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Oral β-Lactam Antibiotics for Pediatric Otitis Media, Rhinosinusitis, and Pneumonia

      ABSTRACT

      Acute otitis media, acute bacterial rhinosinusitis, and community-acquired pneumonia are major drivers of pediatric antibiotic consumption. With many available options and the added challenges of navigating antibiotic allergies and de-escalating from intravenous treatment for children requiring hospitalization, prescribing for these relatively simple infections can be a source of confusion and error. The purpose of this article is to evaluate the pharmacokinetic and pharmacodynamic properties of antibiotics commonly prescribed for these disease states, and to specifically compare antipneumococcal activity between oral beta-lactams.

      KEY WORDS

      INTRODUCTION

      Acute otitis media (AOM), acute bacterial rhinosinusitis (ABRS) and community-acquired pneumonia (CAP) are common childhood infections treated routinely in both inpatient and outpatient settings. Treatment often includes oral antibiotics, either in the outpatient setting or after hospitalization for initial parenteral therapy. There are a wide variety of oral β-lactams and dosing strategies. Significant differences in bacteriologic activity exist owing to variable in vitro susceptibility and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics. Prescribers must be familiar with these concepts to ensure appropriate antibiotic selection and dosage. National consensus guidelines for treatment of pediatric AOM, ABRS, and CAP appropriately prioritize the use of amoxicillin or amoxicillin-clavulanate and restrict oral cephalosporins to second-line therapy in limited and carefully selected clinical scenarios (Table 1;
      • Bradley J.S.
      • Byington C.L.
      • Shah S.S.
      • Alverson B.
      • Carter E.R.
      • Harrison C.
      Pediatric Infectious Diseases Society and the Infectious Diseases Society of America
      The management of community-acquired pneumonia in infants and children older than 3 months of age: Clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.
      ;
      • Chow A.W.
      • Benninger M.S.
      • Brook I.
      • Brozek J.L.
      • Goldstein E.J.
      • Hicks L.A.
      Infectious Diseases Society of America
      IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults.
      ;
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ). However, prescribing practices suggest wider use of these pharmacokinetically inferior agents than may be advisable (
      • Hersh A.L.
      • Fleming-Dutra K.E.
      • Shapiro D.J.
      • Hyun D.Y.
      • Hicks L.A.
      Outpatient Antibiotic Use Target-Setting Workgroup
      Frequency of first-line antibiotic selection among US ambulatory care visits for otitis media, sinusitis, and pharyngitis.
      ).

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      OBJECTIVES

      • 1.
        Describe characteristics of antibiotics best suited for treatment of otitis media, sinusitis, and pneumonia.
      • 2.
        Compare pharmacokinetics and pharmacodynamics of oral cephalosporins to amoxicillin and amoxicillin/clavulanate.
      • 3.
        Recognize superiority of amoxicillin-based regimens over oral cephalosporins for pneumococcal infections.
      • 4.
        Describe nonequivalence of intravenous and oral third-generation cephalosporins for treatment of pencillin-resistant pneumococcal infections.
      • 5.
        Identify situations that may warrant use of oral cephalosporins.
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      TABLE 1National recommendations for selected oral β-lactams
      AgentFirst-line monotherapyAlternative first-line monotherapy
      For patients with non-anaphylaxis allergies to penicillin.
      Second-line monotherapyAlternative second-line monotherapySecond-line, combination therapy
      In combination with clindamycin.
      AmoxicillinAOM, CAP
      Amoxicillin/clavulanateAOM
      If received amoxicillin in the previous 30 days or has concomitant conjunctivitis.
      , ABRS, CAP
      Targeted against H. influenzae.
      AOM
      If failed, first-line therapy was amoxicillin.
      , ABRS
      Given as high dose (90 mg/kg/day twice daily). If failed, first-line therapy was moderate dose (45 mg/kg/day twice daily).
      CefpodoximeAOM, CAP
      Targeted against H. influenzae.
      ,
      For penicillin-susceptible S. pneumoniae only.
      ABRSAOM, ABRS
      CefdinirAOM, CAP
      Targeted against H. influenzae.
      AOM
      CefprozilCAP
      For penicillin-susceptible S. pneumoniae only.
      CefiximeCAP
      Targeted against H. influenzae.
      AOM, ABRS
      Note. AOM, acute otitis media; CAP, community-acquired pneumoniae; ABRS, acute bacterial rhinosinusitis.
      a For patients with non-anaphylaxis allergies to penicillin.
      b In combination with clindamycin.
      c If received amoxicillin in the previous 30 days or has concomitant conjunctivitis.
      d Targeted against H. influenzae.
      e If failed, first-line therapy was amoxicillin.
      f Given as high dose (90 mg/kg/day twice daily). If failed, first-line therapy was moderate dose (45 mg/kg/day twice daily).
      g For penicillin-susceptible S. pneumoniae only.
      This review focuses on the preferred agents, amoxicillin and amoxicillin-clavulanate, and how they differ from less active, yet commonly prescribed oral cephalosporins (e.g., cefdinir, cefpodoxime, and cefprozil) for the management of AOM, ABRS, and CAP. Emphasis is placed on Streptococcus pneumoniae as the primary pathogen. Therefore, other oral cephalosporins (e.g., cefixime, ceftibuten) appearing in guidelines that target non-pneumococcal pathogens (e.g., non-typeable Haemophilus influenzae [NTHi] and Moraxella catarrhalis) are not reviewed here. AOM, ABRS, and CAP present unique challenges to microbiologic assessment and drug development. Unlike bacteremia, urinary tract infections, or skin and soft tissue infections, respiratory cultures are either not routinely obtained or are of low yield for pneumonia. Specimens for cultures are collected even less frequently for AOM and sinusitis because the invasive procedures to collect specimens are typically reserved for complicated and refractory cases requiring surgical intervention. This low frequency of cultures limits the identification of causative pathogens and antimicrobial susceptibility data, and results may not reflect the general population presenting with uncomplicated infections for which this invasive testing is not usually performed. Instead, providers must rely on knowledge of the most common pathogens and regional patterns of antibiotic susceptibility.

      CHILDHOOD VACCINES AND CHANGING EPIDEMIOLOGY

      The microbiology of ABRS is estimated based on AOM because of similar pathogenesis and the relative ease of getting middle-ear fluid compared with sinus aspirates. Before the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the year 2000, most invasive S. pneumoniae infections were caused by the seven serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) included in the vaccine (
      • Hausdorff W.P.
      • Yothers G.
      • Dagan R.
      • Kilpi T.
      • Pelton S.I.
      • Cohen R.
      • Bryant J.
      Multinational study of pneumococcal serotypes causing acute otitis media in children.
      ). After the introduction of PCV7, significant reduction in the proportion of pneumococcal isolates from middle-ear fluid cultures (from 48% to 31%) was reported along with an increase in NTHi reported during the same period (from 41% to 56%;
      • Block S.L.
      • Hedrick J.
      • Harrison C.J.
      • Tyler R.
      • Smith A.
      • Findlay R.
      • Keegan E.
      Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media.
      ;
      • Casey J.R.
      • Pichichero M.E.
      Changes in frequency and pathogens causing acute otitis media in 1995–2003.
      ). After PCV7 was introduced, antibiotic resistance was most frequently attributed to serotype 19A strains of S. pneumoniae. Of specific concern were the multidrug-resistant 19A pneumococcal strains implicated in complicated AOM and coalescent mastoiditis (
      • Pichichero M.E.
      • Casey J.R.
      Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children.
      ). In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced, which included 19A. The PCV13 vaccine is currently a routinely administered childhood vaccine in the United States and other countries. The impact of PCV13 on the bacteriology of AOM has been recently described with two important changes in traditional epidemiology. First, H. influenzae has surpassed S. pneumoniae as the most common pathogen (50–60% vs. 15–25%). Second, the rate of penicillin resistance among S. pneumoniae in these infections has decreased as well (
      • Wald E.R.
      • DeMuri G.P.
      Antibiotic recommendations for acute otitis media and acute bacterial sinusitis: Conundrum no more.
      ).
      After universal immunization of children with conjugate H. influenzae type-B vaccine, more than 90% of H. influenzae infections are due to non-typeable strains. M. catarrhalis account for approximately 10% of ear and sinus infections, and this incidence has not been affected by pneumococcal vaccination (
      • Wald E.R.
      • DeMuri G.P.
      Antibiotic recommendations for acute otitis media and acute bacterial sinusitis: Conundrum no more.
      ). About 30% to 50% of NTHi and almost all isolates of M. catarrhalis in the United States are β-lactamase producers and are, thus, not susceptible to amoxicillin, but require treatment with amoxicillin-clavulanate.
      In contrast to Infectious Diseases Society of America's recommendation to use amoxicillin-clavulanate rather than amoxicillin as first-line therapy for acute bacterial sinusitis, the American Academy of Pediatrics recommends amoxicillin as first-line treatment of uncomplicated acute bacterial sinusitis if antimicrobial resistance is not suspected (
      • Wald E.R.
      • Applegate K.E.
      • Bordley C.
      • Darrow D.H.
      • Glode M.P.
      • Marcy S.M.
      American Academy of Pediatrics
      Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years.
      ). This recommendation includes children aged two years or older with uncomplicated infections and mild to moderate symptoms, who do not attend daycare, and have not received antibiotic therapy in the last four weeks. Given the decline of invasive pneumococcal disease after the widespread use of PCV13, it will be interesting to discover whether amoxicillin will remain a valid first-line therapy in children with AOM and ABRS with a relative increase in proportion of NTHi and M. catarrhalis infections. A recent report has called for reconsideration of empiric treatment with amoxicillin-clavulanate for broadened activity against NTHi at a lower dose (45 mg/kg/day vs. 90 mg/kg/day), given the reduced incidence of penicillin-resistant S. pneumoniae (
      • Wald E.R.
      • DeMuri G.P.
      Antibiotic recommendations for acute otitis media and acute bacterial sinusitis: Conundrum no more.
      ). In contrast to ABRS and CAP in adult patients, NTHi is a less common pathogen in pediatric CAP outside of children with chronic lung disease or obstruction. Thus, amoxicillin alone targeted against S. pneumoniae is standard first-line therapy for pediatric CAP (
      • Bradley J.S.
      • Byington C.L.
      • Shah S.S.
      • Alverson B.
      • Carter E.R.
      • Harrison C.
      Pediatric Infectious Diseases Society and the Infectious Diseases Society of America
      The management of community-acquired pneumonia in infants and children older than 3 months of age: Clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.
      ). The remainder of this review will reflect current guidelines with an emphasis on pharmacodynamic optimization in the treatment of pneumococcal infections, however changing epidemiology makes these dynamic disease states with anticipated correlating changes to empiric therapy selection.

      β-LACTAM MECHANISMS OF ACTION AND RESISTANCE

      β-Lactam antibiotics such as penicillins and cephalosporins act by inhibiting bacterial cell wall synthesis. This bactericidal process is initiated by the irreversible binding of the β-lactam ring, a nitrogen-containing four-membered ring, to penicillin-binding proteins (PBPs) located on the bacterial cell membrane. The most important PBPs are transpeptidases that normally assist in the cross-linking of peptidoglycan, a polymer needed for cell wall structural integrity. As analogs of D-alanyl-D-alanine, the terminal amino acid that normally binds to PBP, β-lactams bind to PBP instead of peptidoglycan. Once bound to the antibiotic, PBP can no longer take part in the cross-linking process, which ultimately results in the loss of cell wall integrity. Furthermore, as peptidoglycan precursors accumulate because of the disruption of cross-linkage, enzymes are triggered to break down existing peptidoglycan in an attempt to reorganize the cell wall (
      • Fisher J.F.
      • Meroueh S.O.
      • Mobashery S.
      Bacterial resistance to β-lactam antibiotics: Compelling opportunism, compelling opportunity.
      ). As no new peptidoglycan can be made, the cell becomes even more unstable and autolysis occurs.
      Mechanisms of β-lactam resistance can generally be categorized as an expression of PBPs with reduced affinity for β-lactams, drug inactivation through β-lactamase enzymes, and alterations to the cell membrane that limit access to PBP. The first two are most common to pathogens encountered in disease states reviewed herein and are described in detail below.
      The mechanism of resistance most common in Gram-positive bacteria is a reduced affinity for PBP to bind to β-lactam antibiotics, as seen in methicillin-resistant S. aureus (MRSA) and penicillin-resistant S. pneumoniae (PRSP). In MRSA, the novel gene mecA confers an expression of PBP2a, a new PBP that replaces all native PBP and cannot bind to any β-lactams except ceftaroline (
      • Berger-Bächi B.
      • Rohrer S
      Factors influencing methicillin resistance in Staphylococci.
      ;
      • Doi Y.
      • Chambers H.F.
      Penicillins and b-lactamase inhibitors.
      ). In contrast, S. pneumoniae develops penicillin resistance through genetic recombination with viridians-group streptococci to express a new PBP which is less susceptible to β-lactam binding (
      • Tomasz A.
      Antibiotic resistance in Streptococcus pneumoniae.
      ). However, this resistance can be overcome with high drug concentrations achievable from maximum doses. For this reason, high-dose amoxicillin (80–90 mg/kg/day divided into in two doses) remains active even in the setting of moderately reduced susceptibility to penicillin (
      • Lund B.C.
      • Ernst E.J.
      • Klepser M.E.
      Strategies in the treatment of penicillin-resistant Streptococcus pneumoniae.
      ;
      • Parker S.
      • Mitchell M.
      • Child J.
      Cephem antibiotics: Wise use today preserves cure for tomorrow.
      ). The remainder of this review will refer only to this high-dose strategy of amoxicillin, although, as reviewed above, some experts suggest that a moderate dose of 45 mg/kg/day divided into two doses may have a role where PRSP is uncommon (
      • Wald E.R.
      • DeMuri G.P.
      Antibiotic recommendations for acute otitis media and acute bacterial sinusitis: Conundrum no more.
      ).
      β-Lactamase acts by cleaving the β-lactam ring, thereby inactivating the antibiotic. β-Lactamase production may be overcome through the use of β-lactamase inhibitors such as clavulanic acid. For example, H. influenzae is a Gram-negative bacterium with β-lactamase–producing variants. In these cases, amoxicillin alone is rendered ineffective, although, when combined with clavulanic acid, enough of the β-lactamase is inactivated to allow the amoxicillin to bind to PBPs, inhibit cell wall synthesis, and induce cellular destruction (
      • Fisher J.F.
      • Meroueh S.O.
      • Mobashery S.
      Bacterial resistance to β-lactam antibiotics: Compelling opportunism, compelling opportunity.
      ). Cephalosporins are also unaffected by these common β-lactamases.
      In terms of combating mechanisms of antimicrobial resistance, an important advantage of cephalosporins is their stability against β-lactamases (
      • Bradley J.S.
      • Byington C.L.
      • Shah S.S.
      • Alverson B.
      • Carter E.R.
      • Harrison C.
      Pediatric Infectious Diseases Society and the Infectious Diseases Society of America
      The management of community-acquired pneumonia in infants and children older than 3 months of age: Clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.
      ). However, β-lactamase production is not a resistance mechanism typically employed by S. pneumoniae. Instead, high antibiotic concentrations are needed to overcome the PBP alterations in typical PRSP. As such, selection of anti-pneumococcal antibiotics in the setting of reduced penicillin susceptibility should prioritize favorable PK profiles to yield high concentrations over broad activity against β-lactamase–producing pathogens. Application of PK-PD principles supports the established conclusion that no oral cephalosporin yields better anti-pneumococcal activity than amoxicillin (
      • Bradley J.S.
      • Byington C.L.
      • Shah S.S.
      • Alverson B.
      • Carter E.R.
      • Harrison C.
      Pediatric Infectious Diseases Society and the Infectious Diseases Society of America
      The management of community-acquired pneumonia in infants and children older than 3 months of age: Clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.
      ;
      • Strachan S.A.
      • Friedland I.R.
      Therapy for penicillin-resistant Streptococcus pneumoniae.
      ).

      β-LACTAMS: GENERAL PK-PD CONCEPTS

      Antibiotic susceptibility is interpreted from the minimum inhibitory concentration (MIC), which is the lowest concentration of antibiotic that prevents visible in vitro growth after a given incubation period (
      • Gill V.J.
      • Fedoro D.P.
      • Witebsky F.G.
      The Clinical and the microbiology laboratory.
      ). Susceptibility breakpoints are established by the Clinical Laboratory Standards Institute (CLSI) to define the MIC below which a given organism is deemed susceptible to a given antibiotic, and these values are used by institutional microbiology laboratories to interpret a pathogen as being susceptible, intermediately susceptible, or resistant to each antibiotic tested. MIC results must be interpreted with caution. Because antibiotic activity depends on the presence of free drugs at the site of infection and MIC testing is performed at a fixed concentration in controlled environments, the antibiotic with the lowest MIC cannot simply be assumed to be the most active (
      • Lodise T.P.
      • Butterfield J.
      Use of pharmacodynamic principles to inform β-lactam dosing: “S” does not always mean success.
      ). Even an antibiotic with a low MIC will not be useful if adequate concentrations cannot be achieved at the site of infection. Prescribers must, therefore, understand both the PD relationships that define goal exposure and the PK profiles of each antibiotic to predict the likelihood of reaching that goal.
      All β-lactam antibiotics exhibit time-dependent killing. The PD parameter predictive of bacteriologic efficacy is the amount of time (T, reported as the percentage of the dosing interval) during which free-drug concentration (f) exceeds the MIC, expressed as % fT > MIC. For example, 50% fT > MIC of a drug dosed every 12 hours means that the free-serum concentrations exceed the MIC for six hours (Figure 1). Generally, bacteriostasis is predicted by fT > MIC of 30% for penicillins and 35% to 40% for cephalosporins. Greater fT > MIC durations of 50% and 60% to 70% are needed for bactericidal activity of penicillins and cephalosporins, respectively. Variation in required fT > MIC between classes represents the slower rate of killing by cephalosporins than penicillins (
      • Craig W.A.
      Pharmacokinetic/pharmacodynamics parameters: Rationale for antibacterial dosing of mice and men.
      ;
      • Drusano G.L.
      Antimicrobial pharmacodynamics: Critical interactions of ‘bug and drug.’.
      ).
      FIGURE 1
      FIGURE 1Free-drug concentration vs. time. f, free-drug concentration; MIC, minimum inhibitory concentration.
      Various PK parameters predict the likelihood of reaching targeted % fT > MIC. Orally administered medications undergo multiple metabolic pathways to get into the body, which is circumvented by the intravenous route. The degree of absorption from the gut and first-pass metabolism in the liver dictate peak concentrations achieved after an oral dose. Although peak concentrations are of less importance than % fT > MIC, initial peaks must be high enough at the beginning of the dosing interval to maintain concentrations above the MIC for an adequate amount of time.
      Additional considerations relevant to both oral and parenteral antibiotics are protein binding and tissue penetration. As only free drug unbound to serum proteins is available to exert antimicrobial activity, excessive protein binding is generally disadvantageous (
      • Drusano G.L.
      Antimicrobial pharmacodynamics: Critical interactions of ‘bug and drug.’.
      ). Penetration into the site of infection is an intuitive and important parameter to consider when selecting antibiotics for a given infection. Using the common example of AOM, penetration of orally administered β-lactams from serum to the middle-ear fluid ranges from 20% to 50% (
      • Craig W.A.
      • Andes D.
      Pharmacokinetics and pharmacodynamics of antibiotics in otitis media.
      ). Middle-ear concentrations routinely exceed MICs, and amoxicillin is eliminated more slowly from the middle-ear fluid than from the serum (
      • Barry B.
      • Muffat-Joly M.
      • Gehanno P.
      • Pocidalo J.J.
      Effect of increased dosages of amoxicillin in treatment of experimental middle ear otitis due to penicillin-resistant Streptococcus pneumoniae.
      ). Other common sites of infection, such as the sinuses, urinary tract, and skin, are even more readily penetrated because of more blood flow and renal elimination. Finally, slow drug elimination, identified as a long half-life, is also desirable for maximal % fT > MIC and the convenience of infrequent dosing once or twice daily.
      These factors taken together indicate that an ideal oral β-lactam is highly absorbed with minimal protein binding and a long elimination half-life. This theoretical ideal oral β-lactam is compared with selected available agents in Table 2. With some variability, oral cephalosporins are generally poorly absorbed, highly protein-bound, and rapidly eliminated. In contrast, amoxicillin and amoxicillin-clavulanate undergo rapid and extensive absorption with relatively low protein binding. The half-life of amoxicillin is generally comparable with the oral cephalosporins, but initial serum concentrations of free, active drugs are much higher. As evidenced by the greater % fT > MIC (Table 2), the favorable pharmacokinetics of amoxicillin yields superior pharmacodynamic exposure. Amoxicillin-clavulanate is not included in Table 2 because clavulanate does not enhance the activity of amoxicillin against S. pneumoniae; breakpoints and PD are exposures identical to amoxicillin alone. For further details and instruction for estimating % fT > MIC, the reader is referred to the comprehensive review by
      • Parker S.
      • Mitchell M.
      • Child J.
      Cephem antibiotics: Wise use today preserves cure for tomorrow.
      .
      TABLE 2Pharmacokinetic characteristics and projected pharmacodynamic exposures of selected oral β-lactams
      AntibioticDoseAbsorption (%)Protein binding (%)Half-life (hours)CLSI BPPK-PD BPEst. % T > MIC, CLSI BP, PSSP
      Ideal agent>35–50
      Amoxicillin45 mg/kg/dose BID89∼201-1.5≤2≤233.3
      Cefpodoxime5 mg/kg/dose BID5021–332–3≤0.5≤0.533.3
      Cefprozil15 mg/kg/dose BID90361.3≤2≤116.6
      Cefdinir14 mg/kg/dose daily or 7 mg/kg/dose BID16–2560–701.7 ± 0.6≤0.5≤0.2510
      Note. BID, Twice daily; BP, breakpoint; CLSI, Clinical Laboratory Standards Institute; Est. % T > MIC, estimated percent time above minimum inhibitory concentration; PD, pharmacodynamic; PK, pharmacokinetic; PSSP, penicillin-susceptible S. Pneumoniae.
      Data from
      • Peric M.
      • Browne F.A.
      • Jacobs M.R.
      • Appelbaum P.C.
      Activity of nine oral agents against gram-positive and gram-negative bacteria encountered in community-acquired infections: Use of pharmacokinetic/pharmacodynamic breakpoints in the comparative assessment of β-lactam and macrolide antimicrobial agents.
      ;
      • Robertson S.
      • Bonapace C.R.
      Food and Drug Administration Office of Clinical Pharmacology Review: Amoxicillin pulsatile release tablets (APC-111).
      ;
      • Harrison C.J.
      • Woods C.
      • Stout G.
      • Martin B.
      • Selvarangan R.
      Susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae, including serotype 19A, and Moraxella catarrhalis paediatric isolates from 2005 to 2007 to commonly used antibiotics.
      ;
      Lupin Pharmaceuticals, Inc
      Cefdinir for oral suspension, USP.
      ;
      • Parker S.
      • Mitchell M.
      • Child J.
      Cephem antibiotics: Wise use today preserves cure for tomorrow.
      ;
      Sandoz Canada, Inc
      Cefprozil powder for oral suspension. Boucherville.
      ;
      West-Ward Pharmaceuticals, Corp
      Amoxicillin powder, for suspension.
      ;
      Pfizer, Inc
      Vantin-Cefpodoxime proxetil granule, for suspension.
      .

      PK-PD OF ORAL β-LACTAMS AGAINST S. PNEUMONIAE

      Although established susceptibility breakpoints consider achievable drug concentrations at recommended doses, MIC is limited in that it is a fixed in vitro metric that does not contribute to changes in drug concentration and activity in vivo (
      • Lodise T.P.
      • Butterfield J.
      Use of pharmacodynamic principles to inform β-lactam dosing: “S” does not always mean success.
      ;

      Weinstein, M. P., Patel, J. B., Campeau, S., Eliopoulos, G. M., Galas, M. F., Humphries, R. M., … Zimmer, B. L. (2018). Performance standards for antimicrobial susceptibility testing (28th ed.). Wayne, PA: Clinical Laboratory Standards Institute. Document M100-S28.

      ). PK-PD breakpoints have been developed to account for these limitations and increase the likelihood of achieving target drug exposures. PK-PD breakpoints combine established MIC breakpoints with expected drug exposure derived from human PK studies, PD drug exposure targets, and MIC distribution within a population (
      • Harrison C.J.
      • Woods C.
      • Stout G.
      • Martin B.
      • Selvarangan R.
      Susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae, including serotype 19A, and Moraxella catarrhalis paediatric isolates from 2005 to 2007 to commonly used antibiotics.
      ;
      • Peric M.
      • Browne F.A.
      • Jacobs M.R.
      • Appelbaum P.C.
      Activity of nine oral agents against gram-positive and gram-negative bacteria encountered in community-acquired infections: Use of pharmacokinetic/pharmacodynamic breakpoints in the comparative assessment of β-lactam and macrolide antimicrobial agents.
      ). Methodology and results vary, but generally for β-lactams, the PK-PD susceptibility breakpoint is the MIC at which the antibiotic is expected to remain above the MIC90 for ≥50% of the dosing interval. MIC90 is the MIC at which 90% of bacteria in a given population are inhibited. This measure is useful because it can be tailored to reflect local resistance patterns or MIC distributions.
      A PK-PD susceptible breakpoint higher than the CLSI susceptible breakpoint indicates superior PK behavior in vivo that may attain PD targets against pathogens reported as nonsusceptible per traditional breakpoints. This finding is true of parenteral ceftriaxone (CLSI susceptible breakpoint ≤ 1 mcg/mL, PK-PD susceptible breakpoint ≤ 2 mcg/mL) and is consistent with its excellent activity and T > MIC after parenteral administration (
      • Fenoll A.
      • Giménez M.J.
      • Robledo O.
      • Aguilar L.
      • Tarragó D.
      • Granizo J.J.
      • Martín-Herrero J.E.
      Influence of penicillin/amoxicillin non-susceptibility on the activity of third-generation cephalosporins against Streptococcus pneumoniae.
      ;
      • Harrison C.J.
      • Woods C.
      • Stout G.
      • Martin B.
      • Selvarangan R.
      Susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae, including serotype 19A, and Moraxella catarrhalis paediatric isolates from 2005 to 2007 to commonly used antibiotics.
      ;

      Weinstein, M. P., Patel, J. B., Campeau, S., Eliopoulos, G. M., Galas, M. F., Humphries, R. M., … Zimmer, B. L. (2018). Performance standards for antimicrobial susceptibility testing (28th ed.). Wayne, PA: Clinical Laboratory Standards Institute. Document M100-S28.

      ). A pathogen with a ceftriaxone MIC of 2 mcg/mL will be reported as nonsusceptible, but exposure is still anticipated to be adequate.
      A PK-PD susceptible breakpoint lower than the CLSI susceptible breakpoint suggests that in vivo drug exposure may not be adequate, even in the pathogen, is reported as susceptible. For example, the PK-PD susceptible breakpoint of cefdinir (≤ 0.25 mcg/mL) is lower than the CLSI susceptible breakpoint (≤ 0.5 mcg/mL). This observation means that for isolates with an MIC > 0.25 mcg/mL up to 0.5 mcg/mL, cefdinir concentrations are unlikely to exceed the MIC90 for 50% of the dosing interval despite being reported as susceptible, which is consistent with the poor absorption and high protein binding of cefdinir (Table 2). In contrast, cefpodoxime provides the highest % fT > MIC of the oral cephalosporins (Table 2), and the PK-PD susceptible breakpoint is identical to the CLSI susceptible breakpoint. This improved drug exposure is consistent with its favorable pharmacokinetic characteristics: relatively higher absorption, lower protein binding, and longer half-life. As demonstrated through these examples, antibiotic PK characteristics can be used to predict likelihood of PD target attainment. These comparisons additionally underscore a critical but often overlooked rule: pneumococcal susceptibility to oral third-generation cephalosporins cannot be inferred from susceptibility to ceftriaxone. Although the parenteral third-generation cephalosporins cefotaxime and ceftriaxone are largely used interchangeably, the same assumption of equivalence cannot be extended to oral third-generation cephalosporins. In vivo exposure, and not in vitro spectrum of activity, is of highest relevance to the treatment of pneumococcal infections.
      Cultures are not routinely collected in the infections reviewed here, requiring prescribers to defer to local patterns of penicillin susceptibility. In the infrequent scenarios, when culture and susceptibility information are available, MICs are not usually reported for every antibiotic that prescribers may be considering. In vitro activity of potential treatment options must often be deduced from reported penicillin MIC, using the CLSI susceptibility breakpoint ≤ 0.06 mcg/mL for oral penicillin. Per CLSI standards, susceptibility to amoxicillin, amoxicillin/clavulanate, cefpodoxime, cefuroxime, cefprozil, and cefdinir may be assumed if penicillin MIC is ≤ 0.06 mcg/mL (

      Weinstein, M. P., Patel, J. B., Campeau, S., Eliopoulos, G. M., Galas, M. F., Humphries, R. M., … Zimmer, B. L. (2018). Performance standards for antimicrobial susceptibility testing (28th ed.). Wayne, PA: Clinical Laboratory Standards Institute. Document M100-S28.

      ). In addition to its favorable PK profile in vivo, amoxicillin is inherently less labile in vitro to elevated penicillin MICs than the oral cephalosporins. As shown in Figure 2, Fenoll et al. (
      • Fenoll A.
      • Giménez M.J.
      • Robledo O.
      • Aguilar L.
      • Tarragó D.
      • Granzio J.J.
      • Coronel P.
      In vitro activity of oral cephalosporins against pediatric isolates of Streptococcus pneumoniae non-susceptible to penicillin, amoxicillin or erythromycin.
      ) confirmed that penicillin-susceptible S. pneumoniae is widely susceptible in vitro to amoxicillin, cefuroxime, cefpodoxime, and cefdinir. Although susceptibility to all three of these oral agents is reduced in the setting of S. pneumoniae intermediately susceptible to penicillin (MIC = 0.12–1 mcg/mL), amoxicillin remained active against 84.7% of isolates while the oral cephalosporins retained activity against less than 40% (
      • Fenoll A.
      • Giménez M.J.
      • Robledo O.
      • Aguilar L.
      • Tarragó D.
      • Granzio J.J.
      • Coronel P.
      In vitro activity of oral cephalosporins against pediatric isolates of Streptococcus pneumoniae non-susceptible to penicillin, amoxicillin or erythromycin.
      ;
      • Fenoll A.
      • Giménez M.J.
      • Robledo O.
      • Aguilar L.
      • Tarragó D.
      • Granizo J.J.
      • Martín-Herrero J.E.
      Influence of penicillin/amoxicillin non-susceptibility on the activity of third-generation cephalosporins against Streptococcus pneumoniae.
      ). Parenteral ceftriaxone maintains even greater activity against S. pneumoniae with reduced susceptibility to penicillin (Figure 2). Although cefdinir in vitro activity is almost identical to cefuroxime and cefpodoxime (Figure 2), it is not absorbed as well and is more highly protein-bound (Table 2). As such, cefuroxime and cefpodoxime are preferred over cefdinir for the treatment of pneumococcal infections (Table 1), which again illustrates the importance of in vivo PK exposure in addition to in vitro activity. Of note, cefuroxime oral liquid has been discontinued and will soon no longer be available. Compounding oral tablets is not advised owing to its bitter taste.
      FIGURE 2
      FIGURE 2In vitro activity of selected antibiotics against S. pneumoniae with varying degrees of penicillin susceptibility. PSSP, penicillin-susceptible S. pneumoniae (minimum inhibitory concentration [MIC] = 0.06 mcg/mL); PISP, penicillin–intermediately susceptible S. pneumoniae (MIC = 0.12 – 1 mcg/mL); PRSP, penicillin-resistant S. pneumoniae (MIC = 2 mcg/mL); CLSI, Clinical Laboratory Standards Institute; BP, breakpoint; PK-PD, pharmacokinetic/pharmacodynamic data from
      • Spangler S.K.
      • Jacobs M.R.
      • Appelbaum P.C.
      Susceptibilities of 177 penicillin-susceptible and –resistant pneumococci to FK 037, cefpirome, cefepime, ceftriaxone, cefotaxime, ceftazidime, imipenem, Biapenem, meropenem, and vancomycin.
      ;
      • Fenoll A.
      • Giménez M.J.
      • Robledo O.
      • Aguilar L.
      • Tarragó D.
      • Granzio J.J.
      • Coronel P.
      In vitro activity of oral cephalosporins against pediatric isolates of Streptococcus pneumoniae non-susceptible to penicillin, amoxicillin or erythromycin.
      ;
      • Fenoll A.
      • Giménez M.J.
      • Robledo O.
      • Aguilar L.
      • Tarragó D.
      • Granizo J.J.
      • Martín-Herrero J.E.
      Influence of penicillin/amoxicillin non-susceptibility on the activity of third-generation cephalosporins against Streptococcus pneumoniae.
      ;
      • Harrison C.J.
      • Woods C.
      • Stout G.
      • Martin B.
      • Selvarangan R.
      Susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae, including serotype 19A, and Moraxella catarrhalis paediatric isolates from 2005 to 2007 to commonly used antibiotics.
      ;

      Weinstein, M. P., Patel, J. B., Campeau, S., Eliopoulos, G. M., Galas, M. F., Humphries, R. M., … Zimmer, B. L. (2018). Performance standards for antimicrobial susceptibility testing (28th ed.). Wayne, PA: Clinical Laboratory Standards Institute. Document M100-S28.

      .
      (This figure appears in color online at www.jpedhc.org.)
      Owing to their superior PK properties, oral amoxicillin and especially parenteral ceftriaxone remain active against S. pneumoniae with reduced susceptibility to penicillin. As such, the Infectious Diseases Society of America pediatric CAP guidelines recommend ceftriaxone as first-line therapy for CAP caused by PRSP, and high-dose intravenous ampicillin as an acceptable alternative. In contrast, oral cephalosporins are not recommended in any capacity for CAP caused by PRSP (Table 1;
      • Bradley J.S.
      • Byington C.L.
      • Shah S.S.
      • Alverson B.
      • Carter E.R.
      • Harrison C.
      Pediatric Infectious Diseases Society and the Infectious Diseases Society of America
      The management of community-acquired pneumonia in infants and children older than 3 months of age: Clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.
      ). However, in the setting of a confirmed very high oral penicillin MIC (i.e., > 2 mcg/mL), the use of a different class of antibiotics altogether is generally advisable.

      PENICILLIN ALLERGY AND CEPHALOSPORIN CROSS-REACTIVITY

      Another common reason for leaving the β-lactam class is a reported drug allergy. Although 10% of the population report being allergic to penicillin, true penicillin allergy only occurs in <1% (
      Centers for Disease Control and Prevention
      Evaluation and diagnosis of penicillin allergy for healthcare professionals.
      ). Current literature proposes that only 10% of documented penicillin allergies are actual IgE-mediated hypersensitivity reactions (i.e., anaphylaxis;
      • Unger N.R.
      • Gauthier T.P.
      • Cheung L.W.
      Penicillin skin testing: Potential implications for antimicrobial stewardship.
      ). About 80% to 90% of reported allergies reflect non-allergic adverse reactions. In patients with an established IgE-mediated hypersensitivity, the risk of similar immediate hypersensitivity reactions to cephalosporins is 1% to 10% This estimation is higher than the risk of developing hypersensitivity reactions to cephalosporins (1–3%) in patients without a history of penicillin allergy (
      • Buonomo A.
      • Nucera E.
      • Pecora V.
      • Rizzi A.
      • Aruanno A.
      • Pascolini L.
      • Schiavino D.
      Cross-reactivity and tolerability of cephalosporins in patients with cell-mediated allergy to penicillins.
      ).
      The same 4-membered β-lactam ring is present in both the cephalosporins and penicillins (
      • Buonomo A.
      • Nucera E.
      • Pecora V.
      • Rizzi A.
      • Aruanno A.
      • Pascolini L.
      • Schiavino D.
      Cross-reactivity and tolerability of cephalosporins in patients with cell-mediated allergy to penicillins.
      ). However, cephalosporins have an additional six-membered dihydrothiazine ring instead of the five-membered thiazolidine ring found in penicillins. Cephalosporins have two side chains that may elicit hypersensitivity reactions, while penicillins only have one side chain. The degradation process of cephalosporins includes more rapid fragmentation, larger intermediate products, and slower haptenization than penicillins. In the process of haptenization, the reactive intermediates of penicillin bind to circulating protein to produce haptens, which induce antigenic activity (
      • Mirakian R.
      • Leech S.C.
      • Krishna M.T.
      • Richter A.G.
      • Huber P.A.
      • Farooque S.
      Standards of Care Committee of the British Society for Allergy and Clinical Immunology
      Management of allergy to penicillins and other β-lactams.
      ). Because these processes are different between the two antibiotic classes, cross-reactivity is likely not clinically significant. In a retrospective study conducted by
      • Buonomo A.
      • Nucera E.
      • Pecora V.
      • Rizzi A.
      • Aruanno A.
      • Pascolini L.
      • Schiavino D.
      Cross-reactivity and tolerability of cephalosporins in patients with cell-mediated allergy to penicillins.
      , cross-reactivity (as determined using a patch test) between cephalosporins and penicillins was higher in first-generation cephalosporins than that of second- and third-generation cephalosporins (
      • Buonomo A.
      • Nucera E.
      • Pecora V.
      • Rizzi A.
      • Aruanno A.
      • Pascolini L.
      • Schiavino D.
      Cross-reactivity and tolerability of cephalosporins in patients with cell-mediated allergy to penicillins.
      ). Their data concluded a cross-reactivity of up to 10.9% in first-generation cephalosporins, but only up to 1.1% in third-generation cephalosporins. Newly developed cephalosporins usually lack antigenic side chains, such as the α-amino group, which may explain reduced cross-reactivity.
      Patients who report a prior penicillin allergy are significantly less likely to receive optimal therapy for serious infections (
      • Blumenthal K.G.
      • Shenoy E.S.
      • Huang M.
      • Kuhlen J.L.
      • Ware W.A.
      • Parker R.A.
      • Walensky R.P.
      The impact of reporting a prior penicillin allergy on the treatment of methicillin-sensitive Staphylococcus aureus bacteremia.
      ). Patients deemed penicillin-allergic are exposed to more vancomycin, fluoroquinolones, and clindamycin, with prolonged hospitalizations and more infections caused by MRSA, VRE, and Clostridium difficile (
      • Macy E.
      • Contreras R.
      Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study.
      ). The likelihood of penicillin-allergic patients receiving and tolerating optimal therapy increases significantly when an allergist/immunologist is involved in care, potentially utilizing a penicillin skin test (PST;
      • Blumenthal K.G.
      • Shenoy E.S.
      • Huang M.
      • Kuhlen J.L.
      • Ware W.A.
      • Parker R.A.
      • Walensky R.P.
      The impact of reporting a prior penicillin allergy on the treatment of methicillin-sensitive Staphylococcus aureus bacteremia.
      ). The Infectious Diseases Society of America recommends PST to rule out hypersensitivity to direct appropriate use of preferred β-lactam therapy (
      • Barlam T.F.
      • Cosgrove S.E.
      • Abbo L.M.
      • MacDougall C.
      • Schuetz A.N.
      • Septimus E.J.
      • Trivedi K.K.
      Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
      ). In PST, the reactive intermediates described above are used as allergenic major and minor determinants. In pediatric patients, intradermal skin tests may be difficult to obtain especially in younger age groups and are not useful in non-IgE–mediated reactions (
      • Mirakian R.
      • Leech S.C.
      • Krishna M.T.
      • Richter A.G.
      • Huber P.A.
      • Farooque S.
      Standards of Care Committee of the British Society for Allergy and Clinical Immunology
      Management of allergy to penicillins and other β-lactams.
      ). An oral challenge test, in which the initial dose is given under observation and continued for five days, is recommended for diagnosing a β-lactam allergy with mild skin rash or maculopapular reaction in children. Employing PST in hospitals to facilitate the use of narrower-spectrum and more effective antibiotics may improve patient outcomes and reduce the development of multidrug-resistant organisms (
      • Barlam T.F.
      • Cosgrove S.E.
      • Abbo L.M.
      • MacDougall C.
      • Schuetz A.N.
      • Septimus E.J.
      • Trivedi K.K.
      Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
      ).

      ORAL CEPHALOSPORINS: ROLE IN THERAPY

      Oral cephalosporins should be used with caution and reserved only as alternatives for patients who have failed or are intolerant of first-line amoxicillin-based therapy, and often in combination with other antibiotics (Table 1). Oral cephalosporin monotherapy is recommended only for penicillin-allergic patients, and only as initial therapy of AOM or for CAP caused by penicillin-susceptible S. pneumoniae.
      Of less immediate concern than poor bacteriologic efficacy in an acute infection, but long term importance is the broad antimicrobial spectrum of the oral cephalosporins. These agents generally have greater activity than amoxicillin and even amoxicillin-clavulanate against Gram-negative pathogens like E. coli and K. pneumoniae, which are not typically implicated in the infections reviewed here (Table 3;

      Weinstein, M. P., Patel, J. B., Campeau, S., Eliopoulos, G. M., Galas, M. F., Humphries, R. M., … Zimmer, B. L. (2018). Performance standards for antimicrobial susceptibility testing (28th ed.). Wayne, PA: Clinical Laboratory Standards Institute. Document M100-S28.

      ). Preferential use of narrow-spectrum antibiotics to limit antibiotic resistance is a key component of antimicrobial stewardship (
      • Barlam T.F.
      • Cosgrove S.E.
      • Abbo L.M.
      • MacDougall C.
      • Schuetz A.N.
      • Septimus E.J.
      • Trivedi K.K.
      Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
      ). In addition to suboptimal exposure against the pathogens of concern, oral cephalosporins provide unnecessarily broad spectra of activity, including pathogens not associated with these infections (Table 3).
      TABLE 3Dosage and in vitro activity of selected oral β-lactams for AOM, CAP, and ABRS
      Drug (brand name)PSSPPISPBL(+) NTHiMSSAEnterics (EC, KP)DoseOral formulations
      Amoxicillin (Amoxil, West-Ward Pharmaceuticals Corp, Columbus, OH)+++/–High dose: Preferred for all indications (AOM, CAP)

      90 mg/kg/day divided BID

      (maximum 2 g/dose)
      125 mg/5 mL, 250 mg/mL

      Bottles (mL): 80, 100, 150

      200 mg/5 mL, 400 mg/5 mL

      Bottles (mL): 50, 75, 100

      Capsule (mg): 250, 500

      Tablet (mg): 500, 875

      Chew tablet (mg): 125, 250
      Amoxicillin-clavulanate (Augmentin, Dr. Reddy's Laboratories, Inc., Princeton, NJ)+++++/–Dosed per amoxicillin component

      (amoxicillin; clavulanate)

      High dose: Preferred

      90 mg/kg/day divided BID

      (maximum 2 g/dose)

      Moderate dose: Permitted in ABRS, low risk of PNSP

      45 mg/kg/day divided BID

      (maximum 875 mg/dose)
      High dose, suspension

      600 mg amoxicillin, 42.9 mg clavulanate/5 mL

      Bottles (mL): 75, 125, 200

      High dose, tablet (extended-release)

      1000 mg amoxicillin, 62.5 mg clavulanate

      Moderate dose, suspension

      200 mg amoxicillin, 28.5 mg clavulanate/5 mL

      400 mg amoxicillin, 57 mg clavulanate/5 mL

      Bottles (mL): 50, 75, 100

      Moderate dose, tablet

      875 mg amoxicillin, 125 mg clavulanate
      Cefdinir (Omnicef, Lupin Pharmaceuticals, Inc., Mumbai, India)++++14 mg/kg/day once daily or divided BID

      (maximum 600 mg/day)
      125 mg/5 mL, 250 mg/5 mL

      Bottles (mL): 60, 100
      Cefpodoxime (Vantin, Pfizer, New York, NY)++++10 mg/kg/day divided BID

      (maximum 200 mg/dose)
      50 mg/5 mL, 100 mg/5 mL

      Bottles (mL): 50, 100

      Tablet (mg): 100, 200
      Cefprozil (Cefzil, Sandoz Canada, Mississauga, Ontario, Canada)+++30 mg/kg/day divided BID

      (maximum 500 mg/dose)
      125 mg/5 mL, 250 mg/5 mL

      Bottles (mL): 50, 75, 100

      Tablet (mg): 250, 500
      Note. ABRS, acute bacterial rhinosinusitis; AOM, acute otitis media; BID, twice daily; CAP, community-acquired pneumoniae; EC, Escherichia coli; KP, Klebsiella pneumoniae; MSSA methicillin-susceptible Staphylococcus aureus; NTHi, non-typeable Haemophilus influenzae; PISP, penicillin-intermediately susceptible S. pneumoniae; PNSP, penicillin-nonsusceptible S. pneumoniae; PSSP, penicillin-susceptible S. pneumoniae. In vitro activity as follows: (+), active in vitro, (–), inactive or poorly active in vitro, and (+/–), active against susceptible strains, but susceptibility is generally variable to low.
      Data from
      Lupin Pharmaceuticals, Inc
      Cefdinir for oral suspension, USP.
      ;
      Dr. Reddy's Laboratories, Inc
      Augmentin (amoxicillin/clavulanate potassium) tablets, powder for oral suspension, and chewable tablets.
      ;
      Sandoz Canada, Inc
      Cefprozil powder for oral suspension. Boucherville.
      ;
      Dr. Reddy's Laboratories Tennessee LLC
      Augmentin ES (amoxicillin and clavulanate potassium) powder for oral suspension.
      ;
      West-Ward Pharmaceuticals, Corp
      Amoxicillin powder, for suspension.
      ;
      Pfizer, Inc
      Vantin-Cefpodoxime proxetil granule, for suspension.
      .

      CONCLUSION

      Amoxicillin remains the oral β-lactam with the greatest activity against S. pneumoniae. For the treatment of pneumococcal infections, oral cephalosporins are inferior to amoxicillin, and their activity cannot be inferred from parenteral cephalosporins like ceftriaxone. As the bacteriology of AOM and ABRS has evolved to a predominance of H. influenzae, amoxicillin-clavulanate will likely emerge as preferred therapy to provide broadened activity against H. influenzae while maintaining optimal treatment of S. pneumoniae, though possibly at a reduced dose given declining penicillin resistance. In addition, the limitations of oral cephalosporins reviewed here may prove to be of lesser significance as S. pneumoniae becomes a less common pathogen in AOM and ABRS.

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      Biography

      Leah Molloy, Clinical Pharmacist Specialist, Pediatric Infectious Diseases, Department of Pharmacy, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI.
      Sasha Barron, Clinical Coordinator, Department of Pharmacy, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI.
      Nadia Khan, Clinical Pharmacist, Department of Pharmacy, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI.
      Evan Abrass, Pediatric Hematology/Oncology and Bone Marrow Transplant Pharmacist, Department of Pharmacy, Seattle Children's Hospital, Seattle, WA.
      Jocelyn Ang, Professor of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan, Detroit Medical Center; Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI.
      Nahed Abdel-Haq, Associate Professor of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan, Detroit Medical Center; Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI.