Gram-Positive Cocci

Staphylococcus CLINICAL SIGNIFICANCE

Many staphylococcal species are classical opportunists colonizing skin and mucous membranes
but may become pathogenic in a species- and strain-dependent manner following breaks in the
cutaneous epithelial barrier through trauma or medical interventions. The recovery of a
staphylococcal isolate always requires assessment of clinical significance to determine whether
it is a contaminant, colonizer, or pathogen.

S. aureus is the clinically most important species, as it is capable of causing a wide range of
human and animal diseases. S. aureus possesses an extensive arsenal of often redundant and
overlapping virulence factors, such as adhesins, enzymes, and toxins, and has various strategies
to evade the host immune response. In addition, the pathogen has become resistant to many of
the therapeutic agents available. National Nosocomial Infection Surveillance and National
Healthcare Safety Network data indicate that S. aureus is the most common cause of
nosocomial pneumonia and skin and soft tissue infections (SSTIs). S. aureus is second only to
CoNS as a cause of primary bacteremia in hospitals.

Disease entities caused by S. aureus can be broadly divided into toxin-mediated diseases and
suppurative infections, comprising SSTIs, organic and systemic infections, and foreign-body-
related infections (FBRIs). SSTIs are the most frequent infections in community-associated S.
aureus infections, including those caused by community-associated MRSA (CA-MRSA). The
spectrum of SSTIs ranges from superficial (impetigo, folliculitis, furuncles/carbuncles,
hydradenitis suppurativa, pyoderma, and wound infections) to deep entities (abscesses,
mastitis, cellulitis, and pyomyositis) to acute life-threatening necrotizing fasciitis and myositis.
Infection of deep sites mayinvolve any body compartments and organ systems resulting in
empyemas, osteomyelitis, arthritis, endocarditis, pneumonia, otitis media, sinusitis, mastoiditis,
and parotitis. Any localized S. aureus infection can become invasive and lead to bacteremia.
Systemic infections comprise primary and secondary bacteremia, meningitis, and endocarditis.
Bacteremia may be complicated by metastatic foci (e.g.,vertebral osteomyelitis).Congenital or
acquired defects in host defense and the presence of foreign bodies may predispose patients to
serious infections.

Besides an acute, aggressive course of infection, S.aureus may cause chronic, persistent, and
relapsing infections often due to a phenotypic subpopulation designated small-colony variants
(SCVs), which present adapted phenotypes for intracellular persistence. Rapid switching
between the normal and the SCV phenotype seems to be a highly dynamic process in both
directions for adaptation to intraand extracellular conditions, respectively; this phenotype
switching also challenges accurate detection in the routine laboratory. SCVs of S.aureus and
other staphylococcal species (e.g., S.epidermidis and S.lugdunensis) have been isolated from
patient swith chronic osteomyelitis, abscesses, and FBRIs as well as from cystic fibrosis patients
with chronic airway infection.

Classical toxin-mediated diseases due to S.aureus include staphylococcal toxic shock syndrome
(TSS), staphylococcal food poisoning, and staphylococcal scalded skin syndrome (SSSS). TSS is
associated with colonization by or infection with an isolate of S. aureus that is positive for TSS
toxin-1 (TSST-1) or, less frequently, fo rother members of the staphylococcal pyrogenic toxin
superantigen (PTSAg) family (primarily staphylococcal enterotoxin B or C). TSS is diagnosed on
clinical grounds and is characterized by high fever, rapid onse thypotension, a diffuse
erythematous rash that becomes desquamating 1 to 2 weeks after onset, and involvement of
three or more organ systems. After its initial description in children, it was associated with
menstruating women who were using highly absorbent tampons. While the incidence of
menstrual TSS decreased due to changes in the tampons’ absorbency and chemical
composition, the frequency of nonmenstrual TSS entities has remained constant since the
1980s. Even though normally no source of infection is confirmed, nonmenstrual TSS is usually
associated with focal postoperative wound or soft tissue infections.

Staphylococcal food poisoning is caused by consumption of food contaminated with one or

more preformed, relatively heat-stable enterotoxins. Nausea, vomiting, abdominal cramps, and
diarrhea occur 2 to 6 h after food ingestion. Symptoms usually subside 8 to 12 h later.

Blisters in bullous impetigo and SSSS are caused by exfoliative (epidermolytic) toxins (ETA and
ETB). SSSS is typically found in neonates and young children. In addition to severe exfoliation
affecting up to 90% or more of the entire body surface (Ritter’s disease), a localized form
(pemphigus neonatorum) with a few blisters is known. Diagnosis is made on the basis of clinical
features, including Nikolsky’s sign, in which the skin wrinkles on gentle pressure.

The other coagulase-positive or -variable staphylococci are members of the skin microbiotas of
various animal species and occasionally cause infections in their hosts. The members of the S.
intermedius/S. pseudintermedius/S. delphini cluster are the most common etiologic agents of
the canine pyoderma. S. hyicus is predominantly associated with the exudative epidermitis
(greasy pig syndrome) in pigs, S. schleiferi subsp. coagulans is found in dogs suffering from
external otitis, and S.aureus subsp. Anaerobius is the etiological agent of abscess disease, a
specific lymphadenitis of sheep and goats. In humans, S. intermedius/S. pseudintermedius
appears to be occasionally responsible for canine-inflicted wound infections, FBRIs, food
poisoning, and invasive infections in immunocompromised patient. Only a few human
infections due to S. schleiferi subsp. coagulans and S. hyicus are known. For S.agnetis, isolates
have been recovered from bovine intramammary infections.
Since 1980, CoNS have been increasingly recognized as nosocomial pathogens, especially S.
epidermidis. S. epidermidis and S. haemolyticus are often referred to as “medium
pathogenicity” staphylococci, as they cause nosocomial infections mainly in patients with
predisposing factors, such as immunodeficiency and/or the presence of indwelling or implanted
foreign polymer bodies. Also, S. lugdunensis and S. saprophyticus may be categorized into this
group. CoNS are less often implicated as the cause of infections of natural tissue.Overall, the
clinical appearance of infections caused by CoNS has been characterized as subtle (associated
with subacute or chronic clinical courses without fulminant signs),and they are seldom life-
threatening. CoNS are the most common cause of nosocomial bloodstream infections typically
associated with central and peripheral intravascular catheters. Most important in the
pathogenesis of FBRIs is the ability of CoNS to colonize the surface of a device by the formation
of a thick, multilayered biofilm. S. epidermidis is the predominant cause of infections associated
with prosthetic vascular grafts, prosthetic orthopedic devices, and cerebrospinal fluid shunts.
CoNS are frequently isolated as causative agents of prosthetic-valve endocarditis; rarely (ca. 5%
of the time), they are involved in infections of (previously damaged) native valve.s Right-sided
native-valve endocarditis is observed in intravenous drug abusers. Virtually any other surgically
inserted materials and devices may become infected by CoNS. CoNS also account for 45 to 75%
of all lateonset bloodstream infections in preterm and low-birthweight neonates in neonatal
intensive care units.

Of all CoNS, S. lugdunensis holds a special position because its infections generally resemble
those caused by S. aureus rather than those caused by other CoNS. It is especially renowned for
causing unusually fulminant cases of native-valve endocarditis in addition to prosthetic-valve
endocarditis(72).Thus,patientswith S.lugdunensis bacteremia should be carefully examined for
signs of endocarditis. Besides causing other invasive infections, this organism is a common
pathogen involved in FBRIs (59). In addition,
S.lugdunensisisnotararecauseofskinabscessesandwound infections, especially below the waist
(73). Based on special urotropic and ecologic characteristics, S. saprophyticus subsp.
saprophyticus is a well-documented causative agent of acute, commonly recurrent, urinary
tract infections in young, otherwise healthy, sexually active women and, less frequently, in
young men or boys. This pathogenisthesecond-most-common(afterEscherichiacoli)
causeofuncomplicatedcystitisamongyoungwomen.While colony counts of ≥100,000 CFU/ml in
two or more cultures of midstream urine usually indicate significant bacteriuria;
lowercountsmaybesignificantinthesymptomaticpatient. Infections due to the recentlydescribed
subspecies S. saprophyticus subsp. bovis have not been reported.
ForvariousotherCoNSspecies(e.g.,S.capitis,S.chromogenes S. cohnii, S. hominis, S. pasteuri, S.
pettenkoferi, S. warneri, and S. xylosus), case reports and series
predominantlyreportingonFBRIshavebeenpublished.Incontrast, S. carnosus, S. condimenti, S.
piscifermentans, S. equorum subsp. linens, and other staphylococcal species involved
mainlyinfoodproductionhavebeenregardedasnonpathogenic staphylococci. Since human
infections due to Macrococcus, Jeotgalicoccus, Nosocomiicoccus, and Salinicoccus have not
been described, these genera are not discussed further in this chapter.

CLINICAL SIGNIFICANCE Streptococcus pyogenes (Group A Streptococci)

S. pyogenes colonizes the human throat and skin and has developed complex virulence
mechanisms to avoid host defenses (29, 30). The upper respiratory tract and skin lesions serve
as primary focal sites of infections and principal
reservoirsoftransmission.S.pyogenescancausesuperficialor deepinfectionsduetotoxin-
mediatedandimmunologically mediated mechanisms of disease. S. pyogenes is the most
common causeof bacterialpharyngitis andimpetigo. Inthe past, S. pyogenes was a common
cause of childbed fever or puerperal sepsis. S. pyogenes is responsible for deep or invasive
infections, especially bacteremia and sepsis, and deep
softtissueinfections,suchaserysipelas,cellulitis,andnecrotizingfasciitis.Lesscommonpresentations
includemyositis, osteomyelitis,septicarthritis,pneumonia,meningitis,endocarditis, pericarditis,
and severe neonatal infections following intrapartum transmission. One or more erythrogenic
exotoxins produced by S. pyogenes may cause a confluent erythematous sandpaper-like rash
characteristic of scarlet fever. While systemic toxic effects occur rarely with scarlet fever, severe
clinical manifestations in streptococcal toxic shock syndrome (STSS) may result from massive
superantigen-inducedcytokineandlymphokineproduction. Nonsuppurative complications
include poststreptococcal glomerulonephritisandacuterheumaticfever.Whileeither of
theseconditions mayfollow pharyngitis,only
glomerulonephritisislinkedwithskininfectionsduetoS.pyogenes.S.
pyogeneshasalsobeenassociatedwithpediatricautoimmune neuropsychiatric disorders (31).
ThecausesoftheemergenceofSTSS,frequentlyaccompaniedbynecrotizingfasciitis,andtheresurgen
ceofinvasive S. pyogenes infections since themid-1980s aremostly unexplained (32). S.
pyogenes remains exquisitely susceptible to penicillin. Efforts to find highly virulent clones
include subtyping of S. pyogenes by serological determination of the surface M protein or
genetic detection of the emm genes, encoding the M protein. However, despite the continuous
exposure and subsequent type-specific immunity, the most prevalentM typesassociated
withSTSS continuetobe M1

386 n BACTERIOLOGY

and M3, together accounting for approximately 50% of invasive infections. Since identical
strains have accounted for less serious infections (33), host factors and comorbid conditions
account for different diseases. The incidence of STSS seems highest among young children,
particularly those with varicella, and the elderly. Other persons at risk include those with
diabetes mellitus, chronic cardiac or pulmonary diseases, HIV infection, and intravenous drug or
alcohol abuse. The risk for severe invasive infection in contacts has been estimated to be 200
times greater than forthegeneralpopulation,butmostcontactsareasymptomatically colonized
(34).

Streptococcus agalactiae (Group B Streptococci)

S.agalactiaewasfirstidentifiedasthecauseofbovinemastitis at theend of the 19thcentury. Since
the 1970s,it has been reported as the cause of invasive neonatal infections. Neonatal infections
present as two different clinical entities: early-onset neonatal disease, characterized by sepsis
and pneumoniawithinthefirst7daysoflife;andlate-
onsetdiseasewithmeningitisandsepsisbetween7daysand3months
ofage.Themostimportantriskfactorforthedevelopmentof
invasiveneonataldiseaseisthecolonizationofthematernal urogenital or gastrointestinal tract by S.
agalactiae, which is
foundin10to30%ofpregnantwomen.Preventionofearlyonsetneonatalinfectionscanbeachievedint
hemajorityof casesbyadministrationofintrapartumantibioticprophylaxis
startingatleast4hoursbeforedelivery.OfficialCDCrecommendationsforthepreventionofneonatalS.
agalactiaeinfections were first issued in 1996 and then revised in 2002 and
2010(35).Theseguidelinesresultedinasubstantialdecline of early-onset neonatal GBS disease.
Invasive S. agalactiae infections of adult patients may be observed as postpartum
infectionsorinimmunocompromisedadultpatientswithalcoholism, diabetes mellitus, cancer, or
HIV infection (36). The spectrum of infections in adult patients includes
pneumonia,bacteremia,meningitis,endocarditis,urinarytractinfections,skinandsofttissueinfectio
ns,andosteomyelitis.

Streptococcus pneumoniae S. pneumoniae is described separately in this section due to its

clinical features that distinguish it from other species of the S. mitis group. S. pneumoniae is the
most frequently

isolated respiratory pathogen in community-acquired

pneumonia(CAP).Inasmanyas30%ofCAPcases,S.pneumoniaecanbefoundinbloodculturesofpatie
nts. S.pneumoniae isalsoamajorcauseofmeningitis,leadingtohighmorbidity and mortality in
pediatric and adult patients. The most frequently observed infection due to S. pneumoniae is
otitis media, with an estimate of one infection for every child up to the age of 6 in the United
States. Other infections due toS.pneumoniaeincludesinusitis,peritonitis,andrarecases of
endocarditis. S. pneumoniae colonizes the upper respiratory tract especially in children, without
evidence of infection. Prevention of pneumococcal infections can be achieved by immunization
with a 23-valent capsular polysaccharide vaccine in adults or the 13-valent conjugate
vaccineinchildren.Widespreaduseofvaccineshasresulted in a reduction of invasive
pneumococcal infections during the past several years but also in changes of the serotypes
responsible for invasive and noninvasive infections (39– 41). The recent introduction of the 13-
valent conjugate vaccine resulted in a general decrease of nasopharyngeal colonization rates
with the vaccine-included serotypes in vaccinated children (42, 43). First data on the impact of
the 13-valent vaccine on the burden of invasive disease in children are also promising (44, 45).

Extensive taxonomic changes have occurred in this group, and strains formerly known as
human S. bovis isolates are designated as different species (see “Taxonomy” above). The group
now includes S. equinus, S. gallolyticus, S. infantarius, and S. alactolyticus. Species from this
group are frequently encountered in blood cultures of patients with bacteremia, sepsis, and
endocarditis. The clinical significance of blood cultures growing streptococci from the S. bovis
group lies in the association of (i) S. gallolyticus subsp. gallolyticus with gastrointestinal
disorders, including colon cancer and chronic liver disease, and (ii) S. gallolyticus subsp.
pasteurianus with meningitis (53–55).

CLINICAL SIGNIFICANCE Members of the genus Neisseria have a high affinity for mucosal
membranes. A wide variety of species can be isolated from humans, including N. gonorrhoeae,
N. cinerea, N. elongata, N. flavescens, N. lactamica, N. meningitidis, N. mucosa, N.
polysaccharea, N. sicca, and N. subflava. Several species are predominantly recovered from
animals, such as N. animalis, N. animaloris, N. zoodegmatis (from throats of cats and dogs) (30),
N. denitrificans (from throats of guinea pigs), N. dentiae (from dental plaques of domestic
cows), N. macacae (fromoropharyngesofrhesusmonkeys),and N. weaveri (from the oral flora of
dogs). Similar to N. elongata, the new species N. bacilliformis likely colonizes the oral cavity and
respiratory tract of humans (10). Most human Neisseria species are considered normal
inhabitants of the
upperrespiratorytractwhichcausediseaseinanopportunisticfashion.Rarely,speciesofanimalorigin
cancausewound infections in humans after bites (31). N. meningitidis mostly appears as a mere
commensal of the human oropharynx yet can cause life-threatening, acute disease in previously
healthyindividuals.N.gonorrhoeae,however,isalwaysconsidered a pathogen, even if obvious
signs of disease are absent. Uncomplicated infection by N. gonorrhoeae (gonorrhea) manifests
most commonly as acute urethritis in men. The major symptoms are urethral discharge,
sometimes associated with dysuria, typically without frequency or urgency. Coinfection of the
preputial (Tyson’s), urethral (Littré’s), andbulbo-
urethral(Cowper’s)glandsispossible.Also,completelyasymptomaticinfectionsoccurinupto10%ofc
ases. Most cases of untreated urethritis resolve spontaneously after several weeks. Further
localized complications after gonococcal urethritis include acute epididymitis, penile edema,
and abscesses of the above-mentioned glands. In women, the endocervix is the primary site of
genital infection. Additionally, N. gonorrhoeae may infect the urethra, therectum,theperi-
urethral(Skene’s)glands,andtheducts ofthegreatervestibular(Bartholin’s)glands.Thesquamous
epitheliumofthevaginaistypicallynotinfectedinsexually mature women.In contrast toinfection
inmen, asymptomaticinfectioninwomenis common(32).Also,ifsymptoms appear, they often
cannot clearly be attributed to infection by N. gonorrhoeae, as concurrent infection by
Chlamydia trachomatisandMycoplasmagenitaliumiscommon.Themain
complaintsincludeincreasedvaginaldischarge,dysuria,and intermenstrual bleeding. Ascension of
the infection may result in pelvic inflammatory disease, which manifests as
variouscombinationsofendometritis,salpingitis,tubo-
ovarianabscess,andperitonitis.Acuteperihepatitis(Fitz-HughCurtis syndrome) can develop
following direct extension of N. gonorrhoeae from the fallopian tube to the liver capsule and
the surrounding peritoneum. While over 80% of rectal infectionsremain
asymptomatic,somepatients complainof acute proctitis. Pharyngeal infection is acquired by oral
sexual exposure and is mostly asymptomatic yet can also cause overt pharyngitis or tonsillitis
(33). While probably lesstransmissiblethanrectalorurethralgonorrhea,itssilent nature and
considerable prevalence among men who have sex with men (MSM) render pharyngeal
infection a common reservoir for gonorrhea in sexually active MSM. Gonococcal conjunctivitis
in adults usually results from autoinoculation or oculogenital or orogenital exposure. If the

34. Neisseria n 637

infection is not treated promptly, corneal ulceration may

rapidlydevelop.Conjunctivitisofthenewborn(ophthalmia neonatorum) is transmitted during
birth and is favored by premature rupture of the membranes and preterm delivery. Historically
a common cause of blindness, it can be prevented by administering a 1% aqueous solution of
silver nitrateor anantibioticointment(usually
containingerythromycin)intotheconjunctivaeafterdelivery.Disseminated
gonococcalinfectionreflectsbacteremicdissemination,possibly generation of immune
complexes, and indirect immunological mechanisms. Disseminated gonococcal infection
complicates fewer than 1% of mucosal infections (34). It usually manifests as septic arthritis and
a characteristic syndrome of polyarthritis and dermatitis and should be suspected in patients
presenting with tenosynovitis, arthritis, and vasculitic skin lesions (35). IMD commonly presents
as meningitis, acute sepsis, or a combination of both. In addition, unusual presentations include
transient mild bacteremia, chronic meningococcal sepsis, pneumonia (mainly by serogroup Y),
septic arthritis, and endocarditis (36). Symptoms of meningitis vary widely and caninclude astiff
neck,headache, confusion, andphotophobia. Lethality of meningococcal meningitis without
sepsiscanbeaslowas3%(37).Sequelae,suchassensorineural hearing loss, developmental delay,
and speech defects, afflict a substantial portion of survivors, yet in a smaller
proportionthaninotherformsofacutebacterialmeningitis (38). Petechial lesions are telltale signs
of meningococcal sepsis, and they can coalesce and become ecchymotic. Nevertheless,
nonpurpuric maculopapular rashes, readily confused with viral exanthems, have also been
associated with meningococcemia. Meningococcal septic shock can take a fulminant course
with a lethality of 30% (39), and plasma concentrations can reach up to 108 meningococci/ ml
(40), which in turn leads to massive activation of
cytokinesandvasoactiveanaphylatoxins.Meningococcalshock syndrome is characterized by
myocardial depression, vasoplegia, capillary leakage, and disseminated intravascular
coagulation (39). Complications of IMD include arthritis, pericarditis,cranialnerve
dysfunction,meningococcalpericarditis, and, rarely, cerebral or spinal infarction. In addition,
adolescent survivors of IMD have been described as sufferingfromaseriesoflong-
termconsequences,including
poorerphysicalandmentalhealth,qualityoflife,andeducationalachievement(41).Bacteremiacanals
omanifestwithoutsignsofsepsis,intheformofchronicmeningococcemia,
aconditionassociatedwithlow-graderelapsingfever,arthritis, and rash (42).
Meningococcalpneumonia has been recognized as an infrequent clinical syndrome for more
than 100years(43).Mostmeningococcalpneumoniasarecaused by serogroup Y and affect adults
disproportionately (44). A precedingviralillness,notablypandemicinfluenza(45),has
beenreportedtopromoteitsdevelopment.N.meningitidisis an uncommon cause of acute
bacterial conjunctivitis and can also be the etiologic agent of urethritis in men. The clinical
significance of Neisseria species other than
N.gonorrhoeaeandN.meningitidisiscoveredin“Evaluation, Interpretation, and Reporting of
Results” at the end of the chapter.