higher serum trough concentrations in this group.34 Substantial effort has been put into developing equations, mostly based on population PK studies, which will potentially lead to better prediction of serum concentrations in the individual patient. In practice, these equations are not able to adequately predict variability and subsequent serum concentrations in the same patient.34 The usefulness of performing therapeutic drug monitoring (TDM) in infants in the first week of life is therefore not clear. In patients with patent ductus arteriosus (PDA), postnatal exposure to indomethacin and ECMO individualized dosing based on TDM should be made.
Aminoglycoside toxicity The main concerns with aminoglycosides are nephro- and ototoxicity. The incidence of aminoglycoside nephrotoxicity in neonates is not well known but seems to be considerably lower than in adults. Although reversible tubular dysfunction has been shown in many studies involving neonates, persistent glomerular filtration impairment has not been conclusively shown in prospective studies.10 Ototoxicity is an infrequent occurrence in neonatal
New dosing strategies for antibacterial agents in the neonate studies. Recent studies with extended dose intervals have failed to demonstrate aminoglycosideinduced hearing loss and no relation to serum concentrations was found.35,36
Aminoglycoside TDM and dosing Aminoglycoside efficacy is related to both peakserum-concentration to MIC ratio (Peak/MIC) and AUC/MIC in clinical and experimental studies. Peak/MIC ratios of 5e10 are desirable for clinical efficacy.37 Commonly accepted trough concentration goals in adults are !2 mg/l but those were based on a three-times-daily schedule; when dosing once a day, most authors keep !1 mg/l as a safe limit.38e40 Based on the aminoglycoside susceptibility of Gram-negative pathogens involved in neonatal septicemia, a reasonable target range for neonates would therefore be peak serum concentrations of 5e10 mg/l for gentamicin, netilmicin and tobramycin and 15e30 mg/l for amikacin. Trough concentration goals are !2 mg/l when dosing three times daily, !0.5e1.0 mg/l for once-daily dosing in gentamicin, netilmicin and tobramycin and 1.5e3 mg/l for amikacin.10 Aminoglycoside dosing in neonates has changed over the recent past to extended dosing intervals.41,42 Although this has been associated with adequate serum concentrations and a lack of toxicity, an increase of efficacy has not yet been demonstrated.35,41,42 Recent studies have demonstrated that serum concentrations as described above can be reached with doses of 3.5e5 mg/kg (gentamicin, tobramycin, netilmicin) and 7.5e 15 mg/kg (amikacin) even without a loading dose.41e43 Efficacy and toxicity have not been clearly related to peak or trough serum concentrations with extended dose intervals and clinically important nephro- and ototoxicity are rare in neonates treated with courses with a duration of less than 7 days. Furthermore, subsequent serum concentrations cannot be adequately predicted in this age group.34 The importance of routine TDM in the first week of life for efficacy and toxicity reasons has therefore been questioned.34,35 In neonatal patients with renal failure, asphyxia and/or who are exposed to drugs or situations that alter PK behavior (e.g. indomethacin, ECMO), repeated TDM is necessary.
Glycopeptides The bactericidal activity of glycopeptide antibiotics is based on the inhibition of bacterial cell wall synthesis. Glycopeptide antibiotics are the drugs
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of choice for methicillin-resistant staphylococcal infections and are widely used as empiric treatment for central-venous-line-related infections in neonates. These infections are often caused by coagulase-negative staphylococci (CONS).44 Given the concerns about development of resistance by overuse of vancomycin, routine prophylaxis with low-dose vancomycin should not be instituted.9,45
Glycopeptide PK The Vd of glycopeptides changes with the amount of body water and is larger in premature neonates. Vancomycin and teicoplanin Vd range from 0.57e0.69 l/kg in term neonates to as high as 0.97 l/kg in prematures.9 Glycopeptide Cl changes with maturation of renal function in the first weeks of life, with a lower clearance for teicoplanin than vancomycin. Clearance in relation to postconceptional age is the main determinant in the PK profile of vancomycin in neonates.9
Glycopeptide toxicity Toxicity related to glycopeptides has often been reported. Infusion-related adverse events have decreased enormously since removal of impurities from early preparations. Studies on vancomycin in neonates have seldom detected nephrotoxicity; some studies found a reversible rise in serum creatinine.9 Again, no relation to serum concentrations peak O40 mg/l and/or trough serum concentration O10 mg/l) has been detected.46 Studies of teicoplanin use in neonates have not demonstrated significant nephrotoxicity.47,48 Information on glycopeptide ototoxicity in neonates is scarce. Teicoplanin-related ototoxicity has not been described in pediatric patients. Vancomycin-induced hearing loss has not been clearly demonstrated in this age group and could not be related to duration of treatment or abnormal peak/trough serum concentrations.35 The usefulness of routine TDM of vancomycin for toxicity reasons is therefore doubtful.
Glycopeptide TDM and dosing Based on in vitro studies, vancomycin trough concentrations should exceed 4e5 mg/l. This is based on the assumption that MICs of most bacteria for which vancomycin is used is !1e2 mg/l and protein binding !50%.49 Concentrations of vancomycin in cerebrospinal fluid (CSF) of 5e10 mg/l are needed for treatment of central nervous system (CNS) infections.50 Vancomycin, in doses
190 of 20e40 mg/kg/day, was effectively used in neonates and infants of varying GAs.9,51,52 Continuous infusion of vancomycin was effective in 13 documented invasive infections in concentrations ranging from 3 to 37.6 mg/l.53 These studies, with relative few numbers of patients, show that a wide range of vancomycin peak and trough concentrations are effective against Gram-positive infections in neonates and infants. This certainly does not substantiate the currently used therapeutic range of 20e40 mg/l for peak and 5e10 mg/l for trough serum concentrations. For teicoplanin serum trough concentrations above the MIC, and preferably O10 mg/l, are correlated with efficacy in adults.54 No clear relation to teicoplanin serum concentrations has been demonstrated in the neonatal population. The clinical and bacteriological response in neonates given daily doses of 8e10 mg/kg, after a loading dose of 10e20 mg/kg, ranges from 80 to 100% in neonates.55 Neonatal dosing of teicoplanin is advised at 8e10 mg/kg after a loading dose of 15e20 mg/kg.55 Routine TDM of peak vancomycin concentrations can be questioned. As discussed before, neither efficacy nor toxicity are related to peak serum concentrations in neonates. Furthermore, it has been shown in neonates that peak serum concentrations O40 mg/l are seldom seen with trough concentrations below 10e15 mg/l.56,57 Microbiological studies indicate the need for sufficiently high trough serum concentrations, so a case can be made for measuring trough serum concentrations. Several dosing regimens, which have been discussed before e especially those with dose intervals exceeding 8 h in very low birthweight infants e have shown that trough serum concentrations can be lower than 5 mg/l, indicating a need for trough level monitoring.58e60 Trough level monitoring should thus be aimed at ascertaining that serum concentrations remain O5 mg/l. The feasibility of tailoring vancomycin dose in neonates with the help of TDM has been shown.61 These studies indicate that TDM using two serum concentrations can predict subsequent serum concentrations reasonably well.
Linezolid Linezolid inhibits bacterial protein synthesis and is relatively bacteriostatic against staphylococci and bactericidal against streptococci. It is used for treating Gram-positive infections in neonates with drug-resistant S. aureus (MRSA), CONS and penicillin-resistant Streptocococcus pneumoniae.
M. de Hoog et al.
Linezolid PK Linezolid is mainly excreted via non-renal pathways (oxidation and reduction). The Vd ranges from 0.65 to 0.81 l/kg, corresponding to total body water. There is a large increase of Cl in the first week of life in both premature and term neonates.62 Cl of neonates after 1 week is higher than in older children and adults.63 The t1/2b ranges from 1.5 to 6 h, depending on GA and PNA.
Linezolid efficacy and dosing Linezolid efficacy was initially thought to be dependent on TOMIC,64 but recent studies indicate that efficacy is related to AUC/MIC; further studies are needed to further clarify these relationships. A recent study has shown that concentrations based on developmental neonatal PK differences will lead to adequate serum concentrations in most neonates when dosing 10 mg/kg three times daily.62
Carbapenems Carbapenems are a class with one of the broadest spectra of antimicrobial activity available, including P. aeruginosa, and are stable against hydrolysis by extended spectrum b-lactamases (ESBL) and AmpC chromosomal b-lactamases. The most important indications for carbapenems are infections due to Gram-negative micro-organisms resistant to cephalosporins and infections with multiple organisms. Although many species of the Enterobacteriaceae, such as Enterobacter cloacae have always been resistant to most cephalosporins because of the production of chromosomal b-lactamases, the increasing incidence of ESBL-producing E. coli and Klebsiella spp. has stimulated the use of carbapenems.65 Furthermore, because of their broad spectrum e with coverage against both Grampositives as well as anaerobes e carbapenems are ideally suited to treat infections with a multifactorial origin or when it is not entirely clear which organisms cause the infection. An example in neonates is the treatment of NEC. Caution should be exercised with extensive treatment, however. Because of its broad spectrum, the colonization resistance is hampered and this might lead to an increased probability of candidal infections. Meropenem is slightly more active against Gram-negatives than imipenem, whereas the latter is more active against Gram-positives. This could be taken into consideration when applying one of the agents.66
New dosing strategies for antibacterial agents in the neonate Like other b-lactams, carbapenems are bactericidal and their efficacy is related to TOMIC. Both imipenem67 and meropenem68 have been studied in preterm neonates. As with other drugs distributing in extracellular fluid, the volume of distribution is increased. For imipenem, Vd was 0.5 (SD 0.1) l/kg, and for meropenem the Vd was 0.74 (range 0.24e1.2) l/kg. The half-lives were around 2.5 h and 3.4 h, respectively, which is substantially longer than the 1 h in adults.66 In both studies, it is concluded that, because of the increased half-life, a twice-daily dose would suffice: 20 mg/kg for imipenem and 15 mg/kg for meropenem, respectively. It should be noted, however, that the halflife of cilastatin, co-administered with imipenem to prevent its degradation by dehydropeptidase-1 is increased to more than 9 hours in preterms and that cilastatin therefore accumulates over time. The effects of this are not clear.67 Adjustments over time are needed because of increasing renal clearance and decreasing volume of distribution after the first days of life.
Treatment of bacterial meningitis and NEC Bacterial meningitis Empiric treatment of bacterial meninigitis, which is more common in the first month of life than at any other time, should take regional differences in epidemiology of micro-organisms into account. Predominant organisms follow the same pattern as early-onset and late-onset neonatal sepsis. The main causative bacteria is group B streptococcus, followed by other Gram-positive (including L. monocytogenes) and Gram-negative microorganisms (30e40%).69 Hydrophilic antibiotics such as b-lactam antibiotics and vancomycin enter CSF more freely in meningitis, unlike lipophilic antibiotics, the uptake of which in CSF is unchanged by inflammation.70 Efficacy is based on the same general principles as described in the introduction. Percentage uptake into the CSF differs enormously between antibiotics.70 CSF penetration by penicillin and ampicillin is 2.1e8.5% and 11e65% of corresponding serum concentrations, respectively.5 Although cefotaxime has a variable CSF penetration in neonates, with a degree of meningeal inflammation and a dependent CSF/serum ratio of 0e0.63, cure rates are high (94e100%) with sterile cultures 24e96 h after commencement of therapy.25,26,71 CSF penetration of ceftazidime is comparable to cefotaxime; CSF penetration of aminoglycosides in neonates has not been studied.
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In adults, CSF penetration is poor but clinical studies show efficacy with once-daily dosing.72 In case of Gram-negative bacterial meningitis, cefotaxime is often combined with an aminoglycoside.25,26 Due to the variable CSF penetration (7e68%), vancomycin cannot be used as the sole antibiotic in Gram-positive meningitis.9 Carbapenems have an increasing role in treating serious infections in the NICU. They are effective against most organisms causing meningitis but have not been tested in meningitis trials in neonates. CSF penetration is similar to that of other b-lactam antibiotics.73 The emergence of resistant Streptococcus pneumoniae and K. pneumoniae infections warrants judicious use.74,75 Overall, initial empiric choice of antibiotics has to cover both Gram-positive and Gram-negative organisms and the drugs of choice still are ampicillin or amoxicillin combined with a third-generation cephalosporin or an aminoglycoside.
Necrotizing enterocolitis Antibiotic treatment of NEC has to cover possible polymicrobial invasion of Gram-negative, Grampositive and anaerobic micro-organisms, and also has to take fungal sepsis into account. In practice, this leads to a commonly used initial combination of amoxicillin, a third-generation cephalosporin or an aminoglycoside and metronidazole.76,77 Vancomycin is often used instead of amoxicillin because of the increasing prevalence of coagulase-negative staphylococci. Other combinations have been tried, such as amoxicillin/clavulanic acid and an aminoglycoside, but have not been formally tested. An institutional antibiotic regimen should take the dominant flora in the NICU into account. On theoretical grounds, the antibacterial components of this therapy can be supplanted by meropenem monotherapy, although no studies in neonates have been performed as yet. Again, increasing carbapenem resistance, when used as first-line therapy, is of concern.
Conclusions The dosing of antibiotics in neonates should reflect current insights into established relationships between dosing regimens, susceptibility of microorganisms and efficacy. Initial empirical antibacterial treatment should reflect institutional microbiological surveillance data. Important concerns about developing resistance have to be weighed in choices of empiric treatment of neonatal sepsis, meningitis and NEC.
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Practice points Disposition of most antibiotics in neonates is strongly influenced by the developmental stage of the neonate. Dosing of most antibiotics in neonates should be based on weight, GA and PNA. There is a lack of quality data on efficacy of antibiotics in neonates. Dosing of antibiotics in neonates should be based on current insights into the use of surrogate markers, such as TOMIC, Cmax/ MIC and AUC/MIC. Currently used dosing regimens of blactam antibiotics in neonates probably leads to a TOMIC that is long enough. Routine therapeutic drug monitoring of aminoglycosides as well as vancomycin is questionable. Extending the dose interval of vancomycin in very low birthweight infants warrants therapeutic drug monitoring. Routine use of meropenem as first-line treatment should be viewed with caution because of the emergence of resistance. Empiric treatment should be based on efficacy, concerns about resistance and information from institutional microbiological surveillance.
Research directions Prospective efficacy studies of antibiotic treatment in neonates. Validation of pharmacodynamic endpoints in neonates. Determination of evidence-based GArelated dose and intervals of antibiotics in neonates.
Acknowledgement Supported in part by grant 1 U10 HD45993-01 (J.N.A.), National Institute of Child Health and Development, Bethesda, MD.
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