Premed · Premed · Microbiology
Lecture 24: Major Bacterial Pathogens
Microbiology
Learning Objectives
By the end of this lecture, students will be able to:
- Identify and describe the major Gram-positive cocci of clinical importance and the diseases they cause
- Identify and describe the major Gram-negative cocci and rods of clinical significance
- Describe the key features of atypical bacteria, spirochetes, and obligate intracellular pathogens
- Associate virulence factors with specific pathogens and disease presentations
- Outline the recommended diagnostic approaches and treatment for major bacterial infections
- Recognize the clinical significance of mycobacteria and spore-forming bacteria
Lecture Content
I. Gram-Positive Cocci
A. Staphylococcus aureus
Staphylococcus aureus is a Gram-positive coccus that characteristically forms clusters on Gram stain. It is catalase-positive and coagulase-positive, which distinguishes it from the coagulase-negative staphylococci. S. aureus is part of the normal flora of the anterior nares, with approximately 30% of the population carrying it on their skin. Its arsenal of virulence factors is extensive and includes protein A, coagulase, hemolysins (particularly alpha-toxin), Panton-Valentine leukocidin (PVL), toxic shock syndrome toxin-1 (TSST-1), exfoliative toxins, enterotoxins, and the capacity for biofilm formation.
The diseases caused by S. aureus span a remarkable range. Skin and soft tissue infections include impetigo, folliculitis, furuncles, carbuncles, cellulitis, and wound infections. Invasive disease manifests as bacteremia, acute endocarditis (notably on previously normal valves), osteomyelitis, septic arthritis, and pneumonia (especially post-influenza necrotizing pneumonia associated with PVL). Toxin-mediated diseases include toxic shock syndrome (caused by TSST-1), food poisoning (caused by heat-stable enterotoxins with a characteristically short 1-to-6-hour onset), and scalded skin syndrome (caused by exfoliative toxins).
MRSA strains carry the mecA gene encoding PBP2a, which renders them resistant to all beta-lactam antibiotics. Community-associated MRSA (CA-MRSA, particularly the USA300 clone) is typically PVL-positive, while hospital-associated MRSA (HA-MRSA) differs in epidemiology and resistance patterns. Treatment of methicillin-susceptible S. aureus (MSSA) relies on nafcillin, oxacillin, or cefazolin, while MRSA requires vancomycin, daptomycin, linezolid, or TMP-SMX for skin infections.
B. Streptococcus pyogenes (Group A Streptococcus, GAS)
Streptococcus pyogenes appears as Gram-positive cocci in chains, is catalase-negative and beta-hemolytic, and carries the Lancefield group A carbohydrate antigen. Its virulence factors include the M protein (which is anti-phagocytic and exists in over 200 types), streptolysin O and S, hyaluronidase, streptokinase, DNase, and streptococcal pyrogenic exotoxins that function as superantigens.
S. pyogenes causes three categories of disease. Suppurative infections include pharyngitis (strep throat), impetigo, erysipelas, cellulitis, necrotizing fasciitis (the dreaded "flesh-eating disease"), and puerperal sepsis. Toxin-mediated diseases include scarlet fever (caused by erythrogenic toxin/Spe) and streptococcal toxic shock syndrome. The post-infectious, immune-mediated (non-suppurative) complications are particularly important. Acute rheumatic fever (ARF) follows pharyngitis but not skin infection and results from molecular mimicry between the M protein and cardiac myosin; it is diagnosed using the Jones criteria and can progress to rheumatic heart disease. Post-streptococcal glomerulonephritis (PSGN) can follow either pharyngitis or skin infection and involves immune complex deposition in the glomeruli.
Diagnosis relies on rapid antigen detection tests (RADT), throat culture, and ASO titers (a rising titer indicates recent infection). Remarkably, no penicillin resistance has ever been documented in S. pyogenes, making penicillin the treatment of choice, with macrolides reserved for penicillin-allergic patients.
C. Streptococcus pneumoniae (Pneumococcus)
Streptococcus pneumoniae appears as lancet-shaped Gram-positive diplococci. It is alpha-hemolytic, optochin-sensitive, and bile-soluble. The polysaccharide capsule, of which over 100 serotypes exist, is the major virulence factor; additional factors include pneumolysin, IgA protease, and autolysin (which releases intracellular contents including pneumolysin upon cell lysis).
S. pneumoniae is the number one cause of community-acquired pneumonia, a leading cause of bacterial meningitis in adults, and a common cause of otitis media in children and sinusitis. Prevention relies on conjugate vaccines (PCV15, PCV20) for children and adults, and the polysaccharide vaccine (PPSV23) for adults. Treatment depends on susceptibility: penicillin when the organism is susceptible, ceftriaxone for intermediate susceptibility, and vancomycin combined with ceftriaxone for meningitis pending susceptibility results.
D. Enterococcus spp. (E. faecalis, E. faecium)
The enterococci are Gram-positive cocci that form chains, are catalase-negative, bile-esculin positive, and grow in 6.5% NaCl. They are normal inhabitants of the gastrointestinal tract and behave as opportunistic pathogens, causing urinary tract infections, bacteremia, subacute endocarditis, intra-abdominal infections, and wound infections.
Enterococci are intrinsically resistant to cephalosporins, low-level aminoglycosides, and TMP-SMX in vivo. VRE is primarily E. faecium carrying the vanA gene, which confers high-level, transferable resistance. Treatment options include ampicillin when susceptible, vancomycin for non-VRE strains, and linezolid or daptomycin for VRE.
<image>A diagnostic algorithm for Gram-positive cocci. Starting point: Gram stain showing Gram-positive cocci. First branch: Clusters vs. Chains/Pairs. Clusters branch: Catalase test -- positive = Staphylococcus; Coagulase test -- positive = S. aureus (with diseases listed: skin infections, bacteremia, endocarditis, TSS, food poisoning; MRSA note), negative = coagulase-negative staphylococci (S. epidermidis -- device infections, S. saprophyticus -- UTIs in young women). Chains/Pairs branch: Catalase test -- negative = Streptococcus/Enterococcus. Hemolysis pattern: Beta-hemolytic -> Lancefield grouping (Group A = S. pyogenes with pharyngitis, necrotizing fasciitis, ARF, PSGN listed; Group B = S. agalactiae with neonatal meningitis/sepsis listed). Alpha-hemolytic -> Optochin-sensitive = S. pneumoniae (pneumonia, meningitis, otitis media); Optochin-resistant = viridans streptococci (S. mutans -- dental caries, S. mitis -- subacute endocarditis). Gamma-hemolytic or variable -> Bile-esculin positive + 6.5% NaCl growth = Enterococcus (UTIs, endocarditis, VRE).</image>
II. Gram-Positive Rods
A. Bacillus anthracis
Bacillus anthracis is a large Gram-positive rod that forms spores, is non-motile, and possesses a poly-D-glutamic acid capsule. It causes anthrax in three forms: cutaneous anthrax (characterized by a black eschar or "malignant pustule"), inhalational anthrax (woolsorter's disease, presenting with a widened mediastinum and high mortality), and gastrointestinal anthrax. Its toxin comprises three components: protective antigen (PA), edema factor (EF), and lethal factor (LF). B. anthracis is classified as a CDC Category A bioterrorism agent. Treatment consists of ciprofloxacin or doxycycline combined with antitoxin, and an anthrax vaccine (AVA) is available for at-risk populations.
B. Clostridium Species
The clostridia are Gram-positive rods that are obligate anaerobes and form spores. C. tetani produces tetanospasmin, which causes spastic paralysis and is prevented with the DTaP/Tdap vaccine. C. botulinum produces botulinum toxin, causing flaccid paralysis through foodborne, wound, or infant (floppy baby) mechanisms. C. perfringens produces alpha toxin (a lecithinase/phospholipase C) that causes gas gangrene (myonecrosis) and also possesses an enterotoxin responsible for food poisoning. Clostridioides difficile (formerly Clostridium difficile) produces toxin A (an enterotoxin) and toxin B (a cytotoxin), causing pseudomembranous colitis. C. difficile infection is associated with antibiotic use, especially clindamycin, fluoroquinolones, and broad-spectrum cephalosporins. Diagnosis employs toxin enzyme immunoassay or PCR for the tcdB gene. Treatment consists of oral vancomycin or fidaxomicin, with fecal microbiota transplantation reserved for recurrent cases.
C. Listeria monocytogenes
Listeria monocytogenes is a Gram-positive rod that is a facultative intracellular pathogen. It displays tumbling motility at 25 degrees Celsius and is beta-hemolytic. Transmission is foodborne, typically through contaminated dairy products (especially unpasteurized), deli meats, and soft cheeses. Populations at particular risk include pregnant women, neonates, the elderly, and immunocompromised individuals. Listeria causes meningitis (in neonates, elderly, and immunocompromised patients), sepsis, granulomatosis infantisepticum in neonates, and chorioamnionitis leading to stillbirth. Treatment is ampicillin with or without gentamicin; importantly, cephalosporins are not effective.
D. Corynebacterium diphtheriae
Corynebacterium diphtheriae is a Gram-positive rod with a club-shaped morphology arranged in a Chinese-letter pattern, characterized by metachromatic (Babes-Ernst) granules. Its phage-encoded diphtheria toxin ADP-ribosylates EF-2 to inhibit protein synthesis. The disease presents as pharyngeal diphtheria with a gray pseudomembrane and "bull neck" lymphadenopathy, and complications include myocarditis and neuropathy. Prevention relies on the DTaP/Tdap vaccine (which contains a toxoid), and the Elek test confirms toxin production. Treatment requires diphtheria antitoxin combined with erythromycin or penicillin.
III. Gram-Negative Cocci
A. Neisseria meningitidis
Neisseria meningitidis appears as Gram-negative kidney-bean-shaped diplococci, is oxidase-positive, and ferments both maltose and glucose. The major disease-causing capsular serotypes are A, B, C, W, and Y. N. meningitidis causes meningitis (often accompanied by a petechial or purpuric rash) and meningococcemia, which can progress to Waterhouse-Friderichsen syndrome with adrenal hemorrhage and DIC. Transmission occurs via respiratory droplets, with nasopharyngeal carriage serving as the reservoir. Prevention relies on meningococcal conjugate vaccines (MenACWY) and MenB vaccines. Treatment is ceftriaxone, and chemoprophylaxis for close contacts involves rifampin, ciprofloxacin, or ceftriaxone.
B. Neisseria gonorrhoeae
Neisseria gonorrhoeae is a Gram-negative diplococcus that is oxidase-positive and ferments glucose only (not maltose). No vaccine exists because of continuous antigenic variation of pili and Opa proteins. It causes urethritis, cervicitis, pelvic inflammatory disease, neonatal ophthalmia neonatorum, and disseminated gonococcal infection manifesting as septic arthritis and dermatitis. Nucleic acid amplification testing (NAAT) is the diagnostic gold standard. Treatment is intramuscular ceftriaxone, though increasing resistance is a serious global concern.
IV. Gram-Negative Rods -- Enterobacterales
The Enterobacterales represent a large family of facultative anaerobic rods that are oxidase-negative and ferment glucose. Key genera include Escherichia, Klebsiella, Salmonella, Shigella, Proteus, Enterobacter, Serratia, and Citrobacter.
A. Escherichia coli Pathotypes
E. coli exhibits remarkable pathotypic diversity. Uropathogenic E. coli (UPEC) uses type 1 pili (FimH) and P pili to cause urinary tract infections and pyelonephritis. Enterotoxigenic E. coli (ETEC) produces a heat-labile toxin (LT, similar to cholera toxin) and a heat-stable toxin (ST, which activates guanylate cyclase), causing the watery diarrhea of traveler's diarrhea. Enterohemorrhagic E. coli (EHEC, serotype O157:H7) produces Shiga-like toxins (Stx1, Stx2) that cause bloody diarrhea and hemolytic uremic syndrome; antibiotics should not be used as they may worsen HUS by increasing toxin release. Enteropathogenic E. coli (EPEC) causes attaching-and-effacing lesions via its T3SS and intimin, producing infantile diarrhea in developing countries. Enteroinvasive E. coli (EIEC) invades colonic epithelium and causes a dysentery syndrome similar to Shigella. Enteroaggregative E. coli (EAEC) demonstrates stacked-brick adherence and causes persistent diarrhea. Neonatal meningitis E. coli (NMEC) possesses the K1 capsule and is the leading cause of Gram-negative neonatal meningitis.
B. Salmonella
Non-typhoidal Salmonella species, including S. enteritidis and S. typhimurium, cause gastroenteritis typically acquired from poultry and eggs. The illness is self-limiting, and antibiotics are reserved for invasive disease or immunocompromised patients. Typhoidal Salmonella (S. typhi and S. paratyphi) causes typhoid or enteric fever characterized by insidious onset, stepwise fever, relative bradycardia, rose spots on the abdomen, and hepatosplenomegaly. The organism is bloodborne, with blood cultures positive during the first week and stool cultures positive during weeks two and three. Chronic carriers harbor the organism in the gallbladder. Treatment options include fluoroquinolones, azithromycin, and ceftriaxone, and vaccines are available (Vi polysaccharide and live Ty21a).
C. Shigella
Shigella has an extremely low infectious dose of approximately 10 organisms and spreads by the fecal-oral route from person to person. It invades colonic epithelium to cause dysentery with bloody, mucoid diarrhea, tenesmus, and fever. S. dysenteriae type 1 produces Shiga toxin, which can lead to HUS. Treatment with azithromycin or ciprofloxacin shortens disease duration and reduces transmission.
D. Other Enterobacterales
Klebsiella pneumoniae possesses a large mucoid capsule and classically causes aspiration pneumonia (producing currant-jelly sputum), urinary tract infections, and liver abscesses (particularly hypervirulent strains prevalent in Asia). It is a common ESBL and CRE producer. Proteus mirabilis demonstrates swarming motility and is urease-positive, promoting the formation of struvite kidney stones (staghorn calculi) in addition to causing urinary tract infections. Yersinia pestis causes plague in bubonic, pneumonic, and septicemic forms, is transmitted by fleas from rodent reservoirs, and is a bioterrorism concern.
V. Other Gram-Negative Rods
A. Pseudomonas aeruginosa
Pseudomonas aeruginosa is a Gram-negative rod that is an obligate aerobe and oxidase-positive, producing the distinctive blue-green pigment pyocyanin and a fruity, grape-like odor. It is a quintessential opportunistic pathogen affecting burn patients, cystic fibrosis patients (where it causes chronic lung infections with mucoid biofilm), and hospitalized patients (causing nosocomial pneumonia, UTIs, wound infections, otitis externa or "swimmer's ear," and hot tub folliculitis). Its intrinsic resistance mechanisms include chromosomal AmpC, multiple efflux pumps, and low outer membrane permeability, and it readily acquires additional resistance determinants. Treatment requires antipseudomonal agents such as antipseudomonal penicillins, ceftazidime, cefepime, carbapenems, aminoglycosides, fluoroquinolones, or polymyxins.
B. Haemophilus influenzae
Haemophilus influenzae is a Gram-negative coccobacillus that requires factors X (hemin) and V (NAD) for growth. Type b strains (Hib) are encapsulated and historically caused meningitis and epiglottitis in unvaccinated children, but the Hib conjugate vaccine has nearly eliminated these diseases. Non-typeable H. influenzae (NTHi) lacks a capsule and commonly causes otitis media, sinusitis, bronchitis, and pneumonia, particularly in patients with COPD.
C. Helicobacter pylori
Helicobacter pylori is a Gram-negative curved rod that is urease-positive (enabling survival in gastric acid) and microaerophilic. It causes chronic gastritis, peptic ulcer disease (both gastric and duodenal), gastric adenocarcinoma, and MALT lymphoma. Diagnosis employs the urea breath test, stool antigen test, biopsy with histology or CLO test, or serology. Treatment involves triple therapy (a proton pump inhibitor plus clarithromycin plus amoxicillin or metronidazole) or bismuth quadruple therapy.
D. Vibrio cholerae
Vibrio cholerae is a Gram-negative curved rod that is oxidase-positive, with serogroups O1 and O139 responsible for epidemic cholera. The cholera toxin ADP-ribosylates Gs-alpha, leading to constitutive cAMP production that drives massive secretory "rice-water" diarrhea (up to 20 liters per day), causing rapid dehydration and death if untreated. Treatment centers on aggressive oral rehydration therapy, which is the cornerstone of management; antibiotics such as doxycycline or azithromycin shorten the clinical course.
<image>An organ-system overview of major Gram-negative bacterial pathogens. A human body silhouette with arrows pointing to affected organ systems. Brain: N. meningitidis (meningitis), H. influenzae type b (meningitis in unvaccinated children), neonatal E. coli K1. Lungs: K. pneumoniae (aspiration pneumonia, currant-jelly sputum), P. aeruginosa (CF, nosocomial pneumonia), H. influenzae NTHi (COPD exacerbation), Legionella (atypical pneumonia). GI tract: Salmonella (gastroenteritis, typhoid), Shigella (dysentery), EHEC O157:H7 (bloody diarrhea, HUS), V. cholerae (rice-water diarrhea), H. pylori (peptic ulcers, gastric cancer), ETEC (traveler's diarrhea). Urogenital: UPEC (UTI, pyelonephritis), N. gonorrhoeae (urethritis, cervicitis, PID), Proteus (struvite stones). Skin/soft tissue: P. aeruginosa (burns, wound infections), Vibrio vulnificus (necrotizing fasciitis from seawater exposure). Blood: N. meningitidis (meningococcemia), Y. pestis (plague). Each pathogen includes a key virulence factor in parentheses.</image>
VI. Atypical Bacteria
Atypical bacteria do not stain well with the Gram stain or have unusual growth requirements that necessitate specialized laboratory techniques.
A. Mycobacterium tuberculosis
Mycobacterium tuberculosis is an acid-fast bacillus visualized with Ziehl-Neelsen or auramine-rhodamine stains. It is extremely slow-growing, with a doubling time of approximately 24 hours, and its mycolic acid-rich cell wall makes it resistant to desiccation, many chemicals, and immune killing.
Tuberculosis presents primarily as pulmonary disease with cough, hemoptysis, night sweats, and weight loss, typically producing upper lobe cavitary lesions. Extrapulmonary tuberculosis can be miliary, meningeal, skeletal (Pott disease), renal, or involve lymph nodes. Granuloma formation with caseous necrosis is the histologic hallmark; the Ghon complex represents primary infection, with reactivation occurring in immunocompromised patients. Diagnosis employs the tuberculin skin test (Mantoux), interferon-gamma release assays (IGRAs), sputum smear and culture, and GeneXpert MTB/RIF (a rapid PCR for both M. tuberculosis and rifampin resistance). Treatment follows the RIPE regimen (rifampin, isoniazid, pyrazinamide, and ethambutol) for two months, followed by rifampin and isoniazid for four additional months. Latent tuberculosis is treated with isoniazid for nine months, rifampin for four months, or the three-month regimen of isoniazid and rifapentine (3HP).
B. Mycoplasma pneumoniae
Mycoplasma pneumoniae is the smallest free-living organism and notably lacks a cell wall, making it intrinsically resistant to all beta-lactam antibiotics. It causes "walking pneumonia," an atypical community-acquired pneumonia with insidious onset and dry cough. Diagnosis is by PCR or serology (cold agglutinins are non-specific). Treatment consists of macrolides (particularly azithromycin), doxycycline, or fluoroquinolones.
C. Chlamydia trachomatis
Chlamydia trachomatis is an obligate intracellular pathogen with a biphasic life cycle: the elementary body is the infectious but metabolically inert form, while the reticulate body is the replicating but non-infectious form. Serotypes D through K cause the most common bacterial sexually transmitted infection (urethritis, cervicitis, pelvic inflammatory disease) as well as neonatal conjunctivitis and pneumonia. Serotypes L1 through L3 cause lymphogranuloma venereum (LGV). Serotypes A through C cause trachoma, the leading infectious cause of blindness worldwide. Treatment is either a single dose of azithromycin or doxycycline for seven days.
D. Spirochetes
Treponema pallidum causes syphilis, which progresses through primary (painless chancre), secondary (maculopapular rash and condylomata lata), latent, and tertiary (gummas, aortitis, tabes dorsalis, and general paresis) stages. Congenital syphilis can also occur. Diagnosis uses darkfield microscopy for primary lesions, non-treponemal screening tests (RPR/VDRL), and treponemal confirmatory tests (FTA-ABS). Penicillin G remains the treatment of choice.
Borrelia burgdorferi causes Lyme disease, transmitted by the Ixodes tick. The characteristic presentation begins with erythema migrans (a bull's-eye rash) and can progress to arthritis, carditis (with AV block), and neuroborreliosis (Bell palsy, meningitis). Treatment is doxycycline for early disease and ceftriaxone for neurologic or cardiac involvement.
Leptospira interrogans causes leptospirosis, a biphasic illness acquired through exposure to water contaminated with animal urine. The severe form, Weil disease, presents with jaundice, renal failure, and hemorrhage.
