MICROBIOLOGY AND IMMUNOLOGY-BACTERIOLOGY usmle step 1 cs exam guide
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140
MICROBIOLOGY AND IMMUNOLOGY-BACTERIOLOGY (continued)
Penicillin and Gram-negative bugs are resistant to benzyl penicillin G but may be susceptible to
gram-negative penicillin derivatives such as ampicillin. The gram-negative outer membrane layer
bugs inhibits entry of penicillin G and vancomycin.
Neisseria Gram-negative cocci.
Gonococci Meningococci
No polysaccharide capsule Polysaccharide capsule
No maltose fermentation Maltose fermentation
No vaccine Vaccine
Causes gonorrhea, septic arthritis, neonatal Causes meningococcemia and
conjunctivitis, PID meningitis, Waterhouse-
Friderichsen syndrome
Haemophilus HaEMOPhilus causes Epiglottitis, Meningitis, Otitis When a child has “flu,” mom
influenzae media, and Pneumonia. Small gram-negative goes to five (V) and dime (X)
(coccobacillary) rod. Aerosol transmission. Most store to buy some chocolate.
invasive disease caused by capsular type B. Vaccine contains type B
Produces IgA protease. Culture on chocolate capsular polysaccharide
agar requires factors V (NAD) and X (hematin) conjugated to diphtheria
for growth. Treat meningitis with ceftriaxone. toxoid or other protein.
Rifampin prophylaxis in close contacts. Does not Given between 2 and 18
cause the flu (influenza virus does). months of age.
Enterobacteriaceae Diverse family including E. coli, Salmonella, Shigella, Think COFFEe:
Klebsiella, Enterobacter, Serratia, Proteus. Capsular
All species have somatic (O) antigen (which is the O antigen
polysaccharide of endotoxin). The capsular (K) Flagellar antigen
antigen is related to the virulence of the bug. The Ferment glucose
flagellar (H) antigen is found in motile species. All Enterobacteriaceae
ferment glucose and are oxidase negative.
Lactose-fermenting These bacteria grow pink colonies on MacConkey’s agar. Lactose is KEE.
enteric bacteria Examples include Klebsiella, E. coli, Enterobacter,
and Citrobacter.
Salmonella vs. Both are non-lactose fermenters; both invade Salmon swim (motile and
Shigella intestinal mucosa and can cause bloody diarrhea. disseminate). Salmonella has
Only SalMonella is Motile and can invade further an animal reservoir; Shigella
and disseminate hematogenously. Symptoms of does not and is transmitted
salmonellosis may be prolonged with antibiotic via “Food, Fingers, Feces, and
treatments, and there is typically a monocyte Flies.”
response. Shigella is more virulent (101 organisms)
than Salmonella (105 organisms).
Yersinia enterocolitica Usually transmitted from pet feces (e.g., puppies), contaminated milk, or pork.
Outbreaks are common in day-care centers. Can mimic Crohn’s or appendicitis;
can disseminate to produce lymphadenitis.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
141
Bugs causing food Vibrio parahaemolyticus and V. vulnificus in S. aureus food poisoning
poisoning contaminated seafood. starts quickly and ends
Bacillus cereus in reheated rice. quickly.
S. aureus in meats, mayonnaise, custard. “Food poisoning from reheated
Clostridium perfringens in reheated meat dishes. rice? Be serious!”
C. botulinum in improperly canned foods (bulging (B. cereus).
cans).
E. coli O157:H7 in undercooked meat.
Salmonella in poultry, meat, and eggs.
Bugs causing diarrhea
Type Species Findings
Bloody diarrhea Campylobacter Comma- or S-shaped organisms;
growth at 42°C; oxidase positive
Salmonella Motile
Shigella Nonmotile; very low ID50;
causes dysentery
Enterohemorrhagic E. coli Shiga-like toxin; can cause HUS
Enteroinvasive E. coli O157:H7; invades colonic
mucosa
Yersinia enterocolitica Day-care outbreaks,
pseudoappendicitis
C. difficile Pseudomembranous colitis
Entamoeba histolytica Protozoan
Watery diarrhea Enterotoxigenic E. coli Traveler’s diarrhea; no
preformed toxin
Vibrio cholerae Comma-shaped organisms; ricewater
stools
C. perfringens Also causes gas gangrene
Protozoa Giardia, Cryptosporidium (in
immunocompromised)
Viruses Rotavirus, adenovirus, Norwalk
virus
Cholera and Vibrio cholerae toxin permanently activates Gs, Cholera turns the “on” on.
pertussis toxins causing rice-water diarrhea. Pertussis turns the “off” off.
Pertussis toxin permanently disables Gi, causing Pertussis toxin also promotes
whooping cough. lymphocytosis by inhibiting
Both toxins act via ADP ribosylation that permanently chemokine receptors.
activates adenyl cyclase (. cAMP).
Legionella Legionnaires’ disease. Gram-negative rod. Gram Think of a French legionnaire
pneumophila stains poorly–use silver stain. Grow on charcoal (soldier) with his silver
yeast extract culture with iron and cysteine. helmet, sitting around a
Aerosol transmission from environmental campfire (charcoal) with his
water source habitat. No person-to-person iron dagger-he is no sissy
transmission. Treat with erythromycin. (cysteine).
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
142
MICROBIOLOGY AND IMMUNOLOGY-BACTERIOLOGY (continued)
Pseudomonas PSEUDOmonas is associated with wound and AERuginosa–AERobic.
aeruginosa burn infections, Pneumonia (especially in Think water connection and
cystic fibrosis), Sepsis (black lesions on skin), blue-green pigment.
External otitis (swimmer’s ear), UTI, Drug use Think Pseudomonas in burn
and Diabetic Osteomyelitis, and hot tub victims.
folliculitis. Aerobic gram-negative rod.
Non-lactose fermenting, oxidase positive.
Produces pyocyanin (blue-green) pigment. Water
source. Produces endotoxin (fever, shock) and
exotoxin A (inactivates EF-2). Treat with
aminoglycoside plus extended-spectrum penicillin
(e.g., piperacillin, ticarcillin).
Helicobacter pylori Causes gastritis and up to 90% of duodenal ulcers. Pylori–think pylorus of
Risk factor for peptic ulcer and gastric carcinoma. stomach. Proteus and
Gram-negative rod. Urease positive (e.g., urease H. pylori are both urease
breath test). Creates alkaline environment. Treat positive (cleave urea to
with triple therapy: (1) bismuth (Pepto-Bismol), ammonia).
metronidazole, and either tetracycline or
amoxicillin; or (2) (more costly) metronidazole,
omeprazole, and clarithromycin.
Zoonotic bacteria
Species Disease Transmission and source
Borrelia burgdorferi Lyme disease Tick bite; Ixodes ticks that live on deer and Bugs From Your Pet
mice Undulate and
Brucella spp. Brucellosis/ Dairy products, contact with animals Unpasteurized dairy
Undulant products give you
fever Undulant fever.
Francisella tularensis Tularemia Tick bite; rabbits, deer
Yersinia pestis Plague Flea bite; rodents, especially prairie dogs
Pasteurella multocida Cellulitis Animal bite; cats, dogs
Gardnerella A pleomorphic, gram-variable rod that causes vaginosis–greenish vaginal discharge with
vaginalis fishy smell; nonpainful. Mobiluncus, an anaerobe, is also involved. Treat with
metronidazole. Clue cells, or vaginal epithelial cells covered with bacteria, are visible
under the microscope.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
143
1° and 2° tuberculosis
Ghon complex TB granulomas (Ghon focus) with lobar and perihilar lymph node involvement. Reflects
1° infection or exposure.
Mycobacteria Mycobacterium tuberculosis (TB, often resistant to TB symptoms include fever,
multiple drugs). night sweats, weight loss,
M. kansasii (pulmonary TB-like symptoms). and hemoptysis (see Color
M. scrofulaceum (cervical lymphadenitis in kids). Image 2).
M. avium-intracellulare (often resistant to multiple
drugs; causes disseminated disease in AIDS).
All mycobacteria are acid-fast organisms.
Leprosy (Hansen’s Caused by Mycobacterium leprae, an acid-fast Hansen’s disease has 2
disease) bacillus that likes cool temperatures (infects forms: lepromatous and
skin and superficial nerves) and cannot be tuberculoid; lepromatous
grown in vitro. Reservoir in United States: is worse (failed cell-mediated
armadillos. immunity); tuberculoid is
Treatment: long-term oral dapsone; toxicity is self-limited.
hemolysis and methemoglobinemia. LEpromatous = LEthal.
Alternate treatments include rifampin and
combination of clofazimine and dapsone.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
Loss of
eyebrows
Nasal
collapse
“Leonine facies” of
lepromatous leprosy
Lumpy
earlobe
Nonimmune host
(usually child)
Infection with Mycobacterium tuberculosis
Partially immune hypersensitized host
(usually adult)
Primary tuberculosis
Reinfection
Secondary tuberculosis
Fibrocaseous
cavitary lesion
Hilar nodes
Ghon focus
(usually
lower lobes)
Ghon
complex
Heals by fibrosis
Immunity and
hypersensitivity
Tuberculin positive
Progressive
lung disease
(HIV, malnutrition)
Death (rare)
Severe bacteremia
Miliary
tuberculosis
Death
Preallergic lymphatic or
hematogenous dissemination
Dormant tubercle bacilli
in several organs
REACTIVATION IN
ADULT LIFE
Reactivation
tuberculosis
of the lungs
Extrapulmonary tuberculosis
- CNS (parenchymal tuberculoma or meningitis)
- Vertebral body (Pott’s disease)
- Lymphadenitis Renal GI
(Adapted, with permission, from Chandrasoma P, Taylor CR. Concise Pathology, 3rd ed. Stamford, CT: Appleton
& Lange, 1998:523.)
144
MICROBIOLOGY AND IMMUNOLOGY-BACTERIOLOGY (continued)
Chlamydiae Chlamydiae are obligate intracellular parasites that Chlamys = cloak (intracellular).
cause mucosal infections. 2 forms: Chlamydia psittaci–notable
1. Elementary body (small, dense), which for an avian reservoir.
Enters cell via endocytosis The chlamydial peptidoglycan
2. Initial or Reticulate body, which Replicates wall is unusual in that it lacks
in cell by fission muramic acid.
Chlamydia trachomatis causes reactive arthritis, Lab diagnosis: cytoplasmic
conjunctivitis, and nongonococcal urethritis. inclusions seen on Giemsa or
C. pneumoniae and C. psittaci cause atypical fluorescent antibody-stained
pneumonia; transmitted by aerosol. smear.
Treatment: erythromycin or tetracycline.
Chlamydia Types A, B, and C–chronic infection, cause ABC = Africa/Blindness/
trachomatis blindness in Africa. Chronic infection.
serotypes Types D-K–urethritis/PID, ectopic pregnancy, L1-3 = Lymphogranuloma
neonatal pneumonia, or neonatal conjunctivitis. venereum.
Types L1, L2, and L3–lymphogranuloma D-K = everything else.
venereum (acute lymphadenitis–positive Neonatal disease acquired by
Frei test). passage through infected
birth canal. Treat with
erythromycin eye drops.
Spirochetes The spirochetes are spiral-shaped bacteria with axial BLT. B is Big.
filaments and include Borrelia (big size),
Leptospira, and Treponema. Only Borrelia can
be visualized using aniline dyes (Wright’s or
Giemsa stain) in light microscopy. Treponema
is visualized by dark-field microscopy.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Attachment and entry
of elementary body
Cell nucleus
Formation of
reticulate body
Multiplication of
reticulate bodies
by binary fission
Reticulate bodies
Reorganization
of reticulate bodies
into elementary bodies
Elementary
bodies
Development
of a large
cytoplasmic
inclusion
Multiplication
ceases
Extracellular
infectious
elementary body
Release
145
Lyme disease Caused by Borrelia burgdorferi, which is transmitted 3 stages of Lyme disease:
by the tick Ixodes. Stage 1–erythema
Classic symptom is erythema chronicum migrans, chronicum migrans,
an expanding “bull’s eye” red rash with central flulike symptoms.
clearing. Also affects joints, CNS, and heart. Stage 2–neurologic and
Mice are important reservoirs. Deer required for cardiac manifestations.
tick life cycle. Stage 3–autoimmune
Treat with tetracycline. migratory polyarthritis.
Named after Lyme, Connecticut; disease is BAKE a Key Lyme pie:
common in northeastern United States. Bell’s palsy, Arthritis, Kardiac
Transmission is most common in summer months. block, Erythema chronicum
migrans.
Treponemal disease Treponemes are spirochetes.
Treponema pallidum causes syphilis.
T. pertenue causes yaws (a tropical infection that is not an STD, although VDRL test
is positive).
Syphilis Caused by spirochete Treponema pallidum. Treat with penicillin G.
1° syphilis Presents with painless chancre (localized disease).
2° syphilis Disseminated disease with constitutional symptoms, Secondary syphilis = Systemic.
maculopapular rash (palms and soles),
condylomata lata.
3° syphilis Gummas, aortitis, neurosyphilis (tabes dorsalis), Signs: broad-based ataxia,
Argyll Robertson pupil (see Color Image 12). positive Romberg, Charcot
Congenital Saber shins, saddle nose, deafness. joints, stroke without
syphilis hypertension.
Argyll Robertson Argyll Robertson pupil constricts with accommodation “Prostitute’s pupil”–
pupil but is not reactive to light. Pathognomonic for 3° accommodates but does not
syphilis. react.
VDRL vs. FTA-ABS is specific for treponemes, turns positive FTA-ABS = Find The
FTA-ABS earliest in disease, and remains positive longest. Antibody-ABSolutely:
VDRL FTA Interpretation 1. Most specific
+ + Active infection 2. Earliest positive
+ – Probably false positive 3. Remains positive the
– + Successfully treated longest
VDRL false positives VDRL detects nonspecific antibody that reacts with VDRL:
beef cardiolipin. Used for diagnosis of syphilis, but Viruses (mono, hepatitis)
many biologic false positives, including viral Drugs
infection (mononucleosis, hepatitis), some drugs, Rheumatic fever and
rheumatic fever, rheumatoid arthritis, SLE, rheumatic arthritis
and leprosy. Lupus and leprosy
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
MICROBIOLOGY AND IMMUNOLOGY-MYCOLOGY
Spores: fungal Most fungal spores are asexual. Both Conidia–asexual fungal spores
coccidioidomycosis and histoplasmosis are (e.g., blastoconidia,
transmitted by inhalation of asexual spores. arthroconidia).
Candida albicans Systemic or superficial fungal infection (budding Alba = white.
yeast with pseudohyphae in culture at 20°C;
germ tube formation at 37°C).
Thrush esophagitis with immunocompromised
patients (neonates, steroids, diabetes, AIDS),
endocarditis in IV drug users, vaginitis
(post-antibiotic), diaper rash.
Treatment: nystatin for superficial infection;
amphotericin B for serious systemic infection.
Systemic mycoses
Disease Endemic location Notes
Coccidioidomycosis Southwestern United States, California. San Joaquin Valley or desert
(desert bumps) “valley fever”
(see Color Image 7)
Histoplasmosis Mississippi and Ohio river valleys. Bird or bat droppings;
intracellular (tiny yeast
inside macrophages)
Paracoccidioidomy- Rural Latin America. “Captain’s wheel” appearance
cosis
Blastomycosis States east of Mississippi River and Central America. Big, Broad-Based
Budding
All of the above are caused by dimorphic fungi, Cold = Mold
which are mold in soil (at lower temperature) and Heat = Yeast
yeast in tissue (at higher/body temperature: 37°C) Culture on Sabouraud’s agar
except coccidioidomycosis, which is a spherule in
tissue. Treat with fluconazole or ketoconazole
for local infection; amphotericin B for systemic
infection. Systemic mycoses can mimic TB
(granuloma formation).
Cutaneous mycoses
Tinea versicolor Caused by Malassezia furfur. Causes hypopigmented skin lesions. Occurs in hot, humid
weather. Treat with topical miconazole, selenium sulfide (Selsun).
Tinea nigra Caused by Cladosporium werneckii. Infection of keratinized layer of skin. Appears as
brownish spot. Treat with topical salicylic acid.
Tinea pedis, Pruritic lesions with central clearing resembling a ring, caused by dermatophytes
tinea cruris, (Microsporum, Trichophyton, and Epidermophyton). See mold hyphae in KOH prep,
tinea corporis, not dimorphic. Pets are a reservoir for Microsporum and can be treated with topical
tinea capitis azoles.
Spherule filled
with endospores
146 MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Broad-based
budding
147
Opportunistic fungal infections
Candida albicans Thrush in immunocompromised (neonates, steroids, diabetes, AIDS), vulvovaginitis
(high pH, diabetes, use of antibiotics), disseminated candidiasis (to any organ),
chronic mucocutaneous candidiasis (see Color Image 9).
Aspergillus fumigatus Allergic bronchopulmonary aspergillosis, lung cavity aspergilloma (“fungus ball”),
invasive aspergillosis. Mold with septate hyphae that branch at a V-shaped (45°)
angle. Not dimorphic.
Cryptococcus Cryptococcal meningitis, cryptococcosis. Heavily encapsulated yeast. Not dimorphic.
neoformans Found in soil, pigeon droppings. Culture on Sabouraud’s agar. Stains with India ink.
Latex agglutination test detects polysaccharide capsular antigen (see Color Image
8).
Mucor and Rhizopus Mucormycosis. Mold with irregular nonseptate hyphae branching at wide angles
spp. (= 90°). Disease mostly in ketoacidotic diabetic and leukemic patients. Fungi also
proliferate in the walls of blood vessels and cause infarction of distal tissue.
Rhinocerebral, frontal lobe abscesses.
Pneumocystis Causes diffuse interstitial pneumonia (PCP). Yeast (originally classified as protozoan).
carinii Inhaled. Most infections asymptomatic. Immunosuppression (e.g., AIDS) predisposes
to disease. Diagnosed by lung biopsy or lavage. Identified by methenamine silver
stain of lung tissue. Treat with TMP-SMX, pentamidine, dapsone. Start prophylaxis
when CD4 drops < 200 cells/mL in HIV patients (see Color Image 17).
Sporothrix Sporotrichosis. Dimorphic fungus that lives on vegetation. When traumatically
schenckii introduced into the skin, typically by a thorn (“rose gardener’s” disease), causes local
pustule or ulcer with nodules along draining lymphatics (ascending lymphangitis).
Little systemic illness. Cigar-shaped budding yeast visible in pus. Treat with
itraconazole or potassium iodide.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
Pseudohyphae
+ budding
yeasts
Rare
fruiting
45° angle bodies
branching
septate
hyphae
5-10-µm yeasts
with wide
capsular halo
Narrow-based
unequal budding
Germ tubes
at 37° C
Irregular broad
(empty-looking)
nonseptate
hyphae,
wide-angle
branching
Candida Aspergillus Cryptoccus Mucor
Yeast forms,
unequal
budding
148
MICROBIOLOGY AND IMMUNOLOGY-PARASITOLOGY
Medically important protozoa
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Organism Disease Transmission Diagnosis Treatment
Entamoeba Amebiasis: bloody diarrhea, Cysts in water Serology and/or Metronidazole
histolytica (dysentery), liver abscess, trophozoites and
RUQ pain or cysts in iodoquinol
stool
Giardia lamblia Giardiasis: bloating, Cysts in water Trophozoites or Metronidazole
(see Color Image flatulence, foul-smelling cysts in stool
5) diarrhea
Cryptosporidium Severe diarrhea in AIDS Cysts in water Cysts on acid- None
Mild disease (watery fast stain
diarrhea) in non-HIV
Toxoplasma Brain abscess in HIV, Cysts in meat Serology, Sulfadiazine +
birth defects (ring-enhancing or cat feces biopsy pyrimethamine
brain lesions)
Plasmodium Malaria: cyclic fever, Mosquito Blood smear Chloroquine
P. vivax headache, anemia, (Anopheles) (primaquine to
P. ovale splenomegaly prevent relapse
P. malariae Malaria–severe (cerebral) caused by
P. falciparum with P. falciparum P. vivax, P. ovale),
sulfadoxine +
pyrimethamine,
mefloquine,
quinine
Trichomonas Vaginitis: foul-smelling, Sexual Trophozoites Metronidazole
vaginalis (see Color greenish discharge; on wet mount
Image 10) itching and burning
Trypanosoma Chagas’ disease (dilated Reduviid bug Blood smear Nifurtimox
cruzi cardiomyopathy, megacolon,
megaesophagus)
Trypanosoma African sleeping sickness Tsetse fly Blood smear Suramin for blood-
T. gambiense borne disease
T. rhodesiense or melarsoprol
for CNS
penetration
Leishmania donovani Visceral leishmaniasis Sandfly Macrophages Sodium
(kala-azar) containing stibogluconate
amastigotes
Babesia Babesiosis: fever and anemia Ixodes tick Blood smear, no RBC Quinine,
pigment, appears clindamycin
as “maltese cross”
Naegleria Rapidly fatal Swimming in Amebas in spinal None
meningoencephalitis freshwater lakes fluid
(enter via
cribriform plate)
149
Medically important helminths
Organism Transmission/disease Treatment
Cestodes (tapeworms)
Taenia solium Undercooked pork tapeworm; larvae cause mass Praziquantel/niclosamide;
lesions in the brain, cysticercosis. albendazole for
cysticercosis
Echinococcus Eggs in dog feces when ingested can cause cysts in Albendazole
granulosus liver; causes anaphylaxis if echinococcal antigens
are released from cysts.
Trematodes (flukes)
Schistosoma Snails are host; cercariae penetrate skin of humans; Praziquantel
causes granulomas, fibrosis, and inflammation
of the spleen and liver.
Clonorchis sinensis Undercooked fish; causes inflammation of the Praziquantel
biliary tract.
Paragonimus Undercooked crab meat; causes inflammation and Praziquantel
westermani 2° bacterial infection of the lung.
Nematodes (roundworms)
Ancylostoma Larvae penetrate skin of feet; intestinal infection can Mebendazole/pyrantel
duodenale cause anemia. pamoate
(hookworm)
Ascaris lumbricoides Eggs are visible in feces; intestinal infection. Mebendazole/pyrantel
(giant roundworm) pamoate
Enterobius Food contaminated with eggs; intestinal infection; Mebendazole/pyrantel
vermicularis causes anal pruritus. pamoate
(pinworm)
Strongyloides Larvae in soil penetrate the skin; intestinal infection. Ivermectin/thiabendazole
stercoralis
Trichinella Undercooked meat, usually pork; inflammation of Thiabendazole
spiralis muscle, periorbital edema.
Dracunculus In drinking water; skin inflammation and ulceration. Niridazole
medinensis
Loa loa Transmitted by deer fly; causes swelling in skin (can Diethylcarbamazine
see worm crawling in conjunctiva).
Onchocerca Transmitted by female blackflies; causes river Ivermectin
volvulus blindness.
Toxocara canis Food contaminated with eggs; causes granulomas Diethylcarbamazine
(if in retina . blindness) and visceral larva migrans.
Wuchereria Female mosquito; causes blockage of lymphatic Diethylcarbamazine
bancrofti vessels (elephantiasis).
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
150
MICROBIOLOGY AND IMMUNOLOGY-PARASITOLOGY (continued)
Parasite hints Findings Organism
Brain cysts, seizures Taenia solium
Liver cysts Echinococcus granulosus
B12 deficiency Diphyllobothrium latum
Biliary tract disease Clonorchis sinensis
Hemoptysis Paragonimus westermani
Portal hypertension Schistosoma mansoni
Hematuria, bladder cancer Schistosoma haematobium
Microcytic anemia Ancylostoma, Necator
Perianal pruritus Enterobius
“Tricky T’s” Chlamydia trachomatis–bacteria, STD.
Trichomonas vaginalis–protozoan, STD.
Trichinella spiralis–worm in undercooked meat.
Trypanosoma–causes Chagas’ disease (T. cruzi) or African sleeping sickness.
Treponema–spirochete; causes syphilis (T. pallidum) or yaws (T. pertenue).
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
151
MICROBIOLOGY AND IMMUNOLOGY-VIROLOGY
DNA viral All DNA viruses except the Parvoviridae are dsDNA. All are dsDNA (like our cells),
genomes All are linear except papovaviruses and except “part-of-a-virus”
hepadnaviruses (circular). (parvovirus) is ssDNA.
RNA viral All RNA viruses except Reoviridae are ssRNA. All are ssRNA (like our
genomes mRNA), except “repeatovirus”
(reovirus) is dsRNA.
Naked viral Naked nucleic acids of most dsDNA (except Viral nucleic acids with the
genome poxviruses and HBV) and (+) strand ssRNA same structure as host
infectivity (˜ mRNA) viruses are infectious. Naked nucleic nucleic acids are infective
acids of (-) strand ssRNA and dsRNA viruses are alone; others require special
not infectious. enzymes (contained in
intact virion).
Naked (nonenveloped) RNA viruses include Naked CPR.
Calicivirus, Picornavirus, and Reovirus.
Enveloped Generally, enveloped viruses acquire their envelopes from plasma membrane when they
viruses exit from cell. Exceptions are herpesviruses, which acquire envelopes from nuclear
membrane.
Virus ploidy All viruses are haploid (with 1 copy of DNA or RNA) except retroviruses, which have
2 identical ssRNA molecules (˜ diploid).
Viral replication
DNA viruses All replicate in the nucleus (except poxvirus).
RNA viruses All replicate in the cytoplasm (except influenza virus and retroviruses).
DNA virus Some general rules–all DNA viruses:
characteristics 1. Are HHAPPPy viruses Hepadna, Herpes, Adeno, Pox,
Parvo, Papova.
2. Are double stranded EXCEPT Parvo (single stranded).
3. Are linear EXCEPT Papovavirus (circular,
supercoiled) and Hepadna
(circular, incomplete).
4. Are icosahedral EXCEPT Pox (complex).
5. Replicate in the nucleus EXCEPT Pox (carries own
DNA-dependent RNA
polymerase).
Naked DNA viruses are PAP = Parvo, You need to be naked for a PAP
Adeno, Papova; enveloped DNA viruses smear.
are HPH = Hepadna, Pox, Herpes.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
152
MICROBIOLOGY AND IMMUNOLOGY-VIROLOGY (continued)
DNA viruses
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Viral Family Envelope DNA Structure Medical Importance
Hepadnavirus Yes DS – partial circular HBV
Acute or chronic hepatitis
Vaccine available–use has increased tremendously
Not a retrovirus but has reverse transcriptase
Herpesviruses Yes DS – linear HSV-1–oral (and some genital) lesions, keratoconjunctivitis
HSV-2–genital (and some oral) lesions
VZV–chickenpox, zoster, shingles
EBV–mononucleosis, Burkitt’s lymphoma
CMV–infection in immunosuppressed patients, especially
transplant recipients; congenital defects
HHV-6–roseola (exanthem subitum)
HHV-8–Kaposi’s sarcoma-associated herpesvirus (KSHV)
Adenovirus No DS – linear Febrile pharyngitis–sore throat
Pneumonia
Conjunctivitis–“pink eye”
Parvovirus No SS – linear (-) B19 virus–aplastic crises in sickle cell disease, “slapped cheeks”
(smallest DNA rash–erythema infectiosum (fifth disease), hydrops fetalis
virus)
Papovavirus No DS – circular HPV–warts, CIN, cervical cancer
JC–progressive multifocal leukoencephalopathy (PML) in HIV
Poxvirus Yes DS – linear Smallpox, although eradicated, could be used in germ warfare
(largest DNA Vaccinia–cowpox (“milkmaid’s blisters”)
virus) Molluscum contagiosum
RNA viruses
RNA Capsid
Viral Family Envelope Structure Symmetry Medical Importance
Picornaviruses No SS + linear Icosahedral Poliovirus–polio-Salk/Sabin vaccines–
IPV/OPV
Echovirus–aseptic meningitis
Rhinovirus–“common cold”
Coxsackievirus–aseptic meningitis
herpangina–febrile pharyngitis
hand, foot, and mouth disease
myocarditis
HAV–acute viral hepatitis
Caliciviruses No SS + linear Icosahedral HEV
Norwalk virus–viral gastroenteritis
Reoviruses No DS linear Icosahedral Reovirus–Colorado tick fever
Segmented (double) Rotavirus–#1 cause of fatal diarrhea in children
Flaviviruses Yes SS + linear Icosahedral HCV
Yellow fever
Dengue
St. Louis encephalitis
West Nile virus
Togaviruses Yes SS + linear Icosahedral Rubella (German measles)
Eastern equine encephalitis
Western equine encephalitis
Retroviruses Yes SS + linear Icosahedral Have reverse transcriptase
HIV–AIDS
HTLV–T-cell leukemia
Orthomyxoviruses Yes SS – linear Helical Influenza virus
Segmented
Paramyxoviruses Yes SS – linear Helical PaRaMyxovirus:
Nonsegmented Parainfluenza–croup
RSV–bronchiolitis in babies; Rx–ribavirin
Measles
Mumps
Rhabdoviruses Yes SS – linear Helical Rabies
Filoviruses Yes SS – linear Helical Ebola/Marburg hemorrhagic fever–often fatal!
Coronaviruses Yes SS + linear Helical Coronavirus–“common cold” and SARS
Arenaviruses Yes SS – circular Helical LCV–lymphocytic choriomeningitis
Meningitis–spread by mice
Bunyaviruses Yes SS – circular Helical California encephalitis
Sandfly/Rift Valley fevers
Crimean-Congo hemorrhagic fever
Hantavirus–hemorrhagic fever, pneumonia
Deltavirus Yes SS – circular Helical HDV
SS, single-stranded; DS, double-stranded; +, + polarity; -, – polarity
153
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
(Adapted, with permission, from Levinson W, Jawetz E. Medical Microbiology and Immunology: Examination and Board Review, 6th ed. New York:
McGraw-Hill, 2000:182.)
154
MICROBIOLOGY AND IMMUNOLOGY-VIROLOGY (continued)
Viral vaccines Live attenuated vaccines induce humoral and cell- Dangerous to give live
mediated immunity but have reverted to virulence vaccines to
on rare occasions. Killed vaccines induce only immunocompromised
humoral immunity but are stable. patients or their
close contacts.
Live attenuated–measles, mumps, rubella, Sabin MMR = measles, mumps,
polio, VZV, yellow fever, smallpox, adenovirus. rubella.
Killed–rabies, influenza, HAV, and Salk polio SalK = Killed.
vaccines.
Egg-based–Flu, MMR, Yellow fever. FRY an egg.
Recombinant–HBV (antigen = recombinant HBsAg).
Viral genetics
Recombination Exchange of genes between 2 chromosomes by crossing over within regions of
significant base sequence homology.
Reassortment When viruses with segmented genomes (e.g., influenza virus) exchange segments. Highfrequency
recombination. Cause of worldwide pandemics.
Complementation When 1 of 2 viruses that infect the cell has a mutation that results in a nonfunctional
protein. The nonmutated virus “complements” the mutated one by making a
functional protein that serves both viruses.
Phenotypic mixing Genome of virus A can be coated with the surface proteins of virus B. Type B protein
coat determines the infectivity of the phenotypically mixed virus. However, the
progeny from this infection has a type A coat and is encoded by its type A genetic
material.
Viral pathogens
Structure Viruses
DNA enveloped Herpesviruses (HSV types 1 and 2, VZV, CMV, EBV), HBV, smallpox virus
viruses
DNA nucleocapsid Adenovirus, papillomaviruses, parvovirus
viruses
RNA enveloped Influenza virus, parainfluenza virus, RSV, measles virus, mumps virus, rubella virus,
viruses rabies virus, HTLV, HIV
RNA nucleocapsid Enteroviruses (poliovirus, coxsackievirus, echovirus, HAV), rhinovirus, reovirus
viruses
Slow virus Virus exists in patient for months to years before it manifests as clinical disease. SSPE
infections (late sequela of measles), PML (reactivation of JC virus) in immunocompromised
patients, especially AIDS.
Segmented viruses All are RNA viruses. They include Bunyaviruses, BOAR.
Orthomyxoviruses (influenza viruses),
Arenaviruses, and Reoviruses. Influenza virus
consists of 8 segments of negative-stranded
RNA. These segments can undergo reassortment,
causing antigenic shifts that lead to worldwide
epidemics of the flu.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
155
Picornavirus Includes Poliovirus, Echovirus, Rhinovirus, PicoRNAvirus = small
Coxsackievirus, HAV. RNA is translated into RNA virus.
1 large polypeptide that is cleaved by proteases PERCH on a “peak” (pico).
into functional viral proteins. Can cause aseptic
(viral) meningitis (except rhinovirus and HAV).
Rhinovirus Nonenveloped RNA virus. Cause of common Rhino has a runny nose.
cold– > 100 serologic types.
Rotavirus Rotavirus, the most important global cause of ROTA = Right Out The
infantile gastroenteritis, is a segmented dsRNA Anus.
virus (a reovirus). Major cause of acute diarrhea
in the United States during winter.
Paramyxoviruses Paramyxoviruses include those that cause parainfluenza (croup), mumps, and measles as
well as RSV, which causes respiratory tract infection (bronchiolitis, pneumonia) in
infants. Paramyxoviruses cause disease in children. All paramyxoviruses have 1
serotype except parainfluenza virus, which has 4.
Mumps virus A paramyxovirus with 1 serotype.
Symptoms: Parotitis, Orchitis (inflammation of Mumps makes your parotid
testes), and aseptic Meningitis. Can cause glands and testes as big as
sterility (especially after puberty). POM-poms.
Measles virus A paramyxovirus that causes measles. Koplik spots 3 C’s of measles:
(bluish-gray spots on buccal mucosa) are Cough
diagnostic. SSPE, encephalitis (1:2000), and Coryza
giant cell pneumonia (rarely, in immuno- Conjunctivitis
suppressed) are possible sequelae. Also look for Koplik spots.
Influenza viruses Enveloped, single-stranded RNA viruses with Killed viral vaccine is major
segmented genome. Contain hemagglutinin mode of protection;
and neuraminidase antigens. Responsible for reformulated vaccine offered
worldwide influenza epidemics; patients at risk each fall to elderly, healthfor
fatal bacterial superinfection. Rapid genetic care workers, etc.
changes.
Genetic shift Reassortment of viral genome (such as when human Sudden Shift is more deadly
flu A virus recombines with swine flu A virus). than graDual Drift.
Genetic drift Minor changes based on random mutation.
Treatment Amantadine and rimantadine useful for influenza A
(especially prophylaxis).
Zanamivir and oseltamivir (neuraminidase inhibitors)
useful for both influenza A and B.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
156
MICROBIOLOGY AND IMMUNOLOGY-VIROLOGY (continued)
Rabies virus Negri bodies are characteristic cytoplasmic Travels to the CNS by migrating
inclusions in neurons infected by rabies virus. in a retrograde fashion up
Has bullet-shaped capsid. Rabies has long nerve axons.
incubation period (weeks to 3 months). Causes
fatal encephalitis with seizures and hydrophobia.
More commonly from bat, raccoon, and skunk bites
than from dog bites in the United States.
Arboviruses Transmitted by arthropods (mosquitoes, ticks). ARBOvirus–ARthropod-
Classic examples are dengue fever (also known BOrne virus, including
as break-bone fever) and yellow fever. A variant flavivirus, togavirus, and
of dengue fever in Southeast Asia is hemorrhagic bunyavirus.
shock syndrome.
Yellow fever Caused by flavivirus, an arbovirus transmitted by Flavi = yellow.
Aedes mosquitos. Virus has a monkey or human
reservoir.
Symptoms: high fever, black vomitus, and jaundice.
Councilman bodies (acidophilic inclusions) may be
seen in liver.
Herpesviruses
Virus Diseases Route of transmission
HSV-1 Gingivostomatitis, keratoconjunctivitis, Respiratory secretions, Get herpes in a
temporal lobe encephalitis, herpes saliva CHEVrolet:
labialis (see Color Image 11) CMV
HSV-2 Herpes genitalis, neonatal herpes Sexual contact, perinatal HSV
VZV Varicella-zoster (shingles), encephalitis, Respiratory secretions EBV
pneumonia (see Color Image 15) VZV
EBV Infectious mononucleosis, Burkitt’s Respiratory secretions,
lymphoma saliva
CMV Congenital infection, mononucleosis Congenital, transfusion,
(negative Monospot), pneumonia sexual contact, saliva,
urine, transplant (see
Color Image 6)
HHV-8 Kaposi’s sarcoma (HIV patients) Sexual contact
Mononucleosis Caused by EBV, a herpesvirus. Characterized by Most common during peak
fever, hepatosplenomegaly, pharyngitis, and kissing years (“kissing
lymphadenopathy (especially posterior auricular disease”).
nodes). Monospot test–heterophil
Peak incidence 15-20 years old. Positive heterophil antibodies detected by
antibody test. Abnormal circulating cytotoxic T agglutination of sheep RBCs.
cells (atypical lymphocytes).
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
157
Tzanck test A smear of an opened skin vesicle to detect Tzanck heavens I do not have
multinucleated giant cells. Used to assay for herpes.
HSV-1, HSV-2, and VZV.
Hepatitis HAV (RNA picornavirus) is transmitted primarily Hep A: Asymptomatic
transmission by fecal-oral route. Short incubation (3 weeks). (usually), Acute, Alone (no
No carriers. carriers; naked ssRNA).
HBV (DNA hepadnavirus) is transmitted primarily Hep B: Blood borne.
by parenteral, sexual, and maternal-fetal routes.
Long incubation (3 months). Carriers. Reverse
transcription occurs; however, the virion enzyme
is a DNA-dependent DNA polymerase.
HCV (RNA flavivirus) is transmitted primarily via Hep C: Chronic, Cirrhosis,
blood and resembles HBV in its course and Carcinoma, Carriers.
severity. Carriers. Common cause of IV drug use
hepatitis in the United States.
HDV (delta agent) is a defective virus that requires Hep D: Defective, Dependent
HBsAg as its envelope. Carriers. on HBV.
HEV (RNA calicivirus) is transmitted enterically Hep E: Enteric, Expectant
and causes water-borne epidemics. Resembles mothers, Epidemics.
HAV in course, severity, incubation. High A and E by fecal-oral route:
mortality rate in pregnant women. “The vowels hit your
Both HBV and HCV predispose a patient to chronic bowels.”
active hepatitis, cirrhosis, and hepatocellular
carcinoma.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
158
MICROBIOLOGY AND IMMUNOLOGY-VIROLOGY (continued)
Hepatitis serologic markers
IgM HAVAb IgM antibody to HAV; best test to detect active hepatitis A.
HBsAg Antigen found on surface of HBV; continued presence indicates carrier state.
HBsAb Antibody to HBsAg; provides immunity to hepatitis B.
HBcAg Antigen associated with core of HBV.
HBcAb Antibody to HBcAg; positive during window period. IgM HBcAb is an indicator of
recent disease.
HBeAg A second, different antigenic determinant in the HBV core. Important indicator of
transmissibility. (BEware!)
HBeAb Antibody to e antigen; indicates low transmissibility.
aIgM in acute stage; IgG in chronic or recovered stage.
bPatient has surface antibody but available antibody is bound to HBsAg.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Coat protein
(HBsAg)
Core (HBcAg)
DNA genome
DNA polymerase
42
nm
Virus particle
(-) (+)
HBsAg
HBeAg
Anti-HBs
Anti-HBe
DNA polymerase
HBV particles Anti-HBc
0 1 2 3 4 5 6 7 8
Months after exposure
Level of
detection
Titer
0 1 2 3 4 5 6 7 8
HBsAg HBsAg
(anti-HBc)
Anti-
HBc
Anti-HBs
(anti-HBc)
Incubation
period
Prodrome,
acute disease Early
Convalescence
Important diagnostic tests
Late
Window period
Test Acute Disease Window Phase Complete Recovery Chronic Carrier
HBsAg + – – +
HBsAb – – + -b
HBcAb +a + + +
159
HIV
Diploid genome (2 molecules
of RNA).
p24 = rectangular nucleocapsid
protein.
gp41 and gp120 = envelope
proteins.
Reverse transcriptase
synthesizes dsDNA from
RNA; dsDNA integrates
into host genome.
HIV diagnosis Presumptive diagnosis made with ELISA (sensitive, ELISA/Western blot tests look
high false-positive rate and low threshold, RULE for antibodies to viral
OUT test); positive results are then confirmed proteins; these tests are
with Western blot assay (specific, high false- often falsely negative in the
negative rate and high threshold, RULE IN test). first 1-2 months of HIV
HIV PCR/viral load tests are increasing in popularity: infection and falsely positive
they allow physician to monitor the effect of drug initially in babies born to
therapy on viral load. infected mothers (anti-gp120
crosses placenta).
AIDS diagnosis = < 200 CD4+,
HIV positive with AIDS
indicator condition (e.g.,
PCP), or CD4/CD8
ratio < 1.5.
HIV immunity
CCR5 mutation Homozygous = immunity. 1% of U.S. Caucasians.
Heterozygous = slower course. 20% of U.S. Caucasians.
CXCR1 mutation Rapid progression to AIDS.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
gp41env
Reverse
transcriptasepol
gp120env
RNA
p17 matrix
protein
p24gag
Capsid Lipid bilayer
(Adapted, with permission, from Levinson W. Medical Microbiology
and Immunology: Examination and Board Review, 8th ed. New
York: McGraw-Hill, 2004:314.)
160
MICROBIOLOGY AND IMMUNOLOGY-VIROLOGY (continued)
Time course of HIV infection
Opportunistic infections and disease in AIDS
Organ system Infection/disease
Brain Cryptococcal meningitis, toxoplasmosis, CMV encephalopathy, AIDS dementia, PML
(JC virus)
Eyes CMV retinitis
Mouth and throat Thrush (Candida albicans), HSV, CMV, oral hairy leukoplakia (EBV)
Lungs Pneumocystis carinii pneumonia (PCP), TB, histoplasmosis
GI Cryptosporidiosis, Mycobacterium avium-intracellulare complex, CMV colitis,
non-Hodgkin’s lymphoma (EBV)
Skin Shingles (VZV), Kaposi’s sarcoma (HHV-8)
Genitals Genital herpes, warts, and cervical cancer (HPV)
Prions Infectious agents that do not contain RNA or DNA (consist only of proteins); encoded by
cellular genes. Diseases include Creutzfeldt-Jakob disease (CJD–rapid progressive
dementia), kuru, scrapie (sheep), and “mad cow disease.” Prions are associated with
spongiform encephalopathy. Normal prions have a-helix conformation; pathologic
prions (like CJD) are ß-pleated sheets.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
ACUTE
Acute symptoms
LATENT IMMUNODEFICIENCY
Opportunistic infections and
malignancies
CD4 lymphocytes
Anti-p24 antibodies
Anti-gp120 antibodies
Virus, p24 antigen
0 1 2 3 4 5 6
Time after infection (months) Time after infection (years)
3 – =10
Relative levels
(Adapted, with permission, from Levinson W. Medical Microbiology and Immunology: Examination and Board
Review, 8th ed. New York: McGraw-Hill, 2004:318.)
161
MICROBIOLOGY AND IMMUNOLOGY-SYSTEMS
Normal flora: Skin–Staphylococcus epidermidis. Neonates delivered by
dominant Nose–S. aureus. cesarean section have
Oropharynx–viridans streptococci. no flora but are rapidly
Dental plaque–Streptococcus mutans. colonized after birth.
Colon–Bacteroides fragilis > E. coli.
Vagina–Lactobacillus, colonized by E. coli and group
B strep.
Common causes
of pneumonia
Causes of
meningitis
CSF findings in meningitis
Pressure Cell type Protein Sugar
Bacterial . .PMNs . .
Fungal/TB . .lymphocytes . .
Viral Normal/. .lymphocytes Normal Normal
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
Children (6 wks-18 yr) Adults (18-40 yr) Adults (40-65 yr) Elderly
Viruses (RSV) Mycoplasma S. pneumoniae S. pneumoniae
Mycoplasma C. pneumoniae H. influenzae Viruses
Chlamydia pneumoniae S. pneumoniae Anaerobes Anaerobes
Streptococcus Viruses H. influenzae
pneumoniae Mycoplasma Gram-negative
rods
Special groups:
Nosocomial (hospital acquired) Staphylococcus, gram-negative rods
Immunocompromised Staphylococcus, gram-negative rods, fungi, viruses,
Pneumocystis carinii–with HIV
Aspiration Anaerobes
Alcoholic/IV drug user S. pneumoniae, Klebsiella, Staphylococcus
Postviral Staphylococcus, H. influenzae
Neonate Group B streptococci, E. coli
Atypical Mycoplasma, Legionella, Chlamydia
Newborn (0-6 mos) Children (6 mos-6 yrs) 6-60 yrs 60 yrs +
Group B Streptococcus N. meningitidis S. pneumoniae
streptococci pneumoniae
E. coli Neisseria Enteroviruses Grammeningitidis
negative rods
Listeria Haemophilus S. pneumoniae Listeria
influenzae type B
Enteroviruses HSV
In HIV–Cryptococcus, CMV, toxoplasmosis (brain abscess), JC virus (PML).
Note: Incidence of H. influenzae meningitis has . greatly with introduction of H. influenzae
vaccine in last 10-15 years.
162
MICROBIOLOGY AND IMMUNOLOGY-SYSTEMS (continued)
Osteomyelitis Most people–S. aureus. Assume S. aureus if no other
Sexually active–Neisseria gonorrhoeae (rare), septic information.
arthritis more common. Most osteomyelitis occurs in
Diabetics and drug addicts–Pseudomonas children.
aeruginosa.
Sickle cell–Salmonella. Elevated ESR.
Prosthetic replacement–S. aureus and S.
epidermidis.
Vertebral–Mycobacterium tuberculosis (Pott’s
disease).
Urinary tract Ambulatory–E. coli (50-80%), Klebsiella (8-10%). UTIs mostly caused by
infections Staphylococcus saprophyticus (10-30%) is the ascending infections. In
2nd most common cause of UTI in young males: babies with congenital
ambulatory women. defects; elderly with enlarged
Hospital–E. coli, Proteus, Klebsiella, Serratia, prostates.
Pseudomonas. UTI–dysuria, frequency,
Epidemiology: women to men–10:1 (short urethra urgency, suprapubic pain.
colonized by fecal flora). Pyelonephritis–fever, chills,
Predisposing factors: flow obstruction, kidney surgery, flank pain, and CVA
catheterization, gynecologic abnormalities, tenderness.
diabetes, and pregnancy.
UTI bugs
Species Features of the organism
Serratia marcescens Some strains produce a red pigment; often SSEEK PP.
nosocomial and drug resistant. Diagnostic markers:
Staphylococcus 2nd leading cause of community-acquired UTI in Leukocyte esterase–
saprophyticus sexually active women. positive = bacterial.
Escherichia coli Leading cause of UTI. Colonies show metallic sheen Nitrite test–positive =
on EMB agar. gram negative.
Enterobacter cloacae Often nosocomial and drug resistant.
Klebsiella pneumoniae Large mucoid capsule and viscous colonies.
Proteus mirabilis Motility causes “swarming” on agar; produces
urease; associated with struvite stones.
Pseudomonas Blue-green pigment and fruity odor; usually
aeruginosa nosocomial and drug resistant.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
163
Sexually transmitted diseases
Disease Clinical features Organism
Gonorrhea Urethritis, cervicitis, PID, prostatitis, epididymitis, Neisseria gonorrhoeae
arthritis, creamy purulent discharge
1° syphilis Painless chancre Treponema pallidum
2° syphilis Fever, lymphadenopathy, skin rashes, condylomata
lata
3° syphilis Gummas, tabes dorsalis, general paresis, aortitis,
Argyll Robertson pupil
Genital herpes Painful penile, vulvar, or cervical ulcers HSV-2
Chlamydia Urethritis, cervicitis, conjunctivitis, Reiter’s Chlamydia trachomatis
syndrome, PID (D-K)
Lymphogranuloma Ulcers, lymphadenopathy, rectal strictures C. trachomatis
venereum (L1-L3)
Trichomoniasis Vaginitis, strawberry-colored mucosa Trichomonas vaginalis
AIDS Opportunistic infections, Kaposi’s sarcoma, HIV
lymphoma
Condylomata Genital warts, koilocytes HPV 6 and 11
acuminata
Hepatitis B Jaundice HBV
Chancroid Painful genital ulcer, inguinal adenopathy Haemophilus ducreyi
Bacterial vaginosis Noninflammatory, malodorous discharge; Gardnerella vaginalis
positive whiff test, clue cells
Pelvic Top bugs–Chlamydia trachomatis (subacute, often Salpingitis is a risk factor for
inflammatory undiagnosed), Neisseria gonorrhoeae (acute, high ectopic pregnancy, infertility,
disease fever). C. trachomatis is the most common STD chronic pelvic pain, and
in the United States (3-4 million cases per year). adhesions.
Cervical motion tenderness (chandelier sign), Other STDs include
purulent cervical discharge. PID may include Gardnerella (clue cells)
salpingitis, endometritis, hydrosalpinx, and and Trichomonas (motile on
tubo-ovarian abscess. wet prep).
Nosocomial infections
Risk factor Pathogen Notes
Newborn nursery CMV, RSV The 2 most common causes
Urinary E. coli, Proteus mirabilis of nosocomial infections are
catheterization E. coli (UTI) and S. aureus
(wound infection).
Respiratory therapy Pseudomonas aeruginosa Presume Pseudomonas
equipment AIRuginosa when AIR or
Work in renal HBV burns are involved.
dialysis unit
Hyperalimentation Candida albicans
Water aerosols Legionella Legionella when water source
is involved.
Infections dangerous ToRCHeS = Toxoplasma, Rubella, CMV, HSV/HIV, Syphilis.
in pregnancy
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
164
MICROBIOLOGY AND IMMUNOLOGY-SYSTEMS (continued)
Bug hints (if all Pus, empyema, abscess–S. aureus.
else fails) Pediatric infection–Haemophilus influenzae (including epiglottitis).
Pneumonia in cystic fibrosis, burn infection–Pseudomonas aeruginosa.
Branching rods in oral infection–Actinomyces israelii.
Traumatic open wound–Clostridium perfringens.
Surgical wound–S. aureus.
Dog or cat bite–Pasteurella multocida.
Currant jelly sputum–Klebsiella.
Sepsis/meningitis in newborn–group B strep.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
MICROBIOLOGY AND IMMUNOLOGY-ANTIMICROBIALS
Antimicrobial therapy
Mechanism of action Drugs
1. Block cell wall synthesis by Penicillin, ampicillin, ticarcillin, piperacillin, imipenem, aztreonam,
inhibition of peptidoglycan cephalosporins
cross-linking
2. Block peptidoglycan synthesis Bacitracin, vancomycin, cycloserine
3. Disrupt bacterial/fungal cell Polymyxins
membranes
4. Disrupt fungal cell Amphotericin B, nystatin, fluconazole/azoles
membranes
5. Block nucleotide synthesis Sulfonamides, trimethoprim
6. Block DNA topoisomerases Quinolones
7. Block mRNA synthesis Rifampin
8. Block protein synthesis at Chloramphenicol, erythromycin/macrolides, lincomycin, clindamycin,
50S ribosomal subunit streptogramins (quinupristin, dalfopristin), linezolid
9. Block protein synthesis at Aminoglycosides, tetracyclines
30S ribosomal subunit
Bactericidal antibiotics Penicillin, cephalosporins, vancomycin, aminoglycosides, fluoroquinolones,
metronidazole.
165
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
–
–
– 7
–
6
A T –
C
5
1, 2
3, 4
8
–
–
30S 30S
50S 50S
9
166
MICROBIOLOGY AND IMMUNOLOGY-ANTIMICROBIALS (continued)
Antibiotics
Penicillin Penicillin G (IV form), penicillin V (oral). Prototype ß-lactam antibiotics.
Mechanism 1. Bind penicillin-binding proteins
2. Block transpeptidase cross-linking of cell wall
3. Activate autolytic enzymes
Clinical use Bactericidal for gram-positive cocci, gram-positive rods, gram-negative cocci, and
spirochetes. Not penicillinase resistant.
Toxicity Hypersensitivity reactions, hemolytic anemia.
Methicillin, nafcillin, dicloxacillin
Mechanism Same as penicillin. Narrow spectrum; penicillinase resistant because of bulkier R group.
Clinical use S. aureus (except MRSA; resistant because of altered penicillin-binding protein target
site).
Toxicity Hypersensitivity reactions; methicillin–interstitial nephritis.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Gram-Positive Bacteria
Penicillin G, V
Nafcillin, oxacillin, methicillin
Ticarcillin, carbenicillin, piperacillin
1st-generation cephalosporins
2nd-generation cephalosporins Cefotetan
3rd-generation cephalosporins
4th-generation cephalosporins
Aztreonam
Imipenem/cilastatin
Vancomycin
**
Gentamicin
Tobramycin
Amikacin
Tetracyclines
Chloramphenicol
Erythromycin
* Required to treat Enterobacter.
Clindamycin
Azithromycin
Amoxicillin, ampicillin
S. epidermidis
S. aureus
Listeria
Group B strep
Group A strep
Enterococci
S. pneumoniae
N. meningitidis
H. influenzae
E. coli
Klebsiella
P. aeruginosa
Enterobacter
Serratia
B. fragilis
Mouth
Gut
Gram-Negative Bacteria Anaerobes
167
Ampicillin, amoxicillin
Mechanism Same as penicillin. Wider spectrum; penicillinase
sensitive. Also combine with clavulanic acid
(penicillinase inhibitor) to enhance spectrum.
AmOxicillin has greater Oral bioavailability than
ampicillin.
Clinical use Extended-spectrum penicillin–certain gram-positive Coverage: ampicillin/
bacteria and gram-negative rods (Haemophilus amoxicillin HELPS
influenzae, E. coli, Listeria monocytogenes, Proteus kill enterococci.
mirabilis, Salmonella, enterococci).
Toxicity Hypersensitivity reactions; ampicillin rash;
pseudomembranous colitis.
Ticarcillin, carbenicillin, piperacillin
Mechanism Same as penicillin. Extended spectrum. TCP: Takes Care of
Clinical use Pseudomonas spp. and gram-negative rods; susceptible Pseudomonas.
to penicillinase; use with clavulanic acid.
Toxicity Hypersensitivity reactions.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
MICROBIOLOGY AND IMMUNOLOGY-ANTIMICROBIALS (continued)
Cephalosporins
Mechanism ß-lactam drugs that inhibit cell wall synthesis but are
less susceptible to penicillinases. Bactericidal.
Clinical use 1st generation (cefazolin, cephalexin)–gram-positive 1st generation–PEcK.
cocci, Proteus mirabilis, E. coli, Klebsiella
pneumoniae.
2nd generation (cefoxitin, cefaclor, cefuroxime)– 2nd generation–HEN
gram-positive cocci, Haemophilus influenzae, PEcKS.
Enterobacter aerogenes, Neisseria spp., Proteus
mirabilis, E. coli, Klebsiella pneumoniae,
Serratia marcescens.
3rd generation (ceftriaxone, cefotaxime, ceftazidime)–
serious gram-negative infections resistant to other
ß-lactams; meningitis (most penetrate the blood-brain
barrier). Examples: ceftazidime for Pseudomonas;
ceftriaxone for gonorrhea.
4th generation (cefepime, cefpiramide)–. activity against
Pseudomonas and gram-positive organisms.
Toxicity Hypersensitivity reactions. Cross-hypersensitivity with
penicillins occurs in 5-10% of patients. .
nephrotoxicity of aminoglycosides; disulfiram-like
reaction with ethanol (in cephalosporins with a
methylthiotetrazole group, e.g., cefamandole).
Aztreonam
Mechanism A monobactam resistant to ß-lactamases. Inhibits cell wall synthesis (binds to PBP3).
Synergistic with aminoglycosides. No cross-allergenicity with penicillins.
Clinical use Gram-negative rods–Klebsiella spp., Pseudomonas spp., Serratia spp. No activity against
gram-positives or anaerobes. For penicillin-allergic patients and those with renal
insufficiency who cannot tolerate aminoglycosides.
Toxicity Usually nontoxic; occasional GI upset.
Imipenem/cilastatin, meropenem
Mechanism Imipenem is a broad-spectrum, ß-lactamase-resistant With imipenem, “the kill is
carbapenem. Always administered with cilastatin LASTIN’ with
(inhibitor of renal dihydropeptidase I) to . ciLASTATIN.”
inactivation in renal tubules.
Clinical use Gram-positive cocci, gram-negative rods, and
anaerobes. Drug of choice for Enterobacter.
Toxicity GI distress, skin rash, and CNS toxicity (seizures)
at high plasma levels.
168 MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Functional
group
lactam
ring
S CH3
CH3
O COOH
ß-
R
N
ß-lactamase
cuts here
H
N
O
Penicillin C
O
lactam
ring
ß-
R1
H
N
O
C
Functional group
R2
Functional g
COO –
roup
S
Cephalosporin
N
ß-lactamase
cuts here
169
Vancomycin
Mechanism Inhibits cell wall mucopeptide formation by binding D-ala D-ala portion of cell wall
precursors. Bactericidal. Resistance occurs with amino acid change of D-ala D-ala to
D-ala D-lac.
Clinical use Used for serious, gram-positive multidrug-resistant organisms, including S. aureus
and Clostridium difficile (pseudomembranous colitis).
Toxicity Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse flushing–“red man syndrome”
(can largely prevent by pretreatment with antihistamines and slow infusion rate).
Well tolerated in general–does NOT have many problems.
Protein synthesis 30S inhibitors: “Buy AT 30, CELL at 50.”
inhibitors A = Aminoglycosides (streptomycin, gentamicin,
tobramycin, amikacin) [bactericidal]
T = Tetracyclines [bacteriostatic]
50S inhibitors:
C = Chloramphenicol [bacteriostatic]
E = Erythromycin [bacteriostatic]
L = Lincomycin [bacteriostatic]
L = cLindamycin [bacteriostatic]
Aminoglycosides Gentamicin, Neomycin, Amikacin, Tobramycin, “Mean” GNATS canNOT
Streptomycin. kill anaerobes.
Mechanism Bactericidal; inhibit formation of initiation complex
and cause misreading of mRNA. Require O2 for
uptake; therefore ineffective against anaerobes.
Clinical use Severe gram-negative rod infections. Synergistic with
ß-lactam antibiotics. Neomycin for bowel surgery.
Toxicity Nephrotoxicity (especially when used with
cephalosporins), Ototoxicity (especially when
used with loop diuretics). Teratogen.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
Ribosomal subunits
A
(30S)
P = growing
peptide chain
A = amino acid
L,E (50S)
T (30S)
Peptidyl
transferase
C
(50S)
Translocase
50S
30S
x x
x
x
PA P A
P
170
MICROBIOLOGY AND IMMUNOLOGY-ANTIMICROBIALS (continued)
Tetracyclines Tetracycline, doxycycline, demeclocycline, Demeclocycline–ADH
minocycline. antagonist; acts as a
Mechanism Bacteriostatic; bind to 30S and prevent attachment Diuretic in SIADH.
of aminoacyl-tRNA; limited CNS penetration.
Doxycycline is fecally eliminated and can be used
in patients with renal failure. Must NOT take
with milk, antacids, or iron-containing
preparations because divalent cations inhibit its
absorption in the gut.
Clinical use Vibrio cholerae, Acne, Chlamydia, Ureaplasma VACUUM THe BedRoom.
Urealyticum, Mycoplasma pneumoniae, Tularemia,
H. pylori, Borrelia burgdorferi (Lyme disease),
Rickettsia.
Toxicity GI distress, discoloration of teeth and inhibition of
bone growth in children, photosensitivity.
Contraindicated in pregnancy.
Macrolides Erythromycin, azithromycin, clarithromycin.
Mechanism Inhibit protein synthesis by blocking translocation; bind to the 23S rRNA of the 50S
ribosomal subunit. Bacteriostatic.
Clinical use URIs, pneumonias, STDs–gram-positive cocci (streptococcal infections in patients
allergic to penicillin), Mycoplasma, Legionella, Chlamydia, Neisseria.
Toxicity GI discomfort (most common cause of noncompliance), acute cholestatic hepatitis,
eosinophilia, skin rashes. Increases serum concentration of theophyllines, oral
anticoagulants.
Chloramphenicol
Mechanism Inhibits 50S peptidyltransferase. Bacteriostatic.
Clinical use Meningitis (Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae).
Conservative use owing to toxicities.
Toxicity Anemia (dose dependent), aplastic anemia (dose independent), gray baby syndrome (in
premature infants because they lack liver UDP-glucuronyl transferase).
Clindamycin
Mechanism Blocks peptide bond formation at 50S ribosomal Treats anaerobes above the
subunit. Bacteriostatic. diaphragm.
Clinical use Treat anaerobic infections (e.g., Bacteroides fragilis,
Clostridium perfringens).
Toxicity Pseudomembranous colitis (C. difficile overgrowth),
fever, diarrhea.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
171
Sulfonamides Sulfamethoxazole (SMX), sulfisoxazole, triple sulfas, sulfadiazine.
Mechanism PABA antimetabolites inhibit dihydropteroate synthase. Bacteriostatic.
Clinical use Gram-positive, gram-negative, Nocardia, Chlamydia. Triple sulfas or SMX for simple UTI.
Toxicity Hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity (tubulointerstitial
nephritis), kernicterus in infants, displace other drugs from albumin (e.g., warfarin).
Trimethoprim
Mechanism Inhibits bacterial dihydrofolate reductase. Bacteriostatic. Trimethoprim = TMP:
Clinical use Used in combination with sulfonamides “Treats Marrow Poorly.”
(trimethoprim-sulfamethoxazole [TMP-SMX]),
causing sequential block of folate synthesis.
Combination used for recurrent UTIs, Shigella,
Salmonella, Pneumocystis carinii pneumonia.
Toxicity Megaloblastic anemia, leukopenia, granulocytopenia.
(May alleviate with supplemental folinic acid.)
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
– Sulfonamides
Dihydrofolic acid
Tetrahydrofolic acid (THF)
THF cofactors
Purines
Dihydropteroate
synthase
– Trimethoprim,
pyrimethamine
Dihydrofolate
reductase
Pteridine + PABA
Thymine Methionine
Glycine
f-met – tRNA
DNA
RNA
DNA
Proteins
Dihydropteroic acid
(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th ed. Stamford, CT: Appleton
& Lange, 1997:762.)
172
MICROBIOLOGY AND IMMUNOLOGY-ANTIMICROBIALS (continued)
Fluoroquinolones Ciprofloxacin, norfloxacin, ofloxacin, sparfloxacin, moxifloxacin, gatifloxacin, enoxacin
(fluoroquinolones), nalidixic acid (a quinolone).
Mechanism Inhibit DNA gyrase (topoisomerase II). Bactericidal. FluoroquinoLONES hurt
Clinical use Gram-negative rods of urinary and GI tracts attachments to your
(including Pseudomonas), Neisseria, some gram- BONES.
positive organisms.
Toxicity GI upset, superinfections, skin rashes, headache,
dizziness. Contraindicated in pregnant women and
in children because animal studies show damage to
cartilage. Tendonitis and tendon rupture in adults;
leg cramps and myalgias in kids.
Metronidazole
Mechanism Forms toxic metabolites in the bacterial cell.
Bactericidal.
Clinical use Antiprotozoal. Giardia, Entamoeba, Trichomonas, GET on the Metro!
Gardnerella vaginalis, anaerobes (Bacteroides, Anaerobic infection below
Clostridium). Used with bismuth and the diaphragm.
amoxicillin (or tetracycline) for “triple therapy”
against H. pylori.
Toxicity Disulfiram-like reaction with alcohol; headache,
metallic taste.
Polymyxins Polymyxin B, polymyxin E. ‘MYXins MIX up membranes.
Mechanism Bind to cell membranes of bacteria and disrupt
their osmotic properties. Polymyxins are
cationic, basic proteins that act like detergents.
Clinical use Resistant gram-negative infections.
Toxicity Neurotoxicity, acute renal tubular necrosis.
Anti-TB drugs Streptomycin, Pyrazinamide, Isoniazid (INH), INH-SPIRE (inspire).
Rifampin, Ethambutol. Isoniazid (INH) used alone for
Cycloserine (2nd-line therapy). TB prophylaxis; all used in
combination for TB
treatment.
All are hepatotoxic.
Isoniazid (INH)
Mechanism . synthesis of mycolic acids. INH Injures Neurons and
Clinical use Mycobacterium tuberculosis. The only agent used Hepatocytes.
as solo prophylaxis against TB. Different INH half-lives in fast
Toxicity Hemolysis if G6PD deficient, neurotoxicity, vs. slow acetylators.
hepatotoxicity, SLE-like syndrome.
Pyridoxine (vitamin B6) can prevent
neurotoxicity.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
173
Rifampin
Mechanism Inhibits DNA-dependent RNA polymerase. Rifampin’s 4 R’s:
Clinical use Mycobacterium tuberculosis; delays resistance to RNA polymerase inhibitor
dapsone when used for leprosy. Used for Revs up microsomal P-450
meningococcal prophylaxis and Red/orange body fluids
chemoprophylaxis in contacts of children with Rapid resistance if used
Haemophilus influenzae type B. alone
Toxicity Minor hepatotoxicity and drug interactions
(. P-450).
Resistance mechanisms for various antibiotics
Drug Most common mechanism
Penicillins/ ß-lactamase cleavage of ß-lactam ring
cephalosporins
Aminoglycosides Modification via acetylation, adenylation, or phosphorylation
Vancomycin Terminal D-ala of cell wall component replaced with D-lac; . affinity.
Chloramphenicol Modification via acetylation
Macrolides Methylation of rRNA near erythromycin’s ribosome-binding site
Tetracycline . uptake or . transport out of cell
Sulfonamides Altered enzyme (bacterial dihydropteroate synthetase), . uptake, or . PABA synthesis
Nonsurgical antimicrobial prophylaxis
Meningococcal Rifampin (drug of choice), minocycline.
infection
Gonorrhea Ceftriaxone.
Syphilis Benzathine penicillin G.
History of TMP-SMX.
recurrent UTIs
Pneumocystis carinii TMP-SMX (drug of choice), aerosolized pentamidine.
pneumonia
Endocarditis with Penicillins.
surgical or dental
procedures
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
174
MICROBIOLOGY AND IMMUNOLOGY-ANTIMICROBIALS (continued)
Antifungal therapy
Amphotericin B
Mechanism Binds ergosterol (unique to fungi); forms membrane Amphotericin “tears” holes in
pores that allow leakage of electrolytes and the fungal membrane by
disrupt homeostasis. forming pores.
Clinical use Used for wide spectrum of systemic mycoses.
Cryptococcus, Blastomyces, Coccidioides,
Aspergillus, Histoplasma, Candida, Mucor
(systemic mycoses). Intrathecally for fungal
meningitis; does not cross blood-brain barrier.
Toxicity Fever/chills (“shake and bake”), hypotension,
nephrotoxicity, arrhythmias (“amphoterrible”).
Nystatin
Mechanism Binds to ergosterol, disrupting fungal membranes. Too toxic for systemic use.
Clinical use “Swish and swallow” for oral candidiasis (thrush); topical for diaper rash or vaginal
candidiasis.
Fluconazole, ketoconazole, clotrimazole, miconazole, itraconazole, voriconazole
Mechanism Inhibit fungal steroid (ergosterol) synthesis.
Clinical use Systemic mycoses. Fluconazole for cryptococcal meningitis in AIDS patients and candidal
infections of all types (i.e., yeast infections). Ketoconazole for Blastomyces, Coccidioides,
Histoplasma, Candida albicans; hypercortisolism.
Toxicity Hormone synthesis inhibition (gynecomastia), liver dysfunction (inhibits cytochrome
P-450), fever, chills.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
(Adapted, with permission, from Katzung BG, Trevor AJ. USMLE Road Map: Pharmacology, 1st ed. New York: McGraw-Hill, 2003:120.)
Blocked by azoles
Blocked by
flucytosine
Disrupted by
griseofulvin
Ergosterol Lanosterol
Nucleic
acids
Purines
Microtubules
Precursors
Cytoplasmic membrane
Blocked by terbinafine
Squalene
Polyenes form
artificial pores
Flucytosine
Mechanism Inhibits DNA synthesis by conversion to fluorouracil, which competes with uracil.
Clinical use Used in systemic fungal infections (e.g., Candida, Cryptococcus).
Toxicity Nausea, vomiting, diarrhea, bone marrow suppression.
Caspofungin
Mechanism Inhibits cell wall synthesis.
Clinical use Invasive aspergillosis.
Toxicity GI upset, flushing.
Terbinafine
Mechanism Inhibits the fungal enzyme squalene epoxidase.
Clinical use Used to treat dermatophytoses (especially onychomycosis).
Griseofulvin
Mechanism Interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing
tissues (e.g., nails).
Clinical use Oral treatment of superficial infections; inhibits growth of dermatophytes (tinea,
ringworm).
Toxicity Teratogenic, carcinogenic, confusion, headaches, . warfarin metabolism.
Antiviral chemotherapy
175
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
(Adapted, with permission, from Katzung BG, Trevor AJ. USMLE Road Map: Pharmacology, 1st ed. New York: McGraw-Hill, 2003:120.)
Viral
adsorption
Viral
release
Penetration
Uncoating
Early protein
synthesis
Nucleic acid
synthesis
Late protein
synthesis and
processing
Packaging
and
assembly
Mammalian
cell
Blocked by
.-globulins
(nonspecific) Blocked by
amantadine
(influenza A)
Blocked by
methimazole
(variola);
protease inhibitors
Blocked by
fomivirsen
(CMV)
Purine, pyrimidine
analogs; reverse
transcriptase
inhibitors
Blocked by
rifampin
(vaccinia)
Blocked by
neuraminidase
inhibitors
(influenza)
176
MICROBIOLOGY AND IMMUNOLOGY-ANTIMICROBIALS (continued)
Amantadine
Mechanism Blocks viral penetration/uncoating; may buffer pH “A man to dine” takes off his
of endosome. Also causes the release of dopamine coat.
from intact nerve terminals. Amantadine blocks influenza
Clinical use Prophylaxis and treatment for influenza A; A and rubellA and
Parkinson’s disease. causes problems with the
Toxicity Ataxia, dizziness, slurred speech. cerebellA.
Rimantidine is a derivative
with fewer CNS side effects.
Zanamivir, oseltamivir
Mechanism Inhibit influenza neuraminidase.
Clinical use Both influenza A and B.
Ribavirin
Mechanism Inhibits synthesis of guanine nucleotides by competitively inhibiting IMP dehydrogenase.
Clinical use RSV, chronic hepatitis C.
Toxicity Hemolytic anemia. Severe teratogen.
Acyclovir
Mechanism Preferentially inhibits viral DNA polymerase when phosphorylated by viral thymidine
kinase.
Clinical use HSV, VZV, EBV. Mucocutaneous and genital herpes lesions. Prophylaxis in
immunocompromised patients.
Toxicity Delirium, tremor, nephrotoxicity.
Ganciclovir
Mechanism Phosphorylation by viral kinase; preferentially inhibits CMV DNA polymerase.
Clinical use CMV, especially in immunocompromised patients.
Toxicity Leukopenia, neutropenia, thrombocytopenia, renal toxicity. More toxic to host enzymes
than acyclovir.
Foscarnet
Mechanism Viral DNA polymerase inhibitor that binds to the FOScarnet = pyroFOSphate
pyrophosphate binding site of the enzyme. Does analog.
not require activation by viral kinase.
Clinical use CMV retinitis in immunocompromised patients
when ganciclovir fails; acyclovir-resistant HSV.
Toxicity Nephrotoxicity.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
177
HIV therapy
Protease inhibitors Saquinavir, ritonavir, indinavir, nelfinavir, Never (navir) tease a pro-
amprenavir. pro-tease inhibitors.
Mechanism Inhibit assembly of new virus by blocking protease
enzyme.
Toxicity GI intolerance (nausea, diarrhea), hyperglycemia,
lipid abnormalities, thrombocytopenia (indinavir).
Reverse transcriptase
inhibitors
Nucleosides Zidovudine (AZT), didanosine (ddI), zalcitabine (ddC),
stavudine (d4T), lamivudine (3TC), abacavir.
Non-nucleosides Nevirapine, delavirdine, efavirenz.
Mechanism Preferentially inhibit reverse transcriptase of HIV;
prevent incorporation of viral genome into host
DNA.
Toxicity Bone marrow suppression (neutropenia, anemia),
peripheral neuropathy, lactic acidosis
(nucleosides), rash (non-nucleosides),
megaloblastic anemia (AZT).
Clinical use Highly active antiretroviral therapy (HAART)
generally entails combination therapy with
protease inhibitors and reverse transcriptase
inhibitors. Initiated when patients have low CD4
counts (< 500 cells/mm3) or high viral load. AZT
is used during pregnancy to reduce risk of fetal
transmission.
Interferons
Mechanism Glycoproteins from human leukocytes that block various stages of viral RNA and DNA
synthesis.
Clinical use IFN-a–chronic hepatitis B and C, Kaposi’s sarcoma. IFN-ß–MS. IFN-.–NADPH
oxidase deficiency.
Toxicity Neutropenia.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
178
MICROBIOLOGY AND IMMUNOLOGY-ANTIMICROBIALS (continued)
Antiparasitic drugs
Ivermectin Onchocerciasis (rIVER blindness treated with IVERmectin).
Mebendazole/ Nematode/roundworm (e.g., pinworm, whipworm) infections.
thiabendazole
Pyrantel pamoate Giant roundworm (Ascaris), hookworm (Necator/Ancylostoma), pinworm (Enterobius).
Praziquantel Trematode/fluke (e.g., schistosomes, Paragonimus, Clonorchis) and cysticercosis.
Niclosamide Cestode/tapeworm (e.g., Diphyllobothrium latum, Taenia species) infections except
cysticercosis.
Pentavalent antimony Leishmaniasis.
Chloroquine, quinine, Malaria.
mefloquine,
atovaquone,
proguanil
Primaquine Latent hypnozoite (liver) forms of malaria (Plasmodium vivax, P. ovale).
Metronidazole Giardiasis, amebic dysentery (Entamoeba histolytica), bacterial vaginitis (Gardnerella
vaginalis), Trichomonas.
TMP-SMX, Pneumocystis carinii pneumonia prophylaxis.
pentamidine
Nifurtimox Chagas’ disease, American trypanosomiasis (Trypanosoma cruzi).
Suramin African trypanosomiasis (sleeping sickness).
Antibiotics to avoid Sulfonamides–kernicterus. SAFE Moms Take Really
in pregnancy Aminoglycosides–ototoxicity. Good Care.
Fluoroquinolones–cartilage damage.
Erythromycin–acute cholestatic hepatitis in mom
(and clarithromycin–embryotoxic).
Metronidazole–mutagenesis.
Tetracyclines–discolored teeth, inhibition of bone
growth.
Ribavirin (antiviral)–teratogenic.
Griseofulvin (antifungal)–teratogenic.
Chloramphenicol–“gray baby.”
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
179
MICROBIOLOGY AND IMMUNOLOGY-IMMUNOLOGY
Lymph node A 2° lymphoid organ that has many afferents, 1 or more efferents. Encapsulated, with
trabeculae. Functions are nonspecific filtration by macrophages, storage/proliferation
of B and T cells, antibody production.
Follicle Site of B-cell localization and
proliferation. In outer cortex.
1° follicles are dense and
dormant. 2° follicles have
pale central germinal
centers and are active.
Medulla Consists of medullary cords
(closely packed lymphocytes
and plasma cells) and
medullary sinuses.
Medullary sinuses
communicate with efferent
lymphatics and contain
reticular cells and macrophages.
Paracortex Houses T cells. Region of cortex between Paracortex enlarges in an
follicles and medulla. Contains high endothelial extreme cellular immune
venules through which T and B cells enter from response (i.e., viral).
blood. In an extreme cellular immune response,
paracortex becomes greatly enlarged. Not well
developed in patients with DiGeorge syndrome.
Lymph drainage
Right lymphatic duct Drains right arm and right half of head.
Thoracic duct Drains everything else.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
Trabecula
Subcapsular
sinus Capillary
supply
Paracortex
(T cells)
Capsule Afferent
lymphatic
Postcapillary
(high endothelial)
venules
Medullary
sinus (macrophages)
Efferent
lymphatic
Vein
Medullary
cords (plasma
cells)
Follicle
of cortex
Artery (B cells)
180
MICROBIOLOGY AND IMMUNOLOGY-IMMUNOLOGY (continued)
Sinusoids of spleen Long, vascular channels in red pulp with fenestrated T cells are found in the
“barrel hoop” basement membrane. Macrophages periarterial lymphatic sheath
found nearby. (PALS) and in the red pulp
of the spleen. B cells are
found in follicles within
the white pulp of the spleen.
Thymus Site of T-cell maturation. Encapsulated. From Think of the Thymus as
epithelium of 3rd branchial pouches. “finishing school” for T cells.
Lymphocytes of mesenchymal origin. Cortex They arrive immature and
is dense with immature T cells; medulla is pale “dense” in the cortex; they
with mature T cells and epithelial reticular cells are mature in the medulla.
and contains Hassall’s corpuscles. Positive selection
(MHC restriction) and negative selection
(nonreactive to self) occur at the corticomedullary
junction.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Red pulp
(RBCs)
Germinal
center
(B cells)
PALS (T cells)
Marginal zone (APCs)
Venous drainage
Central
arteriole
Section of white pulp
Arterial supply
(Adapted, with permission, from Janeway CA, Travers P, Walport M, Capra JD. Immunobiology: The Immune
System in Health and Disease, 4th ed. New York: Garland, 1999.)
181
Differentiation Th1 cells (produce IL-2 and .-interferon)–activate macrophages (increase killing
of B and T cells efficiency of intracellular bacteria) and Tc cells.
Th2 cells (produce IL-4 and IL-5)–help B cells make antibody (B = 2nd letter of alphabet).
*The human cell that produces the IL-4 that induces naive helper T cells to become Th2 cells has not been identified.
Major function of Antibody-mediated immunity (B cells) Cell-mediated immunity (T cells)
B cells and T cells Host defense against infection (opsonize bacteria, Host defense against infection
neutralize toxins and viruses) (especially Mycobacterium
tuberculosis, virus-infected
cells, and fungi)
Allergy (e.g., hay fever, type I hypersensitivity) Allergy (e.g., poison oak, type IV
hypersensitivity)
Autoimmunity Graft and tumor rejection
Regulation of antibody response
(help and suppression)
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
Naive
helper
T cell
(Th0)
Macrophage
IL-12
IL-12-
induced
pathway
IL-4-
induced
pathway
.-
interferon IL-2 IL-4
IL-5
IL-4
* * See legend
Th1
cell
Th2
cell
Cell-mediated immunity Antibody-mediated immunity
B
cell
Activated
macrophage
Activated
cytotoxic
(CD8) cell
Plasma
cell
Microorganisms
(Adapted, with permission, from Levinson W. Medical Microbiology and Immunology: Examination and
Board Review, 8th ed. New York: McGraw-Hill, 2004:398.)
(Adapted, with permission, from Levinson W, Jawetz E. Medical Microbiology and Immunology: Examination
and Board Review, 6th ed. New York: McGraw-Hill, 2000:337.)
182
MICROBIOLOGY AND IMMUNOLOGY-IMMUNOLOGY (continued)
MHC I and II MHC–major histocompatibility complex. Consists Class I–1 polypeptide, with
of 3 class I genes (A, B, C) and 3 class II genes (DP, ß2-microglobulin.
DQ, DR). All nucleated cells have MHC I Class II–2 polypeptides, an
proteins. a and a ß chain.
Antigen-presenting cells (e.g., macrophages and
dendritic cells) have MHC II and MHC I proteins.
Class II are the main determinants of organ rejection.
MHC I antigen loading occurs in RER (viral antigens).
MHC II antigen loading occurs in acidified endosome.
T-cell glycoproteins Helper T cells have CD4, which binds to MHC II Product of CD and MHC = 8
on antigen-presenting cells. Cytotoxic T cells (CD4 × MHC II = 8 = CD8
have CD8, which binds to MHC I on virus- × MHC I).
infected cells. CD3 complex–cluster of
polypeptides associated with
a T-cell receptor. Important
in signal transduction.
Antigen-presenting cells:
1. Macrophage
2. B cell
3. Dendritic cell
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Peptide-binding
groove
Cell membrane
Class II MHC molecule
a ß
Peptide-binding
groove
Cell membrane
a
MHC class I molecule
ß2 microglobulin
IgM
Virus Virus
Plasma
cell
Antibody
TCR
TCR
IL-2
IL-2, IL-4, IL-5
IL-2
IL-1
B
cell
CD8
cell
CD4
cell
Class II MHC
Viral epitope
Viral
epitope
Cytotoxic
T cell
Helper T cell
Class I MHC
APC
Virus-infected cell
CD19
CD20
183
T-cell activation Th activation:
1. Foreign body is phagocytosed by APC
2. Foreign antigen is presented on MHC II and
recognized by TCR on Th cell
3. “Costimulatory signal” is given by interaction
of B7 and CD28
4. Th cell activated to produce IL-2 and .-interferon
Tc activation:
1. Endogenously synthesized (viral or self)
proteins are presented on MHC I and
recognized by TCR on Tc cell
2. IL-2 from Th cell activates Tc cell to kill
virus-infected cell
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
Foreign
body
Antigen
APC
TCR
Antigen
TCR
IL-2
IL-2 receptor
Th
cell
Tc
cell
Virusinfected
cell
MHC II
MHC I
B7
CD28
CD14
CD3
CD3
CD8
CD4
184
MICROBIOLOGY AND IMMUNOLOGY-IMMUNOLOGY (continued)
Antibody structure Variable part of L and H chains recognizes antigens. Constant part of H chain of IgM
and function and IgG fixes complement. Heavy chain contributes to Fc and Fab fractions. Light
chain contributes only to Fab fraction.
Fc:
Constant
Carboxy terminal
Complement-binding
(IgG + IgM only)
Carbohydrate
side chains
Antibody diversity is generated by:
1. Random “recombination” of VJ (light-chain) or VDJ (heavy-chain) genes
2. Random combination of heavy chains with light chains
3. Somatic hypermutation
4. Addition of nucleotides to DNA during “genetic recombination” by terminal deoxynucleotidyl transferase
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Interchain
disulfide
bonds
Intrachain
disulfide
bonds
Light-chain hypervariable regions
Fab
fragment
Fc
fragment
Carboxyl terminal
Amino terminal
Heavy-chain
hypervariable
regions
Hinge region
CH3
CH2
CH3
CH2
CH1
CL
CH1
CL
VL
VH
Opsonization Neutralization
Antibody promotes
phagocytosis
Antibody prevents
bacterial adherence
Antibody activates
complement, enhancing
opsonization and lysis
Membrane
attack complex
(MAC)
C3b
Complement
activation
185
Immunoglobulin Mature B lymphocytes express IgM and IgD on their surfaces. They may differentiate
isotypes by isotype switching (mediated by cytokines and CD40 ligand) into plasma cells
that secrete IgA, IgE, or IgG.
IgG Main antibody in 2° response. Most abundant. Fixes complement, crosses the placenta,
opsonizes bacteria, neutralizes bacterial toxins and viruses.
IgA Prevents attachment of bacteria and viruses to mucous membranes, does not fix
complement. Monomer or dimer. Found in secretions. Picks up secretory component
from epithelial cells before secretion.
IgM Produced in the 1° response to an antigen. Fixes complement but does not cross the
placenta. Antigen receptor on the surface of B cells. Monomer or pentamer.
IgD Unclear function. Found on the surface of many B cells and in serum.
IgE Mediates immediate (type I) hypersensitivity by inducing the release of mediators from
mast cells and basophils when exposed to allergen. Mediates immunity to worms.
Lowest concentration in serum.
Ig epitopes Allotype (polymorphism)–Ig epitope that differs
among members of same species. Can be on
light chain or heavy chain.
Isotype (IgG, IgA, etc.)–Ig epitope common to a Isotype = iso (same). Common
single class of Ig (5 classes, determined by heavy to same class.
chain).
Idiotype (specific for a given antigen)–Ig epitope Idiotype = idio (unique).
determined by antigen-binding site. Hypervariable region is
unique.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
186
MICROBIOLOGY AND IMMUNOLOGY-IMMUNOLOGY (continued)
Important cytokines
IL-1 Secreted by macrophages. Stimulates T cells, B cells, “Hot T-bone stEAk”:
neutrophils, fibroblasts, and epithelial cells to IL-1: fever (hot)
grow, differentiate, or synthesize specific products. IL-2: stimulates T cells
An endogenous pyrogen. IL-3: stimulates bone marrow
IL-2 Secreted by Th cells. Stimulates growth of helper IL-4: stimulates IgE
and cytotoxic T cells. production
IL-3 Secreted by activated T cells. Supports the growth IL-5: stimulates IgA
and differentiation of bone marrow stem cells. Has production
a function similar to GM-CSF.
IL-4 Secreted by Th cells. Promotes growth of B cells.
Enhances class switching of IgE and IgG.
IL-5 Secreted by Th cells. Promotes differentiation of B
cells. Enhances class switching of IgA. Stimulates
production and activation of eosinophils.
IL-6 Secreted by Th cells and macrophages. Stimulates
production of acute-phase reactants and
immunoglobulins.
IL-8 Major chemotactic factor for neutrophils.
IL-10 Secreted by Th2 cells. Stimulates Th2 while
inhibiting Th1.
IL-12 Secreted by B cells and macrophages. Activates NK
and Th1 cells.
.-interferon Secreted by Th cells. Stimulates macrophages.
TNF-a Secreted by macrophages. . IL-2 receptor synthesis
by Th cells. . B-cell proliferation. Attracts and
activates neutrophils. Stimulates dendritic cell
migration to lymph nodes.
Cell surface proteins
Helper T cells CD4, TCR, CD3, CD28, CD40L.
Cytotoxic T cells CD8, TCR, CD3.
B cells IgM, B7, CD19, CD20, CD40, MHC II.
Macrophages MHC II, CD14. Receptors for Fc and C3b.
NK cells Receptors for MHC I, CD16.
All cells except MHC I.
mature red cells
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
187
Complement System of proteins that interact to play a role in GM makes classic cars.
humoral immunity and inflammation. C1, C2, C3, C4–viral
Complement defends against gram-negative bacteria. neutralization.
Activated by IgG or IgM in the classic pathway, C3b–opsonization.
and activated by molecules on the surface of C3a, C5a–anaphylaxis.
microbes (especially endotoxin) in the C5a–neutrophil chemotaxis.
alternate pathway. C5b-9–cytolysis by membrane
attack complex (MAC).
Deficiency of C1 esterase
inhibitor leads to hereditary
angioedema (overactive
complement).
Deficiency of C3 leads to
severe, recurrent pyogenic
sinus and respiratory tract
infections.
Deficiency of C6-C8 leads to
Neisseria bacteremia.
Deficiency of decayaccelerating
factor (DAF)
leads to paroxysmal nocturnal
hemoglobinuria (PNH).
Interferon Interferons (a, ß, .) are proteins that place Interferes with viral protein
mechanism uninfected cells in an antiviral state. Interferons synthesis by:
induce the production of a 2nd protein that 1. a- and ß-interferons
inhibits viral protein synthesis by degrading viral inhibit viral protein
mRNA (but not host mRNA). synthesis
2. .-interferons . MHC I
and II expression and
antigen presentation
in all cells
3. Activates NK cells to
kill virus-infected cells
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
Microbial surfaces
(nonspecific
activators, e.g.,
endotoxin)
C3(H2O) + B + D C3b,Bb
(C3 convertase)
C3 C3b,Bb,C3b + C3a
(C5 convertase)
C5 C5a + MC5b MC5b,6,7
MC5b,6,7,8,9
(membrane
attack
complex)
LYSIS, CYTOTOXICITY
Antigenantibody
complexes
C1 C4b,2b
(C3 convertase)
C3 C3a + C4b,2b,3b
(C5 convertase)
C1
C4
C2
Target cell
membrane (M) C7 C9
C6 C8
Alternative
Classic
C4b,2b
Microbial surfaces
Lectin
Mannan-binding
lectin
Protease
cleaves
C2 and C4
(Adapted, with permission, from Levinson W. Medical Microbiology and Immunology: Examination and Board Review, 8th ed. New York: McGraw-
Hill, 2004:432.)
188
MICROBIOLOGY AND IMMUNOLOGY-IMMUNOLOGY (continued)
Passive vs. active immunity
Active Induced after exposure to foreign antigens. Slow After exposure to Tetanus toxin,
onset. Long-lasting protection (memory). Botulinum toxin, HBV, or
Passive Based on receiving preformed antibodies from Rabies, patients are given
another host. Rapid onset. Short life span of preformed antibodies
antibodies. (passive)–To Be Healed
Rapidly.
Antigen variation Classic examples: Some mechanisms for variation
Bacteria–Salmonella (two flagellar variants), include DNA rearrangement
Borrelia (relapsing fever), Neisseria gonorrhoeae and RNA segment
(pilus protein). rearrangement (e.g.,
Virus–influenza (major = shift, minor = drift). influenza major shift).
Parasites–trypanosomes (programmed
rearrangement).
Anergy Self-reactive T cells become nonreactive without costimulatory molecule.
B cells also become anergic, but tolerance is less complete than in T cells.
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
Hypersensitivity
Type I Anaphylactic and atopic–antigen cross-links IgE First and Fast (anaphylaxis).
on presensitized mast cells and basophils, triggering Types I, II, and III are all
release of vasoactive amines (i.e., histamine). antibody mediated.
Reaction develops rapidly after antigen exposure
due to preformed antibody. Examples include
anaphylaxis, asthma, hives, local wheal and flare.
Type II Antibody mediated–IgM, IgG bind to antigen Cy-2-toxic.
on “enemy”cell, leading to lysis (by complement) Antibody and complement lead
or phagocytosis. Examples include autoimmune to membrane attack complex
hemolytic anemia, Rh disease (erythroblastosis (MAC).
fetalis), Goodpasture’s syndrome, rheumatic fever,
Graves’ disease, bullous pemphigoid, myasthenia
gravis, ITP.
Type III Immune complex–antigen-antibody complexes Imagine an immune complex as
activate complement, which attracts neutrophils; 3 things stuck together:
neutrophils release lysosomal enzymes. Examples antigen-antibodyinclude
PAN, immune complex complement.
glomerulonephritis, SLE, rheumatoid arthritis.
Serum sickness–an immune complex disease Most serum sickness is now
(type III) in which antibodies to the foreign caused by drugs (not serum).
proteins are produced (takes 5 days). Immune Fever, urticaria, arthralgias,
complexes form and are deposited in membranes, proteinuria, lymphadenopathy
where they fix complement (leads to tissue 5-10 days after antigen
damage). More common than Arthus reaction. exposure.
Arthus reaction–a local subacute antibody-mediated Antigen-antibody complexes
hypersensitivity (type III) reaction. Intradermal cause the Arthus reaction.
injection of antigen induces antibodies, which
form antigen-antibody complexes in the skin.
Characterized by edema, necrosis, and activation
of complement. Examples include hypersensitivity
pneumonitis (farmer’s lung), thermophilic
actinomycetes.
Type IV Delayed (T-cell-mediated) type–sensitized T 4th and last–delayed. Cell
lymphocytes encounter antigen and then release mediated; therefore, it is
lymphokines (leads to macrophage activation). not transferable by serum.
4 T’s = T lymphocytes,
Transplant rejections,
TB skin tests, Touching
(contact dermatitis).
ACID:
Anaphylactic and Atopic
(type I)
Cytotoxic (antibody mediated)
(type II)
C* = complement Immune complex (type III)
Delayed (cell mediated)
(type IV)
189
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
………………..
………………..
………………..
………………..
………………..
………………..
………………..
………………..
………………..
Mast cell or basophil
Fc receptor
IgE
Ag
Ag
Cell C*
C*
Ag
Ag
Ag
Ag
Ag
Ag
T
cell
T
cell
190
MICROBIOLOGY AND IMMUNOLOGY-IMMUNOLOGY (continued)
Immune deficiencies
1. . production of:
B cells–Bruton’s X-linked recessive defect in a tyrosine kinase gene associated with low levels of all classes
agammaglob- of immunoglobulins. Associated with recurrent Bacterial infections after 6 months of
ulinemia age, when levels of maternal IgG antibody decline. Occurs in Boys (X-linked).
T cells–Thymic aplasia Thymus and parathyroids fail to develop owing to failure of development of the 3rd and
(DiGeorge 4th pharyngeal pouches. Presents with Tetany owing to hypocalcemia. Recurrent
syndrome) viral and fungal infections due to T-cell deficiency. Congenital defects of heart and
great vessels. 22q11 deletion.
B and T cells– Defect in early stem-cell differentiation. Presents with recurrent viral, bacterial, fungal,
severe combined and protozoal infections. May have multiple causes (e.g., failure to synthesize MHC II
immunodeficiency antigens, defective IL-2 receptors, or adenosine deaminase deficiency).
(SCID)
2. . activation of:
T cells–IL-12 Presents with disseminated mycobacterial infections.
receptor deficiency
B cells–hyper- Defect in CD40 ligand on CD4 T helper cells leads to inability to class switch. Presents
IgM syndrome early in life with severe pyogenic infections. High levels of IgM; very low levels of IgG,
IgA, and IgE.
B cells– X-linked defect in the ability to mount an IgM response to capsular polysaccharides of
Wiskott-Aldrich bacteria. Associated with elevated IgA levels, normal IgE levels, and low IgM levels.
syndrome Triad of symptoms includes recurrent pyogenic Infections, thrombocytopenic
Purpura, Eczema (WIPE).
Macrophages– Failure of .-interferon production by helper T cells. Neutrophils fail to respond to
Job’s syndrome chemotactic stimuli. Presents with recurrent “cold” (noninflamed) staphylococcal
abscesses, eczema, coarse facies, retained primary teeth, and high levels of IgE.
3. Phagocytic cell deficiency:
Leukocyte adhesion Defect in LFA-1 adhesion proteins on phagocytes. Presents early with severe pyogenic
deficiency syndrome and fungal infections and delayed separation of umbilicus.
Chédiak-Higashi Autosomal recessive. Defect in microtubular function and lysosomal emptying of
disease phagocytic cells. Presents with recurrent pyogenic infections by staphylococci and
streptococci, partial albinism, and peripheral neuropathy.
Chronic gran- Defect in phagocytosis of neutrophils owing to lack of NADPH oxidase activity or
ulomatous disease similar enzymes. Presents with marked susceptibility to opportunistic infections
with bacteria, especially S. aureus, E. coli, and Aspergillus. Diagnosis confirmed
with negative nitroblue tetrazolium dye reduction test.
4. Idiopathic dysfunction of:
T cells–chronic T-cell dysfunction specifically against Candida albicans. Presents with skin and mucous
mucocutaneous membrane Candida infections.
candidiasis
B cells–selective Deficiency in a specific class of immunoglobulins–possibly due to a defect in isotype
immunoglobulin switching. Selective IgA deficiency is the most common selective immunoglobulin
deficiency deficiency. Presents with sinus and lung infections; milk allergies and diarrhea are
common.
B cells–ataxia- Defect in DNA repair enzymes with associated IgA deficiency. Presents with cerebellar
telangiectasia problems (ataxia) and spider angiomas (telangiectasia).
MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
191
MICROBIOLOGY AND IMMUNOLOGY-IMMUNOLOGY (continued)
Autoantibodies Autoantibody Associated disorder
Antinuclear antibodies (ANA) SLE
Anti-dsDNA, anti-Smith Specific for SLE
Antihistone Drug-induced lupus
Anti-IgG (rheumatoid factor) Rheumatoid arthritis
Antineutrophil (C-ANCA, P-ANCA) Vasculitis
Anticentromere Scleroderma (CREST)
Anti-Scl-70 Scleroderma (diffuse)
Antimitochondrial 1° biliary cirrhosis
Antigliadin Celiac disease
Anti-basement membrane Goodpasture’s syndrome
Anti-epithelial cell Pemphigus vulgaris
Antimicrosomal Hashimoto’s thyroiditis
Anti-Jo-1 Polymyositis, dermatomyositis
HLA subtypes
B27 Psoriasis, Ankylosing spondylitis, Inflammatory PAIR.
bowel disease, Reiter’s syndrome.
B8 Graves’ disease, celiac sprue.
DR2 Multiple sclerosis, hay fever, SLE, Goodpasture’s.
DR3 Diabetes mellitus type 1.
DR4 Rheumatoid arthritis, diabetes mellitus type 1.
DR5 Pernicious anemia . B12 deficiency, Hashimoto’s
thyroiditis.
DR7 Steroid-responsive nephrotic syndrome.
Transplant rejection
Hyperacute rejection Antibody mediated due to the presence of preformed antidonor antibodies in the
transplant recipient. Occurs within minutes after transplantation.
Acute rejection Cell mediated due to cytotoxic T lymphocytes reacting against foreign MHCs. Occurs
weeks after transplantation. Reversible with immunosuppressants such as cyclosporin
and OKT3.
Chronic rejection Antibody-mediated vascular damage (fibrinoid necrosis); occurs months to years after
transplantation. Irreversible.
Graft-versus-host Grafted immunocompetent T cells proliferate in the irradiated immunocompromised
disease host and reject cells with “foreign” proteins, resulting in severe organ dysfunction.
Major symptoms include a maculopapular rash, jaundice, hepatosplenomegaly, and
diarrhea.
HIGH-YI E LD PRINCIPLES MICROBIOLOGY AND IMMUNOLOGY
192 MICROBIOLOGY AND IMMUNOLOGY HIGH-YI E LD PRINCIPLES
NOTES
High-Yield Clinical
Vignettes
Pharmacodynamics
Autonomic Drugs
Toxicities and Side
Effects
Miscellaneous
H I G H -Y I E L D P R I N C I P L E S I N
Pharmacology
193
“Take me, I am the drug; take me, I am hallucinogenic.”
–Salvador Dali
“I was under medication when I made the decision not to burn the tapes.”
–Richard Nixon
Preparation for questions on pharmacology is straightforward. Memorizing
all the key drugs and their characteristics (e.g., mechanisms,
clinical use, and important side effects) is high yield. Focus on understanding
the prototype drugs in each class. Avoid memorizing obscure
derivatives. Learn the “classic” and distinguishing toxicities of the major
drugs. Do not bother with drug dosages or trade names. Reviewing
associated biochemistry, physiology, and microbiology can be useful
while studying pharmacology. There is a strong emphasis on ANS,
CNS, antimicrobial, and cardiovascular agents as well as on NSAIDs.
Much of the material is clinically relevant. Newer drugs on the market
are also fair game.
194
PHARMACOLOGY-HIGH-YIELD CLINICAL VIGNETTES
28-year-old chemist presents What neurotransmitter Dopamine.
with MPTP exposure. is depleted?
Woman taking tetracycline What are the clinical Rash on sun-exposed regions of
exhibits photosensitivity. manifestations? the body.
African-American man who What is the enzyme Glucose-6-phosphate
goes to Africa develops a deficiency? dehydrogenase.
hemolytic anemia after taking
malarial prophylaxis.
Farmer presents with dyspnea, What caused this, and Insecticide poisoning; inhibition
salivation, miosis, diarrhea, what is the mechanism of acetylcholinesterase.
cramping, and blurry vision. of action?
27-year-old female with a history What do you treat it Bethanechol.
of psychiatric illness now has with?
urinary retention due to a
neuroleptic.
Patient with recent kidney What antifungal drug Ketoconazole.
transplant is on cyclosporine for would result in
immunosuppression. Requires cyclosporine toxicity?
antifungal agent for candidiasis.
Patient is on carbamazepine. What routine workup LFTs.
should always be done?
23-year-old female who is on Why? Rifampin augments estrogen
rifampin for TB prophylaxis and metabolism in the liver,
on birth control (estrogen) gets rendering it less effective.
pregnant.
PHARMACOLOGY HIGH-YI E LD PRINCIPLES
195
PHARMACOLOGY-PHARMACODYNAMICS
Pharmacokinetics
Volume of Relates the amount of drug in the body to the plasma concentration. Vd of plasma
distribution (Vd) protein-bound drugs can be altered by liver and kidney disease.
Vd = amount of drug in the body
plasma drug concentration
Clearance (CL) Relates the rate of elimination to the plasma concentration.
CL = rate of elimination of drug
plasma drug concentration
Half-life (t1/2) The time required to change the amount of drug in the body by 1/2 during elimination
(or during a constant infusion). A drug infused at a constant rate reaches about 94% of
steady state after 4 t1/2.
t1/2 =
0.7 × Vd
CL
Dosage Loading dose = Cp × Vd/F. In patients with impaired renal
calculations Maintenance dose = Cp × CL/F or hepatic function, the
where Cp = target plasma concentration loading dose remains
and F = bioavailability. unchanged, although the
maintenance dose is ..
Elimination of drugs
Zero-order elimination Rate of elimination is constant regardless of C (i.e., constant amount of drug eliminated
per unit time). Cp . linearly with time. Examples of drugs–ethanol, phenytoin, and
aspirin (at high or toxic concentrations).
First-order elimination Rate of elimination is proportional to the drug concentration (i.e., constant fraction of
drug eliminated per unit time). Cp . exponentially with time.
In drugs with first-order kinetics (see left panel above), rate of elimination is
proportional to plasma concentration (Cp); in the case of zero-order elimination
(right panel), the rate is constant and independent of concentration.
HIGH-YI E LD PRINCIPLES PHARMACOLOGY
# of half-lives 1 2 3 3.3
Concentration 50% 75% 87.5% 90%
5 units/h
elimination
rate
2.5 units/h
1.25
units/h
Time (h)
First-order elimination
Plasma concentration (Cp)
2.5 units/h
elimination rate
2.5 units/h
2.5 units/h
Time (h)
Zero-order elimination
Plasma concentration (Cp)
(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed.
Stamford, CT: Appleton & Lange, 1998:5.)
196
PHARMACOLOGY-PHARMACODYNAMICS (continued)
Phase I vs. Phase I (reduction, oxidation, hydrolysis) yields Phase I–cytochrome P-450.
phase II metabolism slightly polar, water-soluble metabolites (often Phase II–conjugation.
still active). Geriatric patients lose phase
Phase II (acetylation, glucuronidation, sulfation) I first.
yields very polar, inactive metabolites (renally
excreted).
Pharmacodynamics
PHARMACOLOGY HIGH-YI E LD PRINCIPLES
100
50
0 0
Percent of maximum effect
0.1 1.0 10 100 1000
Effect of
antagonist
Agonist plus
competitive
antagonist
Agonist
alone
Agonist dose (log scale)
A
100
50
Percent of maximum effect
0.1 1.0 10 100 1000
Agonist
plus irreversible
antagonist
Agonist
alone
Agonist dose (log scale)
B
Effect of
antagonist
(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed. Stamford, CT:
Appleton & Lange, 1998:13-14.)
Shown above are agonist dose-response curves in the presence of competitive and irreversible antagonists. Note the
use of a logarithmic scale for drug concentration. A. A competitive antagonist has an effect illustrated by the
shift of the agonist curve to the right. B. A noncompetitive antagonist shifts the agonist curve downward.
100
50
0
Percent of maximum effect
0.1 1.0 10 100 1000
Drug effect
Dose (log scale)
Kd
Drug binding
EC50
C
(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th
ed. Stamford, CT: Appleton & Lange, 1997:13.)
C. In a system with spare receptors, the EC50 is lower than the Kd, indicating that to achieve 50% of maximum
effect, < 50% of the receptors must be activated. EC50: dose causing 50% of maximal effect. Kd: concentration of
drug required to bind 50% of receptor sites.
197
Therapeutic index TD50 = median toxic dose
ED50 median effective dose
Drug development
HIGH-YI E LD PRINCIPLES PHARMACOLOGY
(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed. Stamford, CT: Appleton
& Lange, 1998:365.)
100
50
0
Percent of maximum effect
0.1 1.0 10 100 1000
Dose (log scale)
Full agonist
Partial
agonist
D
Decreased efficacy
(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th
ed. Stamford, CT: Appleton & Lange, 1997:13.)
Pharmacodynamics (continued)
D. Comparison of dose-response curves for a full agonist and a partial agonist. The partial agonist acts on the same
receptor system as the full agonist but cannot produce an equivalently large effect (it has lower maximal
efficacy) no matter how much the dose is increased. A partial agonist may be more potent (as in the figure),
less potent, or equally potent; potency is an independent factor.
In vitro
studies
Biologic
products
Chemical
synthesis
0
Years (average)
2 4 8-9 20
Animal
testing
Clinical
testing
Marketing
Generics
become
available
IND
(Investigational
New Drug)
NDA
(New Drug
Application)
(Patent expires
20 years after filing
of application)
Lead compound
Efficacy
selectivity
mechanism
Drug metabolism, safety assessment
(Postmarketing
surveillance)
(Is it safe,
pharmacokinetics?)
(Does it
work in
patients?)
Phase 1
Phase 2
(Does it work,
double blind?)
Phase 3
Phase 4
198
PHARMACOLOGY-AUTONOMIC DRUGS
Central and peripheral nervous system
PHARMACOLOGY HIGH-YI E LD PRINCIPLES
Parasympathetic
Sympathetic
Somatic
Cardiac and smooth
muscle, gland cells,
nerve terminals
Sweat glands (only
Ach in sympathetic
nervous system)
Cardiac and smooth
muscle, gland cells,
nerve terminals
Renal vascular
smooth muscle
Skeletal muscle
Medulla
Spinal
cord
ACh
N
ACh
N
ACh
N
ACh
N
ACh
N
ACh
N
ACh
M
ACh
M
Epi, NE
Adrenal medulla
D1
NE
a,ß
(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th ed. Stamford, CT: Appleton
& Lange, 1997:74.)
199
G-protein-linked 2nd messengers
Receptor G-protein class Major functions
a1 q . vascular smooth muscle contraction
a2 i . sympathetic outflow, . insulin release
ß1 s . heart rate, . contractility, . renin release, . lipolysis, . aqueous
humor formation
ß2 s Vasodilation, bronchodilation, . glucagon release
M1 q CNS
M2 i . heart rate
M3 q . exocrine gland secretions
D1 s Relaxes renal vascular smooth muscle
D2 i Modulates transmitter release, especially in brain
H1 q . nasal and bronchial mucus production, contraction of bronchioles,
pruritus, and pain
H2 s . gastric acid secretion
V1 q . vascular smooth muscle contraction
V2 s . H2O permeability and reabsorption in the collecting tubules of
the kidney
HIGH-YI E LD PRINCIPLES PHARMACOLOGY
Receptor
Lipids
PIP2
a1, M1, M3, Gq
H1, V1 IP3 [Ca2+]in
DAG Protein
kinase C
Phospholipase C
ß1, ß2, D1, Gs
H2, V2
Protein kinase A
ATP
cAMP
Receptor Adenylcyclase
a2, M2, D2
Gi
Receptor Adenylcyclase cAMP Protein kinase A
200
PHARMACOLOGY-AUTONOMIC DRUGS (continued)
Autonomic drugs
Circles with rotating arrows represent transporters; ChAT, choline acetyltransferase; ACh,
acetylcholine; AChE, acetylcholinesterase; NE, norepinephrine.
Release of NE from a sympathetic nerve ending is modulated by NE itself, acting on presynaptic a2
autoreceptors, and by ACh, angiotensin II, and other substances.
PHARMACOLOGY HIGH-YI E LD PRINCIPLES
Noradrenergic nerve terminal
ß Adrenoceptor
NE
NE
NE
Uptake 1
–
Cardiac muscle cell
(sinoatrial node)
Release-modulating
receptors
a2
Negative
feedback
A..
M1
–
+
Tyrosine
DOPA
Dopamine
CHOLINERGIC Hemicholinium NORADRENERGIC
Choline
Acetyl-CoA+Choline
ChAT
ACh
ACh
AChE
ACh
Choline
+
Acetate
Cholinoceptor
Tyrosine
Diffusion,
metabolism
–
–
–
–
+
Botulinum
–
Ca2+
+
+
Ca2+
Adrenoceptor
NE
NE
NE
Reserpine
Cocaine,
TCA
Reuptake
Guanethidine
Amphetamine
Vesamicol –
(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology:
Examination & Board Review, 5th ed. Stamford, CT: Appleton & Lange,
1998:42.)
(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed.
Stamford, CT: Appleton & Lange, 1998:42.)
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