in brief

In Brief

The Zainab A. Malik, MD , , , intravenous (IV) routes, whereas peni- Nathan Litman, MD , and cillin V is acid-stable and administered Children’s Hospital at Montefiore ● : and orally. Semisynthetic penicillinase- Bronx, NY resistant penicillins are the drugs of ● : and choice only for -resistant S aureus and S epidermidis, although Author Disclosure ● : , mezlocil- they also are active against strepto- Drs Malik and Litman did not lin, and pipercillin cocci, but not against enterococci. disclose any financial relationships Aminopenicillins, in addition to of- The latter two classes also are called relevant to this In Brief. fering coverage equivalent to that of antipseudomonal penicillins. penicillin G, are active against gram- The basic structure of most com- negative cocci and some En- The Penicillins and Related Drugs. Kuc- mercially available penicillins is a nu- terobacteriaceae. Carboxypenicillins ers A. In: Kucers A, Crowe S, Grayson cleus consisting of a beta-lactam ring and ureidopenicillins have activity ML, Hoy J, eds. The Use of Antibiot- and a side chain. The beta-lactam ring against gram-negative aerobic rods ics: A Clinical Review of Antibacte- confers antibacterial activity, and the such as , rial, , and Antiviral Drugs. side chain determines the agent’s anti- which are resistant to ampicillin. Urei- 5th ed. Oxford, United Kingdom: bacterial spectrum and pharmacologic dopenicillins are more active against Butterworth-Heinemann Publishing; properties. The antibacterial activity of streptococci and Haemophilus sp than 1997:1–250 penicillins, like other beta-lactams, de- Penicillins. Chambers HF. In: Mandell are carboxypenicillins. pends on their inhibition of bacterial GL, Bennett GL, Dolin R, eds. Man- Many anaerobic gram-positive spe- dell, Douglas, and Bennett’s Princi- penicillin-binding proteins (PBPs), cies are susceptible to the penicillins. ples and Practice of Infectious Dis- which are necessary for syn- Most gram-negative anaerobic eases. 6th ed. New York, NY: Elsevier thesis. Certain bacteria, including also are susceptible, with the exception Churchill Livingstone; 2005:281–293 sp, Neisseria gonor- of B fragilis, other Bacteroides sp, and Antimicrobial Agents: Penicillins, Ceph- rhea, Moraxella catarrhalis, Bacteroides some Prevotella sp, which produce alosporins, and Other Beta-lactam sp, and Haemophilus sp, produce peni- beta-lactamases. Strains of Fusobacte- . Petri WA, Jr. In: Hard- cillinases, enzymes that hydrolyze beta- rium varium are often resistant to all man JG, Limbird LE, Gilman AG, eds. lactam rings. These organisms are sus- penicillins. Goodman & Gilman’s The Pharmaco- ceptible only to the penicillins that are Of the natural penicillins, penicillin logical Basis of Therapeutics. 10th ed. New York: McGraw-Hill Medical beta-lactamase-resistant or to beta- G is available commercially as an IM Publishing Division; 2001:1189–1218 lactam/beta-lactamase inhibitor com- preparation (procaine penicillin G or binations. benzathine penillin G) and as IV crys- The natural penicillins are most ac- talline salts (sodium or potassium). Pro- In 1929, Fleming isolated penicillin tive against nonbeta-lactamase- caine penicillin G contains an anes- from the mold Penicillium notatum. It producing gram-positive bacteria such thetic, whereas benzathine penicillin G was introduced into clinical medicine in as S pyogenes, anaerobes, and selected injections are painful. Combinations of 1941 by Florey and associates. The gram-negative cocci such as Neisseria. procaine and benzathine penicillin G penicillins can be divided into five Penicillin V is, for the most part, equiv- are available, the most commonly used classes on the basis of antibacterial alent to penicillin G, except that it is preparation containing 900,000 U of activity, although there is considerable less active against gram-negative in- benzathine penicillin and 300,000 U of overlap among the classes: fections caused by pathogens such as procaine penicillin per 2 mL injection ● Natural penicillins: penicillins G and Neisseria and Haemophilus sp. Penicil- solution. V lin G is acid-labile and usually admin- The international unit of penicillin is ● Penicillinase-resistant penicillins: istered via the intramuscular (IM) or the penicillin activity contained in

Pediatrics in Review Vol.27 No.12 December 2006 471 in brief

0.6 mcg of the crystalline sodium salt of IV/IM penicillin G for dental or surgical reaction for protein when the sulfasali- penicillin G. Thus, 1 mg of pure penicil- procedures in patients who have valvu- cylic test is used. Nafcillin can cause lin G equals 1,600 U. Crystalline salts of lar heart disease, and oral penicillin V or phlebitis with IV administration and penicillin G are highly water-soluble benzathine penicillin G for preventing may cause skin and soft-tissue necrosis and immediately achieve high serum recurrences of rheumatic fever by pre- after accidental subcutaneous extrava- levels when administered intravenously. venting episodes of group A streptococ- sation, sometimes requiring tissue de- Procaine penicillin G is administered by cal pharyngitis. bridement and skin grafting. IM injection and achieves peak serum Penicillinase-resistant penicillins are Oxacillin, cloxacillin, and di- levels in 2 to 3 hours. Detectable serum stable to hydrolysis by staphylococcal cloxacillin are other semisynthetic levels are maintained for up to penicillinase enzyme, making them the penicillinase-resistant penicillins clas- 24 hours. Benzathine penicillin G pro- agents of choice for most sified together as isoxazoyl penicillins. duces more prolonged but lower ther- caused by staphylococci. Methicillin They have an antimicrobial spectrum apeutic serum levels after an IM injec- and nafcillin are the most stable, fol- similar to that of methicillin and naf- tion, and detectible levels are lowed by dicloxacillin, oxacillin, and cillin and are active against staphylo- maintained for 15 to 30 days. cloxacillin. Strains of S aureus and S cocci and streptococci. Crystalline penicillin G administered epidermidis that are resistant to meth- fecalis is largely resistant. Isoxazoyl IV has a half-life of 30 minutes in icillin and the other members of its penicillins are acid-stable and well ab- healthy adults. It is excreted rapidly by class are increasingly emerging. This sorbed orally, reaching peak serum lev- the kidneys, 10% by glomerular filtra- resistance is not mediated by a novel els in 30 to 60 minutes. Significant tion and 90% by active tubular secre- penicillinase enzyme, but by a decrease plasma levels are maintained for up to tion. Probenecid inhibits the tubular in the affinity of bacterial PBPs to the 4 to 6 hours. The doses should be secretion of penicillin G, increasing its drugs. reduced in the presence of severe renal serum half-life, but it rarely is used for Methicillin is not used today be- impairment. These penicillins penetrate this purpose. Penicillin clearance is cause of the high risk of nephritis. well into bones of patients afflicted considerably lower in neonates and in- Clinical features of methicillin-induced with acute osteomyelitis and into septic fants because of their immature renal nephritis include fever, proteinuria, joint effusions. Although isoxazoyl pen- function. The serum half-life in children sterile pyuria, marked eosinophiluria, icillins are highly protein-bound, which younger than 1 week old is 3 hours; by rash, eosinophilia, hematuria, and renal diminishes their extravascular penetra- 14 days of age, it is 1.4 hours. When renal insufficiency. Most affected patients tion, they reach high concentrations in function is fully established in young experience a slow but complete recov- children, the rate of renal clearance of ery after drug cessation; systemic ste- body tissues and extravascular fluids, penicillin G is more rapid than in adults. roid therapy is reserved for severe making them clinically effective. Penicillin G is widely distributed cases. If antimicrobial therapy needs to Antipseudomonal penicillins are throughout all body tissues, and 60% of be continued after development of in- only administered parenterally and are the penicillin in plasma is reversibly terstitial nephritis, the patient should important in the treatment of gram- bound to albumin. Significant concen- be switched to a nonbeta-lactam class negative infections, especially bactere- trations are achieved in the , bile, of antibiotics due to the risk of cross- mias, pneumonias, burn wound infec- , semen, synovial fluid, and intes- sensitization with other penicillins and tions, and urinary tract infections tine. Penicillin G does not enter the . caused by organisms resistant to ampi- cerebrospinal fluid (CSF) readily when Nafcillin, administered IM or IV, also cillin and penicillin G (P aeruginosa, meninges are normal. In the presence of is active against sensitive strains of S indole-positive strains of Proteus, and meningeal inflammation, penicillin aureus and S epidermidis. It is one of Enterobacter sp). concentrations up to 5% of plasma the only penicillins excreted primarily The antibacterial spectra of anti- concentration can be found in the CSF, by hepatic metabolism; thus, dose ad- pseudomonal penicillins and amin- which are therapeutically effective justment is not required in renal failure. openicillins can be broadened by com- against susceptible organisms. In addi- Tissue penetration of nafcillin is similar bining them with beta-lactamase tion to its therapeutic spectrum, peni- to that of other penicillinase-resistant inhibitors. , originally cillin G is effective for prophylaxis in penicillins, and it achieves therapeutic isolated from the mold Streptomyces certain clinical settings, including: IM levels in the CSF for treatment of clavuligerus, also contains a beta- benzathine penicillin G for a contact staphylococcal meningitis. Nafcillin in lactam ring, but unlike the penicillins who has syphilis, oral penicillin V or the urine can cause a false-positive and cephalosporins, the beta-lactam

472 Pediatrics in Review Vol.27 No.12 December 2006 in brief

ring of clavulanic acid has a low level of clavulanic acid and ticarcillin/ the amoxicillin component) in two di- antibacterial activity. However, clavu- clavulanic acid. Current pediatric vided doses. Clavulanic acid does not lanic acid is a potent inhibitor of beta- suspensions of amoxicillin/clavulanic change the of amoxi- lactamases produced by Klebsiella acid are available in a 7:1 ratio. The cillin; it achieves adequate concentra- pneumoniae, Proteus mirabilis, P vul- initial preparation of amoxicillin to cla- tions in peritoneal and pleural fluid, garis, B fragilis, S aureus, Haemophilus vulanic acid in a 4:1 ratio no longer is pus, lymph nodes, and infected tissues, influenzae, and anaerobes. The beta- recommended. A more recent prepara- but not in normal or infected CSF. lactamases produced by Morganella mor- tion has an amoxicillin/clavulanic acid Other combinations of beta-lactam gagnii, Serratia marcescens, Enterobacter ratio of 14:1; the lower dose of clavu- antibiotics with beta-lactamase inhibi- sp, and P aeruginosa are poorly inhibited lanic acid is associated with fewer gas- tors include ampicillin/ and by clavulanate. trointestinal adverse effects. The daily pipercillin/, both of which are The commercially available prepara- dose of amoxicillin/clavulanic acid for available only in preparations designed tions of clavulanic acid are amoxicillin/ children is 45 to 90 mg/kg per day (of for IV administration.

In Brief

Abnormalities in Head Size Oscar H. Purugganan, MD, MPH Neurology: A Signs and Symptoms is associated with some degree of neu- Children’s Evaluation & Rehabilitation Approach. Philadelphia, Pa: Elsevier rologic impairment. Measurements are Center Saunders; 2005:353–369 plotted on standardized charts. The lat- Perspectives on Craniosynostosis. Cohen Albert Einstein College of Medicine est Centers for Disease Control and M. Am J Med Genet. 2005;136A: Bronx, NY 313–326 Prevention growth charts feature Molecular Genetics of Human Micro- curves for 3rd and 97th percentiles, cephaly. Mochida GH, Walsh CA. which are important cut-offs in the Author Disclosure Curr Opin Neurol. 2001;14:151–156 measurement of head circumference. Drs Purugganan and Adam did not The Infant Skull: A Vault of Informa- Special charts are available for children disclose any financial relationships tion. Glass RBJ, Fernbach SK, Norton who have conditions associated with KI, Choi PS, Naidich TP. Radiograph- relevant to this In Brief. disturbances in growth, such as Down ics. 2004;24:507–522 Smith’s Recognizable Patterns of Hu- syndrome, Williams syndrome, and man Malformation. Jones KL. 6th ed. achondroplasia. There also are charts Online Mendelian Inheritance in Man, Philadelphia, Pa: Elsevier Saunders; for very low-birthweight infants. The OMIM™. McKusick-Nathans Institute 2006 head circumferences of preterm infants for Genetic Medicine, Johns Hopkins are adjusted for prematurity until about University (Baltimore, Md) and National Center for Biotechnology Measuring the head circumference is 2 years of age. For children older than 3 Information, National Library of an important element of the pediatric years, head circumferences generally Medicine (Bethesda, Md), 2000. physical examination, especially in the are plotted on the growth curves devel- Available at: http://www.ncbi.nlm. first 3 years after birth, when brain oped by Nellhaus, which are based on nih.gov/omim/ growth is maximal. A series of mea- composite international standards. The CDC Growth Charts: United States. surements over time is more instructive average head size at birth for boys in Kuczmarski RJ, Ogden CL, Grummer- than a single measurement, which can, the United States is about 36 cm and Strawn LM, et al. Advance Data from however, still provide useful informa- for girls is about 35 cm. Vital and Health Statistics. No. 314. Microcephaly refers to a head size Hyattsville, Md: National Center for tion. For example, an abnormal head Health Statistics; 2000. Available at: circumference at birth is a clue to an that is 2 standard deviations (approxi- http://www.cdc.gov/growthcharts early prenatal effect. A head circumfer- mately 3rd percentile) below the mean, Disorders of Cranial Volume and Shape. ence more than 3 standard deviations based on age and sex. Whereas micro- In: Fenichel GM. Clinical Pediatric below or above the mean almost always cephaly means a small head, micren-

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