To date, S pyogenes has remained universally susceptible to penicillin. Therefore, penicillin remains the first-line drug of choice for pharyngeal infections, as well as for complicated or invasive infections.
European surveillance in Italy found that 32% of group A streptococcal isolates exhibited resistance to macrolides. France has reported a steady escalation of erythromycin resistance in group A streptococci (GAS), reaching 23% to date. Portugal identified 11% of GAS isolates as resistant to macrolides. Resistance in other European countries during the 1990s fell between 1% and 7%. 
Invasive GAS isolates were tested for fluoroquinolone susceptibility from 1992-1993 and in 2003 in Ontario, Canada. All isolates were susceptible to levofloxacin. Two of 153 (1.3%) in 1992-1993 and 7 of 160 (4.4%) in 2003 had a levofloxacin minimal inhibitory concentration (MIC) of 2 µg/mL; all 9 had parC mutations, and 8 were serotype M6.
Between October 2003 and September 2006, 482 GAS strains were collected from 45 medical institutions in various parts of Japan. Susceptibility of GAS strains to 8 beta-lactam agents was excellent, with MICs of 0.0005-0.063 µg/mL–1. Macrolide-resistant strains accounted for 16.2% of all strains. Although no strains with high resistance to levofloxacin were found, strains with an MIC of 2-4 µg/mL–1 (17.4%) with intermediate susceptibility were observed. 
In 2006, of 50 GAS isolates examined with antibiotic susceptibility tests, 100% were found to be susceptible to penicillin, ampicillin, cefotaxime, cefazolin, and vancomycin. Eight isolates (16%) exhibited some level of antibiotic resistance. Six were resistant to erythromycin alone, and 2 were resistant to erythromycin and clindamycin (the first clindamycin-resistant isolates reported since 1999). 
Therapy should cover all likely pathogens in the context of clinical settings. Antibiotic selection should be guided by blood culture sensitivity, whenever feasible.
Natural penicillins have good activity against S pyogenes. Various forms of natural penicillins are used for various diseases caused by GAS. The recommendation for S pyogenes pharyngitis in adults is a single intramuscular (IM) dose of benzathine penicillin G 1.2 million units or penicillin V 500 mg PO BID for 10 days. For S pyogenes necrotizing fasciitis in adults, IV penicillin G (up to 24 million units daily in divided doses q4-6h) is recommended.
Penicillin VK is a drug of choice for GAS pharyngitis. It inhibits the biosynthesis of cell-wall mucopeptides. This agent elicits bactericidal effects against sensitive organisms when adequate concentrations are reached and is most effective during the stage of active multiplication.
Amoxicillin is a drug of choice for GAS pharyngitis. It is a derivative of ampicillin and has a similar antibacterial spectrum. With a bactericidal action comparable to penicillin, amoxicillin acts on susceptible bacteria during the multiplication stage by inhibiting cell-wall mucopeptide biosynthesis. It has superior bioavailability and stability to gastric acid and has a broader spectrum of activity than penicillin.
Penicillin G benzathine interferes with the synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. If noncompliance with oral therapy seems likely, parenteral therapy is indicated.
The formulation is painful when administered intramuscularly, and it is often combined with penicillin G procaine to minimize discomfort at the injection site. When this combination is used in a single injection, take care to ensure that an adequate amount of penicillin G benzathine is administered. The combination of 900,000U of penicillin G benzathine and 300,000 U of penicillin G procaine is satisfactory for most children.
Erythromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
In children, age, weight, and the severity of infection determine proper dosage. When twice-daily dosing is desired, the half-total daily dose may be taken every 12 hours. For more severe infections, double the dose.
Oral erythromycin is an acceptable alternative for patients who are allergic to penicillin or cephalosporin antibiotics and is effective in the treatment of streptococcal pharyngitis. Re-emerging macrolide resistance must be considered. Of 708 GAS isolates tested for susceptibility to erythromycin and clindamycin, performed for all pharyngeal GAS isolates recovered at the Children's Hospital of Pittsburgh and a local pediatric practice between September 2001 and May 2002, 68 (9.6%) were macrolide resistant, while all isolates were sensitive to clindamycin. Erythromycin is associated with substantially higher rates of GI side effects compared with other macrolides. Strains of GAS resistant to macrolides have been highly prevalent in some areas of the world and have resulted in treatment failures.
Clarithromycin inhibits bacterial growth, possibly by binding to 50S ribosomal unit, causing RNA-dependent protein synthesis to arrest. It has a similar susceptibility profile to erythromycin, but clarithromycin has fewer adverse effects.
Azithromycin has a similar susceptibility profile to erythromycin, but it has fewer adverse effects. This agent treats mild to moderate microbial infections. Binds to the 50S ribosomal subunit where it blocks transpeptidation.
Cephalexin, a first-generation cephalosporin, arrests bacterial growth by inhibiting bacterial cell wall synthesis. It has bactericidal activity against rapidly growing organisms. The drug's primary activity is against skin flora; cephalexin is used for skin infections and for prophylaxis in minor procedures. Oral cephalosporins are effective in the treatment of streptococcal pharyngitis.
Short-course regimens of oral cephalosporin therapy have been studied and offer obvious advantages from a compliance perspective. However, this must be balanced against the higher cost and unnecessarily broad spectrum of these agents.
Cefadroxil is a first-generation semi-synthetic cephalosporin that arrests bacterial growth by inhibiting bacterial cell wall synthesis. It may be considered for GAS pharyngitis in patients allergic to penicillin (without immediate-type hypersensitivity).
Clindamycin is a lincosamide for the treatment of serious skin and soft-tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci). Clindamycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer ribonucleic acid (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. Patients with invasive GAS infections (eg, necrotizing fasciitis, TSS, sepsis) should be treated with IV penicillin in combination with clindamycin. Because the pathophysiology of invasive GAS infection is largely toxin mediated, the use of a protein synthesis inhibitor (eg, clindamycin) offers a theoretical advantage.
Furthermore, in vivo evidence of the lack of efficacy of penicillin in deep-tissue infections has been observed in animal models. This effect, first described by Eagle in 1952, appears to occur because of the high inoculum of organisms encountered in overwhelming infections (eg, necrotizing fasciitis, myositis, sepsis).
Large concentrations of organisms lead to the rapid attainment of the stationary growth phase, which is associated with decreased expression of cell wall penicillin-binding proteins (PBPs), the molecular targets of penicillin. Decreased expression of PBPs in deep-tissue infections with GAS appears to render penicillin less effective. In contrast, clindamycin retains efficacy. Vigorous supportive care, including fluids, pressors, and mechanical ventilation, is also a critical aspect of management of invasive streptococcal skin and soft-tissue infections. Prompt surgical drainage, débridement, fasciotomy, or amputation may be indicated.
Differentiating a streptococcal carrier with recurrent viral infection from a child with recurrent streptococcal pharyngitis may be difficult. Although most streptococcal carriers do not require medical intervention, situations arise in which eradication of the carrier state is desirable (eg, families in with an inordinate amount of anxiety about streptococci, families in which ping-pong spread has been occurring, situations in which tonsillectomy is considered only because of chronic carriage). A course of clindamycin has been shown to be highly effective in eradicating the carrier state and should be tried in patients with recurrent or frequent episodes of culture-proven pharyngitis.
Some children with recurrent streptococcal pharyngitis (7 culture-proven episodes in the preceding year) may benefit from tonsillectomy.
Vancomycin acts by inhibiting proper cell wall synthesis in gram-positive bacteria. It is indicated for the treatment of serious infections caused by beta-lactam–resistant organisms and in patients who have serious allergies to beta-lactam antimicrobials.
Oritavancin is lipoglycopeptide antibiotic that inhibits cell wall biosynthesis and disrupts bacterial membrane integrity that leads to cell death. It is indicated for treatment of acute bacterial skin and skin structure infections caused by gram-positive bacteria including S aureus (including methicillin-susceptible S aureus and MRSA), S pyogenes, S agalactiae, S dysgalactiae, S anginosus group (S anginosus, S intermedius, S constellatus) and E faecalis (vancomycin-susceptible isolates only).
Dalbavancin is lipoglycopeptide antibiotic that prevents cross-linking by interfering with cell wall synthesis. It is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations observed in humans at recommended doses. It is indicated for treatment of acute bacterial skin and skin structure infections caused by Gram-positive bacteria including Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant S aureus [MRSA]), S pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S anginosus, S intermedius, S constellatus).
Tedizolid is an oxazolidinone antibiotic indicated for skin and skin structure infections caused by susceptible isolates of Gram-positive bacteria including Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, S agalactiae, S anginosus Group (including S anginosus, S intermedius, and S constellatus), and Enterococcus faecalis. Its action is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis.
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