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Gram-Negative Cocci — Full Detail

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1. Classification Overview

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2. General Characteristics of Neisseria

• Morphology: Aerobic gram-negative cocci, 0.6–1.0 µm in diameter, arranged in pairs (diplococci) with flattened adjacent surfaces — resembling coffee beans or kidney beans
• Oxidase positive, catalase positive
• Nonmotile
• Fastidious: Require prompt incubation at 35–37°C in CO₂; need blood, serum, or special media for growth
• Both N. gonorrhoeae and N. meningitidis produce an IgA protease that cleaves mucosal IgA, facilitating colonization
• Carbohydrate utilization (key differential):

• 35 species in genus; only N. gonorrhoeae and N. meningitidis are strict human pathogens; others are commensal upper respiratory tract flora

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3. Neisseria gonorrhoeae

3.1 Physiology and Virulence Factors

3.2 Epidemiology

• Humans are the only natural host
• Transmission: sexual contact (primary)
• ~555,608 cases in the US in 2017 (true incidence estimated twice this); ~78 million new cases worldwide annually
• Most common in: ages 15–24, Black Americans, southeastern US, individuals with multiple sexual partners
• Higher risk of disseminated disease in patients with late complement component deficiencies (C5–C9)
• Carriage is often asymptomatic in females (50%) and symptomatic in most males (90%)

3.3 Clinical Diseases

• Urethritis: purulent urethral discharge, dysuria — onset 2–5 days post-exposure
• Complications: epididymitis, prostatitis, periurethral abscess; recurrent infections → scarring → sterility

• Primary site: endocervix (columnar epithelial cells; NOT squamous cells of vagina)
• Endocervicitis: purulent vaginal discharge, dysuria, abdominal pain
• Pelvic Inflammatory Disease (PID) in 10–20%: salpingitis, tubo-ovarian abscess → ectopic pregnancy, infertility

• Pharyngitis (purulent exudate, often asymptomatic)
• Proctitis (rectal infections in men who have sex with men)
• Ophthalmia neonatorum: purulent conjunctivitis in neonates born through infected birth canal → can rapidly lead to blindness if untreated

• Migratory arthralgia → septic arthritis (wrists, knees, ankles)
• Pustular rash on erythematous base over extremities (dermatitis-arthritis syndrome)
• Gram stain of synovial fluid positive in only 10–30% of cases (culture often negative)

3.4 Laboratory Diagnosis

3.5 Treatment, Prevention, and Control

• Treatment of choice: Ceftriaxone 500 mg IM single dose (with doxycycline if chlamydia co-infection not excluded)
  • High-level resistance to cephalosporins and azithromycin is emerging
  • Previous dual therapy with ceftriaxone + azithromycin is now modified to ceftriaxone alone (due to azithromycin resistance)
• Ophthalmia neonatorum prophylaxis: 1% silver nitrate OR erythromycin ointment (0.5%) applied to newborn eyes
• No effective vaccine available
• Prevention: condoms, spermicides with nonoxynol-9 (partially effective), partner notification

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4. Neisseria meningitidis

4.1 Physiology and Virulence Factors

4.2 Serogroups (based on capsule polysaccharide)

• A, B, C, W-135, X, Y — Six major pathogenic serogroups
• In the US: most common are B, C, Y, W-135
• Serogroup A: responsible for "meningitis belt" epidemics in sub-Saharan Africa
• Serogroup B: particularly difficult to vaccinate against (capsule mimics human neural cell adhesion molecules)

4.3 Epidemiology

• 5–15% of healthy adults are asymptomatic nasopharyngeal carriers
• Colonization followed 7–10 days later by formation of bactericidal antibodies (provides serogroup-specific immunity)
• Disease mostly in children < 5 years and adolescents/young adults (college freshmen)
• Transmission: respiratory droplets and direct contact with oral secretions
• Risk factors: complement deficiencies (C5–C9), asplenia, crowding (military barracks, dormitories), IgG subclass deficiency

4.4 Clinical Diseases

• Purulent inflammation of meninges
• Classic triad: fever, severe headache, nuchal rigidity
• Photophobia, phonophobia, altered consciousness
• High mortality if untreated; 10–15% mortality even with treatment; 20% morbidity with neurological sequelae

• Disseminated bloodstream infection
• Petechial/purpuric rash — small petechiae coalesce into larger hemorrhagic lesions (pathognomonic)
• Thrombosis of small blood vessels → Waterhouse-Friderichsen syndrome: bilateral adrenal hemorrhage → adrenal insufficiency → shock
• DIC (Disseminated Intravascular Coagulation)
• Multiorgan failure; rapidly fatal without treatment

• Meningococcal pneumonia (milder, in patients with underlying pulmonary disease)
• Pleuritis, pericarditis, arthritis (serous membrane involvement)
• Mild pharyngitis (early/asymptomatic colonization)

4.5 Laboratory Diagnosis

4.6 Treatment, Prevention, and Control

• Treatment: IV Penicillin G (if sensitive), Ceftriaxone (drug of choice), or cefotaxime
• Chemoprophylaxis for close contacts: Rifampin (drug of choice), ciprofloxacin (single dose), or ceftriaxone IM
• Close contacts = household members, those with contact with oral secretions

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5. Moraxella catarrhalis

5.1 Key Features

• Formerly called Neisseria catarrhalis then Branhamella catarrhalis; renamed based on genetic analysis
• Unencapsulated gram-negative diplococcus (Harrison's) / some sources describe encapsulated with pili
• Oxidase positive, catalase positive, nonsaccharolytic (does not ferment glucose, maltose, or lactose)
• DNase positive — key differential from Neisseria
• Butyrate esterase positive
• >90% produce β-lactamase (assume penicillin resistance)
• "Hockey puck" colonies: smooth, white, opaque — can be pushed around a plate without disrupting colony integrity
• Grows on blood agar (unlike Neisseria, which requires chocolate agar)
• Poor or no growth on MacConkey agar

5.2 Epidemiology

• Ecologic niche: human respiratory tract
• Nasopharyngeal colonization common in infants (33–100%); decreases with age
• Widespread pneumococcal vaccination has increased M. catarrhalis colonization rates (ecological shift)

5.3 Pathogenesis

• Causes infection by contiguous spread from upper airway colonization
• Adhesin molecules attach to respiratory epithelial cells; intracellular survival in lymphoid tissue
• Sheds outer membrane vesicles that mediate inflammation and deliver β-lactamase (protects co-pathogens like H. influenzae and Strep A)
• New strain acquisition critical in COPD exacerbations

5.4 Clinical Diseases

5.5 Treatment

• Assume penicillin resistance (>90% β-lactamase producers)
• Susceptible to: cephalosporins (oral 2nd/3rd gen), TMP-SMX, β-lactamase inhibitor combinations (amoxicillin-clavulanate), fluoroquinolones, macrolides

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6. Commensal Neisseria Species

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7. Related Genera (Neisseriaceae Family)

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8. Anaerobic Gram-Negative Cocci

• Gram-negative anaerobic cocci
• Normal flora of the mouth, intestine, and vagina
• Rare cause of infection: endocarditis, bacteremia, dental abscesses
• Distinguished by: obligate anaerobe, inability to ferment most carbohydrates, characteristic nitrate reduction

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9. Diagnostic Comparison Summary

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10. Key Clinical Pearls

1. Gonorrhea cannot infect the squamous epithelium of the vagina in postpubescent women — infects only columnar epithelial cells (cervix, fallopian tubes)
2. Disseminated N. gonorrhoeae → classically presents as dermatitis-arthritis syndrome (migratory polyarthritis + pustular rash) — culture often negative; treat empirically
3. Waterhouse-Friderichsen syndrome = bilateral adrenal hemorrhage from N. meningitidis — presents as overwhelming sepsis + purpura + adrenal crisis
4. N. meningitidis vs N. gonorrhoeae: meningitidis uses both maltose AND glucose; gonorrhoeae uses glucose only — mnemonic: "Men use more sugars"
5. Complement deficiency (C5–C9, terminal complement) → increased risk of disseminated Neisseria infections (both species)
6. M. catarrhalis "hockey puck" sign on agar is a quick bedside lab clue
7. Ophthalmia neonatorum prophylaxis with erythromycin eye drops prevents both gonorrheal AND chlamydial neonatal conjunctivitis
8. NAAT has replaced culture for routine gonorrhea diagnosis but culture is still needed for antibiotic susceptibility testing

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