1178 PART 5 Infectious Diseases

Staphylococcus aureus, the most virulent of the many (≥40) staphylococcal species, has demonstrated its versatility by remaining a major

cause of morbidity and mortality worldwide despite the availability

of numerous effective antistaphylococcal antibiotics. S. aureus is a

pluripotent pathogen, causing disease through both toxin- and nontoxin-mediated mechanisms. It is responsible for numerous nosocomial and community-based infections that range from relatively minor

skin and soft tissue infections (SSTIs) to life-threatening systemic

infections.

The “other” staphylococci, coagulase-negative staphylococci, are

less virulent than S. aureus but remain important pathogens in select

settings, such as infections that involve prosthetic devices.

MICROBIOLOGY AND TAXONOMY

Staphylococci, gram-positive cocci in the family Micrococcaceae, form

grapelike clusters on Gram’s stain (Fig. 147-1). These organisms (~1 μm

in diameter) are catalase-positive (unlike streptococcal species), nonmotile, aerobic, and facultatively anaerobic. They are capable of prolonged survival on environmental surfaces under varying conditions.

Some species have a relatively broad host range, including mammals

and birds, whereas the host range for others is quite narrow—i.e., limited to one or two closely related animals.

S. aureus is generally distinguished from other staphylococcal

species by coagulase production, a surface enzyme that converts

fibrinogen to fibrin. However, several of the “coagulase-negative staphylococci,” including S. pseudintermedius and S. argenteus, are coagulase

positive. As a result, description of these other staphylococci as non–S.

aureus staphylococci (NSaS) is more accurate.

S. aureus ferments mannitol, is positive for protein A, and produces

DNAse. On blood agar plates, S. aureus forms golden β-hemolytic colonies; in contrast, most NSaS form small white nonhemolytic colonies.

Latex kits that detect both protein A and clumping factor can distinguish S. aureus from most other staphylococcal species. Point of care

tests also are used for the rapid detection of staphylococcal colonization.

147 Staphylococcal Infections

Franklin D. Lowy

FIGURE 147-1 Gram’s stain of S. aureus in a sputum sample, illustrating

staphylococcal clusters. (From ASM MicrobeLibrary.org. © Pfizer, Inc.)

Matanock A et al: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among

adults aged ≥65 years. MMWR Morb Mortal Wkly Rep 68:1069,

2019.

Subramanian K et al: Pneumolysin binds to the mannose receptor

C type 1 (MRC-1) leading to anti-inflammatory responses and

enhanced pneumococcal survival. Nat Microbiol 4:62, 2019.

Van Der Poll T, Opal SM: Pathogenesis, treatment, and prevention of

pneumococcal pneumonia. Lancet 374:1543, 2009.

■ WEBSITES

American Academy of Pediatrics: Red Book: The report of the

Committee on Infectious Diseases. Available at: aapredbook.aap

publications.org.

Cochrane: Corticosteroids for Bacterial Meningitis. Available at: www

.cochrane.org/CD004405/ARI_corticosteroids-bacterial-meningitis.

U.S. Department of Health and Human Services: Antibiotic

Resistance Threats in the United States 2019. Available at: www.cdc

.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf.

World Health Organization: Summary of WHO Position Paper

on Pneumococcal conjugate vaccines in infants and children under

5 years of age, February 2019. Available at: www.who.int/immunization/

policy/position_papers/who_pp_pcv_2019_summary.pdf.

Newer methods such as matrix-assisted laser desorption/ionization

time-of-flight mass spectrometry (MALDI-TOF) are increasingly

being used for staphylococcal speciation.

Determining whether multiple staphylococcal isolates from different patients are the same or different is often relevant when there is

concern that a nosocomial outbreak of staphylococcal infec

pneumococci are considered a serious threat by the Centers for

Disease Control and Prevention.

The molecular basis of penicillin resistance in S. pneumoniae is

the alteration of penicillin-binding protein (PBP) genes by transformation and horizontal transfer of DNA from related streptococcal

species. Such alteration of PBPs results in lower affinity for penicillins. Depending on the specific PBP(s) and the number of PBPs

altered, the level of resistance ranges from intermediate to high.

For many years, penicillin susceptibility breakpoints have been

defined by MICs as follows: susceptible, ≤0.06 μg/mL and resistant,

≥2.0 μg/mL. However, in vitro results often were not predictive of

the response of a patient to treatment for pneumococcal diseases

other than meningitis. Revised recommendations have been based

on the penicillin G breakpoints established in 2008 by the Clinical

and Laboratory Standards Institute. For IV treatment of meningitis

with at least 24 million units per day in 8 divided doses, the susceptibility breakpoint remains ≤0.06 μg/mL, and MICs of ≥0.12 μg/mL

indicate resistance. For IV treatment of nonmeningeal infections

with 12 million units per day in 6 divided doses, the breakpoints

are ≤2 μg/mL for susceptible organisms and ≥8 μg/mL for resistant

organisms; a dosage of 18–24 million units per day is recommended

for strains with MICs in the intermediate category.

Although guidelines for antibiotic therapy should be driven

in part by local patterns of resistance, guidelines from national

organizations in many countries (e.g., the Infectious Diseases Society of America/American Thoracic Society, the British Thoracic

Society, the European Respiratory Society) lay out evidence-based

approaches. The following guidelines for the treatment of individual sepsis syndromes are based on those advocated by the American

Academy of Pediatrics and published in the 2018 Red Book.

MENINGITIS LIKELY OR PROVEN TO BE DUE TO

S. PNEUMONIAE

In areas of the world with an increased prevalence of resistant

pneumococci, first-line therapy for persons ≥1 month of age is a

combination of vancomycin (adults, 30–60 mg/kg per day; infants

and children, 60 mg/kg per day) and cefotaxime (adults, 8–12 g/d

in 4–6 divided doses; children, 225–300 mg/kg per day in 1 dose

or 2 divided doses) or ceftriaxone (adults, 4 g/d in 1 dose or 2

divided doses; children, 100 mg/kg per day in 1 dose or 2 divided

doses). In low-prevalence areas and where the patient has not

recently traveled, vancomycin is not included in first-line therapy.

If children are hypersensitive to β-lactam agents (penicillins and

cephalosporins), rifampin (adults, 600 mg/d; children, 20 mg/d

in 1 dose or 2 divided doses) can be substituted for cefotaxime or

ceftriaxone and added as a second agent. A repeat lumbar puncture

should be considered after 48 h if the organism is not susceptible

to penicillin and information on cephalosporin sensitivity is not

yet available, if the patient’s clinical condition does not improve or

deteriorates, or if dexamethasone has been administered interfering

with the ability to interpret clinical responses in the deteriorating

patient. When antibiotic sensitivity data become available, treatment should be modified accordingly. If the isolate is sensitive

to penicillin, vancomycin can be discontinued and penicillin can

replace the cephalosporin, or cefotaxime or ceftriaxone can be continued alone. If the isolate displays any resistance to penicillin but is

susceptible to the cephalosporins, vancomycin can be discontinued

and cefotaxime or ceftriaxone continued. If the isolate exhibits any

resistance to penicillin and is not susceptible to cefotaxime and

ceftriaxone, vancomycin and high-dose cefotaxime or ceftriaxone

can be continued and rifampin may be added. Data support the use

of corticosteroids in high-income countries but do not appear to

have a beneficial effect in low-income countries. This discrepancy

in the efficacy of corticosteroids may be related to differences in

availability of appropriate and timely medical care. Glucocorticoids

significantly reduce rates of mortality, severe hearing loss, and

neurologic sequelae in adults and should be administered to those

with community-acquired bacterial meningitis. If dexamethasone is

given to either adults or children, it should be administered before

or in conjunction with the first antibiotic dose.

SEPSIS (EXCLUDING MENINGITIS)

In previously well children with noncritical illness, therapy with

a recommended antibiotic should be instigated at the usually recommended dosages: ampicillin 200 mg/kg/day (doses 6h apart),

cefotaxime, 75–225 mg/kg/day (doses 8 h apart), ceftriaxone, 50–75

mg/kg/day (doses 12–24 h apart) or penicillin G, 250,000–400,000

units/kg per day (in divided doses 4–6 h apart). For critically ill

children, including those who have myocarditis or multilobular

pneumonia with hypoxia or hypotension, vancomycin may be

added if the isolate may possibly be resistant to β-lactam drugs,

with its use reviewed once susceptibility data become available.

If the organism is resistant to β-lactam agents, therapy should be

modified on the basis of clinical response and susceptibility to other

antibiotics. Clindamycin or vancomycin can be used as a first-line

agent for children with severe β-lactam hypersensitivity, but vancomycin should not be continued if the organism is shown to be

sensitive to other non-β-lactam antibiotics.

For outpatient management, oral amoxicillin (45–90 mg/kg/

day, doses 8 h apart) provides effective treatment for virtually all

cases of pneumococcal pneumonia. Cephalosporins, which are far

more expensive, offer no advantages over amoxicillin. Levofloxacin

(500–750 mg/d as a single dose) and moxifloxacin (400 mg/d as a

single dose) also are highly likely to be effective in the United States

except in patients who come from closed populations where these

drugs are used widely or who have themselves been treated recently

with a quinolone. Clindamycin (600–1200 mg/d every 6 h) is effective in 90% of cases and azithromycin (500 mg on day 1 followed by

250–500 mg/d) or clarithromycin (500–750 mg/d as a single dose)

in 80% of cases. Treatment failure resulting in bacteremic disease

due to macrolide-resistant isolates has been amply documented in

patients given azithromycin empirically. As noted above, rates of

resistance to all these antibiotics are relatively low in some countries

and much higher in others; high-dose amoxicillin remains the best

option worldwide.

The optimal duration of treatment for pneumococcal pneumonia is uncertain, but its continuation for at least 5 days once

the patient becomes afebrile appears to be a prudent approach—

although in adults, 5 days in total will usually suffice. Cases with a

second focus of infection (e.g., empyema or septic arthritis) require

longer therapy.

ACUTE OTITIS MEDIA

Amoxicillin (80–90 mg/kg per day) is recommended for infants

<6 months of age and those 6–23 months of age with bilateral disease. Observation and symptom-based treatment without antibiotics are advocated for nonsevere illness and an uncertain diagnosis

in children 6 months to 2 years of age and nonsevere illness (even if

the diagnosis seems certain) in children >2 years of age. Although

the optimal duration of therapy has not been conclusively established, a 10-day course is recommended for younger children and

for children with severe disease at any age. For children >6 years

old who have mild or moderate disease, a course of 5–7 days is

considered adequate. Patients whose illness fails to respond should

be reassessed at 48–72 h. If acute otitis media is confirmed and

antibiotic treatment has not been started, administration of amoxicillin should be commenced. If antibiotic therapy fails, a change

is indicated. Failure to respond to second-line antibiotics (such as

high-dose amoxicillin-clavulanate) as well indicates that myringotomy or tympanocentesis may need to be undertaken in order to

obtain samples for culture.

The above recommendations can also be followed for the treatment of sinusitis. Detailed information on the further management

of these conditions in children has been published by the American

Academy of Pediatrics, the American Academy of Family Physicians, the Pediatric Infectious Diseases Society, and the Infectious

Diseases Society of America.

1177CHAPTER 146 Pneumococcal Infections

■ PREVENTION

Measures to prevent pneumococcal disease include vaccination against

S. pneumoniae and influenza viruses, reduction of comorbidities that

increase the risk of pneumococcal disease, and prevention of antibiotic

overuse, which fuels pneumococcal resistance.

Capsular Polysaccharide Vaccines The 23-valent pneumococcal polysaccharide vaccine (PPSV23), containing 25 μg of each capsular

polysaccharide, has been licensed for use since 1983. Recommendations for its use vary by country. The U.S. Advisory Committee on

Immunization Practices (ACIP) recommends PPSV23 for all persons

≥65 years of age and for those 2–64 years of age who have underlying

medical conditions that put them at increased risk for pneumococcal

disease or, if infected, disease of increased severity (Table 146-1; see

also www.cdc.gov/vaccines/schedules). The committee updated their

recommendations to include the combined use of pneumococcal

conjugate vaccine followed by PPSV23 in at-risk individuals (see

“Polysaccharide–Protein Conjugate Vaccines,” below). Revaccination

5 years after the first dose is recommended for persons >2 years of

age who have underlying medical conditions but not routinely for

those whose only indication is an age of ≥65 years. PPSV23 does not

induce an anamnestic response, and antibody concentrations wane

over time; thus revaccination is particularly important for individuals

with conditions resulting in loss of antibody. Concerns about repeated

revaccination have focused on safety (i.e., local reactions) and the

induction of immune hyporesponsiveness. Neither the clinical relevance nor the biologic basis of hyporesponsiveness is clear, but, given

the possibility of its occurrence, more than one revaccination has not

been recommended.

The effectiveness of PPSV23 against IPD, pneumococcal pneumonia, all-cause pneumonia, and death is controversial, with wide

variation in observations. The many published meta-analyses of PPSV

efficacy have often reached opposing conclusions with regard to a

given clinical entity. Generally, observational studies cite greater effectiveness than do controlled clinical trials. The consensus is that PPSV is

effective against IPD but is less effective against nonbacteremic pneumococcal pneumonia. However, the results of some published trials,

observational studies, and meta-analyses contradict this view. Effectiveness is often lower in the elderly and in immunodeficient patients

whose condition is associated with reduced antibody responses to

vaccines than in younger, healthier populations. When PPSV is effective, the duration of protection following a single dose of vaccine is

estimated to be ~5 years.

What is not disputed is that improved pneumococcal vaccines are

needed for adults. Even in the setting of routine pneumococcal conjugate vaccination of infants (which indirectly protects adults from

vaccine-serotype strains), disease caused by serotypes not represented in

the conjugate vaccine continues to be a significant burden among adults.

Polysaccharide–Protein Conjugate Vaccines Infants and

young children respond poorly to PPSV, which contains T cell–

independent antigens. Consequently, another class of pneumococcal

vaccines, the PCVs, were developed specifically for infants and young

children. The first product, a 7-valent PCV, was licensed in 2000 in the

United States. Two PCV products—containing 10 and 13 serotypes,

respectively—are commercially available as of 2020. The serotypes

included in these PCV formulations are important causes of IPD and

antibiotic resistance among young children. Randomized controlled trials have demonstrated a high degree of efficacy of PCVs against vaccineserotype IPD as well as efficacy against pneumonia, otitis media,

nasopharyngeal colonization, and all-cause mortality. PCVs are recommended by the World Health Organization for inclusion in routine

childhood immunization schedules worldwide, especially in countries

with high infant mortality rates. To date 144 countries have PCV in

their National Immunization program, 16 are planning introduction,

and 34 have no national decision.

The introduction of PCV in high-income settings has resulted in a

>90% reduction in vaccine-serotype IPD among the whole population.

This decline has been noted not only in those age groups immunized

but also in adults and is attributable to the near elimination of vaccineserotype nasopharyngeal colonization in immunized infants, which

reduces spread to adults. This protection of unimmunized community

members through vaccination of a subset of the community is termed

the indirect effect. Increases in colonization with—and concomitantly

in disease due to—non-vaccine-serotype strains (i.e., replacement

colonization and disease) have been seen. The scale of replacement

disease has varied geographically with the impact eroding vaccine

impact significantly in the elderly in the UK while having relatively

little impact in the USA (see “Epidemiology,” above). Since vaccine-serotype strains are more commonly resistant to antibiotics than are nonvaccine serotypes, use of PCV has also resulted in substantial declines

in the proportion and absolute rates of drug-resistant pneumococcal

disease. The ACIP recommendations for the use of conjugate vaccines can be found at www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/

pneumo.html. PCV has been shown to prevent pneumococcal infection

in HIV-infected adults. In the United States, PCV13 followed by a dose

of PPSV23 is now recommended for all immunocompromised children and adults. Until 2019 this was also the U.S. recommendation for

those ≥65 years of age, but that recommendation has been modified.

Shared decision-making with a physician should determine whether

PCV13 in addition to PPSV23 is used in otherwise healthy adults

≥65 years of age. Two new extended-valency vaccines containing

upwards of 15 serotypes—VAXNEUVANCE (Merck) and PREVNAR

20 (Pfizer)—were licensed in 2021.

Other Prevention Strategies Pneumococcal disease can be

averted through the prevention of illnesses that predispose individuals to pneumococcal infections. Relevant measures include smoking

cessation and influenza vaccination, as well as improved management

and control of diabetes, HIV infection, heart disease, and lung disease.

Finally, the reduction of antibiotic misuse is a strategy for the prevention of pneumococcal disease in that antimicrobial resistance directly

and indirectly perpetuates organism transmission and disease in the

community.

■ GLOBAL HEALTH

Pneumococcal infections are estimated to cause ~317,000 annual deaths

worldwide among children 1–59 months of age, accounting for 9.7 % of

the 3.2 million all-cause deaths and 38% of all pneumonia deaths in this

age group in 2015. Reliable estimates of adult cases and deaths globally

are more difficult to establish because of limited data from parts of

the world where most disease occurs. Rates of pneumococcal disease

and mortality vary substantially across geographic settings, with the

highest rates in selected countries of sub-Saharan Africa and southern

Asia, where risk factors for pneumococcal disease—including HIV

infection, lack of breast feeding of infants and children, malnutrition,

sickle cell disease, and limited access to medical care—are prevalent.

Serotypes causing disease exhibit some heterogeneity across geographic

settings, but a small number of serotypes universally account for the

preponderance of disease in the absence of vaccination; accordingly,

vaccine development and vaccination programs are globally relevant.

Reductions in disease from pneumococcal infections are anchored in

prevention through the inclusion of pneumococcal vaccines in infant

immunization programs, timely assessment and appropriate treatment

of persons with pneumococcal infections, and reduction of risk factors

for pneumococcal disease. The availability of vaccines for the prevention of adult pneumococcal disease, particularly among the elderly, is

currently restricted to high-income countries, with virtually no availability in low-income countries where most cases of disease exist.

■ FURTHER READING

Krone CL et al: Immunosenescence and pneumococcal disease: An

imbalance in host–pathogen interactions. Lancet Respir Med 2:141,

2014.

Mackenzie GA et al: Effect of the introduction of pneumococcal

conjugate vaccination on invasive pneumococcal disease in The

Gambia: A population-based surveillance study. Lancet Infect Dis

16:703, 2016.

1178 PART 5 Infectious Diseases

Staphylococcus aureus, the most virulent of the many (≥40) staphylococcal species, has demonstrated its versatility by remaining a major

cause of morbidity and mortality worldwide despite the availability

of numerous effective antistaphylococcal antibiotics. S. aureus is a

pluripotent pathogen, causing disease through both toxin- and nontoxin-mediated mechanisms. It is responsible for numerous nosocomial and community-based infections that range from relatively minor

skin and soft tissue infections (SSTIs) to life-threatening systemic

infections.

The “other” staphylococci, coagulase-negative staphylococci, are

less virulent than S. aureus but remain important pathogens in select

settings, such as infections that involve prosthetic devices.

MICROBIOLOGY AND TAXONOMY

Staphylococci, gram-positive cocci in the family Micrococcaceae, form

grapelike clusters on Gram’s stain (Fig. 147-1). These organisms (~1 μm

in diameter) are catalase-positive (unlike streptococcal species), nonmotile, aerobic, and facultatively anaerobic. They are capable of prolonged survival on environmental surfaces under varying conditions.

Some species have a relatively broad host range, including mammals

and birds, whereas the host range for others is quite narrow—i.e., limited to one or two closely related animals.

S. aureus is generally distinguished from other staphylococcal

species by coagulase production, a surface enzyme that converts

fibrinogen to fibrin. However, several of the “coagulase-negative staphylococci,” including S. pseudintermedius and S. argenteus, are coagulase

positive. As a result, description of these other staphylococci as non–S.

aureus staphylococci (NSaS) is more accurate.

S. aureus ferments mannitol, is positive for protein A, and produces

DNAse. On blood agar plates, S. aureus forms golden β-hemolytic colonies; in contrast, most NSaS form small white nonhemolytic colonies.

Latex kits that detect both protein A and clumping factor can distinguish S. aureus from most other staphylococcal species. Point of care

tests also are used for the rapid detection of staphylococcal colonization.

147 Staphylococcal Infections

Franklin D. Lowy

FIGURE 147-1 Gram’s stain of S. aureus in a sputum sample, illustrating

staphylococcal clusters. (From ASM MicrobeLibrary.org. © Pfizer, Inc.)

Matanock A et al: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among

adults aged ≥65 years. MMWR Morb Mortal Wkly Rep 68:1069,

2019.

Subramanian K et al: Pneumolysin binds to the mannose receptor

C type 1 (MRC-1) leading to anti-inflammatory responses and

enhanced pneumococcal survival. Nat Microbiol 4:62, 2019.

Van Der Poll T, Opal SM: Pathogenesis, treatment, and prevention of

pneumococcal pneumonia. Lancet 374:1543, 2009.

■ WEBSITES

American Academy of Pediatrics: Red Book: The report of the

Committee on Infectious Diseases. Available at: aapredbook.aap

publications.org.

Cochrane: Corticosteroids for Bacterial Meningitis. Available at: www

.cochrane.org/CD004405/ARI_corticosteroids-bacterial-meningitis.

U.S. Department of Health and Human Services: Antibiotic

Resistance Threats in the United States 2019. Available at: www.cdc

.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf.

World Health Organization: Summary of WHO Position Paper

on Pneumococcal conjugate vaccines in infants and children under

5 years of age, February 2019. Available at: www.who.int/immunization/

policy/position_papers/who_pp_pcv_2019_summary.pdf.

Newer methods such as matrix-assisted laser desorption/ionization

time-of-flight mass spectrometry (MALDI-TOF) are increasingly

being used for staphylococcal speciation.

Determining whether multiple staphylococcal isolates from different patients are the same or different is often relevant when there is

concern that a nosocomial outbreak of staphylococcal infections is due

to a common point source (e.g., a contaminated medical instrument).

Molecular typing methods, such as pulsed-field gel electrophoresis

and sequence-based techniques (e.g., staphylococcal protein A [SpA]

typing), have been used for this purpose. More recently, whole-genome

sequencing has emerged as the gold standard for discrimination among

different isolates.

S. AUREUS INFECTIONS

■ EPIDEMIOLOGY

S. aureus is both a commensal and an opportunistic pathogen. Approximately 20–40% of healthy persons are colonized with S. aureus, with

a smaller percentage (~10%) persistently colonized with the same

strain. The rate of colonization is elevated among type 1 diabetics,

HIV-infected patients, patients undergoing hemodialysis, injection

drug users, and individuals with skin damage. The anterior nares and

oropharynx are frequent sites of human colonization, although the

skin (especially when damaged), vagina, axilla, and perineum also are

often colonized. These colonization sites serve as potential reservoirs

for future infections.

Most individuals who develop S. aureus infections become infected

with a strain that is already a part of their own commensal flora.

Breaches of the skin or mucosal membrane allow S. aureus to initiate

infection. Person-to-person transmission of S. aureus also occurs,

most frequently from direct personal contact with an infected body

site. Spread of staphylococci in aerosols of respiratory or nasal secretions from heavily colonized individuals, although rare, has been

reported.

Some diseases increase the risk of S. aureus infection; diabetes, for

example, combines an increased rate of S. aureus colonization and

the use of injectable insulin with the possibility of impaired leukocyte function. Individuals with congenital or acquired qualitative or

quantitative defects of polymorphonuclear leukocytes (PMNs) are at

increased risk of S. aureus infections; this group includes neutropenic

patients (e.g., those receiving chemotherapeutic agents), those with

chronic granulomatous disease, and those with autosomal dominant

hyperimmunoglobulin E (Job syndrome) or Chédiak-Higashi syndrome. Other groups at risk include individuals with end-stage renal

disease, HIV infection, skin abnormalities, or prosthetic devices.

S. aureus is a leading cause of health care–associated infections

(Chap. 142). It is the most common cause of surgical wound infections

and is second only to NSaS as a cause of primary bacteremia. These

1179CHAPTER 147 Staphylococcal Infections

formation of a fibrinous capsule, or infection spreads to the adjoining

tissue or into the bloodstream.

In toxin-mediated staphylococcal disease, infection is not invariably present. For example, in staphylococcal food poisoning, once the

heat-stable enterotoxin has been released into food, symptoms can

develop in the absence of viable bacteria. In staphylococcal toxic shock

syndrome (TSS), conditions allowing toxin elaboration at colonization

sites (e.g., the presence of a superabsorbent tampon) suffice for initiation of clinical illness.

The S. aureus Genome The complete genomes of S. aureus

strains are now readily available. Among the interesting revelations are (1) the high degree of nucleotide sequence similarity of

the core genomes of different strains; (2) the acquisition of a relatively

large amount of genetic information by horizontal transfer from

other bacterial species; and (3) the presence of unique “pathogenicity” or “genomic” islands—mobile genetic elements that contain

clusters of enterotoxin and exotoxin genes and/or antimicrobial resistance determinants. Among the genes in these islands is mecA, the

gene responsible for methicillin resistance. Methicillin resistance–

containing islands have been designated staphylococcal cassette

chromosome mec (SCCmec). There are different SCCmec types that

range in size from ~20 to 60 kb. Among the more common SCCmec

types, types 1–3 are traditionally associated with nosocomial MRSA

isolates, whereas types 4–6 have been associated with epidemic

CA-MRSA strains.

A relatively limited number of MRSA clones have been responsible for most community- and hospital-associated infections

worldwide. A comparison of these strains with those from earlier

outbreaks (e.g., the phage 80/81 strains from the 1950s) has revealed

preservation of the nucleotide sequence over time. This observation

suggests that these strains possess determinants that facilitate survival and spread.

Regulation of Virulence Gene Expression In both

toxin-mediated and non-toxin-mediated diseases due to S.

aureus, the expression of virulence determinants associated with

infection depends on a series of regulatory genes (e.g., accessory gene

regulator [agr] and staphylococcal accessory regulator [sar]) that

coordinately control the expression of many virulence genes. The

isolates are often resistant to multiple antibiotics; thus, available therapeutic options may be limited. In the community, S. aureus remains

an important cause of SSTIs, respiratory infections, and, especially

among injection drug users, infective endocarditis. The increasing use

of home infusion therapy also poses a risk of community-acquired

staphylococcal infections.

In the past three decades, there has been a dramatic change in

the epidemiology of infections due to methicillin-resistant S. aureus

(MRSA). In addition to its major role as a nosocomial pathogen, MRSA

has become an established community-based pathogen. Numerous

outbreaks of community-associated MRSA (CA-MRSA) infections

have been reported in both rural and urban settings in widely separated

regions throughout the world.

This trend appears to be due in part to the dramatic increase in

MRSA colonization found in the community in different parts of the

world. Outbreaks of CA-MRSA infections have occurred among such

diverse groups as children, prisoners, athletes, Native Americans, and

drug users. Risk factors common to these outbreaks include poor

hygienic conditions, close contact, contaminated material, and damaged skin. In some geographic regions of the world, the infections have

been caused by a single CA-MRSA strain, while in others a variety of

CA-MRSA strains have been responsible. In the United States, strain

sequence type 8 (PFGE type USA300) has been the predominant clone

(Fig. 147-2). Although the majority of infections caused by these

strains have involved the skin and soft tissue, 5–10% have been invasive and potentially life-threatening. CA-MRSA strains have also been

responsible for an increasing number of nosocomial infections. Of

concern has been the enhanced capacity of CA-MRSA to cause disease

in immunocompetent individuals.

■ PATHOGENESIS

General Concepts S. aureus is a pyogenic pathogen known for its

capacity to induce abscess formation at both local and distant sites (i.e.,

metastatic infections). This classic pathologic response to S. aureus

defines the framework within which the infection will progress. The

bacteria elicit an inflammatory response characterized by an initial

intense infiltration of PMNs and a subsequent infiltration of macrophages and fibroblasts. Either the host cellular response (including

the deposition of fibrin and collagen) contains the infection with the

FIGURE 147-2 Global distribution of community-associated MRSA. Dotted lines indicate possible route of dissemination. Estimates of the areas are shown where infection

with the main strains—i.e., ST1 (green), ST8 (red), ST30 (blue), and ST80 (grey hatched)—have been reported. +, Panton Valentine Leukocidin (PVL)-positive strains; –, PVLnegative strains; ±, PVL-positive and -negative strains. (Reproduced with permission from FR DeLeo, M Otto, BN Kreiswirth, HF Chambers: Community-associated meticillinresistant Staphylococcus aureus. Lancet 375:1557, 2010.)

1180 PART 5 Infectious Diseases

regulatory gene agr is part of a quorum-sensing signal transduction

pathway that senses and responds to bacterial density. Staphylococcal

surface proteins are synthesized during the bacterial exponential

growth phase in vitro. In contrast, many secreted proteins, such as α

toxin, the enterotoxins, and assorted enzymes, are released during the

post–exponential growth phase in response to transcription of the

effector molecule of agr, RNAIII.

These regulatory genes appear to serve a similar function in vivo.

Successful invasion requires the sequential expression of these different

bacterial elements. Bacterial adhesins are needed to initiate colonization of host tissue surfaces. The subsequent release of various enzymes

enables the colony to obtain nutritional support and permits bacteria

to spread to adjacent tissues. Studies with strains in which these regulatory genes are inactivated show reduced virulence in several animal

models of S. aureus infection.

Pathogenesis of Invasive S. aureus Infection Staphylococci

are opportunists. For these organisms to invade the host and cause

infection, some or all of the following steps are necessary: contamination and colonization of host tissue surfaces, breach of cutaneous or

mucosal barriers, establishment of a localized infection, invasion, evasion of the host response, and metastatic spread. Colonizing strains or

strains transferred from other exposures are introduced into damaged

skin, a wound, or the bloodstream. Recurrences of S. aureus infections

are common, apparently because of the capacity of these pathogens to

persist in a quiescent state in various tissues, and then to cause recrudescent infections when suitable conditions arise.

S. AUREUS COLONIZATION OF BODY SURFACES The anterior nares

and oropharynx are primary sites of staphylococcal colonization. In

the nares, colonization appears to involve the attachment of S. aureus

to keratinized epithelial cells. Other factors that contribute to colonization include the influence of other resident nasal flora and their

bacterial density, host factors, and nasal mucosal damage (e.g., that

resulting from inhalational drug use). Other colonized body sites, such

as damaged skin, the groin, and the oropharynx, may be particularly

important reservoirs for CA-MRSA strains.

INOCULATION AND COLONIZATION OF TISSUE SURFACES Staphylococci may be introduced into tissue as a result of minor abrasions (e.g.,

mosquito bites), administration of medications such as insulin, or establishment of IV access with catheters. After introduction into a tissue

site, bacteria replicate and colonize the host tissue surface. A family of

structurally related S. aureus surface proteins referred to as MSCRAMMs

(microbial surface components recognizing adhesive matrix molecules)

play an important role as mediators of adherence to these different sites.

By adhering to exposed matrix molecules (e.g., fibrinogen, collagen,

fibronectin), MSCRAMMs, such as clumping factor and collagen-binding

protein, enable the bacteria to colonize different host tissue surfaces;

these proteins contribute to the pathogenesis of invasive infections such

as endocarditis and septic arthritis by facilitating the adherence of S.

aureus to surfaces with exposed fibrinogen or collagen.

Although NSaS are classically known for their ability to elaborate

biofilms and to colonize prosthetic devices, S. aureus also possesses

the genes responsible for biofilm formation, such as the intercellular

adhesion (ica) locus. Binding to these devices occurs in a stepwise

fashion, involving staphylococcal adherence to serum constituents that

have coated the device surface and subsequent biofilm elaboration. S.

aureus is thus a frequent cause of biomedical device–related infections.

INVASION After colonization, staphylococci replicate at the initial

site of infection, elaborating enzymes that include serine proteases,

hyaluronidases, thermonucleases, and lipases. These enzymes facilitate

bacterial survival and local spread across tissue surfaces. The lipases

may facilitate survival in lipid-rich areas such as the hair follicles,

where S. aureus infections are often initiated.

Constitutional findings may result from either localized or systemic

infections. The staphylococcal cell wall—consisting of alternating

N-acetyl muramic acid and N-acetyl glucosamine units in combination with an additional cell wall component, lipoteichoic acid—can

initiate an inflammatory response that includes the sepsis syndrome.

Staphylococcal alpha (α) toxin is a critical staphylococcal toxin. It

causes pore formation in various eukaryotic cells and can also initiate

an inflammatory response with findings suggestive of sepsis. The S.

aureus toxin Panton-Valentine leukocidin is cytolytic to PMNs, macrophages, and monocytes. Strains elaborating this toxin have been

epidemiologically linked with cutaneous and more serious infections

(i.e., pneumonia) caused by strains of CA-MRSA.

EVASION OF HOST DEFENSE MECHANISMS Staphylococci have many

host immune evasion strategies that are crucial to their survival. They

possess an antiphagocytic polysaccharide microcapsule. Most human

S. aureus infections are due to strains with capsular types 5 and 8.

The zwitterionic (both negatively and positively charged) S. aureus

capsule also plays a critical role in the induction of abscess formation.

Protein A, an MSCRAMM unique to S. aureus, acts as an Fc receptor,

binding the Fc portion of IgG subclasses 1, 2, and 4 and preventing

opsonophagocytosis by PMNs. Both chemotaxis inhibitory protein of

staphylococci (CHIPS, a secreted protein) and extracellular adherence

protein (EAP, a surface protein) interfere with PMN migration to sites

of infection. There are a number of cytolytic toxins, including α toxin

and Panton Valentine toxin, that are secreted by staphylococci that

cause lysis of different host cells and contribute to host tissue damage.

An additional potential mechanism of S. aureus evasion is its capacity for intracellular survival. Both professional and nonprofessional

phagocytes internalize staphylococci. Internalization by these cells may

provide a sanctuary that protects bacteria against the host’s defenses.

This phenomenon appears to be especially relevant for hepatic Kupffer

cells during staphylococcal bacteremias. The intracellular environment

favors the phenotypic expression of S. aureus small-colony variants,

which are found in patients receiving antimicrobial therapy (e.g., with

aminoglycosides) and in those with cystic fibrosis or osteomyelitis.

These variants, whether intra- or extracellular, may facilitate prolonged

staphylococcal survival in different tissue sites and enhance the likelihood of recurrences. Finally, S. aureus can survive within PMNs and

may use these cells to spread and seed other tissue sites.

PATHOGENESIS OF COMMUNITY-ACQUIRED MRSA INFECTIONS A

number of specific virulence determinants contribute to the pathogenesis of CA-MRSA infections. A strong epidemiologic association

links the presence of the gene for the Panton-Valentine leukocidin with

SSTIs and with necrotizing post-influenza pneumonia. Other determinants that play a role in the pathogenesis of these infections include the

arginine catabolic mobile element (ACME), a cluster of unique genes

that may facilitate evasion of host defense mechanisms; phenol-soluble

modulins, a family of cytolytic peptides; and α toxin.

Host Response to S. aureus Infection The primary host response

to S. aureus infection is the recruitment of PMNs. These cells are

attracted to infection sites by bacterial components such as formylated

peptides or peptidoglycan as well as by the cytokines tumor necrosis

factor (TNF) and interleukins 1 and 6, which are released by activated

macrophages and endothelial cells.

Although most individuals have antibodies to staphylococci, it is not

clear that antibody levels are qualitatively or quantitatively sufficient

to protect against infection. Anticapsular and anti-MSCRAMM antibodies facilitate opsonization in vitro and have been protective against

infection in several animal models; however, they have not yet successfully prevented staphylococcal infections in clinical trials.

Pathogenesis of Toxin-Mediated Disease S. aureus produces

three types of toxin: cytotoxins, pyrogenic toxin superantigens, and

exfoliative toxins. Both epidemiologic data and studies in animals

suggest that antitoxin antibodies are protective against illness in TSS,

staphylococcal food poisoning, and staphylococcal scalded-skin syndrome (SSSS). Illness develops after toxin synthesis and absorption and

the subsequent toxin-initiated host response.

ENTEROTOXIN AND TOXIC SHOCK SYNDROME TOXIN 1 (TSST-1) The

pyrogenic toxin superantigens are a family of small-molecular-size,

structurally similar proteins that are responsible for two diseases:

TSS and food poisoning. TSS results from the ability of TSST-1 and

1181CHAPTER 147 Staphylococcal Infections

TABLE 147-1 Common Illnesses Caused by Staphylococcus aureus

Skin and Soft Tissue Infections

Folliculitis

Abscess, furuncle, carbuncle

Cellulitis

Impetigo

Mastitis

Surgical wound infections

Musculoskeletal Infections

Septic arthritis

Osteomyelitis (hematogenous or contiguous spread)

Pyomyositis

Psoas abscess

Respiratory Tract Infections

Ventilator-associated or nosocomial pneumonia

Septic pulmonary emboli

Postviral pneumonia (e.g., influenza)

Empyema

Bacteremia and Its Complications

Sepsis, septic shock

Metastatic foci of infection (kidney, joints, bone, lung)

Infective endocarditis

Infective Endocarditis

Injection drug use–associated

Native-valve

Prosthetic-valve

Nosocomial

Device-Related Infections (e.g., intravascular catheters, prosthetic joints)

Toxin-Mediated Illnesses

Toxic shock syndrome

Food poisoning

Staphylococcal scalded-skin syndrome

Invasive Infections Associated with Community-Acquired MethicillinResistant S. aureus

Necrotizing fasciitis

Waterhouse-Friderichsen syndrome

Necrotizing pneumonia

Purpura fulminans

enterotoxins to function as T-cell mitogens. In the normal process of

antigen presentation, the antigen is first processed within the cell, and

peptides are then presented in the major histocompatibility complex

(MHC) class II groove, initiating a measured T-cell response. In contrast, TSST-1 and enterotoxins bind directly to the invariant region of

MHC—outside the MHC class II groove. TSST-1 and the enterotoxins

can then bind T-cell receptors via the vβ chain; this binding results

in a dramatic overexpansion of T-cell clones (up to 20% of the total

T-cell population). The consequence of this T-cell expansion is a

cytokine storm, with the release of inflammatory mediators that

include interferon γ, IL-1, IL-6, TNF-α, and TNF-β. The resulting

multisystem disease produces a constellation of findings that mimic

those found in endotoxin shock; however, the pathogenic mechanisms

differ.

A different region of the enterotoxin molecule is responsible for

the symptoms of food poisoning. The enterotoxins are heat stable and

can survive conditions that kill the bacteria. Illness results from the

ingestion of preformed toxin; as a result, the incubation period is short

(1–6 h). The toxin stimulates the vagus nerve and the vomiting center

of the brain. It also appears to stimulate intestinal peristaltic activity.

EXFOLIATIVE TOXINS AND SSSS The exfoliative toxins are responsible

for SSSS, most commonly seen in newborns. The toxins that produce

disease in humans are of two serotypes: ETA and ETB. These toxins

are serine proteases that cleave desmosomal cadherins in the superficial layer of the skin, triggering exfoliation. The result is a split in the

epidermis at the granular level, which is responsible for the superficial

desquamation of the skin that typifies this illness.

■ DIAGNOSIS

Staphylococcal infections are readily diagnosed by Gram’s stain

(Fig. 147-1) and microscopic examination of abscess contents or

of infected tissue. Routine cultures of infected material usually are

positive; blood cultures are sometimes positive even when infections

are localized to extravascular sites. S. aureus is rarely a blood culture

contaminant. Polymerase chain reaction (PCR)–based assays are now

often used for the rapid diagnosis of S. aureus infection. A number of

point-of-care tests are available to screen patients for colonization with

MRSA. Determining whether patients with documented S. aureus

bacteremia also have infective endocarditis or a metastatic focus of

infection remains a diagnostic challenge. Uniformly positive cultures

of blood collected over time suggest an endovascular infection such

as endocarditis (see “Bacteremia, Sepsis, and Infective Endocarditis,”

below).

■ CLINICAL SYNDROMES

(Table 147-1)

Skin and Soft Tissue Infections S. aureus causes a variety of

cutaneous infections. Common factors predisposing to S. aureus cutaneous infection include chronic skin conditions (e.g., eczema), skin

damage (e.g., insect bites, minor trauma), injections (e.g., in diabetes,

injection drug use), and poor personal hygiene. These infections are

characterized by the formation of pus-containing blisters, which often

begin in hair follicles and spread to adjoining tissues. Folliculitis is a

superficial infection that involves the hair follicle, with a central area

of purulence (pus) surrounded by induration and erythema. Furuncles

(boils) are more extensive, painful lesions that tend to occur in hairy,

moist regions of the body and extend from the hair follicle to become

a true abscess with an area of central purulence. Carbuncles are most

often located in the lower neck and are even more severe and painful,

resulting from the coalescence of other lesions that extend to a deeper

layer of the subcutaneous tissue. In general, furuncles and carbuncles

are readily apparent, with pus often expressible or discharging from

the abscess. Other cutaneous S. aureus infections include impetigo

and cellulitis. S. aureus is one of the most common causes of surgical

wound infections.

Mastitis develops in 1–3% of nursing mothers. This infection of

the breast, which generally presents within 2–3 weeks after delivery, is characterized by findings that range from cellulitis to abscess

formation. Systemic signs, such as fever and chills, are often present in

more severe cases.

Musculoskeletal Infections S. aureus is a common cause of bone

infections—both those resulting from hematogenous dissemination

and those arising from contiguous spread from a soft tissue site. Hematogenous osteomyelitis in children most often involves the long bones.

Infections present with fever and bone pain or with a child’s reluctance

to bear weight. The white blood cell count and erythrocyte sedimentation rate are often elevated. Blood cultures are positive in ~50% of

cases. When necessary, bone biopsies for culture and histopathologic

examination are usually diagnostic.

In adults, hematogenous osteomyelitis involving the long bones is

less common. However, vertebral osteomyelitis is among the more common clinical presentations. Vertebral bone infections are most often

seen in patients with endocarditis, those undergoing hemodialysis,

diabetics, and injection drug users. These infections may present with

intense back pain and fever but may also be clinically occult, presenting as chronic back pain with low-grade fever. S. aureus is the most

common cause of epidural abscess, a complication that can result in

neurologic compromise. Patients report difficulty voiding or walking