BACTERIAL INFECTIONS

Staphylococcal and
streptococcal infections

scopically, Staph. aureus are Gram-positive cocci that tend to form

clusters on solid media. Identification is usually confirmed by positive catalase, coagulase and DNase tests. Typing is now possible
by molecular methods such as pulsed-field gel electrophoresis.
Skin and soft tissue infections include impetigo, ecthyma, folliculitis, furuncles, carbuncles, hydradenitis suppuritiva, mastitis
and cellulitis. Deeper infections may occur after trauma, surgery
or insertion of foreign material, and include wound infections,
bursitis, septic arthritis and osteomyelitis.
Bacteraemia and metastatic infections (Figures 1 and 2) occur
when Staph. aureus overcomes local defence mechanisms and
spreads via the bloodstream. Bacteraemia can follow a localized
infection, or the organism may colonize an intravenous catheter;
it may cause nonspecific clinical features (e.g. fever, chills, rigors)
and can lead to metastatic infections such as endocarditis, pericarditis, pneumonia, pulmonary abscess, empyema, bursitis, septic
arthritis, osteomyelitis and pyomyositis. The diagnosis is confirmed
by cultures of blood and appropriate clinical specimens.
Treatment is with a parenteral antistaphylococcal antibiotic
(e.g. flucloxacillin). Aminoglycoside antibiotics exhibit synergistic activity in vitro and are often given in endocarditis and other
severe infections. In patients who are allergic to penicillin or
have MRSA bacteraemia, the drug of choice is vancomycin (dose
titrated according to serum levels, and given with caution in renal
failure). Purulent collections should be aspirated or drained. It is
standard practice to treat bacteraemia from a known, removable
source (e.g. an intravenous cannula) for 2 weeks, and bacteraemia
from all other causes (known and unknown) for 4 weeks; the aim
is to prevent metastatic infection. Treatment of prosthetic-valve
endocarditis is discussed in MEDICINE 33:4, 66.

Este Trk
Nick Day

Staphylococcal infections
The genus Staphylococcus currently contains 35 species, all of
which are part of the normal skin and mucous membrane flora of
humans and animals. The coagulase enzyme-producing Staphylococcus aureus is the most important pathogen, causing various
pyogenic infections and toxin-mediated illnesses in normal hosts.
Other species are collectively termed coagulase-negative staphylococci. These are generally considered non-pathogenic, apart from
Staph. epidermidis, which causes nosocomial bacteraemia and
device-related infections, and Staph. saprophyticus, which is a
common cause of urinary tract infection (UTI).
Staph. aureus: the main site of carriage is the anterior nares. The
carriage rate in adults is 2040%, depending on seasonal and local
epidemiological factors. Some groups (e.g. medical staff, those with
type 1 diabetes, haemodialysis patients, intravenous drug-users)
appear to be particularly prone to colonization with Staph. aureus.
Carriers transfer the organism to the skin, where trauma may provide a portal of entry leading to local, deep or systemic infection.
The spread of methicillin-resistant Staph. aureus (MRSA), which is
intrinsically resistant to all -lactam antibiotics, is a major concern,
as is the recent emergence of isolates with reduced susceptibility
or resistance to vancomycin (e.g. vancomycin-intermediate Staph.
aureus, vancomycin-resistant Staph. aureus).
Staph. aureus has several putative determinants of pathogenicity, including cell wall constituents, surface proteins,
toxins and enzymes, and specific cell wall-bound adhesins. It
secretes enzymes including catalase, coagulase, clumping factor,
hyaluronidase, -lactamases and DNase, and produces extracellular
toxins, some directly cytotoxic (haemolysins, leukocidins) and
some that act as superantigens causing polyclonal proliferation
of T cells (toxic shock syndrome toxin-1 (TSST-1), enterotoxins,
epidermolytic toxins). Host factors that particularly predispose to
Staph. aureus infection include inborn defects in neutrophil function, diabetes, and the presence of foreign material. Nasal carriers
are more likely to develop nosocomial bacteraemia, though the
associated mortality may be lower.
Staph. aureus grows rapidly aerobically and anaerobically
on blood agar and other non-selective solid media. Most strains
produce -haemolysis within 2436 hours on blood agar. Micro-

1 Psoas abscess caused by Staphylococcus aureus.

Este Trk is Clinical Research Fellow in the Oxford University Clinical

Research Unit, Viet Nam. Conflict of interests: none declared.
2 L1/2 discitis caused by
Staphylococcus aureus.

Nick Day is Director of the WellcomeMahidolOxford Tropical Medicine

Research Programme, Thailand. Conflict of interests: none declared.

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Toxin-mediated diseases
Staphylococcal food poisoning presents with vomiting
and diarrhoea within hours of ingestion of foods containing
enterotoxin-producing bacteria. Treatment is symptomatic.
Staphylococcal scalded-skin syndrome is caused by epidermolytic toxin-producing Staph. aureus and is usually seen in children.
Clinical presentation ranges from bullous impetigo to severe,
generalized, exfoliative dermatitis with systemic upset. It is usually treated with parenteral antibiotics, supportive skin care and
careful management of fluid and electrolyte losses.
Toxic shock syndrome is caused by TSST-1 and other related
staphylococcal enterotoxins. The menstrual form is associated
with tampon use, the non-menstrual form with vaginal infections,
contraceptive devices, abortion, childbirth and surgical procedures.
The clinical case definition includes fever, hypotension, desquamating rash and involvement of three or more organ systems.
Management requires aggressive fluid resuscitation, removal of
any tampon, and parenteral antistaphylococcal antibiotics.

cal reactions, antigenic composition and genetic analysis. Three

patterns of haemolysis are seen on blood agar plates partial
haemolysis (-haemolysis), complete haemolysis (-haemolysis)
and non-haemolysis. -haemolytic streptococci produce a greenish discoloration of blood agar, hence the term viridans streptococci. -haemolytic streptococci are classified into Lancefield
serogroups, determined by antigenic differences between cell wall
carbohydrates. Streptococci lacking a recognizable group antigen
are identified by their biochemical reactions, and placed taxonomically using molecular techniques such as DNA hybridization and
ribosomal RNA sequencing.
Group A Streptococcus (Strep. pyogenes) is an important human
bacterial pathogen, causing acute pharyngitis and various cutaneous and systemic infections. There are several pathogenic determinants, including M protein and a hyaluronic acid capsule, both of
which are antiphagocytic. Exotoxins (A, B, C, mitogenic factor and
streptococcal superantigen), haemolysins (streptolysins O and S)
and enzymes (DNases, hyaluronidase and streptokinase) are also
produced. Group A streptococci grow rapidly aerobically and
anaerobically on blood agar and other non-selective solid media.
They produce -haemolysis within 2436 hours on blood agar.
Microscopically, they are Gram-positive cocci that grow in pairs or
short chains. Identification is usually confirmed by streptococcal
grouping by latex agglutination.
Streptococcal pharyngitis is a common childhood infection,
spread by droplet and presenting after a 24-day incubation period
with acute sore throat, fever, malaise and headache. Examination
reveals an inflamed pharynx, tonsillar enlargement with a purulent
exudate, and tender regional lymphadenopathy. Treatment is with
oral penicillin for 10 days.
Skin and soft tissue infections group A Streptococcus causes
various skin and soft tissue infections, including erysipelas, cellulitis and necrotizing fasciitis.
Streptococcal toxic shock syndrome can be defined as any
streptococcal infection associated with sudden onset of shock
(systolic blood pressure 90 mm Hg) and multi-organ failure
(two or more of the following renal impairment, coagulopathy,
hepatic impairment, adult respiratory distress syndrome, generalized rash that may desquamate, soft tissue necrosis). Streptococcal
M protein is thought to have a major role in the pathogenesis by
forming complexes with fibrinogen that bind to integrins on the
surface of circulating neutrophils. The activated neutrophils cause
endothelial cell damage and consequent vascular leakage and
hypercoagulability, leading to hypotension and organ damage.
Management is with prompt, aggressive surgical debridement of
suspected deep-seated streptococcal infection, intravenous broadspectrum antibiotic therapy, and intensive-care support. Once a
streptococcal cause is confirmed, high-dose benzylpenicillin and
clindamycin can be given.
Scarlet fever results from infection with an organism that
produces an erythrogenic toxin. These toxins are superantigens;
two (SPE A and SPE B) resemble Staph. aureus enterotoxins at
the molecular level. A scarlatinal rash occurs (Figure 3), usually
on the second day of the illness, and spreads from the upper
chest to the trunk, neck and extremities, sparing the palms and
soles. The rash fades over 1 week and is followed by extensive
desquamation. Severe forms of disease are characterized by fever
and marked systemic toxicity. Treatment is with penicillin.

Coagulase-negative staphylococci are skin commensals. Often

previously dismissed as culture contaminants, they are becoming
important as pathogens. Staph. saprophyticus causes communityacquired UTI. Staph. epidermidis causes nosocomial bacteraemia
and prosthetic device-related infections. Other species that have
been associated with infection include Staph. haemolyticus,
Staph. lugdunensis and Staph. schleiferi. The organisms adhere to
prosthetic material, then form multilayered clusters that become
embedded in an exopolysaccharide matrix, forming a biofilm. The
biofilm protects the organisms from phagocytic cells and reduces
the penetration of antibiotics.
Coagulase-negative staphylococci grow rapidly aerobically and
anaerobically on blood agar and other non-selective solid media.
Microscopically, they are Gram-positive cocci that form clusters
on solid media. Identification is usually confirmed by negative
coagulase and DNase tests. Nosocomial isolates are usually
multiply antibiotic resistant (mainly plasmid-mediated). Typing
of coagulase-negative staphylococci is performed by molecular
methods, because biochemical tests are unreliable.
Staph. epidermidis is the most common cause of nosocomial
bacteraemia and is often associated with intravascular catheters
or prosthetic material. It is increasingly a problem in special-care
baby units, and in patients with haematological malignancies.
Staph. epidermidis is the most common cause of early prostheticvalve endocarditis and a rare cause of native-valve endocarditis
(see MEDICINE 33:4, 66). It is also the most common organism
causing CSF shunt infection. Other infections include mediastinitis,
prosthetic joint infections and vascular graft infections. Treatment
involves removal of the infected prosthetic material, if possible,
and appropriate antibiotic therapy (e.g. vancomycin, teicoplanin),
followed by long-term suppressive antibiotic therapy.

Streptococcal infections
Streptococci are Gram-positive cocci that grow in pairs or chains.
They are readily distinguished from staphylococci by their Gramstain appearance and by a negative catalase test. More than
30 species have been identified; those discussed below are the
most pathogenic in humans. Classification of streptococci is
complex and based on features including haemolysis, biochemi-

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and other chronic conditions. Prevention using a pneumococcal

vaccine has been recommended in those at increased risk. Resistance to penicillin is increasing worldwide, but high-level resistance
remains uncommon in the UK.
Strep. pneumoniae has several adhesins that enable it to bind
to epithelial cell receptors. It produces a capsule, which helps it to
evade phagocytosis. C-polysaccharide (a teichoic acid constituent
of the cell wall containing choline phosphate) is unique to Strep.
pneumoniae and is responsible for the reaction between pneumococci and C-reactive protein, which leads to complement activation.
The organism grows in chains in liquid media, but often appears
on Gram-stain as lanceolate diplococci. It is -haemolytic on
blood agar, produces a negative catalase reaction and is optochin
sensitive. Serotypes are based on antigenic differences between
capsular polysaccharides.
Otitis media and sinusitis are most commonly caused by Strep.
pneumoniae. Treatment is with oral amoxicillin.
Meningitis following the Haemophilus influenzae type b and
meningococcus group C vaccination campaigns, Strep. pneumoniae
is probably the most common cause of adult bacterial meningitis in the UK. It is also the most common organism isolated in
patients with meningitis following head injury. Treatment is with
intravenous ceftriaxone or benzylpenicillin (if fully sensitive).
Pneumonia Strep. pneumoniae is the most common cause of
adult pneumonia. Symptoms are fever, malaise, productive cough
and pleuritic chest pain. Examination reveals pyrexia, tachycardia, tachypnoea and signs of pulmonary consolidation. Chest
radiography shows lobar or segmental consolidation. Treatment
is intravenous ampicillin or cefuroxime. Complications include
parapneumonic effusion, empyema, lung abscess, bacteraemia
and meningitis.
Others Strep. pneumoniae is the main cause of spontaneous
bacterial peritonitis in children, and sometimes a cause in adults,
particularly with IUDs. Less common are endocarditis, pericarditis,
septic arthritis, osteomyelitis, epidural and brain abscesses, and
soft tissue infections. Unusual pneumococcal infections in a young
adult may suggest underlying HIV infection.

3 The rash of scarlet fever

in group A streptococcal
bacteraemia.

Rheumatic fever acute rheumatic fever is an autoimmune

disease caused by immunological cross-reactivity between streptococcal M proteins and cardiac antigens, and is a delayed sequela
of streptococcal pharyngitis. It mainly affects 615-year-olds,
particularly in the developing world. Non-suppurative inflammatory lesions involve the heart, joints, skin, subcutaneous tissues
and CNS. Damage to the heart valves may result in progressive
valvular lesions and cardiac failure. Diagnosis is based on various
symptoms and signs, originally described as major criteria (carditis, polyarthritis, chorea, subcutaneous nodules, erythema marginatum) and minor criteria (fever, arthralgia, heart block, raised
inflammatory markers). The revised Jones criteria also require
evidence of recent streptococcal infection (positive throat culture,
rapid streptococcal antigen test, increased streptococcal antibody
titre). Treatment is with analgesics and/or anti-inflammatory drugs
(aspirin or corticosteroids).
Post-streptococcal glomerulonephritis results from crossreactivity between streptococcal M proteins and host antigens,
and follows streptococcal pharyngitis or pyoderma. It is an acute
inflammatory disorder of the renal glomerulus associated with
diffuse proliferative glomerular lesions. Clinical features include
symptoms and signs of renal failure, hypertension and oedema.
Laboratory features include anaemia, raised ESR, renal impairment,
low C3 levels, haematuria, proteinuria, RBC casts in the urine and
raised streptococcal antibody titres. Diagnosis is based on clinical
features and confirmatory evidence of recent streptococcal infection. Treatment is directed towards management of acute problems
(e.g. hypertension, fluid overload, acute renal failure) and eradication of the causative organism with penicillin (to prevent further
transmission of the nephritogenic clone). The prognosis is good,
though a few patients develop chronic glomerulonephritis.

Strep. agalactiae (group B Streptococcus) is an important pathogen in pregnant and post-partum women and in neonates. The
prevalence of asymptomatic vaginal colonization in pregnant
women is 540%. The rate of vertical transmission in neonates
born to women colonized at the time of delivery is 50%. The
most devastating infections (bacteraemia and meningitis) occur
in neonates, but group B streptococci also cause bacteraemia in
adults. Less commonly, they cause pneumonia, endocarditis,
arthritis, osteomyelitis, skin and soft tissue infections, meningitis,
ocular infections and UTI.
Group B streptococci are facultatively anaerobic, -haemolytic
diplococci that grow readily on various media. Definitive identification is based on detection of the group B-specific cell wall
antigen by latex agglutination. They can be subclassified into nine
serotypes based on capsular polysaccharide determinants.
Infections of the female genital tract during pregnancy,
group B streptococci may cause asymptomatic bacteriuria, cystitis
or, less often, pyelonephritis. Colonized pregnant women are at
significantly increased risk of premature rupture of membranes,
post-partum fever, endometritis and wound infection. Rarely, pelvic
abscess, septic shock or septic thromboembolism occurs.

Group C and G streptococci cause pharyngitis, deep pyogenic

infections, and bacteraemic invasive disease including endocarditis. Life-threatening infection occurs particularly in patients
with coexisting medical conditions. Treatment is with penicillin.
Although post-streptococcal glomerulonephritis has been associated with group C streptococcal pharyngitis, neither group C nor
group G streptococci appear to cause acute rheumatic fever.
Strep. pneumoniae (pneumococcus) is a common bacterial pathogen of humans found in the nasopharynx of 2040% of children
and 1020% of adults. Colonization and infection rates are seasonal, increasing during the winter. Strep. pneumoniae is a major
cause of otitis media, sinusitis, meningitis and pneumonia. Less
commonly, it causes bacteraemia, peritonitis, endocarditis, pericarditis, septic arthritis, osteomyelitis, soft tissue infections, and
epidural and brain abscesses. Predisposing factors include defects
in antibody formation, complement deficiency, neutropenia, hyposplenism, extremes of age, alcoholism, diabetes, renal impairment

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Neonatal infections early-onset infection (onset < 7 days after

birth) is associated with maternal factors (age < 20 years, previous miscarriage, premature or prolonged rupture of membranes,
intra-partum fever) and prematurity (delivery at < 37 weeks
gestation). Early-onset infection presents with septicaemia (60%),
pneumonia (30%) or meningitis (10%). Mortality is 28% in term
infants and is inversely proportional to birth weight. Late-onset
infection (7 days to 3 months) presents at a mean age of 24 days
with bacteraemia, meningitis, osteomyelitis or septic arthritis.
Uncommon foci include cellulitis, adenitis, otitis media, conjunctivitis, empyema, peritonitis, endocarditis and deep abscesses.
Treatment is with high-dose intravenous penicillin.
Bacteraemia invasive group B streptococcal infection causes
considerable morbidity and mortality in adults. In the non-pregnant
population, the incidence increases with age; men are more commonly affected. Diabetes, liver disease, neurological conditions,
malignancy, renal or urological disease, cardiopulmonary disease
and HIV infection predispose to invasive infection. Bacteraemia is
the most common presentation. Other syndromes include pneumonia, septic arthritis, osteomyelitis, skin and soft tissue infections
and meningitis. Treatment of adult infection is with high-dose
intravenous benzylpenicillin (or vancomycin in those allergic to
penicillin). Mortality in non-pregnant adults is 2132%.

4 Purpuric rash in a patient with Streptococcus suis bacteraemia.

and residency in an ICU. The most common clinical isolates are

Enterococcus faecalis (8090%) and E. faecium (510%). The
prevalence of E. faecium, including multi-drug-resistant strains
resistant to vancomycin, is increasing.
These organisms often exhibit unusual patterns of antimicrobial
susceptibility and resistance. Penicillin or ampicillin are the antibiotics of choice in most uncomplicated infections. Vancomycin
or teicoplanin is an alternative for penicillin allergy or penicillinresistant organisms. Combinations of cell wall-active agents (penicillin, ampicillin or vancomycin) and aminoglycosides have been
used in enterococcal bacteraemia, endocarditis and meningitis.
Treatment of vancomycin-resistant enterococci remains a major
problem; most experience has been gained with the streptogramins,
but linezolid (an oxazolidinone) is increasingly used.
UTIs are usually nosocomial and associated with catheterization
or instrumentation. They may present as cystitis or pyelonephritis,
or, less commonly, prostatitis or perinephric abscesses.
Bacteraemia is usually nosocomial and often polymicrobial.
Potential sources include UTI, intra-abdominal or pelvic sepsis,
wounds, intravascular catheters and biliary sepsis. Increasingly,
there are reports of primary enterococcal bacteraemia in patients
with severe underlying illness or immunosuppression; these are
usually monomicrobial and come from a presumed gastrointestinal
source. Metastatic infection is rare. Although enterococci are not
as intrinsically virulent as other streptococcal species, the mortality associated with enterococcal bacteraemia is high (4268%),
reflecting its tendency to occur in severely debilitated patients.
Endocarditis is discussed MEDICINE 33:4, 66.
Other clinical syndromes enterococci are often found as part
of a mixed flora in intra-abdominal, pelvic, wound or soft tissue
infection; their significance in this setting is unclear because these
infections often respond to treatment without activity against
enterococci. Meningitis can occur in patients who have suffered
head trauma or undergone neurosurgery, or as a complication of
bacteraemia or endocarditis.

Viridans streptococci are usually commensals in the gastrointestinal, respiratory and female genital tracts. They are most prevalent in the oral cavity. Infections usually occur in predisposed or
immunocompromised hosts. Viridans streptococci are considered
to be of low pathogenicity; their principal virulence trait is an ability to adhere to cardiac valves, leading to endocarditis.
Viridans streptococci are facultatively anaerobic, Gram-positive
cocci that grow on blood agar and other non-selective solid media.
They are mainly -haemolytic and are catalase negative. Although
some isolates react with Lancefield grouping antisera, they do
not conform to specific serogroups and many isolates are nongroupable. Molecular techniques have now enabled genotypic
differentiation, which has subsequently been found to correlate
with phenotypic differences in biochemical tests.
Endocarditis is discussed in MEDICINE 33:4, 66.
Others certain species (Strep. mutans) have a strong association with dental caries. They occasionally cause bacteraemia and
septic shock in neutropenic patients. They are an uncommon cause
of meningitis and pneumonia.
Enterococci were originally included in Lancefield group D, but are
now classified separately from the non-enterococcal species Strep.
bovis and Strep. equinis. They are facultative anaerobes that are
able to grow under extreme conditions, and are widely distributed
in soil and water, in the gastrointestinal tract, and occasionally in
oropharyngeal and vaginal secretions and on the skin. They are
intrinsically relatively resistant to -lactams and aminoglycosides
and can acquire resistance to various antimicrobial agents, including vancomycin. Enterococci are a significant cause of nosocomial
infections, including UTI, bacteraemia, endocarditis and intraabdominal and pelvic infections. Less commonly, they cause skin
and soft tissue infections, meningitis, respiratory tract infections
and neonatal sepsis. Risk factors include severe underlying disease, prolonged hospital stay, previous surgery, previous antibiotic
therapy, renal failure, presence of a urinary or vascular catheter,

MEDICINE 33:5

Strep. bovis causes endocarditis and bacteraemia, the latter often

associated with colonic carcinoma and hepatic cirrhosis. It is an
-haemolytic Streptococcus and is identified by biochemical tests
and Lancefield serogrouping (group D). Unlike the enterococci,
Strep. bovis is highly susceptible to penicillin.
Strep. suis is increasingly recognized as a cause of bacterial meningitis and septicaemia in South East Asia (Figure 4). The major
neurological sequela is deafness. Predisposing factors include contact with pigs or undercooked pork, alcoholism and splenectomy.
The organism is -haemolytic and is identified by biochemical
tests and serotyping. Treatment is with benzylpenicillin.

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