11/23/2017

MICROBIOLOGY AND IMMUNOLOGY-BACTERIOLOGY usmle step 1 cs exam guide

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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

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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.)

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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

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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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