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Oral cephalosporins, such as cefuroxime (Ceftin), may be used in children who are allergic to penicillin. Recent research indicates that the degree of cross reactivity between penicillin and second- and third-generation cephalosporins is low (less than 10% to 15%), and avoidance is no longer recommended.25 Because of their broad-spectrum coverage, third-generation cephalosporins in particular may have an increased risk of selection of resistant bacteria in the community.26 High-dose azithromycin (Zithromax; 30 mg per kg, single dose) appears to be more effective than the commonly used five-day course, and has a similar cure rate as high-dose amoxicillin/clavulanate.8 , 27 , 28 However, excessive use of azithromycin is associated with increased resistance, and routine use is not recommended.8 Trimethoprim/sulfamethoxazole is no longer effective for the treatment of AOM due to evidence of S. Intramuscular or intravenous ceftriaxone (Rocephin) should be reserved for episodes of treatment failure or when a serious comorbid bacterial infection is suspected.2 One dose of ceftriaxone may be used in children who cannot tolerate oral antibiotics because it has been shown to have similar effectiveness as high-dose amoxicillin.30 , 31 A three-day course of ceftriaxone is superior to a one-day course in the treatment of nonresponsive AOM caused by penicillin-resistant S. pneumoniae .31 Although some children will likely benefit from intramuscular ceftriaxone, overuse of this agent may significantly increase high-level penicillin resistance in the community.2 High-level penicillin-resistant pneumococci are also resistant to first- and third-generation cephalosporins. Antibiotic therapy for AOM is often associated with diarrhea.8 , 10 , 32 Probiotics and yogurts containing active cultures reduce the incidence of diarrhea and should be suggested for children receiving antibiotics for AOM.32 There is no compelling evidence to support the use of complementary and alternative treatments in AOM.8. Children with persistent, significant AOM symptoms despite at least 48 to 72 hours of antibiotic therapy should be reexamined.8 If a bulging, inflamed tympanic membrane is observed, therapy should be changed to a second-line agent.2 For children initially on amoxicillin, high-dose amoxicillin/clavulanate is recommended.8 , 10 , 28. For children with an amoxicillin allergy who do not improve with an oral cephalosporin, intramuscular ceftriaxone, clindamycin, or tympanocentesis may be considered.4 , 8 If symptoms recur more than one month after the initial diagnosis of AOM, a new and unrelated episode of AOM should be assumed.10 For children with recurrent AOM (i.e., three or more episodes in six months, or four episodes within 12 months with at least one episode during the preceding six months) with middle ear effusion, tympanostomy tubes may be considered to reduce the need for systemic antibiotics in favor of observation, or topical antibiotics for tube otorrhea.8 , 10 However, tympanostomy tubes may increase the risk of long-term tympanic membrane abnormalities and reduced hearing compared with medical therapy.33 Other strategies may help prevent recurrence (Table 4) .34 – 37. Check for undiagnosed allergies leading to chronic rhinorrhea. In 1929, Alexander Fleming isolated penicillin from a strain of Penicillium notatum  (84). By 1941, benzylpenicillin could be produced in sufficient quantity to treat several infected patients. Clinical trials with the agent, conducted by Florey and colleagues, were successful and during World War II, benzylpenicillin was used to treat patients with streptococcal, gonococcal, and treponemal infections. Shortages of the agent continued until the late 1940s when production of large amounts of drug became possible by a deep-fermentation procedure (85). Since then, many synthetic penicillins have been developed, but resistance to the agents has increased. Despite the emergence of resistance to penicillins and the development of other classes of anti-infective agents, the penicillins remain one of the most important anti-infective classes of drugs well into the nineties. In fact, penicillin G is still the drug of choice for many types of infections, including syphilis and certain types of endocarditis. Chemical Structure (Figure 1) The basic chemical structure of all penicillins consists of a beta-lactam ring, a thiazolidine ring, and a side chain (6-aminopenicillanic acid). The antibacterial activity of the penicillins lies within the beta-lactam ring. Any alteration in this ring structure forms penicilloic acid and the antibacterial activity of the compound is lost. The side chain varies with each penicillin compound and generally determines the spectrum of activity, as well as the pharmacokinetic properties of the compound. There are several natural penicillins (penicillin dihydro F, X, and K), of which benzylpenicillin (penicillin G) is the most active and is the only natural penicillin used clinically (164). Manipulations of the side chain have produced compounds that are stable against certain bacteria, such as Staphylococcus aureus , which produce beta-lactamase enzymes (penicillinase). The side chain sterically inhibits the beta-lactamase hydrolysis of the beta-lactam ring. Other penicillin compounds have side chains, which are stable against beta-lactamases produced by gram-negative rods. Side chain changes can also increase the bacterial permeability of the compound and can result in increased oral absorption from the intestinal tract by rendering oral agents more stable to gastric acid breakdown (167, 186). Classification of Penicillins and Spectrum of Activity. The penicillin compounds can be divided into categories based upon their spectrum of activity ( Table 1). Minimum inhibitory concentration ( MIC) data for 50% and 90% of specific organisms are located in Tables 2 and 3 (10, 70, 150, 228, 245, 255, 257, 261). For gram-negative organisms and anaerobes, resistance in up to 15% of strains is possible; therefore MIC90s must be interpreted cautiously. Penicillin G is a natural penicillin that is produced directly from fermentation of Penicillium crysogenum . Penicillin V is a derivative of penicillin G and because of similarities in spectrum of activity, is considered a natural penicillin. The natural penicillins have activity against non-beta-lactamase producing gram-positive cocci, including viridans streptococci, group A streptococci, Streptococcus pneumoniae , and anaerobic streptococcus ( Peptostreptococcus , Peptococcus  sp.). Enterococcus  sp. Other potential organisms with susceptibility include non-penicillinase producing strains of Staphylococcus aureus  and coagulase-negative Staphylococcus , however because of the high likelihood of resistance, it is inappropriate to use natural penicillins as empiric treatment for a suspected Staphylococcal  infection unless the organism’s susceptibility is known. The natural penicillins have activity against Clostridium sp. (excluding Clostridium difficile ) and Actinomyces  sp. Activity against gram-negative cocci is limited and includes Neisseria meningitidis , non- penicillinase producing Neisseria gonorrheae , and Pasteurella multocida . Similar to staphylococcal  infection, natural penicillins should not be used for treatment of gonorrhea due to the increased potential of a resistant organism and subsequent treatment failure. The anaerobic coverage of penicillin V is less than that of penicillin G. Natural penicillins also have excellent activity against the spirochete, Treponema pallidum , the causative organism of syphilis. The agents in this group are also known as the antistaphylococcal penicillins. The addition of an isoxazolyl side chain to the penicillin compound protects the beta-lactam ring from acid hydrolysis by penicillinases produced by Staphylococcus  sp. Methicillin, the first agent synthesized in this group, is rarely used currently due to a higher incidence of occurrence of interstitial nephritis and is no longer commercially available in the United States. Nafcillin and oxacillin are the agents commonly used parenterally, while dicloxacillin is available for oral use. These agents have activity against Staphylococcus  sp (including penicillinase-producing strains). Strains of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus  epidermidis  (MRSE) exist and can be the prevalent Staphylococcal  organism in certain areas, such as certain hospitals or wards within the hospital. These organisms are not sensitive to the penicillinase-resistant penicillins. as compared to the natural penicillins, based on MIC data, use of the penicillinase-resistant penicillins is acceptable (i.e. the MICs are low enough relative to achievable serum concentrations) for use against these organisms. Clinically, in serious, life-threatening infections where a gram-positive organism is suspected, combinations of penicillin G plus a penicillinase-resistant penicillin can be utilized to achieve maximal streptococcal and staphylococcal  coverage. A notable exception to the gram-positive coverage of this class of penicillins is the Enterococci.
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