Treatment Strategies

Antimicrobial Therapy for ¡-Streptococcal Disease

Superficial Disease

¡-Haemolytic streptococci have remained exquisitely sensitive to penicillin. It is normal to give 10 days of treatment with penicillin V to fully treat streptococcal pharyngitis and prevent RF, although there is some preliminary evidence to suggest that 5 days of azithromycin will suffice (Bisno etal. 2002). Up to 30% of streptococcal sore throats treated with penicillin may relapse, possibly because of the internalisation of bacteria into buccal or tonsillar epithelial cells (Sela etal. 2000; Kaplan and Johnson 2001). Macrolides have a theoretical advantage over P-lactams because of intracellular penetration. Such compounds may afford the best eradication rate. Although macrolides have traditionally been considered as alternatives to P-lactams in patients with penicillin allergy, it is noteworthy that up to 45% of GAS isolates are reported to be resistant to macrolides in certain European countries. In the United Kingdom the incidence of erythromycin resistance is lower, at around 5-10%.

For impetigo initial empiric oral systemic treatment directed against both S. aureus and S. pyogenes (e.g. flucloxacillin) is normally combined with agents to clear carriage of the organisms. Notably, the use of topical fusidic acid may be of little benefit, as only approximately half of GAS are sensitive to this drug, and many S. aureus strains are now demonstrating fusidin resistance.

Invasive ¡P-Haemolytic Disease

For invasive P-haemolytic disease intravenous treatment with penicillin (or ceftriaxone) is mandatory, at least until an initial response is observed. Most authorities now recommend the use of clindamycin alongside penicillin, because it has been shown to improve outcome both in animal models of invasive streptococcal disease and in clinical studies (Stevens etal. 1988; Stevens, Bryant and Yan 1994; Zimbelman, Palmer and Todd 1999). Clindamycin appears to inhibit the synthesis or release of many streptococcal virulence factors such as superantigen toxins and cell-wall components (Gemmell etal. 1981; Brook, Gober and Leyva 1995; Sriskandan etal. 1997).

In some cases of invasive GBS disease an aminoglycoside is added to ¡-lactam therapy for the first 2 weeks. This is particularly true for neonatal GBS disease.

Surgery for ¡-Streptococcal Disease

In addition to appropriate antibiotic therapy it is essential that cases of invasive disease be examined for evidence of tissue necrosis or gangrene. This may present subtly, and many cases will require surgical exploration. All necrotic tissue must be removed promptly, and reexploration at daily intervals may be necessary (Stamenkovic and Lew 1984; Heitmann etal. 2001). Early liaison with plastic surgery specialists can facilitate appropriate debridement. Following extensive surgery the patient remains at risk of nosocomial infection.

Immunological Therapies

Intravenous immunoglobulin (IVIG) is recommended as an adjunct to treatment of severe invasive GAS infection, in particular those cases complicated by STSS. Although there are no controlled trials to support its use in treatment, anecdotal reports and a retrospective clinical study suggest that there are some benefits (Lamothe etal. 1995; Kaul et al. 1999). A European clinical trial was abandoned because of difficulties in patient recruitment, though initial responses were promising (Darenberg etal. 2003). Although the cost of the proposed doses of IVIG is likely to be high, surprisingly there are no preclinical studies that have yet demonstrated the efficacy of IVIG.

There are many mechanisms that may explain the apparent efficacy of IVIG. Firstly, IVIG-mediated neutralisation of superantigenic toxins leads to recovery from STSS, and secondly, it has been shown that IVIG can assist in the opsonisation of GAS in nonimmune hosts (Skansen-Saphir etal. 1994; Norrby-Teglund etal. 1996; Basma etal. 1998). Of course, IVIG is likely to contain an abundance of polyclonal antistreptococcal antibodies, including antibodies to a wide range of secreted virulence factors, which may be of importance in disease progression.

Phage Therapy

Although antibiotic resistance has not yet affected therapy for P-haemolytic streptococcal disease substantially, the identification of novel compounds that can specifically target pathogens is welcome. Recently, purified recombinant phage lytic enzymes (lysins) have been demonstrated to have excellent rapid bactericidal activity. Although not developed to a degree that would allow systemic use, phage lytic enzyme has been recently used to successfully eradicate pharyngeal carriage of S. pyogenes (Nelson, Loomis and Fischetti 2001).

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