Staphylococcal Infections

Staphylococcal infections are usually caused by the organism S aureus. However, the incidence of infections due to S epidermidis and other CoNS has been steadily increasing in recent years. This article focuses on S aureus but also discusses infections caused by CoNS when important differences exist.

S aureus is a gram-positive coccus that is both catalase- and coagulase-positive. Colonies are golden and strongly hemolytic on blood agar. They produce a range of toxins, including alpha-toxin, beta-toxin, gamma-toxin, delta-toxin, exfoliatin, enterotoxins, Panton-Valentine leukocidin (PVL),[7] and toxic shock syndrome toxin–1 (TSST-1).[8] The enterotoxins and TSST-1 are associated with toxic shock syndrome. PVL is associated with necrotic skin[9] and lung infections and has been shown to be a major virulence factor for pneumonia[10] and osteomyelitis.[11]  CoNS, particularly S epidermidis, produce an exopolysaccharide (slime) that promotes foreign-body adherence and resistance to phagocytosis.

Nienaber et al have demonstrated that methicillin-susceptible S aureus (MSSA) isolates causing endocarditis are more likely to be from a specific clonal cluster (CC30) and to possess specific virulence genes as compared to MSSA isolates from the same regions causing soft tissue infection. Isolates from patients with endocarditis were more likely to possess genes for 3 different adhesins and 5 different enterotoxins. The gene for PVL was found in the minority of both groups.[12]

S aureus has evolved to develop numerous immune evasion strategies to combat neutrophil-mediated killing, such as neutrophil activation, migration to the site of infection, bacterial opsonization, phagocytosis, and subsequent neutrophil-mediated killing. As many as 40 immune-evasion molecules of S aureus are known, and new functions are being identified for these evasion proteins.[13]

In a study of 42 S lugdunensis isolates, most isolates were able to form at least a weak biofilm, but the amount of biofilm formed by isolates was heterogeneous with poor correlation between clinical severity of disease and degree of biofilm formation.[14]

United States

Up to 80% of people are eventually colonized with S aureus. Most are colonized only intermittently; 20-30% are persistently colonized. Colonization rates in health care workers, persons with diabetes, and patients on dialysis are higher than in the general population. The anterior nares are the predominant site of colonization in adults; carriage here has been associated with the development of bacteremia.[15] Other potential sites of colonization include the throat,[16] axilla, rectum, and perineum. The rate of MRSA hand colonization among health care workers has been shown to exceed 4% (over 8% in North America).[17]

International

S aureus infection occurs worldwide. Pyomyositis due to S aureus is more prevalent in the tropics.

Mortality due to staphylococcal infections varies widely. Untreated S aureus bacteremia carries a mortality rate that exceeds 80%. The mortality rate of staphylococcal toxic shock syndrome is 3-5%. Infections due to CoNS usually carry a very low mortality rate. Because these infections are commonly associated with prosthetic devices, the most serious complication is the need to remove the involved prosthesis, although prosthetic valve endocarditis may lead to death.

Risk factors associated with increased mortality among patients with S aureus bacteremia include thrombocytopenia, an elevated score on the Charlson Comorbidity Index, MRSA infection, admission to an intensive care unit, and prior exposure to antibiotics.[18, 19]

Race

Staphylococcal infections have no reported racial predilection.

Sex

The vaginal carriage rate of staphylococcal species is approximately 10% in premenopausal women. The rate is even higher during menses.

Age

Staphylococcal species colonize many neonates on the skin, perineum, umbilical stump, and GI tract. The staphylococcal colonization rate in adults is approximately 40% at any given time.

The mortality rate of S aureus bacteremia in elderly persons is markedly increased.[20]

Common manifestations of staphylococcal infections include the following types of infections. The history obtained usually depends on the type of infection the organism causes.

• Skin infections (Many individuals who present with community-acquired skin infections are initially misdiagnosed with spider bites. These infections are often due to methicillin-resistant S aureus [MRSA])

  • Folliculitis

  • Furuncles

  • Impetigo (bullous)

  • Wound infections

  • Scalded skin syndrome

• Soft tissue infections (pyomyositis, septic bursitis, septic arthritis)

• Toxic shock syndrome

• Purpura fulminans[21]

• Endocarditis

• Osteomyelitis

• Pneumonia

• Food poisoning

• Staphylococcal infections of prosthetic devices, including prosthetic joints and heart valves and vascular shunts, grafts, and catheters (these are increasing in incidence, mostly likely because of the increase in staphylococcal line-related bacteremias ^{[22, 23]} )

• Urinary tract infection

Physical findings include the following:

• Skin and soft-tissue infections

  • Erythema

  • Warmth

  • Draining sinus tracts

  • Superficial abscesses

  • Bullous impetigo

• Toxic shock syndrome

  • Fever greater than 38.9°C

  • Diffuse erythroderma - Deep, red, "sunburned" appearance

  • Hypotension

  • Desquamation - Occurs 7-14 days after onset of illness, usually involves palms and soles

• Endocarditis

  • Regurgitant murmur

  • Petechiae or other cutaneous lesions

    Embolic lesions in patient with Staphylococcus aureus endocarditis.
    Close-up view of embolic lesions in patient with Staphylococcus aureus endocarditis.

  • Fever

Predisposing factors for staphylococcal infections include the following:

• Neutropenia or neutrophil dysfunction

• Diabetes

• Intravenous drug abuse

• Foreign bodies, including intravascular catheters

• Trauma

Colonization with S aureus is common. Skin-to-skin and skin-to-fomite contact are common routes of acquisition.[24, 25] Isolates can be spread by coughing or sneezing.[26] Evidence has also shown that S aureus can be spread between men during sex with other men.[27] Pets can also serve as household reservoirs.[28] The rate of MRSA hand colonization among health care workers has been shown to exceed 4% (over 8% in North America).[17]

Obtain cultures (with susceptibilities) as appropriate for the site of infection. Blood cultures may be positive for staphylococcal species, even when results from other cultures are negative. Obtain blood cultures from all patients with serious infections.

Deck et al have demonstrated a high sensitivity for S aureus (99.5%) and CoNS from positive blood cultures using a PNA FISH method. Turnaround times were less than 30 minutes.[29]

Patients with S aureus bacteremia should undergo repeat cultures after starting appropriate therapy. Patients with persistent bacteremia (after ≥3 days of appropriate therapy) are more likely to have underlying endocarditis.

CBC count usually reveals leukocytosis with a left shift (bands). Patients with chronic staphylococcal infection may have thrombocytosis.

Erythrocyte sedimentation rate and C-reactive protein may be helpful in patients with subacute or chronic infections such as osteomyelitis.

Teichoic acid antibody titers in patients with continuous S aureus bacteremias suggest a deep-seated (not intravenous line) focus (eg, endocarditis, abscess, osteomyelitis).

Screening tests for nasal colonization with methicillin-resistant S aureus (MRSA) are not predictive of the subsequent development of MRSA pneumonia (sensitivity, 23%) or MRSA bloodstream infection (sensitivity, 24%).[30]

Patients with S aureus or S lugdunensis bacteremia should undergo echocardiography.[31] Some experts recommend transesophageal echocardiography (TEE) in all patients without contraindications to rule out S aureus endocarditis.[32] Several scoring systems have been developed to be more selective in this determination.[33] High-risk factors for endocarditis include persistence of positive blood cultures for 5 days or longer while on appropriate antibiotic therapy, presence of a long-term indwelling intravenous catheter or device, and presence of a prosthetic heart valve.

Promptly start antimicrobial therapy when S aureus infection is documented or strongly suspected. Appropriate choices depend on local susceptibility patterns.[3] Initiation of subinhibitory concentrations of antibiotics may lead to increased production of PVL.[34] The Infectious Diseases Society of America (IDSA) has published detailed guidelines on the treatment of methicillin-resistant S aureus (MRSA) infections.[35]

Patients are defined as having uncomplicated MRSA bacteremia if endocarditis has been excluded; there are no implanted prostheses; follow-up blood cultures performed on specimens obtained 2 to 4 days after the initial positive set do not grow MRSA; defervescence occurs within 72 hours of initiating effective therapy; and there is no evidence of metastatic sites of infection. Such patients can be treated for 14 days with a low relapse/failure rate.[35, 36]

Temporary intravascular devices should be promptly removed if infection is suspected.[4] Long-term intravascular devices should be removed if infection with S aureus is documented.

Multiple decolonization regimens have been used in patients with recurrent staphylococcal infection. Treatment with topical mupirocin, chlorhexidine gluconate washes, and oral rifampin plus doxycycline for 7 days eradicated MRSA colonization in hospitalized patients.[5] Household members should avoid sharing personal hygiene items; decolonization of all household members should be recommended to patients with recurrent skin and soft tissue infections or to patients with multiple household members who experience skin and soft tissue infections.[37]

Abscesses must be drained. Infections involving a prosthetic joint usually require removal of the prosthesis. Other infections involving a prosthetic device, such as a prosthetic heart valve or implanted intravascular device, may or may not require removal of the device.

Consultation with an infectious disease specialist should be obtained for all patients with S aureus bacteremia. Doing so results in improved adherence to IDSA guidelines, decreased in-hospital mortality, and earlier discharge.[38] Pharmacist intervention through vancomycin dosing has been shown to improve survival rates in a retrospective study of patients with MRSA bacteremia.[6]

Historically, isolates resistant to oxacillin (commonly referred to as MRSA) were resistant to most agents other than vancomycin, but these isolates were limited to nosocomial infections. In the 1990s, many reports appeared describing community-acquired MRSA infections that were susceptible to various non–beta-lactam antibiotics. As such, patients with serious staphylococcal infections should be initially started on agents active against MRSA until susceptibility results are available.[39, 40, 41] Many CoNS are oxacillin-resistant. The duration of treatment depends on the type of infection encountered. Treatment of methicillin-susceptible S aureus (MSSA) bacteremia with cefazolin has been shown to improve survival rates and decrease toxicity in comparison to antistaphylococcal penicillins.[42, 43] S aureus endocarditis may require a prolonged course of antibiotics, although recent studies suggest it may be possible to switch many patients with endocarditis or complicated bacteremia to oral therapy after an initial course of 10 to 14 days of IV antimicrobial therapy.[44, 45, 46, 47]

Although many strains of MRSA that cause community-acquired infection are susceptible to trimethoprim-sulfamethoxazole, treatment with trimethoprim-sulfamethoxazole has been associated with clinical failure, especially in the presence of significant tissue damage.[48] Clindamycin decreased the repeat infection rate in one study of patients receiving incision and drainage for small skin abscesses compared with placebo trimethoprim-sulfamethoxazole.[49]

Vancomycin-resistant isolates have been reported; isolates with an increased minimum inhibitory concentration (MIC) to vancomycin are becoming more common and include both MRSA and MSSA.[50] Consensus guidelines no longer recommend dosing vancomycin based on trough levels of 15-20 mcg/mL,[51]  but instead recommend dosing vancomycin based on the area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC) with a target of 400-600 mg*hour/L.[52] .The results of such testing are often delayed .Because of these drawbacks and the availability of less nephrotoxic and more effective alternatives , vancomycin has a very limited role in treating staphylococcal infections.[53, 46]

In a study of 296 consecutive MRSA bacteremia episodes, several factors were predictive of high vancomycin MIC, including age older than 50 years, prior vancomycin exposure, history of MRSA bacteremia, history of chronic liver disease, and presence of a nontunneled catheter.[54]  

In a small study (40 subjects) with MRSA bacteremia, the combination of ceftaroline plus daptomycin was found to have lower in-hospital mortality rate as compared to vancomycin or daptomycin monotherapy.[55] The addition of daptomycin to cefazolin or cloxacillin did not result in improved outcomes in patients with MSSA bacteremia.[56]

Class Summary

Empiric antimicrobial therapy should be comprehensive and cover all likely pathogens in the context of the clinical setting.

Cefazolin

First-generation semisynthetic cephalosporin that arrests bacterial cell wall synthesis, inhibiting bacterial growth. Primarily active against skin flora, including S aureus (MSSA). Typically used alone for skin and skin-structure coverage. IV and IM dosing regimens are similar.

Ceftaroline (Teflaro)

Fifth-generation cephalosporin antimicrobial with activity against aerobic gram-negative bacteria, anaerobic gram-positive bacteria, and aerobic gram-positive bacteria, including MRSA.

Cefuroxime (Ceftin, Zinacef)

Second-generation cephalosporin with activity against respiratory aerobic gram-negative organisms, including Haemophilus influenza, and aerobic gram-positive aerobic organisms, including Streptococcus pyogenes and MSSA.

Dicloxacillin (Dycill, Dynapen)

Binds to one or more penicillin-binding proteins, which, in turn, inhibits synthesis of bacterial cell walls. For treatment of infections caused by penicillinase-producing staphylococci susceptible to methicillin (MSSA). Also active against most nonenterococcal streptococci. May use to initiate therapy when staphylococcal infection is suggested.

Nafcillin (Nallpen in Dextrose)

Preferred therapy for methicillin-susceptible S aureus (MSSA) staphylococci infections. Use parenteral therapy initially in severe infections. Oxacillin may be substituted for nafcillin based on hospital formulary. Change to oral therapy as condition warrants.

Dalbavancin (Dalvance)

Dalbavancin is a lipoglycopeptide antibiotic that prevents cross-linking by interfering with cell wall synthesis. It is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations observed in humans at recommended doses. It is indicated for treatment of acute bacterial skin and skin structure infections caused by gram-positive bacteria including S aureus (including MSSA and MRSA ), S pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S anginosus, S intermedius, S constellatus).

Oritavancin (Orbactiv)

Oritavancin is lipoglycopeptide antibiotic that inhibits cell wall biosynthesis and disrupts bacterial membrane integrity that leads to cell death. It is indicated for treatment of acute bacterial skin and skin structure infections caused by gram-positive bacteria including S aureus (including methicillin-susceptible S aureus and MRSA), S pyogenes, S agalactiae, S dysgalactiae, S anginosus group (S anginosus, S intermedius, S constellatus) and E faecalis (vancomycin-susceptible isolates only).

Telavancin (Vibativ)

Lipoglycopeptide antibiotic that is a synthetic derivative of vancomycin. Inhibits bacterial cell wall synthesis by interfering with polymerization and cross-linking of peptidoglycan. Unlike vancomycin, telavancin also depolarizes the bacterial cell membrane and disrupts its functional integrity. Indicated for complicated skin and skin structure infections caused by susceptible gram-positive bacteria, including Staphylococcus aureus (both methicillin-resistant and methicillin-susceptible strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis (vancomycin-susceptible isolates only).

Linezolid (Zyvox)

Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteriostatic against staphylococci (MSSA/MRSA).

The FDA warns against the concurrent use of linezolid with serotonergic psychiatric drugs, unless indicated for life-threatening or urgent conditions. Linezolid may increase serotonin CNS levels as a result of MAO-A inhibition, increasing the risk of serotonin syndrome.

Vancomycin

Its role is quite limited because of difficulty I achieving adequate levels and the availability safer and more effective antibiotics

Tedizolid (Sivextro)

Tedizolid is an oxazolidinone antibiotic indicated for skin and skin structure infections caused by susceptible isolates of Gram-positive bacteria including Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, S agalactiae, S anginosus Group (including S anginosus, S intermedius, and S constellatus), and Enterococcus faecalis. Its action is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis.

Doxycycline (Acticlate, Adoxa, Vibramycin, Doryx)

Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. Active against MSSA/MRSA. Less active against coagulase-negative staphylococci.

Minocycline (Minocin, Solodyn)

Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. Active against MSSA/MRSA. Less active against coagulase-negative staphylococci. Doxycycline (Vibramycin) is used more commonly than minocycline.

Clindamycin (Cleocin)

Lincosamide for treatment of serious skin and soft tissue staphylococci infections. Also effective against aerobic and anaerobic streptococci (except enterococcal). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Daptomycin (Cubicin)

Indicated to treat complicated skin and skin structure infections caused by S aureus (including MRSA strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, and Enterococcus faecalis. Also indicated for right-sided endocarditis due to S aureus. First of new antibiotic class called cyclic lipopeptides. Binds to bacterial membranes and causes rapid membrane potential depolarization, thereby inhibiting protein, DNA, and RNA synthesis and ultimately causing cell death.

Quinupristin/dalfopristin (Synercid)

Belongs to the streptogramin group of antibiotics. Mechanism of action is similar to macrolides/lincosamides. Inhibits protein synthesis and is usually bacteriostatic. Also an option for methicillin-resistant S aureus (MRSA) infections.

Tigecycline (Tygacil)

A glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. Inhibits bacterial protein translation by binding to 30S ribosomal subunit, and blocks entry of amino-acyl tRNA molecules in ribosome A site. Indicated for complicated skin and skin structure infections and complicated intra-abdominal infections. Active against S aureus (including MRSA), as well as most streptococci, enterococci (including VRE), and gram-negative organisms (including anaerobes).

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Sulfatrim Pediatric)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Active against most staphylococci (MSSA), including some strains resistant to methicillin (MRSA).

Delafloxacin (Baxdela)

New oral and intravenous fluoroquinolone with activity against MRSA. The best of this class for MRSA, although not a preferred agent, as it is new and quite expensive.

Many hospitals have implemented screening for methicillin-resistant S aureus (MRSA) infections upon admission to an intensive care unit. Topical decolonization therapy and contact isolation of patients who test positive for MRSA has been shown to decrease MRSA infection rates.[24]

A nationwide Veterans Administration hospital program of nasal surveillance, contact precautions, and hand hygiene reduced ICU healthcare-associated MRSA infections by 62% and non-ICU healthcare-associated MRSA infections by 45%.[57]

Nonantibiotic methods to reduce nasal S aureus colonization are emerging. A study by Steed et al showed nasal application of a nonantibiotic alcohol-based antiseptic (Nozin Nasal Sanitizer advanced antiseptic from Global Life Technologies, Corp) was effective in reducing S aureus and total bacterial carriage, suggesting the usefulness of this approach as a safe, effective, and convenient alternative to antibiotic treatment. Seventy-eight of 387 healthcare providers screened (20.2%) tested positive for S aureus infection. Of 39 subjects who tested positive for S aureus infection who completed the study, 20 received antiseptic and 19 received placebo treatment. Antiseptic treatment reduced S aureus colony-forming units from baseline by 99% (median) and 82% (mean) (P< 0.001). Total bacterial colony-forming units were reduced by 91% (median) and 71% (mean) (P< 0.001).[58]

Complications of S aureus bacteremia include septic arthritis, osteomyelitis, pyomyositis, endocarditis, and pneumonia.

The prognosis of staphylococcal infections varies widely depending on the site of infection and the underlying condition. Overall, the prognosis is good, with full recovery in most patients who receive appropriate therapy.

For excellent patient education resources, visit eMedicineHealth's Women's Health Center. Also, see eMedicineHealth's patient education article Toxic Shock Syndrome.