Gram-Positive Cocci

Why they matter

• Sheer burden: S. aureus is the leading cause of purulent skin and soft tissue infection, osteomyelitis, septic arthritis, and both native- and prosthetic-valve endocarditis in the US, and is among the most lethal causes of bloodstream infection.
• Resistance: methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) drive empiric regimen choice; IDSA guidance on MRSA and on skin/soft tissue infection is built around whether purulence and MRSA risk are present.
• Vaccine-preventable disease: S. pneumoniae remains a leading cause of community-acquired pneumonia, otitis media, sinusitis, and bacterial meningitis in adults, and conjugate vaccination (ACIP/CDC) has substantially reduced invasive pneumococcal disease and shifted it toward non-vaccine serotypes.

Who gets infected

• S. aureus: nasal carriers (roughly a third of adults are colonized at any time), people who inject drugs, hemodialysis patients, diabetics, and anyone with indwelling hardware or catheters.
• S. pyogenes: school-age children (pharyngitis peaks ages 5–15), with post-streptococcal rheumatic fever and glomerulonephritis clustering in children and in resource-limited settings.
• S. pneumoniae: extremes of age, asplenia and sickle cell disease, HIV, alcohol use disorder, and chronic cardiopulmonary disease.
• Enterococcus: hospitalized, instrumented, or antibiotic-exposed patients — the classic post-cephalosporin "selection" organism.
• Group B Streptococcus: neonates (early- and late-onset sepsis), pregnant patients, and older adults with diabetes.

Branch point 1 — catalase

• Catalase-positive: Staphylococcus. The enzyme degrades hydrogen peroxide, blunting the neutrophil oxidative burst — which is why catalase-positive organisms dominate infections in chronic granulomatous disease.
• Catalase-negative: Streptococcus and Enterococcus.

Branch point 2 — within staphylococci

• Coagulase-positive: S. aureus; coagulase converts fibrinogen to fibrin, walling off abscesses. Golden colonies, ferments mannitol on mannitol salt agar.
• Coagulase-negative: S. epidermidis (novobiocin-sensitive, biofilm on prosthetic material) and S. saprophyticus (novobiocin-resistant, cystitis in young women).

Branch point 3 — hemolysis and biochemical tests

• Alpha-hemolytic: S. pneumoniae is optochin-sensitive and bile-soluble (autolysin-mediated), lancet-shaped diplococci; viridans streptococci are optochin-resistant and bile-insoluble.
• Beta-hemolytic: S. pyogenes is bacitracin-sensitive and PYR-positive; S. agalactiae is bacitracin-resistant, hippurate-positive, and *CAMP test*–positive.
• Gamma (non-hemolytic): Enterococcus grows in bile-esculin agar and 6.5% NaCl; S. bovis/gallolyticus group grows in bile-esculin but not high salt.

Virulence hardware worth knowing

• Protein A (S. aureus): binds the Fc portion of IgG, inhibiting opsonization and complement fixation.
• Superantigens: TSST-1 and streptococcal pyrogenic exotoxins bridge MHC class II to the T-cell receptor Vβ region outside the antigen groove, causing polyclonal T-cell activation.
• Exfoliative toxin: cleaves desmoglein-1 → staphylococcal scalded skin syndrome.
• Capsule: the single most important pneumococcal virulence factor and the basis of the quellung reaction and of conjugate vaccines; IgA protease allows mucosal colonization.
• M protein (S. pyogenes): antiphagocytic and the substrate for molecular mimicry.
• mecA encodes PBP2a (low beta-lactam affinity) → MRSA; vanA/vanB replace terminal D-Ala-D-Ala with D-Ala-D-Lac → VRE.

Colonization to invasion

• Barrier breach: S. aureus colonizes the anterior nares and skin; a break from trauma, surgery, injection drug use, eczema, or a catheter delivers organisms into tissue. Adhesins (fibronectin-binding proteins, clumping factor) anchor bacteria to exposed matrix and to fibrin on damaged or prosthetic valves — the mechanistic reason S. aureus causes acute, destructive endocarditis on previously normal valves.
• Mucosal escape: S. pneumoniae colonizes the nasopharynx; IgA protease and capsule permit persistence, and aspiration or eustachian/sinus obstruction converts colonization into pneumonia, otitis, or sinusitis. Hematogenous seeding of the meninges follows bacteremia, which is why asplenia and complement/antibody defects convert colonization into fulminant disease.

Tissue injury

• Abscess formation: coagulase and staphylokinase build then remodel a fibrin wall, producing a walled-off purulent collection that antibiotics penetrate poorly — the pathophysiologic basis for the rule that source control (incision and drainage) precedes antibiotics in IDSA skin and soft tissue infection guidance.
• Pore-forming toxins: alpha-toxin and Panton-Valentine leukocidin lyse leukocytes and epithelium, generating tissue necrosis, cavitary or hemorrhagic pneumonia, and rapidly progressive cellulitis.
• Pneumolysin damages alveolar epithelium and activates complement; the resulting neutrophil-rich alveolar exudate with capillary leak produces lobar consolidation and rust-colored sputum from lysed erythrocytes.

Toxin- and immune-mediated syndromes

• Superantigen shock: massive IL-1, IL-2, TNF release → vasodilation, capillary leak, diffuse erythroderma, and multiorgan failure without the need for bacteremia — hence blood cultures are typically negative in staphylococcal toxic shock.
• Preformed enterotoxin: heat-stable, acts on gut neural receptors → vomiting within hours of eating, no fever, no invasion.
• Molecular mimicry: anti–M protein antibodies cross-react with cardiac myosin and valve glycoproteins (rheumatic fever, weeks after pharyngitis), while nephritogenic strains deposit immune complexes in glomeruli (PSGN), producing a nephritic picture that antibiotic treatment does not prevent.

Staphylococcus aureus

• Skin and soft tissue: furuncle, carbuncle, or abscess with fluctuance and surrounding erythema; risk factors are injection drug use, diabetes, and prior MRSA colonization. Purulence favors S. aureus; nonpurulent spreading cellulitis favors streptococci.
• Bacteremia and endocarditis: acute high fever, rapid valve destruction, tricuspid involvement with septic pulmonary emboli in people who inject drugs; left-sided disease causes embolic stroke and new murmur.
• Bone and joint: osteomyelitis (most common cause overall) and monoarticular septic arthritis in a hot, swollen knee.
• Toxin syndromes: toxic shock syndrome — fever, hypotension, diffuse macular erythroderma with late desquamation of palms and soles, multiorgan involvement; classically tampon or nasal-packing associated but increasingly postsurgical. Scalded skin syndrome in neonates and young children with positive Nikolsky sign. Food poisoning within 1–6 hours of mayonnaise, custard, or meats.
• Pneumonia: post-influenza or ventilator-associated; PVL strains cause necrotizing, cavitary disease in previously healthy young patients.

Streptococcus pyogenes

• Pharyngitis with tonsillar exudate, tender anterior cervical nodes, fever, and absent cough; scarlet fever, impetigo (honey-crusted), erysipelas (sharply demarcated, raised), and necrotizing fasciitis with pain out of proportion to exam plus systemic toxicity.

Streptococcus pneumoniae

• Lobar pneumonia with abrupt rigor, pleuritic pain, and consolidation; meningitis with fever, headache, neck stiffness, and altered mentation — the most common adult cause; otitis media and sinusitis in children; overwhelming sepsis in asplenia.

Enterococcus

• Urinary tract infection after instrumentation, intra-abdominal/biliary infection, and subacute endocarditis — colonic source (as with S. gallolyticus) should prompt colonoscopy for occult malignancy.

Group B Streptococcus

• Early-onset neonatal sepsis/pneumonia within the first week, late-onset meningitis after; maternal chorioamnionitis, endometritis, and UTI; invasive disease in older diabetics.

Initial studies

• Gram stain of the sterile-site specimen: gram-positive cocci in clusters (staphylococci) versus chains/pairs (streptococci, enterococci); CSF showing lancet-shaped gram-positive diplococci is essentially diagnostic of pneumococcus.
• Blood cultures: two sets from separate sites before antibiotics. Any S. aureus bacteremia is treated as true infection, never a contaminant — unlike coagulase-negative staphylococci from a single bottle.

Confirmatory and syndrome-specific testing

• Culture with susceptibilities is the gold standard; MALDI-TOF and rapid molecular blood-culture panels now shorten identification and detect *mecA*/*vanA*.
• Pharyngitis: IDSA recommends applying clinical criteria (*Centor*/McIsaac score: fever, tonsillar exudate, tender anterior cervical adenopathy, absence of cough) then a rapid antigen detection test; a negative RADT in a child should be backed up with throat culture, and testing is discouraged when features suggest a viral cause.
• Pneumonia: chest imaging plus, per the ATS/IDSA community-acquired pneumonia guideline, blood and sputum cultures in severe disease or when MRSA/*Pseudomonas* is suspected; urinary pneumococcal antigen is an option in severe disease.
• Meningitis: CSF with neutrophilic pleocytosis, markedly elevated protein, and low glucose (low CSF:serum glucose ratio); obtain blood cultures and give antibiotics without delay — CT before LP only for focal deficits, papilledema, seizure, immunocompromise, or altered consciousness.
• Endocarditis: transthoracic echocardiography first, transesophageal if negative or nondiagnostic with persistent suspicion or prosthetic material; apply the modified Duke criteria (typical organism in persistently positive blood cultures plus echocardiographic evidence of endocardial involvement).
• Post-streptococcal disease: anti-streptolysin O and anti-DNase B titers support recent infection; diagnose acute rheumatic fever with the revised Jones criteria (AHA, 2015), and PSGN by nephritic urine sediment with low C3.
• MRSA nasal PCR has a high negative predictive value for MRSA pneumonia and is used to de-escalate empiric vancomycin.

Staphylococcus aureus

• Source control first: incision and drainage is the primary therapy for a cutaneous abscess (IDSA skin and soft tissue infection guideline); antibiotics are added for systemic signs, large or multiple lesions, or immunocompromise.
• Empiric coverage for suspected MRSA: vancomycin, or linezolid/daptomycin as alternatives. Oral options for purulent outpatient infection include trimethoprim-sulfamethoxazole, doxycycline, or clindamycin.
• Vancomycin dosing: per the 2020 IDSA/ASHP/PIDS/SIDP consensus, dose to a 24-hour AUC with a target AUC/MIC of 400–600; the old 15–20 mcg/mL trough goal has been retired. Monitor renal function.
• Directed therapy for MSSA: an antistaphylococcal penicillin (nafcillin, oxacillin) or cefazolin — both outperform vancomycin for MSSA bacteremia, so de-escalation is mandatory once susceptibilities return.
• Key resistance caveats: daptomycin is inactivated by pulmonary surfactant and must never be used for pneumonia (use linezolid or vancomycin); clindamycin requires a D-test to exclude inducible erm-mediated resistance; ceftaroline is the anti-MRSA cephalosporin.
• Toxin-mediated disease: add a protein-synthesis inhibitor (clindamycin or linezolid) to suppress toxin production in toxic shock and necrotizing infection, with IVIG considered in severe cases.

Streptococci and enterococci

• Pneumococcal meningitis: vancomycin plus a third-generation cephalosporin, with adjunctive dexamethasone started before or with the first antibiotic dose to reduce hearing loss and neurologic sequelae.
• Enterococcal endocarditis: ampicillin plus ceftriaxone, or ampicillin plus gentamicin, per the AHA infective endocarditis statement; VRE requires linezolid or daptomycin.
• Penicillin allergy: cephalosporin cross-reactivity is only about 1–3% and is driven by shared R1 side chains, not the beta-lactam ring — a distant rash is not a reason to withhold cefazolin.

Prevention

• Pneumococcal vaccination (ACIP): conjugate vaccine series in infants and routine adult vaccination for older adults and younger adults with risk conditions including asplenia, sickle cell disease, HIV, and CSF leak.
• Intrapartum GBS prophylaxis (ACOG): penicillin G for colonized or high-risk laboring patients; cefazolin for low-risk penicillin allergy, clindamycin only if the isolate is susceptible, otherwise vancomycin.
• Secondary rheumatic fever prophylaxis: monthly intramuscular benzathine penicillin G (AHA).

• Catalase then coagulase: the two-step algorithm resolves most stems. Gram-positive cocci in clusters, catalase-positive, coagulase-positive = S. aureus; novobiocin resistance points to S. saprophyticus in a sexually active young woman with dysuria.
• Optochin and bile solubility separate the alpha-hemolytics: pneumococcus is sensitive and soluble; viridans streptococci (S. mutans → caries, S. sanguinis → subacute endocarditis after dental work) are neither.
• Single best next step for a fluctuant abscess is incision and drainage, not antibiotics. Conversely, the single best next step in suspected bacterial meningitis is blood cultures and immediate empiric antibiotics plus dexamethasone — never delay for imaging in the absence of focal findings.
• The association examiners love: S. gallolyticus (bovis) bacteremia or endocarditis → colonoscopy for colorectal carcinoma. Similarly, S. aureus bacteremia in a patient who injects drugs → tricuspid endocarditis with septic pulmonary emboli.
• Timing distinguishes post-streptococcal sequelae: PSGN follows pharyngitis or impetigo by roughly 1–3 weeks and is not prevented by antibiotics; rheumatic fever follows pharyngitis only (not skin infection) by 2–4 weeks and is prevented by treating the pharyngitis.
• **Distractor to avoid — cephalosporins for *Enterococcus***: intrinsic resistance from low-affinity PBPs. Also avoid daptomycin for pneumonia (surfactant inactivation) and avoid reflexively quoting a vancomycin trough of 15–20; AUC-guided dosing to AUC/MIC 400–600 is current standard.
• Toxin versus invasion: staphylococcal food poisoning is preformed enterotoxin with vomiting in 1–6 hours and no fever; toxic shock is superantigen-driven with erythroderma, hypotension, and typically negative blood cultures — the absence of bacteremia does not exclude it.
• Encapsulated organisms in asplenia: pneumococcus is the leading killer; children with sickle cell disease receive daily penicillin prophylaxis through early childhood along with conjugate vaccination.

• Staphylococcus aureus: Catalase-positive, coagulase-positive; most common cause of skin/soft tissue infections
• Streptococcus pyogenes (Group A): Beta-hemolytic; causes pharyngitis, scarlet fever, post-infectious sequelae (rheumatic fever, PSGN)
• Streptococcus pneumoniae: Alpha-hemolytic; optocin-sensitive; leading cause of CAP and meningitis in susceptible populations
• Enterococcus: Gamma-hemolytic; intrinsically resistant to cephalosporins and clindamycin; requires ampicillin or vancomycin
• Streptococcus agalactiae (Group B): Bacitracin-resistant; causes neonatal meningitis and sepsis; screen pregnant women at 35-37 weeks

• S. aureus: Abscesses, osteomyelitis, toxic shock syndrome (TSST-1), empiric choice for diabetic foot ulcers
• S. pyogenes: Sore throat + strawberry tongue + sandpaper rash (scarlet fever); glomerulonephritis 2 weeks post-infection
• S. pneumoniae: Pneumonia with "rusty sputum," meningitis with positive Gram stain in CSF, bacteremia in asplenic patients
• Enterococcus: UTI, endocarditis (especially with prosthetic valves)
• Group B Strep: Fever in infant <3 months; chorioamnionitis in pregnancy

• Confusing Streptococcus species hemolysis: α-hemolytic (S. pneumoniae, viridans), β-hemolytic (S. pyogenes, S. agalactiae), γ-hemolytic (Enterococcus)
• Treating Enterococcus with cephalosporins: These are intrinsically resistant; use ampicillin or vancomycin
• Missing post-infectious complications: PSGN (S. pyogenes) occurs even with treatment; rheumatic fever requires anti-inflammatory prophylaxis

• S. aureus: Nafcillin/oxacillin (susceptible); vancomycin/daptomycin (MRSA)
• S. pyogenes: Penicillin G or amoxicillin; cephalosporins acceptable
• S. pneumoniae: Ceftriaxone or cefotaxime (respiratory); vancomycin + ceftriaxone (meningitis)
• Enterococcus: Ampicillin (UTI/bacteremia); vancomycin (ampicillin-resistant)
• Group B Strep: Penicillin G (neonatal/maternal); cefotaxime alternative