Staphylococci

Staphylococci are a common cause of bacterial infections. Staphylococci are named for their microscopic appearance, the name coming from Greek words meaning ‘bunch of grapes’ and ‘berry’. First described in 1880 by Ogston as an important cause of abscesses in humans, staphylococci are among the most common causes of bacterial colonization and infection in the community and in hospitals.

Staphylococcal infections are those caused by bacteria of the genus Staphylococcus. Different species of staphylococci are responsible for a range of disorders, including skin infections such as pustules, abscesses, and boils, and a rash in newborn babies (see necrolysis, toxic epidermal); pneumonia; toxic shock syndrome in menstruating women; urinary tract infection; and food poisoning. If the bacteria enter the circulation, they may cause septicaemia or septic shock, infectious arthritis, osteomyelitis, or bacterial endocarditis. 

Staphylococcus aureus is a species of Staphylococcus bacterium that produces toxins, causing a range of staphylococcal infections.

Staphylococci in detail - technical

Essentials

Staphylococci are Gram-positive bacteria that form clusters, but can occur singly, in pairs, chains, or tetrads. They are classically distinguished from other ‘Gram-positives’ by presence of catalase, an enzyme that degrades hydrogen peroxide (H2O2). S. aureus is distinguished from other coagulase-negative staphylococci, which are generally less virulent, by the presence of coagulase, an enzyme that coagulates plasma. Many toxins and regulatory elements enhance virulence in staphylococci.

Epidemiology

Colonization—staphylococci are skin commensals. About 20% of adults are persistently colonized by S. aureus, 60% are intermittently colonized, and 20% are never colonized. High-risk groups for S. aureus colonization include infants, insulin-dependent diabetics, intravenous drug users, HIV-positive patients, and individuals undergoing either haemo- or peritoneal dialysis.

Methicillin-resistant S. aureus (MRSA)—risk factors for MRSA colonization and infection among hospitalized patients include antibiotic exposure, surgery, nursing-home residence, or high MRSA ‘colonization pressure’, i.e. frequent exposure to colonized or infected patients. However, MRSA is no longer only a hospital-related infection, with community-associated MRSA affecting individuals without health care exposures.

Clinical features

S. aureus infection—clinical syndromes can be divided into three groups: (1) Illness due to release of toxins, leading to disease at sites often remote from infection—including (a) staphylococcal scalded skin syndrome—release of epidermolytic toxins leads to bullae and desquamation; (b) food-borne illness due to preformed toxin—a heat-stable superantigen toxin produces sudden vomiting and diarrhoea; (c) toxic shock syndrome—superantigen toxins cause multisystem organ dysfunction; may be menstrual (e.g. tampon-associated) or nonmenstrual. (2) Illness due to local tissue destruction and abscess formation—including (a) impetigo, folliculitis, and cellulitis; (b) furuncles and carbuncles; (c) mastitis; (d) pyomyositis; (e) septic bursitis; (f) septic arthritis; (g) osteomyelitis; (h) epidural abscess; (i) pneumonia; (j) urinary tract infection. (3) Hematogenous infection—including bacteraemia and endocarditis.

Coagulase-negative staphylococci—most infections with these skin commensals are the consequence of medical interventions leading to foreign bodies, e.g. prosthetic joints or heart valves, indwelling intravascular catheters or grafts, or peritoneal catheters. Conditions include endocarditis (5–8% of native valve infections, c.40% of prosthetic valve infections), intravascular catheter infections (6–27% of vascular-catheter infections), prosthetic joint infections (up to 38% of arthroplasty infections), peritoneal dialysis, catheter infections, and postoperative ocular infections.

Diagnosis

Diagnosis relies on characteristic clinical and epidemiological features, supported by positive cultures from the relevant clinical site, with identification (when appropriate) of exotoxin-positive strains. Outbreak and epidemiological investigations use molecular fingerprinting techniques to assess relatedness of staphylococci.

Treatment

Aside from supportive care, the mainstays of therapy are (1) prompt drainage of infected foci; and (2) antimicrobials—(a) coagulase-negative staphylococci—vancomycin is the mainstay of therapy because of the high rates of methicillin resistance; (b) S. aureus—antimicrobial choice should be based on the local prevalence of MRSA and the clinical severity of illness; a bactericidal agent, preferably a β-lactam, is used whenever possible; oral agents active against MRSA include clindamycin, trimethoprim/sulfamethozaxole, doxycycline, minocycline, linezolid; glycopeptides (i.e. vancomycin or teicoplainin) have been the usual therapy of severe infections due to MRSA, but vancomycin resistance is emerging.

Prevention

Prevention of illness due to S. aureus, particularly MRSA, relies on proactive infection control measures, including (1) surveillance for MRSA colonization; (2) imposed grouping (cohorting) of infected and colonized patients; (3) barrier precautions—e.g. gowning and gloving by health care staff; (4) improved hand hygiene; (5) cleaning patients—e.g. with chlorhexidine; (6) improved environmental cleaning; (7) antimicrobial stewardship.

Better strategies for treatment and salvage of infected catheters or methods for treatment of biofilm may improve treatment of coagulase-negative staphylococcal infections. No vaccines are available.

Introduction and historical perspective

Staphylococci are named for their microscopic appearance, the name coming from Greek words meaning ‘bunch of grapes’ and ‘berry’. First described in 1880 by Ogston as an important cause of abscesses in humans, staphylococci are among the most common causes of bacterial colonization and infection in the community and in hospitals.

Staphylococcus aureus, the pre-eminent human staphylococcus, has adapted efficiently to improvements in therapeutics. In the 1940s, shortly after the introduction of penicillin, penicillin-resistant S. aureus was noted in the United Kingdom and the United States of America, and by the end of the decade 50% of isolates were resistant. From 1940 to 1960, a particularly invasive clone of penicillin-resistant S. aureus, ‘phage type 80/81’, caused pandemic hospital infections. Following the introduction of methicillin, that strain faded from concern only to be replaced in subsequent decades with endemic health care-associated methicillin-resistant S. aureus (MRSA) that frequently was resistant to multiple antimicrobial classes. Most recently, reminiscent of the 1940 to 1960 experience, invasive strains of community-associated MRSA (CA-MRSA) have emerged rapidly in some communities among otherwise healthy individuals. Coagulase-negative staphylococci infections, in contrast, are infecting implanted devices and occurring in association with health care, thereby filling a niche created by medical success.

Microbiology and molecular genetics

Staphylococci stain purple (‘positive’) with Gram’s stain and form grape-like clusters, but can occur singly, in pairs, in chains, or in tetrads. Of 32 staphylococcal species, 16 colonize or infect humans. Classically, staphylococci are distinguished from other ‘Gram-positives’ by the presence of catalase, an enzyme that degrades H2O2. S. aureus is distinguished from other staphylococci by the presence of coagulase, an enzyme that coagulates plasma. Most laboratories use latex agglutination tests to detect coagulase; other assays include the tube coagulase and free coagulase tests.

Outbreak and epidemiological investigations use molecular ‘fingerprinting’ techniques to assess relatedness of staphylococci, i.e. bacteriophage typing, pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), polymerase chain reaction (PCR), or toxin or ‘housekeeping’ gene identification.

Pathogenesis

The infectiveness of staphylococci depends in part on bacterial factors that promote growth, colonization, invasiveness (i.e. regulation and virulence determinants), and antibiotic resistance and in part on host susceptibility (e.g. presence of diabetes mellitus).

Regulation and virulence determinants

Regulation determinants ‘autoregulate’ staphylococci based on environmental conditions or host factors. The major S. aureus regulatory gene is the accessory gene regulator (agr) that facilitates intercell communication. This and other systems may have roles in tissue destruction (through exoprotein production) and endocarditis (through adhesin regulation).

Virulence determinants, e.g. peptidoglycan, lipoteichoic acids, protein toxins, and biofilm, enhance bacterial pathogenicity but can also activate patient protective mechanisms. Peptidoglycan, an important component of Gram-positive bacterial walls, and lipoteichoic acids, bound to the plasma membrane, are implicated in triggering the inflammatory response in humans that can enhance bacterial killing. Exoproteins and ‘superantigens’ (i.e. antigens that lead to nonspecific immune activation) can be released by S. aureus to cause a severe immune response or disease remote from infection, while local toxins, e.g. Panton–Valentine leucocidin (PVL), may increase bacterial invasiveness. Biofilm, an extracellular complex of polysaccharides, enhances binding to foreign objects (e.g. intravascular catheters) and serves as a bacterial sanctuary from host defences and antimicrobials.

Antimicrobial resistance

S. aureus resistance to β-lactams is mediated by β-lactamases (penicillin resistance) or, more commonly, by altered enzymes responsible for cell wall formation (methicillin resistance). Penicillinases propagate by plasmids or phage transfer; methicillin resistance results from spread of a genomic island of DNA called the staphylococcal chromosomal cassette (SCC). The SCC carries the mecA gene (termed SCCmec). The product of mecA is penicillin-binding protein 2a (PBP2a), which has low affinity for methicillin and enables cell wall synthesis in spite of active antibiotics. SCCmec type IV primarily is associated with CA-MRSA, while types I, II, and III are associated primarily with hospital strains.

Glycopeptides (i.e. vancomycin or teicoplanin) have been the usual therapy of severe infections due to MRSA. However, vancomycin resistance is emerging among MRSA. Two resistance patterns exist: (1) vancomycin- (or glycopeptide-) intermediate S. aureus (VISA or GISA) and (2) vancomycin-resistant S. aureus (VRSA). The VISA phenotype has vancomycin minimum inhibitory concentrations (MICs) of 4 to 8 μg/ml, and is thought to arise from thickening of the cell wall, changes in agr function, and changes in cell metabolism that arise from subinhibitory exposure to vancomycin. VRSA have higher MICs (≥16 μg/ml) due to a gene (vanA) that has been passed from vancomycin-resistant Enterococcus faecalis to S. aureus. Clinical isolates of VRSA (six so far) have been reported in the United States of America only. Although new agents (linezolid and daptomycin) exist for therapy of MRSA and could be used for VISA/VRSA, fledgling resistance has been reported.

Resistance to antimicrobials in the macrolide–lincosamide–streptogramin (MLS) group is not predictably concordant. Clindamycin resistance can be inducible, producing misleading susceptibility phenotypes in automated testing that are erythromycin resistant and, seemingly but erroneously, clindamycin susceptible, or constitutive (readily detected resistance to erythromycin and clindamycin). The double-disc diffusion test, or D test, will detect inducible clindamycin resistance. Clindamycin therapy is unreliable in organisms with either inducible or constitutive resistance.

Among the coagulase-negative staphylococci, 80% of isolates are resistant to methicillin due to the action of mecA. Laboratory testing of coagulase-negative staphylococci is complicated by heterotypic expression of methicillin resistance, which may lead to deceptively low methicillin MICs. PCR testing for mecA or slide agglutination testing for PBP2a will reveal resistance; methicillin or oxacillin will not effectively treat such strains.

Epidemiology of Staphylococcus aureus

Colonization

Among staphylococci, as a general rule, colonization precedes infection. S. aureus colonizes multiple sites but predominately the anterior nares. Some CA-MRSA may share the ability of coagulase-negative staphylococci to colonize intact skin. Among adults, 20% are persistently colonized by S. aureus, 60% are intermittently colonized, and 20% are never colonized. Methicillin-susceptible S. aureus (MSSA) colonization prevalence rates are about 30% in the community. High-risk groups for S. aureus colonization include infants, insulin-dependent diabetics, intravenous drug users, HIV-positive patients, and patients undergoing either haemodialysis or peritoneal dialysis. Host factors promoting colonization may be antibiotic treatment and polymorphisms in host genes.

Health care-associated MRSA

Health care-associated MRSA infection causes significant morbidity and mortality, and has been associated with 29% longer stays and 36% greater hospital charges for patients with MRSA compared to MSSA bacteraemia. Among hospitalized patients, risk factors for MRSA colonization and infection include antibiotic exposure, surgery, nursing home residence, or high MRSA ‘colonization pressure’, i.e. frequent exposure to colonized or infected patients.

There is a large ‘resistance iceberg’ for MRSA; the ratio of infected-to-colonized patients may reach 1:3, which complicates control measures. Uncleaned hands of health care workers probably represent a major vector for MRSA cross-transmission. Another mechanism of staphylococcal transmission is bacterial shedding from nares of colonized patients or staff, which can be enhanced by rhinitis. Spread via contaminated environmental surfaces may account for an additional 10 to 15% of MRSA transmissions in health care settings.

CA-MRSA

MRSA are no longer exclusively nosocomial pathogens. They have been affecting people without exposure to health care. Although CA-MRSA colonization rates have lagged behind those of MSSA, infection rates for those colonized with CA-MRSA are up to 10 times higher than rates for those colonized with MSSA.

Worldwide, CA-MRSA infections have been mainly due to only a few PFGE types, e.g. USA300 strain. Rates of infection with USA300 CA-MRSA are rising and in some locations have exceeded MSSA infection rates. Risk factors for infection or colonization with CA-MRSA include African American race, HIV infection, drug use, tattooing, and situations and environments associated with increased person-to-person contact such as military service, jails, homosexual contacts, sports activity, and children’s day care.

Secular trends and morbidity

Overall trends in hospitalizations for S. aureus infections suggest an increasing burden of illness. Trends fostering increases include aging of populations in western societies with increased comorbidities and use of prosthetic devices such as joint replacements; the emergence of CA-MRSA, which is occurring in addition to, not in place of, community-associated MSSA; and use of broad-spectrum antibiotics. In the United States of America, it has been estimated that about 9 of every 1000 hospitalizations may be due to S. aureus, and about 43% of S. aureus admissions are due to MRSA. Mortality rates among patients infected with S. aureus are 15 to 34% in various studies. Clinical factors enhancing the likelihood of death include pneumonia, older age, diabetes, inadequate therapy, and failure to drain infected foci. With spread of CA-MRSA into hospitals, the epidemiology and control of nosocomial MRSA may change.

Prevention: Staph aureus

General interventions

Prevention of illness due to S. aureus, particularly MRSA, relies on proactive infection control measures. These may include surveillance for MRSA colonization to detect the resistance iceberg, barrier precautions (use of gowning and gloving) for care of infected and colonized patients, imposed grouping (cohorting) of infected and colonized patients, isolation wards, improved hand hygiene, antimicrobial stewardship, cleaning patients with chlorhexidine, improved environmental cleaning, and use of intensive care unit ‘monitors’ to promote adherence to infection control measures.

MRSA

Studies of MRSA control suggest that multiple simultaneous interventions can reduce colonization and infection rates. Highly promoted among packages or bundles of interventions are hospital admission surveillance nasal cultures for MRSA colonization. These are recommended in high-risk units or when other control measures fail to reduce MRSA infection rates. The role of decolonization of patients detected by surveillance is currently controversial. The strongest support for decolonization comes from outbreak investigations, particularly in neonatal units. The risks/benefits of screening and decolonization programmes, and their impact on overall nosocomial infection rates, warrant evaluation.

CA-MRSA

Control of CA-MRSA presents distinct challenges. The feasibility of contact precautions or isolation of infected persons in the community may be limited. Additionally, the role of fomites in transmission of CA-MRSA is unknown, and community environmental decontamination may be difficult. Current guidelines for people with CA-MRSA infections and their community contacts include proper dressings for infected areas, hand hygiene, washing clothes contaminated with infected secretions, and avoiding contact sports while lesions exist. If infection is recurrent or spreading in specific settings, such as families, search for and decolonization of carriers may be useful.

Agents useful for decolonization

Potential agents used for staphylococcal decolonization include topical agents (mupirocin, chlorhexidine, tea tree oil) or short courses of systemic antimicrobials. Mupirocin 2% is effective for decolonization but has not been shown to reduce nosocomial infection rates and is of limited use when mupirocin resistance occurs. Tea tree oil, from the Ti (or Tea) tree (Melaleuca alternifolia, Myrtaceae), has been effective for some colonized patients. Chlorhexidine gluconate has potent antibacterial effects for decolonizing skin or as a nasal gel. Assiduous application of approved detergents/disinfectants or bleach can decontaminate the environment.

Clinical features: Staph aureus

Risk factors for infection

Groups commonly at risk of colonization and infection include AIDS patients, intravenous drug users, and patients with diabetes mellitus. Multiple risk factors for S. aureus infection often coexist. For example, haemodialysis and peritoneal dialysis patients are at increased colonization risk and have high-risk foreign bodies. Conditions that predispose specifically to tissue invasion include skin trauma, haematomas, burns, or chronic diseases (e.g. dermatitis or psoriasis); surgical wounds; indwelling vascular catheters; and postviral sequelae such as influenza-related mucosal damage. Rarer conditions associated with increased risks of staphylococcal infection include Chédiak–Higashi syndrome and Job’s syndrome.

Clinical syndromes

S. aureus infection syndromes can be divided into three groups: (1) illness due to release of toxins, leading to disease at sites often remote from infection; (2) illness due to local tissue destruction and abscess formation; and (3) haematogenous infection. Therapy for these syndromes is based on the use of active drugs at appropriate dosages with appropriate concern for common side effects and toxicities.

Toxin-related syndromes
Staphylococcal scalded skin syndrome

In 1878, staphylococcal scalded skin syndrome (SSSS), or Ritter’s disease, was described in 297 children by the German physician Ritter von Rittershain. After release of epidermolytic toxins by S. aureus, patients develop bullae and desquamation. Though clinically impressive, this superficial desquamation can be distinguished clinically and histologically from deeper exfoliative illnesses such as toxic epidermal necrolysis (TEN). In SSSS, skin separation occurs within the epidermis, at the stratum granulosum, while in TEN, separation occurs deeper, at the dermal–epidermal junction, leading to more severe skin loss. The absence of mucosal disease in SSSS also distinguishes these syndromes.

SSSS occurs more commonly in children. Disease may be generalized or localized (i.e. bullous impetigo), and the burden of S. aureus may be low. Nasal or mucosal colonization may cause disease. When cases occur in epidemics, such as in neonatal units, patients and health care workers should be screened for carriage. Diagnosis relies on the characteristic clinical and epidemiological features and is supported by identification of exotoxin-positive strains colonizing or infecting clinical sites. Treatment involves topical or systemic antibiotics for infected sites and supportive care for areas of skin/soft tissue destruction.

Food-borne illness due to preformed toxin

S. aureus can produce a heat-stable superantigen toxin that can persist even after cooking has eradicated the organism. Ingestion of toxin in contaminated, often unrefrigerated, food can result in epidemic gastrointestinal disease. There is a short incubation of only 2 to 6 h, followed by sudden vomiting (82%), diarrhoea (68%), and occasionally fever (16%). The differential diagnosis includes other short-incubation toxin-mediated gastrointestinal pathogens such as Bacillus cereus and toxins (Chapter 9.2). Treatment involves supportive care, particularly rehydration. The illness is typically self-limited, lasting less than 12 h.

Toxic shock syndrome

Staphylococcal toxic shock syndrome is caused by superantigen toxins released by S. aureus, resulting in multisystem organ dysfunction. Staphylococcal toxic shock is clinically similar to streptococcal toxic shock (high fever, mental confusion, erythroderma, diarrhoea, hypotension, and renal failure), but streptococcal toxic shock is typically associated with invasive infection such as necrotizing fasciitis while staphylococcal toxic shock may be precipitated by clinically minor infections that are overshadowed by the systemic effects of the toxin.

Staphylococcal toxic shock occurs in two major forms, menstrual (e.g. tampon-associated) and nonmenstrual. In women with vaginal colonization by S. aureus, it is presumably the favourable microenvironment during menses that leads to increased production of toxin (TSST-1).

Management of staphylococcal toxic shock relies on systemic antimicrobial therapy (Table 1), supportive care, and prompt drainage of infected/colonized foci. Common adjunctive therapies such as intravenous immunoglobulin to bind free toxin and antibacterials (especially clindamycin) with activity at the ribosome, which decreases bacterial protein (toxin) synthesis, have a theoretical rationale and some support from animal models; however, clinical data are limited.

Illness due to local tissue invasion/destruction

S. aureus and β-haemolytic streptococci cause approximately 80% of soft tissue infections. S. aureus is the aetiological agent of 37 to 65% of native monoarticular joint infections in healthy adults and of 75% of joint infections in rheumatoid arthritis. Osteomyelitis, either of haematogenous or contiguous origin, is caused by S. aureus or coagulase-negative staphylococci in more than 50% of cases. Any local infection can lead to secondary bacteraemia and haematogenous seeding of distant sites.

Impetigo, folliculitis, and cellulitis

The most superficial S. aureus infections are impetigo, folliculitis, and cellulitis. Impetigo is limited to the epidermis, folliculitis to the hair follicles, and cellulitis to the dermis and/or the subcutaneous fat. Impetigo can appear as small round honey-crusted lesions on the skin, primarily on exposed areas. Impetigo typically is caused by streptococci; in the United Kingdom, S. aureus is an infrequent cause. However, bullous impetigo is a clinical variant (caused by S. aureus phage type 71), reported in up to 10% of impetigo cases. Initially, the lesions can be vesicles that enlarge into bullae containing clear or yellow fluid.

Table 1 Therapy of toxic shock due to S. aureus
Drug Dosage Duration/comment
For penicillin-susceptible S. aureus:
  • Duration based on focus of infection
  • Adequate drainage is critical
  • Data to support adjunctive use of immunoglobulin and/or clindamycin are needed
Penicillina 2–4 MU IV every 4 h
Ampicillin 1–2 g IV every 4–6 h
Ampicillin + sulbactam 1.5–3 g IV every 6 h
For methicillin-susceptible S. aureus:
Oxacillin/flucloxacillina 1–2 g IV every 4–6 h
Cefazolin 1–2 g IV every 8 h
For methicillin-resistant S. aureus (or β-lactam allergy):
Vancomycina 1 g IV every 12 h
Clindamycinb 600 mg IV every 8 h
Daptomycin 6 mg/kg IV every 24 h
Teicoplanin At least 400 mg IV BID
Linezolidb 600 mg IV every 12 h
Quinupristin/dalfopristin 7.5 mg/kg every 12 h
Intravenous immunoglobulin Dosage not standardized

BID, twice daily; IV, intravenously.

a First-line agent.

b These agents may be useful for reduction of protein synthesis and toxin production, but require further study.

Cellulitis is typically due to streptococci, but when associated with penetrating trauma, furuncles, or carbuncles S. aureus should be considered. Diagnosis depends on the clinical appearance and the presence of purulence that can be cultured. However, aspirates of cellulitic areas are positive in fewer than one-third of cases and bacteraemia is rare.

Treatment of impetigo (Table 2) should reflect local antibiotic resistance patterns. Topical therapy may be effective for limited disease, though EMRSA-16, one of two predominant MRSA types in the United Kingdom, often shows high-level mupirocin resistance. Systemic therapy should be used in patients with impetigo who have many lesions or who fail topical therapy. In areas where CA-MRSA prevalence exceeds 10%, initial therapy should be directed by local susceptibility patterns.

Suspicion of more invasive infection, such as necrotizing fasciitis, should be high in cases of soft tissue infections with disproportionate pain, bullae, haemorrhagic or necrotic lesions, cutaneous anaesthesia, rapid progression of lesions, gas in the tissues, presence of risk factors, and when laboratory tests show elevated creatine kinase, acidosis, leucocytosis, or C-reactive protein exceeding 13 mg/litre. Necrotizing infections should prompt inpatient antibiotic therapy assuming MRSA and urgent surgical consultation.

Furuncles and carbuncles

Furuncles and carbuncles are deep suppurative infections that occur in the dermis and originate at hair follicles. Infection can be limited to small lesions that appear as painful nodules, sometimes with necrotic centres. Confluence leads to the formation of carbuncles. Several members of a family may be affected. Mild lesions cause limited systemic complaints, whereas fever, malaise, or symptoms and signs of sepsis can occur with extensive disease.

Table 2 Therapy of impetigo and mild soft tissue lesions caused by S. aureus
Therapy Drug Dosage Duration
Topical Mupirocin 2% ointment TID 14 days
Fusidic acid 2% cream TID
Oral For penicillin-susceptible S. aureus: 5 days
Amoxicillin 250–500 mg PO TID or 875 mg PO BID
Amoxicillin + clavulanate 250–500 mg PO TID or 875 mg/125 mg PO BID
Penicillin VKa 250–500 mg PO QID
For methicillin-susceptible S. aureus:
Dicloxacillina 250 mg PO QID
Cefalexin 500 mg PO QID
For methicillin-resistant S. aureus (or b-lactam allergy):
Clindamycin (Erys, Clins, or D-test negative) 300–450 mg PO QID
Trimethoprim/sulfamethoxazole 1–2 double-strengthb tablets PO BID
Doxycycline 100 mg PO BID
Minocycline 100 mg PO BID
Linezolid 600 mg po BID

BID, twice daily; Clins, clindamycin-sensitive; D, double-disc diffusion; Erys, erythromycin-sensitive; PO, by mouth; QID, four times daily; TID, three times daily.

a First-line agent.

b 160 mg trimethoprim and 800 mg sulfamethoxazole in a double-strength tablet.

Furunculosis is caused increasingly by the emerging pathogen CA-MRSA and has been attributed to the presence of PVL toxin, although the causal role requires validation. Additionally, toxin-containing S. aureus has been associated with more fulminant courses in which skin lesions, pneumonia, a sepsis-like picture, or even Waterhouse–Friderichsen syndrome occur. PVL occurs in about 2% of MSSA and most CA-MRSA.

Drainage, spontaneously or surgically, is the mainstay of therapy. Early furuncles may be treated by application of moist heat to stimulate drainage. Lesions on the face, lesions with cellulitis (especially exceeding 5 cm in diameter), or the presence of systemic symptoms and/or signs (fever, chills, or haemodynamic changes) should lead to use of antistaphylococcal antibiotics (Table 3) in addition to drainage. Oral agents are sufficient in most cases, but in severe infections or for bacteraemia parenteral agents should be used.

Mastitis

Mastitis is most commonly caused by S. aureus, occurs in 1 to 3% of nursing mothers typically within 3 weeks of birth, and may lead to breast abscesses. Infection can appear as a painful nodule or a draining abscess. Therapy (Table 3) should include topical moist heat, oral antimicrobials with efficacy against S. aureus (and MRSA in endemic areas), and abscess incision and drainage.

Pyomyositis

Pyomyositis, or primary bacterial abscess of skeletal muscle, is most common in the tropics where ‘tropical pyomyositis’ can account for 1 to 4% of hospital admissions. In nontropical areas the syndrome is uncommon. S. aureus is the cause in about 95% of tropical cases and about 70% of other cases. Associations are with muscle trauma (20–50% of cases), HIV infection, and possibly Toxocara canis infection.

Symptoms develop subacutely over 2 to 3 weeks with variable degrees of fever, muscle pain, swelling, and induration. Large lower extremity and trunk muscles are most commonly affected. Regional lymphadenopathy is typically absent. Diagnosis relies on clinical suspicion, helpful radiographic findings (i.e. gas or soft tissue swelling on plain radiographs, abscess or muscle enlargement on ultrasound examination, inflammation, oedema, or focal abscess in muscles on MRI or CT, and the results of aspirating the lesion. Antibacterial therapy for S. aureus (Table 3) and open or radiographically assisted percutaneous drainage of abscesses are essential parts of therapy.

Septic bursitis

Infection can occur in any of the approximately 160 bursae found in humans, but septic bursitis usually affects prepatellar or olecranon bursae, usually is a result of trauma. It is due to S. aureus in more than 80% of cases but is accompanied by bacteraemia in 8% or less. Diagnosis relies on clinical recognition of the characteristic findings of fever and pain, swelling, redness, and warmth in the area of an affected bursa. Leucocytes and S. aureus are found if there is enough bursal fluid to aspirate.

Treatment of septic bursitis includes appropriate antimicrobials (Table 4) and, if possible, drainage. Treatment failures have been described when erythromycin is used as the sole agent. Localized infection with no systemic signs may be treated with oral therapy, since high antimicrobials levels are achieved in bursal fluid. Adequate drainage is important. Patients with systemic signs or symptoms or who are immunocompromised should receive parenteral therapy.

Patients who present within 7 days of developing symptoms may be treated successfully with antibiotics and aspiration every 1 to 3 days. In this situation, bursal fluid may become sterile within 4 days and therapy should be continued for an additional 5 days. Surgical intervention is needed only for patients whose fluid remains infected or cannot be aspirated because the bursa is deep, who have foreign or necrotic material in the bursal space, or who need exploration or removal of the bursa because of recurrences.

Septic arthritis

S. aureus is the most common cause of nonprosthetic monoarticular septic arthritis. The typical pathogenesis is haematogenous seeding, but traumatic direct inoculation can occur. Important differential diagnoses include gonococcal infection in adolescents and adults and urosepsis pathogens and crystal-induced arthropathies in older patients. Because joint destruction is rapid, prompt diagnosis through joint aspiration is essential.

The mainstays of therapy are antimicrobials (Table 4) and prompt joint drainage by serial aspiration; arthroscopy (preferred for knee, shoulder, and ankle) with irrigation, lysis of adhesions, and removal of purulent material; or open drainage (useful for hip or shoulder infections to protect blood supply to femoral or humeral heads, and in instances where repeated aspirates or arthroscopy fail). S. aureus can be a cause of infected prosthetic joints, which may have a more indolent atypical presentation.

Table 3 Therapy of cellulitis, abscess, mastitis, furunculosis, and pyomyositis caused by S. aureus
Therapy Drug Dosage Duration/comment
Oral For penicillin-susceptible S. aureus:
  • 5 days for cellulitis
  • For deeper infection duration depends on proper drainage when necessary and clinical response
  • With incision and drainage, lesions with <5 cm of cellulitis in immunocompetent patients may be cured without systemic antibiotics
  • For deeper infection duration depends on proper drainage when necessary and clinical response
  • Early change to oral therapy may be employed in stabilizing, nonbacteraemic patients
  • May have a future role
Amoxicillin 250–500 mg PO TID or 875 mg PO BID
Amoxicillin + clavulanate 250–500 mg PO TID or 875 mg/125 mg PO BID
Penicillin VKa 250–500 mg PO QID
For methicillin-susceptible S. aureus:
Dicloxacillina 500 mg PO QID
Cefalexin 500 mg PO QID
For methicillin-resistant S. aureus (or b-lactam allergy):
Clindamycin (Erys, Clins, or D-test negative) 300–450 mg PO QID
Trimethoprim/sulfamethoxazole 1–2 double-strengthb tablets PO BID
Doxycycline 100 mg PO BID
Minocycline 100 mg PO BID
Linezolid 600 mg PO BID
Erythromycinc 250 mg PO every 6 h or 500 mg PO every 12 h
Parenteral For penicillin-susceptible S. aureus:
Penicillina 2–4 MU IV every 4 h
Ampicillin 1–2 g IV every 4–6 h
Ampicillin + sulbactam 1.5–3 g IV every 6 h
For methicillin-susceptible S. aureus:
Oxacillin/flucloxacillina 1–2 g IV every 4–6 h
Cefazolin 1–2 g IV every 8 h
For methicillin-resistant S. aureus (or b-lactam allergy):
Vancomycina 1 g IV every 12 h
Erythromycinc 250 mg IV every 6 h or 500 mg IV every 12 h
Clindamycin (Erys, Clins, or D-test negative) 600 mg IV every 8 h
Linezolid 600 mg IV every 12 h
Daptomycin 4 mg/kg IV every 24 h
Quinupristin/dalfopristin 7.5 mg/kg every 12 h
Tigecycline 100 mg initially, then 50 mg IV every 12 h
Dalbavancin, oritavancin, telavancin  

BID, twice daily; Clins, clindamycin-sensitive; D, double-disc diffusion; Erys, erythromycin-sensitive; PO, by mouth; QID, four times daily; TID three times daily; IV, intravenously.

a First-line agent.

b 160 mg trimethoprim and 800 mg sulfamethoxazole in a double-strength tablet.

c In many areas high rates of resistance should prevent empiric use of erythromycin.

Osteomyelitis

S. aureus osteomyelitis results from bacteraemia or contiguous spread from a soft tissue focus or chronic ulcer. Risk groups are patients with diabetes mellitus, those with vascular disease or at risk for haematogenous infection (i.e. haemodialysis), children, and elderly people.

Diagnosis usually depends on radiographic studies. Plain radiographs may show evidence of periosteal reaction, and nuclear triple-phase imaging may demonstrate focal persistent uptake in bone. The most sensitive test for osteomyelitis is MRI, which will demonstrate changes within bone and bone marrow. The most specific test is CT, which will reveal the presence of periosteal reaction or other bony changes not evident on plain radiographs. ‘Probing to bone’ in the case of a chronic ulcer is highly sensitive for a diagnosis of osteomyelitis. The microbiological diagnosis of osteomyelitis relies on positive blood or bone cultures; superficial wound or sinus track culture results are not reliable and may be misleading.

Table 4 Therapy of septic bursitis and septic arthritis caused by S. aureus
Therapy Drug Dosage Duration/comment
Oral For penicillin-susceptible S. aureus: For septic bursitis, continue therapy for 5 days after aspirates become sterile (with early change to oral therapy in nonbacteraemic patients). For septic arthritis, therapy should be continued for 4 weeks
Amoxicillin 250–500 mg PO TID or 875 mg PO BID
Amoxicillin + clavulanate 250–500 mg PO TID or 875 mg/125 mg PO BID
Penicillin VKa 250–500 mg PO QID
For methicillin-susceptible S. aureus:
Dicloxacillina 500 mg PO QID
Cefalexin 500 mg PO QID
For methicillin-resistant S. aureus (or b-lactam allergy):
Clindamycin (Erys, Clins, or D-test negative) 300–450 mg PO QID
Trimethoprim/sulfamethoxazole 1–2 double-strengthb tablets PO BID
Doxycycline 100 mg PO BID
Minocycline 100 mg PO BID
Ciprofloxacin or levofloxacin 500 mg PO BID or 500 mg PO once daily
With  
Rifampin 300 mg PO every 12 h
Linezolid 600 mg PO BID
Erythromycinc 250 mg PO every 6 h or 500 mg PO every 12 h
Parenteral For penicillin-susceptible S. aureus:
Penicillina 2–4 MU IV every 4 h
Ampicillin 1–2 g IV every 4–6 h
Ampicillin + sulbactam 1.5–3 g IV every 6 h
For methicillin-susceptible S. aureus:
Oxacillin/flucloxacillina 1–2 g IV every 4–6 h
Cefazolin 1–2 g IV every 8 h
For methicillin-resistant S. aureus (or b-lactam allergy):
Vancomycina 1 g IV every 12 h
Linezolid 600 mg IV every 12 h

BID, twice daily; Clins, clindamycin-sensitive; D, double-disc diffusion; Erys, erythromycin-sensitive; PO, by mouth; QID, four times daily; TID three times daily; IV, intravenously.

a First-line agent.

b 160 mg trimethoprim and 800 mg sulfamethoxazole in a double-strength tablet.

c In many areas high rates of resistance should prevent empiric use of erythromycin.

Therapy for osteomyelitis includes drainage of pus (acute osteomyelitis) or debridement of areas of avascular or ‘dead’ bone (sequestra in chronic osteomyelitis) and antibacterials with activity against the culture-proven pathogen(s). The duration of therapy sufficient to eradicate the organism and prevent relapse is based on common experience and usually is 4 to 6 weeks. Children with acute haematogenous S. aureus osteomyelitis may be treated with surgical drainage of purulent collections and short-course intravenous therapy (e.g. 1 week) followed by oral therapy for 4 to 6 weeks as outpatients. Initial choice for therapy is based on the presence of MSSA or MRSA (Table 5); copathogens may require broader therapy. An open-label study showed that for diabetic foot infections, linezolid performed as well as ampicillin–sulbactam for infected ulcers or osteomyelitis.

Epidural abscess

Epidural abscesses occur adjacent to vertebral osteomyelitis and are medical/surgical emergencies. Enlarging epidural sites can compress the spinal cord or reduce vascular supply through thrombophlebitis. About 50% of cases follow haematogenous spread from known or occult trauma or from parenteral use of illicit drugs, while about 30% result from contiguous spread. S. aureus accounts for more than 60% of cases. Risks for MRSA infection include recent health care exposure or rising CA-MRSA rates.

Symptoms and physical findings progress at variable rates, sometimes rapidly, through four stages: (1) back pain at the infected level, (2) pain radiating in the distribution of affected nerve roots, (3) motor weakness (including bladder and bowel dysfunction) and sensory deficit at the appropriate level, and (4) paralysis. The triad of back pain, fever, and neurological findings is highly suggestive of epidural abscess.

MRI or CT scanning is most useful for evaluating epidural abscesses. For diagnosis and therapy, a space-occupying lesion in the epidural space requires surgical evaluation and emergency laminectomy/decompression or drainage by interventional radiography. Preoperative neurological status predicts outcome. Broad empirical antimicrobial therapy should include coverage for MRSA (Table 6) and Gram-negative bacilli. if MSSA infection is diagnosed, β-lactams are preferred over glycopeptides.

Table 5 Therapy of osteomyelitis caused by S. aureus
Therapy Drug Dosage Duration
Parenteral For penicillin-susceptible S. aureus: 4–6 weeks IV
Penicillina 2–4 MU IV every 4 h
Ampicillin 1–2 g IV every 4–6 h
Ampicillin + sulbactam 1.5–3 g IV every 6 h
For methicillin-susceptible S. aureus:
Oxacillin/flucloxacillina 1–2 g IV every 4–6 h
Cefazolin 1–2 g IV every 8 h
For methicillin-resistant S. aureus (or b-lactam allergy):
Vancomycina 1 g IV every 12 h
Linezolid 600 mg IV every 12 h

IV, intravenously.

a First-line agent.

Pneumonia

S. aureus pneumonia can result from haematogenous spread or direct inoculation following mucosal damage. S. aureus causes less than 10% of cases of community-acquired pneumonia but causes approximately 20 to 30% of cases of nosocomial pneumonia. Case fatality of S. aureus pneumonia ranges from 8% to more than 30%. Risks for a more severe course include MRSA, acute respiratory distress syndrome (ARDS), comorbidities, and renal dysfunction.

S. aureus is a cause of postviral, particularly postinfluenzal, pneumonia. Patients may report a biphasic illness. CA-MRSA may cause a necrotizing pneumonia with more severe course. Additionally, S. aureus pneumonia may be associated with complications such as empyema, lung abscesses, and bronchopleural fistulae. Lung abscess must be differentiated radiographically from pneumatocele, a common and relatively benign complication of staphylococcal pneumonia.

Diagnostic studies for patients with pneumonia in the presence of staphylococcal bacteraemia or embolic-appearing lesions on chest imaging should seek an intravascular source (e.g. endocarditis or infectious thrombophlebitis). Therapy (Table 7) should include use of an active drug for at least 8 days in less complicated cases or longer if pulmonary involvement is secondary to an intravascular infection, presence of MRSA, or complications such as emboli or empyema. Surgical drainage is indicated for empyema. Daptomycin should be avoided because of its poorer activity in pulmonary infections. Linezolid may emerge as a drug of choice for MRSA pneumonia based on its greater penetration due to smaller molecule size and putative clinical benefit.

Urinary tract infections

S. aureus urinary tract infections (UTIs) result from ascending infection in catheterized patients or haematogenous seeding, which may lead to renal carbuncles (abscesses). Staphylococcal UTIs should prompt consideration of sources of bacteraemia such as endovascular infection. Clinically, patients with renal abscesses have fever and flank pain, but urinary complaints may be absent and urinalyses and urine cultures may be negative. Renal ultrasonography or CT may show a range of findings from ‘lobar nephronia’ (renal phlegmon) to large multilocular abscesses. Treatment may require percutaneous or open drainage; antimicrobial therapy (Table 8) should reflect results of cultures.

Table 6 Therapy of epidural abscess caused by S. aureus
Therapy Drug Dosage Duration
Parenteral For penicillin-susceptible S. aureus: ≥6 weeks IV
Penicillina 2–4 MU IV every 4 h
Ampicillin 1–2 g IV every 4–6 h
Ampicillin + sulbactam 1.5–3 g IV every 6 h
For methicillin-susceptible S. aureus:
Oxacillin/flucloxacillina 1–2 g IV every 4–6 h
Cefazolin 1–2 g IV every 8 h
For methicillin-resistant S. aureus (or b-lactam allergy):
Vancomycina 1 g IV every 12 h
Linezolid 600 mg IV every 12 h
Daptomycin 6 mg/kg IV every 24 h

IV, intravenously.

a First-line agent.

Haematogenous infections
Bacteraemia

S. aureus is among the commonest causes of bacteraemia in hospitals and the community. It causes 18 to 27% of endocarditis cases, is responsible for 13% of nosocomial bloodstream infections, and causes up to 78% of cases of intravascular catheter-related thrombophlebitis. Rates of community-associated S. aureus bacteraemia in the United States of America are estimated at 17/100 000 people, similar to rates of invasive Streptococcus pneumoniae infection, with mortality of 10 to 20%, depending on underlying illnesses. In Oxfordshire, England, the incidence of nosocomial MRSA bacteraemia increased from 50/100 000 admissions in 1997 to 300/100 000 admissions in 2004, increasing the overall burden of S. aureus disease.

S. aureus in blood should always be considered a true pathogen. Bacteraemia has traditionally been categorized as ‘health care-associated’ (i.e. onset more than 2 days after admission) and ‘community-associated’ (i.e. onset within 2 days of admission). Complications of bacteraemia include endocarditis (itself a major cause of bacteraemia) and ‘metastatic’ seeding of distant sites, especially joints, bone, kidney, and skin. An estimated 13% of nosocomial bacteraemias with S. aureus include endocarditis.

Table 7 Therapy of pneumonia due to S. aureus
Drug Dosage Duration/comment
For penicillin-susceptible S. aureus:
  • 8–14 days for uncomplicated infection
  • Requires longer courses if empyema, lung abscess, or bacteraemia present
Penicillina 2–4 MU IV every 4 h
Ampicillin 1–2 g IV every 4–6 h
Ampicillin + sulbactam 1.5–3 g IV every 6 h
For methicillin-susceptible S. aureus:
Oxacillin/flucloxacillina 1–2 g IV every 4 h
Cefazolin 1–2 g IV every 8 h
For methicillin-resistant S. aureus (or b-lactam allergy):
Vancomycina 1 g IV every 12 h
Linezolid 600 mg IV every 12 h

IV, intravenously.

a First-line agent.

The principles of therapy for S. aureus bacteraemia include evaluation for endocarditis; use of a parenteral agent; removal of infected foci (i.e. catheters or abscesses); and use of a bactericidal agent, preferably a β-lactam, whenever possible. Occasionally, uncomplicated bacteraemia with drainage of infected foci and no embolic sites may respond to only 14 days of therapy (Table 9), however, more often, prolonged bacteraemia, residual disease, undrained foci of infection, infected clots, or endocarditis all warrant longer therapy (at least 4 weeks).

Endocarditis 

Many features of endocarditis are nonspecific (fever, tachycardia, arthralgias and myalgias, wasting, and back pain). Finding a new cardiac (especially diastolic) murmur or septic emboli provides strong supportive evidence. Other suggestive findings include petechiae, Janeway’s lesions, mycotic aneurysms of arterial vessels (with resultant pain, vascular leak, or adjacent deep venous thrombosis), discitis or osteomyelitis (particularly vertebral disease), and neurological complications such as septic infarcts or mycotic cerebrovascular aneurysms. Conduction abnormalities, e.g. AV delay, may be noted in the presence of myocardial abscess. In the setting of right-sided endocarditis, septic pulmonary emboli are common.

Table 8 Therapy of urinary tract infection due to S. aureus
Drug Dosage Duration/comment
For penicillin-susceptible S. aureus:
  • 7 days for ascending infection
  • ≥ 14 days for renal abscess, bacteraemia, or complicated infection (duration is based on resolution of infected foci and/or use of drainage)
Penicillina 2–4 MU IV every 4 h
Ampicillin 1–2 g IV every 4–6 h
Ampicillin + sulbactam 1.5–3 g IV every 6 h
For methicillin-susceptible S. aureus:
Oxacillin/flucloxacillina 1–2 g IV every 4 h
Cefazolin 1–2 g IV every 8 h
For methicillin-resistant S. aureus (or b-lactam allergy):
Vancomycina 1 g IV every 12 h
Linezolid 600 mg IV every 12 h

IV, intravenously.

a First-line agent.

Table 9 Therapy of bacteraemia, without endocarditis, due to S. aureus
Drug Dosage Duration/comment
For penicillin-susceptible S. aureus:
  • 14 days with removable focus of infection
  • Longer course of therapy for complicated infection
Penicillina 2–4 MU IV every 4 h
Ampicillin 1–2 g IV every 4–6 h
Ampicillin + sulbactam 1.5–3 g IV every 6 h
For methicillin-susceptible S. aureus:
Oxacillin/flucloxacillina 1–2 g IV every 4–6 h
Cefazolin 1–2 g IV every 8 h
For methicillin-resistant S. aureus (or b-lactam allergy):
Vancomycina 1 g IV every 12 h
Daptomycina 6 mg/kg IV every 24 h
Teicoplanin At least 400 mg IV BID
Linezolid 600 mg IV every 12 h
Quinupristin/dalfopristin 7.5 mg/kg every 12 h
Sodium fusidate 500 mg IV every 8 h
Dalbavancin, oritavancin, telavancin May have future role

BID, twice daily; IV, intravenously.

a First-line agent.

The presence of multiple positive blood cultures is a necessary criterion for diagnosis of endocarditis in the untreated patient. Diagnosis is aided by specific criteria (e.g. modified Duke’s criteria). Transthoracic echocardiography is indicated as a noninvasive method to evaluate the presence of cardiac vegetations in those with low pretest probability of disease; individuals with nondiagnostic studies or worsening clinical course should undergo transoesophageal echocardiogram. Patients with high clinical risk, despite nondiagnostic transoesophageal studies, should be restudied after 7 to 10 days.

Therapy for staphylococcal endocarditis requires a bactericidal antibiotic (Tables 10-12). In general, therapy should last for 4 (in uncomplicated disease) to 6 or more (in the setting of metastatic infection, perivalvular abscess, or other complications) weeks. Combination therapies (agents given with either vancomycin or β-lactams) have not been demonstrated to improve outcomes in native valve endocarditis but are commonly used. For example, the addition of gentamicin for 3 to 5 days shortens the duration of bacteraemia by about 1 day but does not influence outcome. Addition of rifampicin for bacteraemic patients with putative failure of therapy (e.g. bacteraemia or fever persisting for more than 4–5 days) is a common strategy. Rifampicin is recommended as part of the standard treatment of prosthetic valve endocarditis.

The average time to clearance of S. aureus from the bloodstream is 5 days of β-lactam or 1 week of vancomycin therapy. Prolonged bacteraemia should prompt a closer evaluation of antibiotic MICs (especially for vancomycin), a search for sequestered sites of infection or undrained foci, or a myocardial or valvular abscess. Increasing vancomycin dosing has not been demonstrated clearly to improve outcomes, although consensus supports increased trough levels of 15 to 20 mcg/ml (requiring close monitoring of renal function) for strains with upper-end susceptible MICs. Indications for surgical valve replacement include new congestive heart failure (associated with higher mortality), failure to clear the bloodstream, recurrent emboli, and myocardial or valvular abscess.

Table 10 Therapy of native valve left-sided endocarditis due to S. aureus
Drug Dosage Duration/comment
For penicillin-susceptible S. aureus: 4–6 weeks after negative cultures
Penicillina 2–4 MU IV every 4 h  
Ampicillin 1–2 g IV every 4–6 h  
Ampicillin + sulbactam 1.5–3 g IV every 6 h  
For methicillin-susceptible S. aureus:  
Oxacillin/flucloxacillina 2 g IV every 4 h  
Cefazolin 1–2 g IV every 8 h  
For methicillin-resistant S. aureus (or b-lactam allergy):  
Vancomycina 1 g IV every 12 h  
Teicoplanina At least 400 mg IV BID  
Linezolid 600 mg IV every 12 h  
Quinupristin/dalfopristin 7.5 mg/kg every 12 h  
Daptomycin 6 mg/kg IV every 24 h  
Sodium fusidate 500 mg IV every 8 h  
Trimethoprim/sulfamethoxazole 320 mg/1600 mg IV every 12 h  
Above therapies can be used with:  
Gentamicinb (3–5 days at start of therapy) 1 mg/kg IV every 8 h  

BID, twice daily; IV, intravenously.

a First-line agent.

b Gentamicin therapy is optional, and has not been demonstrated to change clinical outcomes.

Table 11 Therapy of native valve right-sided endocarditis due to S. aureus
Drug Dosage Duration/comment
β-Lactams As for left-sided disease (Table 10) 4–6 weeks after negative cultures
Vancomycina As for left-sided disease (Table 10)
Daptomycina 6 mg/kg IV every 24 h
Above therapies can be used with:
Gentamicinb 1 mg/kg IV every 8 h 3–5 days at start of therapy, or combined therapy with β-lactam for MSSA infection
Ciprofloxacin/rifampicinb 750 mg/300 mg PO BID For use in patients with tricuspid valve endocarditis who can not/will not be admitted for intravenous therapy

BID, twice daily; IV, intravenously; PO, by mouth.

a First-line agent.

b Use is indicated in only limited circumstances. Gentamicin therapy is optional and has not been shown to improve clinical outcomes.

Table 12 Therapy of prosthetic valve endocarditis due to S. aureus
Drug Dosage Duration/comment
For penicillin-susceptible S. aureus:
Penicillina 2–4 MU IV every 4 h  
Ampicillin 1–2 g IV every 4–6 h  
Ampicillin + sulbactam 1.5–3 g IV every 6 h  
For methicillin-susceptible S. aureus:
Oxacillin/flucloxacillina 2 g IV every 4 h ≥6 weeks
With    
Rifampicin 300 mg PO/IV every 8 h ≥6 weeks
And    
Gentamicin 1 mg/kg IV every 8 h 3–5 days at start of therapy
Cefazolin(second choice for MSSA) 1–2 g IV every 8 h  
For methicillin-resistant S. aureus (or b-lactam allergy):
Vancomycina 1 g IV every 12 h  
With    
Rifampicin 300 mg PO/IV every 8 h ≥6 weeks
And    
Gentamicin 1 mg/kg IV every 8 h 3–5 days at start of therapy

IV, intravenously; PO, by mouth.

a First-line agent.

Clinical syndromes: coagulase-negative staphylococci

Coagulase-negative staphylococci are generally less virulent than S. aureus. Most infections with these organisms are the consequence of medical progress, related to foreign bodies (e.g. prosthetic joints or heart valves, indwelling intravascular catheters or grafts, or peritoneal catheters), and occur in association with health care. Syndromes caused by coagulase-negative staphylococci include endocarditis (5–8% of native valve infections, c.40% of prosthetic valve infections), intravascular catheter infections (6–27% of vascular catheter infections), prosthetic joint infections (up to 38% of arthroplasty infections), peritoneal dialysis catheter infections, and postoperative ocular infections. Production of biofilm by coagulase-negative staphylococci aids infection of both intravascular and peritoneal catheters. Therapy for infections with coagulase-negative staphylococci and side effects and toxicities are outlined in Tables 13 and 14.

Bacteraemia and infected vascular catheters

Clinical features and diagnosis

Coagulase-negative staphylococci are the most commonly reported bacteria in positive blood cultures; however, unlike S. aureus, coagulase-negative staphylococci are frequently blood culture contaminants. Typical rates of blood culture contamination by skin flora are approximately 2 to 3%; higher rates may be a sign of poor phlebotomy technique.

Table 13 Therapy for coagulase-negative staphylococcal infections
Indication Drug Dosage Duration
Bacteraemia (with prompt catheter removal) Vancomycina 1 g IV every 12 h 10–14 days
Oxacillin/flucloxacillin (methicillin-susceptible S. epidermidis) 1–2 g IV every 4 h  
Bacteraemia (with attempted catheter salvage) Vancomycin catheter lock (for catheter salvage) 1–5 mg/ml vancomycin, mixed with 50–100 U heparin or normal saline, to fill catheter lumen (total 2–5 ml of solution) when catheter not in use 14 days
Vancomycina 1 g IV every 12 h 10–14 days
Oxacillin/flucloxacillin (methicillin-susceptible S. epidermidis) 1–2 g IV every 4 h  
Prosthetic valve endocarditis Vancomycina 1 g IV every 12 h ≥6 weeks
with  
   Rifampicina 300 mg PO/IV every 8 h  
and  
   Gentamicin 1 mg/kg IV every 8 h  
Oxacillin/flucloxacillin (methicillin-susceptible S. epidermidis) 1–2 g IV every 4 h  
Peritoneal dialysis-associated peritonitis Vancomycina 30–50 mg vancomycin per litre of dialysate given intraperitoneally 10–21 days
Or
Vancomycin 1 g IV once, then based on levels (keep trough >10–15 mcg/ml) 10–21 days

IV, intravenously; PO, by mouth.

a First-line agent.

Infected intravascular catheters are common sources of coagulase-negative staphylococcal bloodstream infections. However, given the association of S. epidermidis and contaminated blood cultures, a careful physical examination for signs of catheter infection is critical to determine whether a single positive blood culture represents true infection and/or an infected catheter. Suggestive findings include fever, erythema at or purulence expressible from the site of catheter insertion, or tenderness.

Methods to enhance the identification of true bloodstream infection as opposed to contamination include proper skin preparation and obtaining at least two sets of blood cultures from sites separated by location and time. The use of quantitative catheter tip cultures (more than 15 colonies) or differential time to positivity (more than 2 h) for peripheral compared to catheter-drawn blood cultures helps assess whether a catheter is infected.

Management of bacteraemia and catheter infection

An approach for management of presumed infected catheters is to remove the catheter when the index of suspicion is high and/or the patient is unstable, with insertion of a new catheter at an uninvolved site. When likelihood of infection is unclear and the patient is stable, the catheter can be changed over a guidewire and the tip cultured. Positive tip cultures should prompt removal of the replacement catheter and new catheter insertion at a different site. A negative culture may allow the replacement catheter to remain in place, although its risk of subsequent infection is increased by the exchange process.

Parenteral vancomycin is the mainstay of therapy for vascular catheters infected by methicillin-resistant coagulase-negative staphylococci, and should be continued for 7 to 14 days unless there is metastatic seeding requiring longer treatment. Antibiotic lock therapy (Table 13) may be useful in carefully selected patients for ‘line salvage’. The presence of tenderness along the course of a tunnelled catheter is highly predictive of failure of medical management and should lead to catheter removal.

Endocarditis

Multiple positive blood cultures with coagulase-negative staphylococci may indicate the presence of infective endocarditis. More than 80% of patients with prosthetic valve infection have persistent fever, deep valve involvement (e.g. infection of the sewing ring or valve dysfunction, dehiscence, or abscess), and/or cardiac conduction abnormalities. Infections within the first 6 to 12 months following surgery typically reflect acquisition of the organism in the perioperative period and may have a higher likelihood of complicated infection.

Diagnosis of prosthetic valve infection should be sought aggressively when multiple positive cultures with coagulase-negative staphylococci have been obtained in the postcardiac operative period. Physical examination usually shows fever and a new or worsening murmur or valve dysfunction. Evaluation includes serial blood cultures to document degree and persistence of bacteraemia, electrocardiography to search for conduction delay, and echocardiography or angiography for documentation of valve function. Therapy for prosthetic valve endocarditis should include parenteral vancomycin (for methicillin-resistant strains), gentamicin, and/or rifampicin (Table 13).

Table 14 Information on indications and toxicity for selected drugs
Drug class Indications/use Side effects/toxicities
Semisynthetic penicillins
  • Flucloxacillin
  • Oxacillin
Drugs of choice in penicillin-resistant MSSA infection Interstitial nephritis (which limits methicillin use in adults)
Nafcillin Not effective in MRSA infection Neutropenia (nafcillin)
Dicloxacillin  CA-MRSA may equal or exceed 50% prevalence in some areas Elevated transaminases (oxacillin, nafcillin)
 Range of prevalence of nosocomial MRSA is 2–70%  
Adequate incision and drainage of infected foci is critical  
First-generation cephalosporins
  • Cefazolin
  • Cefalexin
Alternative agents for penicillin-resistant, MSSA infection 15% cross-reaction for penicillin-allergic patients
Not effective in MRSA infection Hypersensitivity
CA-MRSA may equal or exceed 50% prevalence in some areas Eosinophilia
Range of prevalence of nosocomial MRSA is 2–70%  
Adequate incision and drainage of infected foci is critical  
Penicillins and aminopenicillins
  • Penicillin
  • Ampicillin
  • Amoxicillin
  • Ampicillin + sulbactam
  • Amoxicillin + clavulanate
Penicillin is the drug of choice in known penicillin-sensitive S. aureus infection Hypersensitivity
Duration of therapy and indications similar to those of oxacillin  
Glycopeptides
  • Vancomycin
  • Teicoplanin
  • Dalbavancin
  • Oritavancin
  • Telavancin
Indicated for MRSA infections or MSSA infections in penicillin-allergic patients 3–11% of patients given vancomycin may develop anaphylactoid reaction (i.e. ‘red man’ or ‘red-neck’ syndrome) due to overly rapid infusion
Indicated for coagulase-negative staphylococcal infections Nephrotoxicity with vancomycin (0–7% alone, 14–20+% in conjunction with aminoglycoside) and teicoplanin (5%)
MRSA that are vancomycin susceptible but have increased MIC may require higher doses Neutropenia with vancomycin (1–2%)
Vancomycin trough levels should be 10–15 mg/litre and monitored closely in the setting of renal dysfunction; ≥15 if vancomycin MIC >1 mcg/ml Erythematous rash with teicoplanin (7%)
Teicoplanin levels should be >10 mg/litre in bacteraemia and >20 mg/litre in endocarditis  
Lincosamide
Clindamycin Indicated for nonsevere MRSA infections that are erythromycin and clindamycin susceptible or that are erythromycin resistant and double-disc diffusion (D) test is negative 20% of patients develop diarrhoea
An option for nonsevere MSSA infections in penicillin-allergic patients Increased risk of Clostridium difficile-associated diarrhoea (10%)
Tetracyclines
  • Doxycycline
  • Minocycline
  • Tigecycline
Not recommended in children aged <8 years Photosensitivity
Bacteriostatic, not recommended for bacteraemia or severe infections Eosinophilia
Recent review in osteomyelitis demonstrated success rate in over 80%; retained foreign body in osteomyelitis may lead to failure SLE-like reaction with minocycline
Likely need additional agent for treatment of long duration (i.e. rifampicin or fluoroquinolone) to prevent emergence of resistance Pseudotumour cerebri or vestibular toxicity
Potency/activity of drugs: tigecycline > minocycline > doxycycline > tetracycline Antianabolic
Drug class Indications/use Side effects/toxicities
Dihydrofolate reductase inhibitors
Trimethoprim/sulfamethoxazole Higher failure rate as compared with vancomycin in MSSA endocarditis seen in one study Hypersensitivity, may progress to erythema multiforme and/or Stevens–Johnson syndrome
MRSA endocarditis success equivalent to vancomycin Macrocytic anaemia
TMP/SMX resistance may be common among nosocomial MRSA (up to 50%) but is generally uncommon among CA-MRSA (<10%)
  • Photosensitivity
  • Methaemoglobinaemia (rare)
Fluoroquinolones
  • Ciprofloxacin
  • Gatifloxacin
  • Gemifloxacin
  • Levofloxacin
  • Lomefloxacin
  • Moxifloxacin
  • Ofloxacin
  • Norfloxacin
  • Pefloxacin
  • Others
Should not be used as monotherapy due to rapid emergence of resistance Neurological (0.9–11% delirium and/or seizures)
May possibly be used with other agents (e.g. TMP/SMX, rifampicin) Arthropathy, tendinitis, tendon rupture
Ciprofloxacin or levofloxacin in combination with rifampicin may be an option for patients with uncomplicated tricuspid valve endocarditis who cannot/will not be admitted; or those with skin/soft tissue infection with CA-MRSA Hypoglycaemia
Rifamycins
Rifampicin Part of combination treatment of prosthetic valve endocarditis, or in setting of endovascular infection with a foreign body Gastrointestinal complaints
Should be used with another agent given rapid acquisition of resistance Hepatitis
Myeloid suppression
  Acute tubular necrosis or acute interstitial nephritis
  SLE-like syndrome
Macrolides
  • Erythromycin
  • Clarithromycin
  • Azithromycin
May be used in penicillin-allergic patients for skin/soft tissue infections Gastrointestinal complaints (prokinetic)
Should be used with caution based on local susceptibility to erythromycin in S. aureus and emergence of resistance QT prolongation in conjunction with other medications
Oxazolidinones
Linezolid Comparable indications to vancomycin; of use in therapy for MRSA or VISA/VRSA Myelosuppression
Data suggest better efficacy than vancomycin for pneumonia and skin/soft tissue infections with MRSA Serotonin syndrome
Has been used for bacteraemia in small open label trials Peripheral neuropathy
Bacteriostatic Lactic acidosis (due to mitochondrial toxicity)
Limited clinical experience  
Lipopeptides
Daptomycin Bactericidal Myopathy, especially with higher doses or in the setting of renal insufficiency
May have use in VISA/VRSA Resistance has been noted to develop on therapy  
Not indicated for treatment of pneumonia  
‘Noninferior’ to vancomycin for right-sided endocarditis and uncomplicated bacteraemia with S. aureus and possibly better for MRSA  
Streptogramins
Quinupristin/dalfopristin May have use in soft tissue infections, bacteraemia, or osteomyelitis in settings where other agents are not available/useful Phlebitis (30%)—limits general usefulness
May have use in MRSA or VISA/VRSA infections Arthralgias (9.1%)
Presence of inducible or constitutive clindamycin resistance (i.e. MLS resistance) may indicate elevated MICs for quinupristin/dalfopristin Myalgias (6.6%)
Drug class Indications/use Side effects/toxicities
Sodium fusidate Topical therapy for impetigo Thrombophlebitis (parenteral use)
May be used parenterally in therapy of MRSA bacteraemia or endocarditis, depending on susceptibility Reversible jaundice (parenteral use)
Should not be used in newborns Thrombocytopenia (parenteral use)

CA, community-acquired; MIC, minimum inhibitory concentration; MLS, macrolide–lincosamide–streptogramin, MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; SLE, systemic lupus erythematosus; TMP/SMX, trimethoprim/sulfamethoxazole, VISA/VRSA, vancomycin-intermediate/vancomycin-resistant S. aureus.

Peritoneal dialysis-associated peritonitis

Peritoneal dialysis catheter infection is characterized by abdominal pain, cloudy exchange fluid, and peritoneal fluid containing predominantly polymorphonuclear leucocytes (more than 100 leucocytes/mm3). To improve diagnostic yield of peritoneal dialysate fluid cultures, 2 to 3 ml of fluid can be inoculated into thioglycolate broth or blood culture bottles.

Therapy for catheter-associated S. epidermidis peritonitis depends on susceptibility results. For susceptible organisms, β-lactams, trimethoprim/sulfamethoxazole, and vancomycin have all been effective, and both parenteral and oral antibiotics have been used. However, if methicillin-resistant S. epidermidis is suspected, vancomycin therapy (Table 13) with monitoring of serum levels may be indicated. Therapy can consist of either systemic or intraperitoneal antimicrobial administration. Intraperitoneal therapy is advantageous because it allows continued ambulatory care and therapy directly to the site of infection. Catheter salvage is frequently possible, but relapses may lead to catheter removal.

Other organisms

S. saprophyticus is a common cause of UTIs (20% of UTIs in women 16–35 years old). S. lugdunensis has been reported as a cause of endocarditis, including native valves, and bloodstream infection; its true incidence is not clear given the lack of speciation of most coagulase-negative staphylococci in many laboratories. S. lugdunensis infections have been characterized by a clinical course more like that of S. aureus, with valve destruction a prominent part of the illness.

Likely developments in the near future

Future directions in the management of S. aureus infections include vaccine development, new antimicrobials, enhanced understanding of epidemiology and control of nosocomial-associated and CA-MRSA, and evaluation and control of the emergence of VISA/VRSA. A bivalent vaccine containing S. aureus polysaccharides 5 and 8 briefly reduced risk of bacteraemia in haemodialysis recipients in a prospective study published in 2002. Further testing of booster doses of the vaccine to demonstrate increased efficacy is in progress. An additional target for vaccine synthesis is the PVL toxin, which may provide protection against CA-MRSA. Another preventive measure may be screening for nasal or skin colonization with MRSA, with subsequent decolonization of colonized persons. However, populations that require screening (i.e. universal or targeted screening), actions to pursue among the colonized, and efficacy and costs of such a programme are all variables that require further clarification. The promise of such a strategy may be control of MRSA and reduction of the costs and morbidity associated with MRSA infection.

New glycopeptides (telavancin, oritavancin, and dalbavancin) and existing agents with evolving indications (daptomycin, linezolid) may improve treatment options for MRSA and VISA/VRSA. Better strategies for treatment and salvage of infected catheters with catheter coating (e.g. with chlorhexidine) or methods for treatment of biofilm may improve treatment of coagulase-negative staphylococci.

Further reading 

 
 
Baddour LM, et al. (2005). Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation, 111, e394–434. [Guidelines in the United States of America for the treatment of infective endocarditis, including staphylococcal endocarditis.]
 
Darouiche RO (2006). Spinal epidural abscess. N Engl J Med, 355, 2012–20. [Review of clinical features and therapy of epidural abscess.]
 
Drees M, Boucher H (2006). New agents for Staphylococcus aureus endocarditis. Curr Opin Infect Dis, 19, 544–50. [A review of new and soon to arrive therapy for S. aureus.] 
 
Elliott TS, et al. (2004). Guidelines for the antibiotic treatment of endocarditis in adults: report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother, 54, 971–81. [Guidelines in the United Kingdom for the treatment of infective endocarditis, including staphylococcal endocarditis.]
 
Fowler VG Jr, et al. (2005). Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA, 293, 3012–21. [Interesting data regarding the epidemiology of S. aureus endocarditis.]
 
Gemmell CG, et al. (2006). Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother, 57, 589–608. [United Kingdom review of the evidence for practices in control and treatment of MRSA infection.]
 
Grundmann H, et al. (2006). Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet, 368, 874–85. [A recent review of the emergence of community-associated MRSA infections.]
 
Heldman AW, et al. (1996). Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy. Am J Med, 101, 68–76. [A comparison of oral ciprofloxacin with rifampin vs parenteral agents in the treatment of right-sided endocarditis.]
 
Huang SS, Datta R, Platt R (2006). Risk of acquiring antibiotic-resistant bacteria from prior room occupants. Arch Int Med. 166, 1945–51. [Evidence to support the risk of nosocomial and environmental spread of MRSA.]
 
Klevens RM, et al. (2006). Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 1992–2003. Clin Infect Dis, 42, 389–91.
 
Lipsky BA, Itani K, Norden C (2004). Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Inf Dis, 38, 17–24. [A trial examining linezolid in the treatment of diabetic foot infections.]
 
Markowitz N, Quinn EL, Saravolatz LD (1992). Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Ann Int Med, 117, 390–8. [Parenteral trimethoprim/sulfamethoxazole is compared with vancomycin in this double-blind randomized trial.]
 
Mermel LA, et al. (2001). Guidelines for the management of intravascular catheter-related infections. Clin Inf Dis, 32, 1249–72. [Guidelines for the treatment of catheter-related bloodstream infections; includes information about antibiotic lock in coagulase-negative staphylococcal infections.]
 
Mulligan ME, et al. (1993). Methicillin-resistant Staphylococcus aureus: a consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and management. Am J Med, 94, 313–28. [A review of nosocomial MRSA colonization and infection. Reviews strategies for decolonization of carriers.][CrossRef] 
 
Ruhe JJ, et al. (2005). Use of long-acting tetracyclines for methicillin-resistant Staphylococcus aureus infections: case series and review of the literature. Clin Inf Dis, 40, 1429–34. [A review of tetracyclines in treatment of MRSA infections.]
 
Safdar N, Fine JP, Maki DG (2005). Meta-analysis: methods for diagnosing intravascular device-related bloodstream infection. Ann Int Med, 142, 451–66. [Summary of studies and most effective methods for diagnosis of catheter-related bloodstream infections.]
 
Shorr AF, Kunkel MJ, Kollef M (2005). Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. J Antimicrob Chemother, 56, 923–9. [Pooled data from two randomized trials show efficacy of linezolid.]
 
Stevens DL, et al. (2005). Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Inf Dis, 41, 1373–406. [Guidelines for the treatment of soft tissue infections.]
 
Wertheim HF, et al. (2004). Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet, 364, 703–5.[CrossRef]
 
Wertheim HF, et al. (2004). Mupirocin prophylaxis against nosocomial Staphylococcus aureus infections in nonsurgical patients: a randomized study. Ann Int Med, 140, 419–25. [Two studies that evaluate the impact of nasal colonization, and decolonization, in infection rates of hospitalized patients.]
 
Wyllie DH, Crook DW, Peto TE (2006). Mortality after Staphylococcus aureus bacteraemia in two hospitals in Oxfordshire, 1997–2003: cohort study. BMJ, 333, 281. [Epidemiology of S. aureus bacteraemia in the United Kingdom is reviewed in this cohort study.]
 
Zimmermann B 3rd, Mikolich DJ, Ho G Jr (1995). Septic bursitis. Semin Arthritis Rheum, 24, 391–410. [Review of the treatment of septic bursitis.]