Staphylococcal and
streptococcal infections
ME TorokNPJ Day
Abstract
Staphylococcal and streptococcal infections are common infectious diseases and can range from mild, superficial skin infections to severe, life-threatening systemic infections. Staphylococcus aureus, group A streptococcus, andStreptococcus pneumoniaeare the three major path-ogens. The prevalence of invasive infections caused by community-asso-ciated meticillin-resistantS. aureusand group A streptococcus appears to be increasing. The emergence of drug resistance (e.g. meticillin and glyco-peptide resistance inS. aureus, macrolide resistance in group A strepto-cocci and penicillin resistance in S. pneumoniae), is concerning and a potential threat to successful treatment.Streptococcus suishas recently emerged as an important human pathogen.
Keywords community-acquired MRSA; group A streptococci; group B streptococci;Staphylococcus aureus;Streptococcus bovis;Streptococcus pneumoniae;Streptococcus suis; viridans streptococci
Staphylococci
The genus Staphylococcus currently contains 35 species, all of which are part of the normal skin and mucous membrane flora of humans and animals.S. aureusis the most important pathogen, causing various pyogenic infections and toxin-mediated illnesses in normal hosts. Other species are collectively termed ‘coagulase-negative staphylococci’. These are generally considered non-pathogenic, apart fromStaphylococcus epidermidis, which causes nosocomial (hospital-associated) bacteraemia and device-related infections, andStaphylococcus saprophyticus, which is a common cause of urinary tract infection.
Staphylococcus aureus
S. aureusis carried in the anterior nares of 20e40% of adults, depending on seasonal and local epidemiological factors. Some groups (e.g. medical staff, patients with type 1 diabetes, hae-modialysis patients, intravenous drug users) appear to be particularly prone to colonization with S. aureus. Carriers transfer the organism to the skin, where trauma can provide a portal of entry, leading to local, deep, or systemic infection. The global spread of meticillin-resistant S. aureus(MRSA), which is
intrinsically resistant to all b-lactam antibiotics, is a major concern.1 Over the past few years, infections caused by community-associated MRSA (CA-MRSA) in previously healthy people have emerged as a significant clinical problem.2Another
concern is the emergence of isolates with reduced susceptibility or resistance to vancomycin [e.g. vancomycin-intermediate S. aureus(VISA), heterogeneous VISA (hVISA) and vancomycin-resistant S. aureus (VRSA)].3 hVISA strains appear to be susceptible to vancomycin but contain a subpopulation of cells resistant to vancomycin. Patients at most risk of infection by hVISA, VISA and VRSA appear to be those with previous expo-sure to vancomycin.
Pathogenesis: S. aureus has several putative determinants of pathogenicity, including cell wall constituents, surface proteins, toxins and enzymes, and specific cell wall-bound adhesins. It secretes enzymes, including catalase, coagulase, clumping factor, hyaluronidase,b-lactamases and DNase, and produces extracel-lular toxins, some of which are directly cytotoxic (haemolysins, leukocidins) and some of which act as superantigens, causing polyclonal proliferation of T cells (toxic shock syndrome toxin-1 (TSST-1), enterotoxins, epidermolytic toxins). The Pantone Valentine leucocidin (PVL) is a cytotoxin that causes leucocyte destruction and tissue necrosis. Although there is a strong epidemiological association of CA-MRSA infections and PVL production, its role in the pathogenesis and spread of infection is controversial. In a mouse sepsis model, PVL-negative strains of CA-MRSA were as lethal as wild-type strains and caused comparable skin disease.4In a study of 31 strains collected from patients with infections of varying severity, the quantity of PVL production in vitro did not correlate with the severity of infec-tion. Host factors that particularly predispose to S. aureus infection include inborn defects in neutrophil function, diabetes mellitus, and the presence of foreign material. Nasal carriers are more likely to develop nosocomial bacteraemia, though the associated mortality may be lower.
Microbiology: S. aureus grows rapidly aerobically and anaerobically on blood agar and other non-selective solid media. Most strains are b-haemolytic. Microscopically, S. aureusis apparent as Gram-positive cocci that tend to form clusters on solid media. Identification is usually confirmed by positive catalase, coagulase and DNase tests. Typing is now
What’s new?
C Community-associated MRSA and Streptococcus suis have emerged as significant human pathogens over the past few years.
C Increasing antimicrobial resistance among Staphylococcus
aureusandStreptococcus pneumoniaeisolates is of growing concern and threatens successful treatment of these infections. C There are limited data on the use of newer antimicrobial agents (e.g. linezolid, daptomycin and ceftobiprole) in the treatment of MRSA infections.
ME TorokMA MRCP FRCPathis a Consultant in Infectious Diseases in the Department of Infectious Diseases, Addenbrooke’s Hospital, Cambridge, UK. Competing interests: none declared.
NPJ DayMA MRCPis Director of the WellcomeeMahidoleOxford Tropical
Medicine Research Programme, Hospital for Tropical Diseases, Bangkok, Thailand. Competing interests: none declared.
performed by molecular methods (e.g. pulsed-field gel elec-trophoresis, multi-locus sequence typing, SCCmec typing or spatyping).
Clinical manifestations:S. aureusis a major cause of skin and soft-tissue infections including impetigo, ecthyma (ulcerative pyoderma), folliculitis, furuncles, carbuncles, erysipelas, cellu-litis and necrotizing fasciitis (seeMedicine37(11), pp. 603e609). Over the past few years, outbreaks of CA-MRSA infection have been reported in children, Alaskan natives, Pacific islanders, prisoners, sports teams and military personnel.2CA-MRSA has
become the most common cause of skin and soft-tissue infections presenting to emergency departments in the USA.5
The incidence ofS. aureusbacteraemia, and the proportion of bacteraemic episodes caused by MRSA, has also increased over the past few years.6 It can be divided into two categories:
community-acquired bacteraemia (onset <2 days post-hospital admission) and hospital-acquired (onset2 days after hospital admission). Metastatic infections such as endocarditis, pericar-ditis, pneumonia, pulmonary abscesses, empyema, septic bursitis, septic arthritis, pyomyositis and discitis osteomyelitis can occur (Figures 1 and 2). The diagnosis is confirmed by cultures of blood and appropriate clinical specimens. Patients withS. aureusbacteraemia should have an echocardiogram to look for endocarditis. Investigations for metastatic infection should be guided by symptoms (e.g. magnetic resonance scan of spine to exclude suspected vertebral discitis or osteomyelitis). Management:treatment ofS. aureusinfections depends on the nature of the primary focus and the presence or absence of metastatic infection. Flucloxacillin is the drug of choice in meticillin-sensitive S. aureus (MSSA) infections, whereas van-comycin (or teicoplanin) is used in MRSA infections and peni-cillin-allergic patients. The role of the newer Gram-positive antimicrobial agents (e.g. linezolid, daptomycin, ceftobiprole) in the treatment of MRSA infections remains to be established. Aminoglycosides exhibit synergistic activityin vitroand are often used in endocarditis and other severe infections. Skin and soft-tissue infections usually respond to 7e14 days of antibiotic therapy. Deeper infections, such as deep abscesses, septic arthritis or osteomyelitis, often require drainage of the focus and more prolonged antimicrobial therapy. Catheter-related bacter-aemia is treated with removal of the catheter and 14 days’ intravenous therapy. Bacteraemia of unknown source or endo-carditis is treated with a minimum of four weeks’ intravenous therapy. The treatment of endocarditis is discussed elsewhere (seeMedicine37(11), pp. 582e585). In prosthetic device-related infection, the device should be removed and the infection treated with prolonged (4e6 weeks) intravenous therapy. In cases where the device cannot be removed (e.g. vascular graft infection), oral suppressive antimicrobial therapy should be continued indefinitely.
Toxin-mediated diseases:S. aureuscan also cause a number of toxin-mediated diseases, such as food poisoning, scalded skin syndrome, and toxic shock syndrome. Staphylococcal food poisoning presents with vomiting and diarrhoea within hours of ingestion of foods containing enterotoxin-producing bacteria. Treatment is symptomatic.
Staphylococcal scalded skin syndrome is caused by epi-dermolytic toxin-producing S. aureus and is usually seen in children. Clinical presentation ranges from bullous impetigo to severe, generalized, exfoliative dermatitis with systemic upset. It is usually treated with intravenous antibiotics, supportive skin care and careful management of fluid and electrolyte losses.
Toxic shock syndrome is caused by TSST-1 and other related staphylococcal enterotoxins. The menstrual form is associated with tampon use, the non-menstrual form with vaginal infec-tions, contraceptive devices, abortion, childbirth and surgical procedures. The clinical case definition includes fever, hypo-tension, desquamating rash and involvement of three or more organ systems. Management requires aggressive fluid resuscita-tion, removal of any tampon, and parenteral anti-staphylococcal antibiotics.
Coagulase-negative staphylococci
Coagulase-negative staphylococci (CoNS) are skin commensals. Often dismissed as culture contaminants, they are becoming increasingly recognized as pathogens.7 S. saprophyticus is a common cause of community-acquired urinary tract infection. S. epidermidis causes nosocomial bacteraemia and prosthetic device-related infections. Other species that have been associated with infection include Staphylococcus haemolyticus, Staphylo-coccus lugdunensis and Staphylococcus schleiferi. These organ-isms adhere to prosthetic material and become embedded in an exopolysaccharide matrix, forming a biofilm. The biofilm protects the organisms from phagocytic cells and reduces the penetration of antibiotics.
Microbiology: coagulase-negative staphylococci grow rapidly aerobically and anaerobically on blood agar and other non-selective solid media. Microscopically, they are Gram-positive cocci that form clusters on solid media. Identification is usually confirmed by negative coagulase and DNase tests. Nosocomial isolates usually multiply antibiotic-resistant (mainly plasmid-mediated). Typing of coagulase-negative staphylococci is per-formed by molecular methods, because biochemical tests are unreliable.
Clinical manifestations:S. saprophyticusis a common cause of cystitis in young women. It is treated with oral antibiotics (e.g. trimethoprim, nitrofurantoin or ciprofloxacin).
S. epidermidis is the most common cause of nosocomial bacteraemia and is often associated with intravascular catheters or prosthetic material. It is also the most common cause of early prosthetic-valve endocarditis (seeMedicine37(11), pp. 582e585) and cerebrospinal fluid shunt infections. Other infections include peritoneal dialysis catheter-associated peritonitis, bacteraemia in immunocompromised patients and neonates, sternal osteomye-litis, prosthetic joint infections, vascular graft infections and post-surgical endophthalmitis.
Management: treatment of coagulase-negative staphylococcal infections usually requires removal of the intravascular catheter or infected prosthetic device and intravenous antibiotic therapy (e.g. vancomycin or teicoplanin). Where the foreign material cannot be removed, prolonged intravenous antibiotic therapy is required, and is often followed by long-term oral suppressive therapy.
Streptococci
Streptococci are catalase-negative Gram-positive cocci that grow in pairs or chains. More than 30 species have been identified; those discussed below are the most pathogenic in humans. Classification of streptococci is complex and based on a number of features including haemolysis pattern on blood agar, biochemical reactions, antigenic composition, and genetic ana-lysis. Three patterns of haemolysis are seen on blood agar: partial haemolysis (a-haemolysis); complete haemolysis (b-haemol-ysis); and non-haemolysis. a-Haemolytic streptococci produce a greenish discoloration of blood agar, hence the term ‘viridans streptococci’.b-Haemolytic streptococci are classified into Lan-cefield serogroups, determined by antigenic differences between cell wall carbohydrates. Streptococci lacking a recognizable group antigen are identified by their biochemical reactions, and
placed taxonomically using molecular techniques such as DNA hybridization and ribosomal RNA sequencing.
Group A streptococcus
Group A streptococcus (Streptococcus pyogenes) is a major human pathogen, causing acute pharyngitis and variety of cutaneous and systemic infections. There are several pathogenic determinants, including M protein and a hyaluronic acid capsule, both of which are anti-phagocytic. Exotoxins (A, B, C, mitogenic factor and streptococcal superantigen), haemolysins (streptoly-sins O and S) and enzymes (DNases, hyaluronidase and strep-tokinase) are also produced.8
Microbiology: group A streptococci grow rapidly aerobically and anaerobically on blood agar and other non-selective solid media and are b-haemolytic. Microscopically, they are Gram-positive cocci that grow in pairs or short chains. Identification is usually confirmed by streptococcal grouping using latex agglutination.
Clinical manifestations:streptococcal pharyngitis is a common childhood infection, spread by droplet and presenting after a 2e4-day incubation period with fever, sore throat, inflamed pharynx, tonsillar enlargement, and tender regional lymph-adenopathy. Treatment is with oral penicillin for 10 days.
Group A streptococcus also causes various skin and soft tissue infections, including erysipelas, cellulitis and necrotizing fas-ciitis, which are described elsewhere (see Medicine 37(11), pp. 603e609). The incidence of severe, invasive infections appears to be increasing9but the reason for this is not clear.
Streptococcal toxic shock syndrome can be defined as any streptococcal infection associated with sudden onset of shock (systolic blood pressure 90 mm Hg) and multi-organ failure (defined as two or more of the following: renal impairment; coagulopathy; hepatic impairment; adult respiratory distress syndrome; generalized rash that may desquamate; soft-tissue necrosis). Streptococcal M protein is thought to have a major role in the pathogenesis by forming complexes with fibrinogen that bind to integrins on the surface of circulating neutrophils. The activated neutrophils cause endothelial cell damage and conse-quent vascular leakage and hypercoagulability, leading to hypotension and organ damage. Management is with prompt, aggressive surgical debridement of suspected deep-seated strep-tococcal infection, intravenous broad-spectrum antibiotic therapy, and intensive-care support. Once a streptococcal cause is confirmed, treatment can be rationalized to intravenous ben-zylpenicillin and clindamycin.
Scarlet fever results from infection with an organism that produces an erythrogenic toxin (Figure 3). These toxins are superantigens; two (SPE A and SPE B) resemble S. aureus enterotoxins at the molecular level. A scarlatinal rash occurs, usually on the second day of the illness, and spreads from the upper chest to the trunk, neck and extremities, sparing the palms and soles. The rash fades over one week and is followed by extensive desquamation. Severe forms of disease are character-ized by fever and marked systemic toxicity. Treatment is with penicillin.
Acute rheumatic fever is an autoimmune disease caused by immunological cross-reactivity between streptococcal M proteins
and cardiac antigens, and is a delayed sequela of streptococcal pharyngitis. It mainly affects 6e15-year olds, particularly in the developing world. Non-suppurative inflammatory lesions involve the heart, joints, skin, subcutaneous tissues and central nervous system. Damage to the heart valves can result in progressive valvular lesions and cardiac failure. Diagnosis is based on the revised Jones criteria.10Treatment is with
analge-sics and/or anti-inflammatory drugs (aspirin or corticosteroids). Post-streptococcal glomerulonephritis results from cross-reactivity between streptococcal M proteins and host antigens, and follows streptococcal pharyngitis or pyoderma. It is an acute inflammatory disorder of the renal glomerulus, associated with diffuse proliferative glomerular lesions and presents with acute renal failure. Diagnosis is based on clinical features and confir-matory evidence of recent streptococcal infection. Treatment is directed towards management of acute problems (e.g. hyper-tension, fluid overload, acute renal failure) and eradication of the causative organism with penicillin (to prevent further trans-mission of the nephritogenic clone). The prognosis is good, although a few patients develop chronic glomerulonephritis. Group C and G streptococci
Group C and G streptococci areb-haemolytic streptococci that colonize the nasopharynx, skin and genital tract and cause infections similar to group A streptococcus. These include pharyngitis, skin and soft-tissue infections, septic arthritis, oste-omyelitis, pneumonia, endocarditis, puerperal sepsis, neonatal sepsis and bacteraemia. Post-streptococcal glomerulonephritis has been associated with group C streptococci. The treatment of choice for both group C and G streptococcal infections is peni-cillin (or vancomycin in penipeni-cillin-allergic patients). Penipeni-cillin tolerance is a feature of group C streptococci and synergistic gentamicin therapy has been recommended for the therapy of severe infections.
Streptococcus pneumoniae
S. pneumoniae(pneumococcus) is a common bacterial pathogen of humans found in the nasopharynx of 20e40% of children and 10e20% of adults. Colonization and infection rates are seasonal, increasing during the winter.S. pneumoniaeis a major cause of otitis media, sinusitis, pneumonia and meningitis. Less commonly, it causes bacteraemia, peritonitis, endocarditis, pericarditis, septic arthritis, osteomyelitis, soft-tissue infections,
and epidural and brain abscesses. Predisposing factors include defects in antibody formation, complement deficiency, neu-tropenia, hyposplenism, extremes of age, alcoholism, diabetes, and chronic diseases.
Pathogenesis:S. pneumoniaehas several adhesins that enable it to bind to epithelial cell receptors. It produces a capsule that helps it to evade phagocytosis. ‘C-polysaccharide’ (a teichoic acid constituent of the cell wall containing choline phosphate) is unique to S. pneumoniae and is responsible for the reaction between pneumococci and C-reactive protein, which leads to complement activation.
Microbiology:S. pneumoniaegrows in chains in liquid media, but often appears on Gram stain as lanceolate diplococci. It is a-haemolytic on blood agar, produces a negative catalase reaction, and is sensitive to optochin. Serotypes are based on antigenic differences between capsular polysaccharides. Resistance to penicillin and macrolides is increasing worldwide, ranging from 1 to 90% in different geographical areas.11High-level penicillin
resistance remains uncommon in the UK (3.8% of invasive isolates in 2007) but resistance to erythromycin is somewhat higher at 9%.12
Clinical manifestations:worldwide,S. pneumoniaeis the most common cause of otitis media, community-acquired pneumonia and bacterial meningitis. It is also the predominant organism isolated in patients with meningitis following head injury. S. pneumoniae also causes sinusitis, bacteraemia, para-pneu-monic effusion, empyema, lung abscess, septic arthritis, osteo-myelitis, spontaneous bacterial peritonitis and endocarditis. S. pneumoniae infections are more common in HIV-infected persons and young people presenting with invasive disease should be offered an HIV test.
Treatment:the treatment ofS. pneumoniaeinfections depends on the site of infection and drug susceptibility pattern of the organism. Infections such as otitis media and sinusitis can be treated with oral amoxicillin (or moxifloxacin if the patient is penicillin-allergic). Treatment of pneumonia is with oral or intravenous amoxicillin, depending on disease severity. Alter-natives in penicillin-allergic patients are doxycycline, erythro-mycin or clarithroerythro-mycin. Bacteraemia is treated with intravenous benzylpenicillin. Meningitis is initially treated with intravenous ceftriaxone; vancomycin can be added if there is a high risk of penicillin resistance (e.g. patient from abroad). If the isolate is found to be fully susceptible (penicillin MIC <0.06 mg/L), treatment can be rationalized to benzylpenicillin. If the isolate has intermediate penicillin susceptibility (penicillin MIC 0.12e 1.0 mg/L), treatment should continue with ceftriaxone. Adjunc-tive corticosteroids have been recommended for the treatment of adult bacterial meningitis,13 but more recent data from the developing world are less supportive of their use.14,15
Prevention: invasive disease can be prevented by vaccina-tion. The pneumococcal polysaccharide vaccine, which contains 23 serotypes, has been recommended in those patients aged>65 years and those at increased risk (e.g. age >65 years, asplenia/hyposplenism, chronic respiratory,
cardiac, renal or liver diseases, diabetes, immunosuppres-sion, cochlear implants, cerebrospinal fluid leaks). In 2006, the pneumococcal conjugate vaccine, which contains seven serotypes, was added to the UK routine childhood immuni-zation schedule.
Group B streptococcus
Group B streptococcus (Streptococcus agalactiae) is an important pathogen in pregnancy, post-partum women, and in neonates. The prevalence of asymptomatic vaginal colonization in preg-nant women is 5e40%. The rate of vertical transmission in neonates born to women colonized at the time of delivery is 50%. The most devastating infections (bacteraemia and menin-gitis) occur in neonates, but group B streptococci can also cause bacteraemia in adults.
Microbiology:group B streptococci are facultatively anaerobic, b-haemolytic diplococci that grow readily on various media. Definitive identification is based on detection of the group B-specific cell wall antigen by latex agglutination. They can be sub-classified into nine serotypes based on capsular polysaccharide determinants.
Clinical features: group B streptococci are important patho-gens in pregnancy and can cause asymptomatic bacteriuria, cystitis or, less often, pyelonephritis. Colonized pregnant women are at significantly increased risk of premature rupture of membranes, post-partum fever, endometritis and wound infection. Rarely, pelvic abscess, septic shock or septic throm-boembolism occurs.
Group B streptococci are also important causes of neonatal sepsis. Early-onset infection (onset<7 days after birth) is asso-ciated with certain maternal risk factors (age<20 years, previous miscarriage, premature or prolonged rupture of membranes, intra-partum fever) and prematurity (delivery at <37 weeks’ gestation) and presents with septicaemia (60%), pneumonia (30%) or meningitis (10%). Mortality is 2e8% in term infants and is inversely proportional to birth weight. Late-onset infection (7 dayse3 months) presents with bacteraemia, meningitis, osteomyelitis or septic arthritis. Uncommon foci include cellu-litis, adenitis, otitis media, conjunctivitis, empyema, peritonitis, endocarditis and deep abscesses. Treatment is with high-dose intravenous benzylpenicillin.
Invasive group B streptococcal infection causes considerable morbidity and mortality in adults. In the non-pregnant pop-ulation, the incidence increases with age; men are more commonly affected. Diabetes, liver disease, neurological condi-tions, malignancy, renal or urological disease, cardiopulmonary disease and HIV infection predispose to invasive infection. Bac-teraemia is the most common presentation. Other syndromes include pneumonia, septic arthritis, osteomyelitis, skin and soft-tissue infections, and meningitis. Treatment of adult infection is with high-dose intravenous benzylpenicillin (or vancomycin in those allergic to penicillin). Mortality in non-pregnant adults is 21e32%.
Viridans streptococci
Viridans streptococci are commensals in the gastrointestinal, respiratory and female genital tracts and are most prevalent in
the oral cavity. They are considered to be of low pathogenicity, apart from their propensity to adhere to cardiac valves and cause endocarditis. Some species (e.g. Streptococcus mutans) have a strong association with dental caries.
Viridans streptococci are facultatively anaerobic, catalase-negative Gram-positive cocci that grow on blood agar and other non-selective solid media, and are mainly a-haemolytic. Although some isolates react with Lancefield grouping antisera, they do not conform to specific serogroups and many isolates are non-groupable. In the past, the terminology applied to the vir-idans group of streptococci was confusing and inconsistent. Molecular techniques have now enabled genotypic differentia-tion, which has subsequently been found to correlate with phenotypic differences in biochemical tests. At present, clinically significant species can be assigned to one of the following groups: anginosus group; mitis group; mutans group; salivarius group.
The viridans streptococci are a major cause of native valve endocarditis, usually in patients with underlying valve disease. They can also cause bacteraemia (particularly in neutropenic patients), meningitis, and pneumonia.
Viridans streptococci were previously uniformly susceptible to penicillin but resistance to penicillin is increasing, particularly in nosocomial bloodstream isolates from immunocompromised patients. Although viridans streptococci are resistant to amino-glycosides (when traditional breakpoints are used), synergistic bactericidal activity has been seen with penicillin and amino-glycosides. Thus, a combination of penicillin and gentamicin is usually used to treat endocarditis (see Medicine 37(11), pp. 582e585).
Streptococcus bovis
S. bovis causes endocarditis and bacteraemia, the latter often associated with colonic malignancy or hepatic cirrhosis. It is an a-haemolytic streptococcus and is identified by biochemical tests and Lancefield serogrouping (group D). It is highly susceptible to penicillin, which is the drug of choice.
Streptococcus suis
S. suiswas previously considered to be predominantly an animal pathogen but is increasingly being recognized as a cause of bacterial meningitis and septicaemia in humans (Figure 4).16In 2005, a large outbreak of 215 cases occurred in China associated with a high mortality rate (62%).17Predisposing factors include
contact with pigs or undercooked pork, alcoholism and splenec-tomy. The organism is a-haemolytic and is identified by biochemical tests and serotyping. Treatment is with
benzylpenicillin. A
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Practice points
C Staphylococci and streptococci are commensal organisms that can cause a wide variety of conditions ranging from skin and soft tissue infections to severe, life-threatening infections C Patients who are systemically unwell should be admitted for
appropriate investigations and intravenous antibiotic therapy C Drug-resistance in these organisms is increasing and empirical
