Staphylococcal skin infections in children: rational drug therapy recommendations

Staphylococcus aureus remains one of the most common and troublesome of bacteria causing disease in humans, despite the development of effective antibacterials and improvement in hygiene. The organism is responsible for over 70% of all skin and soft tissue infections in children and accounts for up to one-fifth of all visits to pediatric clinics. Skin and soft tissue infections that are predominantly caused by S. aureus include bullous and non-bullous impetigo, folliculitis, furunculosis, carbunculosis, cellulitis, surgical and traumatic wound infections, mastitis, and neonatal omphalitis. Other skin and soft tissue infections may also be caused by S. aureus but are often polymicrobial in origin and require special consideration. These include burns, decubitus ulcers (particularly in the perianal region), puncture wounds of the foot, as well as human and mammalian bites. Treatment of staphylococcal skin infections varies from topical antiseptics to prolonged intravenous antibacterials, depending on severity of the lesions and the health of the child. The treatment of choice for oral antibacterials remains the penicillinase-resistant penicillins such as flucloxacillin. Cefalexin and erythromycin are suitable cost-effective alternatives with broader cover, although care must be taken with the use of macrolides because of development of resistance to multiple families of antibacterials, particularly the lincosamides. Other cephalosporins such as cefadroxil and cefprozil are also effective, can be given once daily and have a better tolerability profile -- while azithromycin has a further advantage of a 3-day course. However, all of these agents are more expensive. Although the antibacterials have been given for 10 days in most clinical trials, there is no evidence that this duration is more effective than a 7-day course. In children requiring intravenous therapy, ceftriaxone has a major advantage over other antibacterials such as sulbactam/ampicillin and cefuroxime in that it can be given once daily and may, therefore, be suitable for outpatient treatment of moderate-to-severe skin infections. Newer-generation cephalosporins and loracarbef are also effective and have a broader spectrum of activity, but do not offer any added benefit and are significantly more expensive. Skin and soft tissue infections due to methicillin-resistant S. aureus (MRSA) are still relatively uncommon in children. Well children with community-acquired MRSA infections can be treated with clindamycin or trimethoprim-sulfamethoxazole (cotrimoxazole), but must be observed closely for potentially severe adverse effects. In severe infections, vancomycin remains the treatment of choice, while intravenous teicoplanin and clindamycin are suitable alternatives. Linezolid and quinupristin/dalfopristin are currently showing great promise for the treatment of multi-resistant Gram-positive infections. While the choice of antibacterial is important, supportive management, including removal of any infected foreign bodies, surgical drainage of walled-off lesions, and regular wound cleaning, play a vital role in ensuring cure.     

A practical guide to the treatment of complicated skin and soft tissue infections

Complicated skin and soft tissue infections (SSTIs) remain a common reason for hospitalisation. Optimal management of complicated SSTIs begins with a physical examination, and obtaining the complete social and medical history of the patient. Empirical intravenous antibacterial therapy is guided by expected pathogens, patient factors and diagnostic procedure reports, such as the Gram-stained smear of discharge or exudates. The majority of community-acquired SSTIs are caused by Staphylococcus aureus and beta-haemolytic streptococci. On the basis of recent surveillance data, 80-90% of these pathogens remain susceptible to cefazolin or oxacillin. Consequently, a first generation cephalosporin or an antistaphylococcal penicillin remains the first line empirical therapy for community-acquired skin and soft tissue infections. Vancomycin may be an appropriate alternative when vancomycin-resistant S. aureus is highly suspected on the basis of patient history and co-morbid conditions. With the global emergence and spread of macrolide-resistant S. aureus and beta-haemolytic streptococci, clindamycin rather than a macrolide is the recommended agent for empirical antibacterial therapy of community-acquired SSTIs in penicillin-allergic patients. Nosocomial complicated SSTIs are predominantly caused by S. aureus, Pseudomonas aeruginosa, Enterococcus spp., Escherichia coli and other Enterobacteriaceae. Piperacillin/tazobactam with or without vancomycin is the preferred agent for empirical treatment depending on local resistance statistics. The newer fluoroquinolones may have a role in the treatment of complicated SSTIs, especially in penicillin-allergic patients. More clinical studies are needed before a formal recommendation can be made. Many of the newer antimicrobial agents such as the carbapenems, oxazolidinones and streptogramins have been shown to be effective for the treatment of complicated SSTIs. However, because of their proven activity against highly resistant organisms including methicillin-resistant S. aureus and vancomycin-resistant enterococci (oxazolidinones and streptogramins), and Gram-negative bacilli producing extended spectrum beta-lactamases (carbapenems), these antibacterials should be reserved for life-threatening situations and/or when resistant pathogens are suspected. Complicated skin and soft tissue infections are often associated with exudates, ulcerations, fluid collections or abscesses. Adequate debridement of devitalized tissues and drainage of abscesses and fluid collections in addition to systemic antibacterial therapy is an integral part of appropriate management.     

Daptomycin: a review of its use in the management of complicated skin and soft-tissue infections and Staphylococcus aureus bacteraemia

Daptomycin (Cubicin) is the first of a new class of antibacterials, the cyclic lipopeptides, and is approved for use in the treatment of complicated skin and soft-tissue or skin-structure infections (hereafter referred to as cSSTI) caused by Gram-positive bacteria and Staphylococcus aureus bacteraemia including right-sided infective endocarditis.Daptomycin has activity in vitro against a wide variety of Gram-positive bacteria, including meticillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci.When administered as a once-daily intravenous infusion, daptomycin was not inferior to standard parenteral therapy (vancomycin or semi-synthetic penicillins) in terms of clinical and microbiological efficacy in patients with cSSTI or S. aureus bacteraemia with or without infective endocarditis (including MRSA infection) and was well tolerated.With the advantage of once-daily administration and a low potential for drug interactions, daptomycin is a useful addition to the range of parenteral antibacterial agents available for the treatment of patients with cSSTI or S. aureus bacteraemia with or without right-sided infective endocarditis. Efficacy against both meticillin-susceptible S. aureus (MSSA) and MRSA infections makes daptomycin suitable for empirical therapy in patients with serious Gram-positive infections.     

Antibiotic resistance in Staphylococcus aureus and its relevance in therapy

Staphylococcus aureus is a major cause of infections. Only approximately 20% of the strains remain sensitive to penicillin. Beta-lactamase stable penicillins such as flucloxacillin form the mainstay of treatment of staphylococcal infection. Meticillin-resistant S. aureus (MRSA) are resistant to all beta-lactam antibiotics. Glycopeptide antibiotics are effective against most MRSA strains but, in the last few years, isolates of MRSA that have reduced susceptibility to glycopeptides (glycopeptide-intermediate S. aureus) have been isolated. Some strains exhibit frank resistance to glycopeptides (vancomycin-resistant S. aureus). Infections due to these strains are difficult to treat. This review summarises the therapeutic options for MRSA, glycopeptide-intermediate S. aureus and vancomycin-resistant S. aureus. Novel therapeutic strategies such as immunotherapy and vaccines are also discussed.     

Peritoneal dialysis. Prevention and control of infection

In spite of the reduction in peritonitis and catheter-related infection rates in patients undergoing peritoneal dialysis, these infections remain major sources of morbidity and transfer to haemodialysis. Touch contamination at the time of doing the exchanges is still a major cause of peritonitis and leads to Gram-positive organisms (coagulation-negative staphylococcus) being the most common pathogens. Newer exchange techniques have reduced this incidence but the more serious pathogens (Staphylococcal aureus, pseudomonas and fungi) remain a major problem. Treatment has to be immediate, and hence empirical, giving adequate cover for both Gram-positive and Gram-negative organisms. The use of vancomycin as an initial antibacterial has been discontinued because of the problem of vancomycin-resistant enterococcus. Recent guidelines advocate the use of a first generation cephalosporin combined with ceftazidime (if the urine output is >100 ml/day) or an aminoglycoside in anuric patients. Subsequent therapy changes are made upon bacterial isolation and sensitivities. Vancomycin is reserved for methicillin-resistant staphylococcus. Peritoneal catheter-related infections (exit site and tunnel) are predominantly caused by S. aureus and pseudomonal organisms and can be difficult to eradicate. Tunnel infections invariably involve the catheter dacron cuffs and therefore are more likely to lead to peritonitis; in this situation catheter removal is the treatment of choice. Treatment of exit-site infections is with oral antibacterials (penicillinase-resistant penicillins, cefalexin). Vancomycin is avoided if possible. The identification that nasal carriage of S. aureus predisposes to exit-site and tunnel infections has led to prophylactic regimens to combat this problem. Mupirocin applied at the exit site leads to a reduction in catheter-related infections and peritonitis.     

Telavancin: a novel lipoglycopeptide for serious gram-positive infections

Telavancin, a once-daily dosing lipoglycopeptide derived from vancomycin, has a broad-spectrum microbiologic activity against gram-positive bacteria, including vancomycin-resistant staphylococci. Telavancin displays a dual mode of action and a rapid bactericidal killing. The in vitro activity of telavancin is superior to vancomycin and comparable with, or greater than, linezolid, daptomycin and other novel lipoglycopeptides. Telavancin is effective against gram-positive pathogens in animal models of soft tissue infections and deep-seated infections including endocarditis, pneumonia and bacteremia. Clinical experience with telavancin in Phase II and III studies for complicated skin and skin structure infections have demonstrated similar efficacy and tolerability compared with standard anti-staphylococcal beta-lactams and vancomycin. Telavancin is in Phase III studies for nosocomial pneumonia. Telavancin seems to be promising as a novel agent for empiric therapy or as an alternative agent in serious infections caused by clinically important resistant gram-positive pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin intermediate-susceptible S. aureus, vancomycin-resistant S. aureus and vancomycin-resistant enterococci.     

Investigational new drugs for the treatment of resistant pneumococcal infections

Antibiotic resistance in Streptococcus pneumoniae is not only increasing with penicillin but also with other antimicrobial classes including the macrolides, tetracyclines and sulfonamides. This trend with antibiotic resistance has highlighted the need for the further development of new anti-infectives for the treatment of pneumococcal infections, particularly against multi-drug resistant pneumococci. Several new drugs with anti-pneumococcal activity are at various stages of development and will be discussed in this review. Two new cephalosporins with activity against S. pneumoniae include ceftobiprole and RWJ-54428. Faropenem is in a new class of beta-lactam antibiotics called the penems. Structurally, the penems are a hybrid between the penicillins and cephalosporins. Sitafloxacin and garenoxacin are two new quinolones that are likely to have a role in treating pneumococcal infections. Oritavancin and dalbavancin are glycopeptides with activity against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus spp. as well as multi-drug resistant pneumococci. Tigecycline is the first drug in a new class of anti-infectives called the glycycyclines that has activity against penicillin-resistant pneumococci.     

Treatment strategies for methicillin-resistant Staphylococcus aureus infections in pediatrics

Staphylococcus aureus is an important pathogen that frequently causes clinical disease in children. A wide array of illnesses can be caused by this common pathogen ranging from non-invasive skin infections to severe, life-threatening sepsis. Additionally, as antibacterials have been used to eradicate S. aureus, it has developed resistance to these important therapeutic agents. Methicillin-resistant S. aureus (MRSA) has become an increasing problem in pediatric patients over the past decade. In this review, we discuss the epidemiology, pathogenesis, and treatment options available in treating MRSA infections in children. Specifically, we address the importance of abscess drainage in the treatment of skin and soft tissue infections, the most common clinical manifestation of MRSA infections, and highlight the various agents that are available for treating this common infection. In severe, life-threatening invasive MRSA infections the primary therapeutic option is vancomycin. In cases of MRSA toxic shock syndrome the addition of clindamycin is necessary. In other invasive MRSA infections, such as pneumonia and musculoskeletal infections, the empiric treatment of choice is clindamycin. Finally, newer agents and additional treatment options are discussed.     

Retapamulin: an antibacterial with a novel mode of action in an age of emerging resistance to Staphylococcus aureus

Staphylococcus aureus (S. aureus) is the leading cause of nosocomial infections and responsible for more than 11 million skin and soft tissue infections annually. Impetigo is a common skin infection and the most common bacterial skin infection in children aged two to five years. The emergence of S. aureus isolates resistant to commonly utilized antibacterials for skin infections (beta-lactams, erythromycin, fluoroquinolones and mupirocin) makes successful treatment an ongoing challenge. To treat skin infections such as impetigo, antibacterials with a short dosing schedule and low propensity to develop resistance should be used. In 2007, retapamulin was the first agent for human use approved in the pleuromutilin class of antibacterials in the United States (U.S.), and is the first topical antibacterial indicated to treat impetigo in over 20 years. In vitro, retapamulin is highly potent against S. aureus and has a lower propensity to develop resistance than mupirocin. In clinical studies, the convenient five-day b.i.d. (twice-daily) dosing of retapamulin is highly effective against impetigo due to methicillin- susceptible S. aureus and Streptococcus pyogenes and may play an important role in limiting the development of resistance against systemic agents.     

Drug treatment of pneumococcal pneumonia in the elderly

Streptococcus pneumoniae has been recognised as a major cause of pneumonia since the time of Sir William Osler. Drug-resistant S. pneumoniae (DRSP), which have gradually become resistant to penicillins as well as more recently developed macrolides and fluoroquinolones, have emerged as a consequence of indiscriminate use of antibacterials coupled with the ability of the pneumococcus to adapt to a changing antibacterial milieu. Pneumococci use cell wall choline components to bind platelet-activating factor receptors, colonise mucosal surfaces and evade innate immune defenses. Numerous virulence factors that include hyaluronidase, neuraminidase, iron-binding proteins, pneumolysin and autolysin then facilitate cytolysis of host cells and allow tissue invasion and bloodstream dissemination. Changes in pneumococcal cell wall penicillin-binding proteins account for resistance to penicillins, mutations in the ermB gene cause high-level macrolide resistance and mutations in topoisomerase IV genes coupled with GyrA gene mutations alter DNA gyrase and lead to high-level fluoroquinolone resistance. Risk factors for lower respiratory tract infections in the elderly include age-associated changes in oral clearance, mucociliary clearance and immune function. Other risks for developing pneumonia include poor nutrition, hypoalbuminaemia, bedridden status, aspiration, recent viral infection, the presence of chronic organ dysfunction syndromes including parenchymal lung disease and recent antibacterial therapy. Although the incidence of infections caused by DRSP is rising, the effect of an increase in the prevalence of resistant pneumococci on mortality is not clear. When respiratory infections occur, rapid diagnosis and prompt, empirical administration of appropriate antibacterial therapy that ensures adequate coverage of DRSP is likely to increase the probability of a successful outcome when treating community-acquired pneumonia in elderly patients, particularly those with multiple risk factors for DRSP. A chest x-ray is recommended for all patients, but other testing such as obtaining a sputum Gram's smear is not necessary and should not prolong the time gap between clinical suspicion of pneumonia and antibacterial administration. The selection of antibacterials should be based upon local resistance patterns of suspected organisms and the bactericidal efficacy of the chosen drugs. If time-dependent agents are chosen and DRSP are possible pathogens, dosing should keep drug concentrations above the minimal inhibitory concentration that is effective for DRSP. Treatment guidelines and recent studies suggest that combination therapy with a beta-lactam and macrolide may be associated with a better outcome in hospitalised patients, and overuse of fluoroquinolones as a single agent may promote quinolone resistance. The ketolides represent a new class of macrolide-like antibacterials that are highly effective in vitro against macrolide- and azalide-resistant pneumococci. Pneumococcal vaccination with the currently available polysaccharide vaccine is thought to confer some preventive benefit (preventing invasive pneumococcal disease), but more effective vaccines, such as nonconjugate protein vaccines, need to be developed that provide broad protection against pneumococcal infection.     

Optimising antimicrobial therapy in diabetic foot infections

Foot infections are common and the most serious lower extremity complication contributing to amputations, particularly in patients with diabetes mellitus. Infection is most often a consequence of foot ulcerations, which typically follows trauma to a neuropathic foot. Foot infections may be classified as mild, moderate and severe; this largely determines the approach to therapy. Gram-positive bacteria are the sole causative pathogens for most mild and moderate infections. These infections can usually be treated with culture-based narrow-spectrum antibacterials along with appropriate surgical debridement in an outpatient setting. In contrast, severe infections are often polymicrobial, requiring hospitalisation and treatment with broad-spectrum antibacterials along with appropriate medical and surgical interventions. The initial empirical antibacterial regimen may be tailored based on the results of culture and sensitivity tests from properly obtained specimens. Several antibacterial regimens have demonstrated effectiveness in randomised controlled trials, but no single regimen has shown superiority. Managing diabetic foot osteomyelitis is particularly controversial and requires reliable cultures to select an appropriate antibacterial regimen. Surgical resection of the infected and necrotic bone favours a good outcome in chronic osteomyelitis. The recommended duration of antibacterial therapy ranges from 1 to 4 weeks for soft tissue infection, to >6 weeks for unresected osteomyelitis. The incidence of meticillin-resistant Staphylococcus aureus infection is increasing in both the healthcare setting and the community. This should be considered when selecting an antibacterial, especially if the patient does not improve with initial antibacterial therapy. Certain other organisms, such as Pseudomonas aeruginosa and Enterococcus spp., while potentially pathogenic, are often colonisers that do not require targeted therapy.     

Linezolid

Linezolid is an oxazolidinone antibacterial agent that acts by inhibiting the initiation of bacterial protein synthesis. Cross-resistance between linezolid and other inhibitors of protein synthesis has not been demonstrated. Linezolid has a wide spectrum of activity against gram-positive organisms including methicillin-resistant staphylococci, penicillin-resistant pneumococci and vancomycin-resistant Enterococcus faecalis and E. faecium. Anerobes such as Clostridium spp., Peptostreptococcus spp. and Prevotella spp. are also susceptible to linezolid. Linezolid is bacteriostatic against most susceptible organisms but displays bactericidal activity against some strains of pneumococci, Bacteroides fragilis and C. perfringens. In clinical trials involving hospitalised patients with skin/soft tissue infections (predominantly S. aureus), intravenous/oral linezolid (up to 1250 mg mg/day) produced clinical success in >83% of individuals. In patients with community-acquired pneumonia, success rates were >94%. Preliminary clinical data also indicate that twice daily intravenous/oral linezolid 600 mg is as effective as intravenous vancomycin 1 g in the treatment of patients with hospital-acquired pneumonia and in those with infections caused by methicillin-resistant staphylococci. Moreover, linezolid 600 mg twice daily produced >85% clinical/microbiological cure in vancomycin-resistant enterococcal infections. Linezolid is generally well tolerated and gastrointestinal disturbances are the most commonly occurring adverse events. No clinical evidence of adverse reactions as a result of monoamine oxidase inhibition has been reported.     

Bacterial skin infections in the elderly: diagnosis and treatment

Skin and soft tissue infections are quite common in elderly people. A number of special conditions and circumstances need to be considered in the diagnosis and therapy. It is important to try to establish the causative organism, exclude other cutaneous disorders and identify precipitating factors. Treatment modalities include antiseptics, topical and systemic antibacterials, dressings and biotherapy. Skin infections presenting with erythema, blisters, pustules, and ulcerations or in body folds are described in detail. Cellulitis and infected ulcers are the most commonly encountered cutaneous infections in the elderly. Accurate and quick diagnosis and treatment are imperative to prevent significant morbidity and mortality. Appropriate antibacterials, antiseptics and dressings are necessary depending on the severity of the clinical presentation and resistance patterns. Laboratory tests, such as skin swabs, to establish the exact pathogen take time and the results might represent colonisation rather than infection of the skin. Cellulitis should be clinically distinguished from erysipelas and necrotising fasciitis. The latter is a life-threatening condition, which in the majority of cases requires surgical debridement of the infected tissue. Blisters and honey-coloured crusts are typical features of impetigo. It is very contagious and close contacts should be examined. Folliculitis is a commonly seen skin infection, which often responds to the use of antiseptics and topical antibacterials. More severe pustular skin eruptions, such as furunculosis and carbunculosis, usually require treatment with systemic antibacterials. Intertrigo and erythrasma have a predilection for the body folds, especially the axillae and groin, and topical therapy is usually sufficient. Secondary skin infections are often the result of persistent pruritus associated with increasing dryness of the aging skin. Emollients and antihistamines are useful measures. Primary cutaneous disorders and systemic diseases should be excluded with the aid of appropriate investigations, such as blood tests and skin biopsy. Staphylococcus aureus and beta-haemolytic streptococci are the most common causative organisms of cutaneous infections.     

Lipopeptides,focusing on daptomycin,for the treatment of Gram-positive infections

The increasing incidence of serious infections caused by antibiotic-resistant Gram-positive bacteria has led to the development of new spectrum-specific agents. One such agent is Cubicin? (daptomycin for injection), the first member of a new class of antibacterials called cyclic lipopeptides. Daptomycin has rapid, concentration-dependent bactericidal activity against most clinically significant Gram-positive pathogens, including vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and vancomycin-intermediate and -resistant S. aureus. This cyclic lipopeptide has a unique mechanism of action and exhibits a relatively prolonged concentration-dependent postantibiotic effect in vitro. In September 2003 the US FDA approved daptomycin for the treatment of complicated skin and skin-structure infections. With its once-daily dosing, excellent safety profile and low potential for resistance, daptomycin is a welcome new addition to the armamentarium against Gram-positive infections.     

Lipopeptides, focusing on daptomycin, for the treatment of Gram-positive infections

The increasing incidence of serious infections caused by antibiotic-resistant Gram-positive bacteria has led to the development of new spectrum-specific agents. One such agent is Cubicin (daptomycin for injection), the first member of a new class of antibacterials called cyclic lipopeptides. Daptomycin has rapid, concentration-dependent bactericidal activity against most clinically significant Gram-positive pathogens, including vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and vancomycin-intermediate and -resistant S. aureus. This cyclic lipopeptide has a unique mechanism of action and exhibits a relatively prolonged concentration-dependent postantibiotic effect in vitro. In September 2003 the US FDA approved daptomycin for the treatment of complicated skin and skin-structure infections. With its once-daily dosing, excellent safety profile and low potential for resistance, daptomycin is a welcome new addition to the armamentarium against Gram-positive infections.     

Daptomycin

Daptomycin, the first in a class of agents known as lipopeptides, is a novel antimicrobial agent used for the treatment of gram-positive infections. The compound has a distinctive mechanism of action that exerts its bactericidal activity by disrupting plasma membrane function without penetrating into the cytoplasm. The agent has received much interest because of its activity against multidrug-resistant, gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and glycopeptide-intermediate and -resistant S. aureus. Daptomycin demonstrates concentration-dependent killing and is eliminated primarily by glomerular filtration. It was approved in September 2003 for the treatment of complicated skin and soft tissue infections. It has a safety profile similar to other agents commonly administered to treat gram-positive infections. Daptomycin is a welcome addition to the antimicrobial armamentarium for the treatment of bacterial infections. Further clinical experience with this compound will help define its role in the treatment of resistant gram-positive organisms.     

Linezolid: a new antibiotic

The U.S. Food and Drug Administration recently approved linezolid for the treatment of patients with methicillin-resistant staphylococcal and vancomycin-resistant enterococcal infections. This oxazolidinone antibacterial agent represents the first approved antibiotic of a new structural class in 35 years. Linezolid is a synthetic compound that acts by inhibiting the initiation complex formation in bacterial protein synthesis, a mechanism of action distinct from other commercially available antibiotics. Thus, cross-resistance between linezolid and other current antimicrobial agents has not been demonstrated to date. Linezolid has a wide spectrum of in vitro activity against Gram-positive organisms, including methicillin-resistant staphylococci, penicillin-resistant pneumococci and vancomycin-resistant enterococci. Some anaerobes, such as Clostridium spp., Peptostreptococcus spp. and Prevotella spp. are also susceptible to linezolid. In addition, linezolid has exhibited good efficacy in experimental animal models of acute otitis media, endocarditis and meningitis due to many common aerobic Gram-positive bacteria. In clinical trials involving hospitalized patients with skin/soft tissue infections, community-acquired pneumonia and serious Gram-positive bacterial infections, linezolid appeared to be an effective treatment option, comparable in efficacy to vancomycin.     

Optimal treatment of infected diabetic foot ulcers

Foot ulceration can lead to devastating consequences in diabetic patients. They are not only associated with increased morbidity but also mortality. Foot infections result as a consequence of foot ulceration, which can occasionally lead to deep tissue infections and osteomyelitis; both of which can result in loss of limb. To prevent amputations prompt diagnosis and treatment is required. Understanding the pathology of the diabetic foot will help in the planning of appropriate investigations and treatment. Clinical diagnosis of infection is based on the presence of discharge from the ulcer, cellulitis, warmth and signs of toxicity; though the latter is uncommon. Deep tissue samples from the ulcer and/or blood cultures should be taken before, but without delaying the start of antibacterial treatment in limb and life-threatening infections. In milder infections wound sampling may direct appropriate antibacterial treatment. Staphylococcus aureus, followed by streptococci are the most common organisms causing infection and antibacterial treatment should be targeted against these organisms in mild infection possibly with monotherapy. But in serious infections combination therapy is required because these are usually caused by multiple organisms including anaerobes. Drug-resistant organisms are becoming more prevalent and methicillin-resistant infections can be treated effectively with a number of oral antibacterials either as monotherapy or in combination. Surgical treatment with debridement, for example, callus removal or drainage of pus form an important part of diabetic foot ulcer management especially in the presence of infection. Occasionally limited surgery including dead infected bone removal may be necessary for resolution of infection. Amputation is sometimes required as a last resort for limb or life preservation.     

Linezolid: a review of its use in the management of serious gram-positive infections

Linezolid is the first of a new class of antibacterial drugs, the oxazolidinones. It has inhibitory activity against a broad range of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae. The drug also shows activity against certain anaerobes, including Clostridium perfringens, C. difficile, Peptostreptococcus spp. and Bacteroidesfragilis. In controlled phase III studies, linezolid was as effective as vancomycin in the treatment of patients with infections caused by methicillin-resistant staphylococci and also demonstrated efficacy against infections caused by VRE. Further phase III studies have demonstrated that linezolid is an effective treatment for patients with nosocomial pneumonia, for hospitalised patients with community-acquired pneumonia, and for patients with complicated skin or soft tissue infections (SSTIs). In these studies, linezolid was as effective as established treatments, including third-generation cephalosporins in patients with pneumonia, and oxacillin in patients with complicated SSTIs. Oral linezolid 400 or 600mg twice daily was as effective as clarithromycin 250mg twice daily or cefpodoxime proxetil 200mg twice daily in the treatment of patients with uncomplicated SSTIs or community-acquired pneumonia. Linezolid is a generally well tolerated drug. The most frequently reported adverse events in linezolid recipients were diarrhoea, headache, nausea and vomiting. Thrombocytopenia was also documented in a small proportion (about 2%) of patients treated with the drug. CONCLUSIONS: Linezolid has good activity against gram-positive bacteria, particularly multidrug resistant strains of S. aureus (including GISA), Enterococcus faecium and E. faecalis (including VRE). In controlled clinical trials, linezolid was as effective as vancomycin in eradicating infections caused by methicillin-resistant Staphylococcus spp. and has demonstrated efficacy against infections caused by VRE. As the level of resistance to vancomycin increases among S. aureus and enterococci, linezolid is poised to play an important role in the management of serious gram-positive infections.     

Doripenem

Doripenem is a new member of the carbapenem class of beta-lactam antibiotics with broad-spectrum coverage of Gram-positive, Gram-negative and anaerobic pathogens similar to imipenem and, especially, meropenem. This parenteral antibiotic may offer slightly more activity than meropenem against selected pathogens, including coverage of some strains of Pseudomonas aeruginosa strains not susceptible to the other antipseudomonal carbapenems. Empiric therapy with doripenem, as with other antipseudomonal carbapenems, may be useful in hospital and intensive care unit settings where multidrug resistance has emerged, especially in Gram-negative enteric pathogens. When P. aeruginosa or multidrug-resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci are involved, doripenem must be used in combination. Doripenem has a broad spectrum of activity against many common hospital pathogens, including P. aeruginosa and Burkholderia cepacia, which is similar to meropenem.