INFECTIOUS DISEASES Dr. S. Walmsley, Dr. A. McGeer, Dr. J. Keystone, and Dr. A. Phillips Veera Bharatwal and Ryan Foster, editors Christine Brezden, associate editor BACTERIA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 ANTIVIRALS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Non-Nucleoside Polymerase Inhibitors AEROBIC BACTERIA . . . . . . . . . . . . . . . . . . . . . . . . 3 Nucleoside Analogs Glossary of Bacterial Terms Gram Positive Cocci FUNGI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Gram Positive Bacilli Primary Pathogenic Fungi Gram Negative Cocci Opportunistic Fungi Gram Negative Bacilli ANTIFUNGALS. . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 ANAEROBIC BACTERIA. . . . . . . . . . . . . . . . . . . . . 15 Polyenes Gram Positive Cocci Imidazoles Gram Positive Bacilli Triazoles Gram Negative Bacilli PARASITES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 OTHER BACTERIA UNDETECTABLE . . . . . . . . . 17 BY GRAM STAIN PARASITES (PROTOZOA) . . . . . . . . . . . . . . . . . 40 Acid-Fast Intestinal and Vaginal Spirochetes Blood and Tissue Intracellular Parasitic Bacteria Miscellaneous PARASITES (HELMINTHS). . . . . . . . . . . . . . . . . 44 Intestinal ANTIMICROBIALS. . . . . . . . . . . . . . . . . . . . . . . . . . 20 Blood and Tissue General Principles Summary Tables ANTIPARASITICS. . . . . . . . . . . . . . . . . . . . . . . . . 50 Anti-Protozoal Drugs ANTIBACTERIALS . . . . . . . . . . . . . . . . . . . . . . . . . 22 Anti-Malarial Drugs Cell Wall Synthesis Inhibitors (-cidal) Anti-Helminthic Drugs Protein Synthesis Inhibitors - Via 50S Ribosome (-static) INFECTIONS IN THE COMPROMISED. . . . . . 52 - Via 30S Ribosome (-cidal) HOST - Via 30S Ribosome (-static) HIV and AIDS Folic Acid Metabolism Inhibitors (-static) Transplant or Leukemia/Lymphoma DNA Gyrase Inhibitors (-cidal) Febrile Neutropenia DNA-Directed RNA Polymerase Inhibitors (-cidal) DNA Complex Damaging Agents (-cidal) FEVER OF UNKNOWN ORIGIN . . . . . . . . . . . . . 58 ANTIMYCOBACTERIALS . . . . . . . . . . . . . . . . . . . . 26 Anti-Tuberculosis Drugs Anti-M. Avium-IntracellulareComplex Drugs Anti-Leprosy Drugs VIRUSES. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 27 DNA VIRUSES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Herpes Viruses Papovavirus Adenoviruses RNA VIRUSES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Picorna Viruses Orthomyxo Viruses Paramyxo Viruses Toga Viruses Rhabdo Viruses MCCQE 2000 Review Notes and Lecture Series Infectious Diseases 1 BACTERIA Notes GGrraamm PPoossiittiivvee Gram Negative capsule peptidoglycan layer cytoplasmic membrane DNA ribosomes plasmid outer membrane (with lipopolysaccarides) flagellum Figure 1. General Schematic of Bacterial Structure Major Shapes Complex Formations cocci clusters bacilli or rods chains spiral forms diplococci pleomorphic Figure 2. Bacterial Morphology Drawings by Muyuki Fukuma GLOSSARY OF BACTERIAL TERMS Virulence Factors o Flagella • protein filament tails that propel the bacteria o Pili • shorter than flagella, serve as adherence factors • some bacteria use sex pili for reproduction o Capsules • protective layer surrounding cell membranes, usually made of secreted carbohydrate residues Endospores o metabolically dormant forms of bacteria, may lie dormant for years • only Bacillusand Clostridium Toxins o Exotoxins • proteins released by bacteria that cause disease independent of the bacteria • neurotoxins act on nerves or motor endplates • enterotoxins act on the GI, etc... o Endotoxins • normal part of the bacterium that may be shed while living, or released during cell lysis causing disease processes (i.e. septic shock) Infectious Diseases 2 MCCQE 2000 Review Notes and Lecture Series AEROBIC BACTERIA Notes GRAM POSITIVE COCCI Staphylococcusaureus(S.aureus) o microbiology • Gram positive, catalase-positive cocci in grape-like clusters/tetrads • its production of catalase differentiates it from Streptococcus • coagulase-positive more virulent than coagulase-negative strains o mode of transmission • normal flora of human skin, respiratory and gastrointestinal tracts • colonizes axilla, perineum and nasal mucosa; 40-50% of healthy adults are colonized in anterior nares • person-to-person transmission and via contaminated fomites • risk factors for infection include: broken skin, young, old, foreign bodies • important cause of hospital-acquired infections o clinical features EXOTOXIN DEPENDENT • staphylococcal gastroenteritis (enterotoxin) • sudden onset of vomiting and diarrhea • associated with cream, ham, poultry • toxic shock syndrome (TSS toxin-1) • from focal infections and/or colonization • sudden onset of high fever, nausea and vomiting, watery diarrhea • desquamation of skin on palms and soles • hypotension, renal/liver dysfunction • associated with tampon use/nasal packing • scalded skin syndrome (exfoliative toxin) • generalized desquamation and bullae formation • resembles massive scalding • usually neonates with infection of severed umbilicus or children with skin infections DIRECT INVASION • abscess formation • acute inflammation and abscess formation involving many extracellular toxins (e.g. coagulase, hemolysin, leucocidin, staphylokinase, etc...) • skin, soft tissue infections are very frequent • folliculitis, cellulitis, mastitis, wound infections (most common cause) • furuncles (boils), carbuncles (cluster of boils) • impetigo (contagious pyoderma) • bacteremia • metastatic focal infection in 15% if undertreated • endocarditis is a complication • endocarditis • can affect normal valves • a common cause of endocarditis in drug-addicts • tricuspid valve involvement unique to IV drug users • osteomyelitis • often history of preceding skin infection (50%), or trauma • septic arthritis • pneumonia • uncommon but severe • often occurs after influenza infection or in those with COPD or chronic bronchitis • acute bacterial meningitis (uncommon) o diagnosis (applicable to all Staphylococcusstrains) • specimens: surface swab, blood, pus, tracheal aspirate or CSF for culture • smears of pus or sputum • catalase and coagulase tests o treatment • 95% are penicillin-resistant (beta-lactamase production) • beta-lactamase-resistant penicillins (e.g. cloxacillin), cephalosporins, or clindamycin are drugs of choice • minor skin infections may be treated without oral/IV antibiotics (i.e. drainage, warm saline soaks +/– topical bacitracin or fusidic acid) Methicillin-Resistant Staphyloccusaureus(MRSA) o resistance to methicillin and nafcillin via change in penicillin-binding proteins • often in hospitals, transmitted by health-care workers MCCQE 2000 Review Notes and Lecture Series Infectious Diseases 3 AEROBIC BACTERIA Notes . . . CONT. o infections require IV vancomycin • eradication with topical mupirocin to nares and washing with chlorhexidine soap • contact isolation should be enforced Staphylococcusepidermidis(S.epidermidis) o microbiology • Gram positive cocci, catalase-positive, coagulase negative, sensitive to novobiocin o mode of transmission • colonizes skin ubiquitously and intestinal tract • person-to-person transmission o pathogenic mechanisms • adheres to prosthetic surfaces using slime layer • highly resistant to antibiotics o clinical features • foreign body infections: prosthetic joints, prosthetic heart valves, shunts, catheters, intravenous lines, intravascular grafts • frequent contaminant in blood cultures o treatment • vancomycin is drug of choice (for serious infections) since resistant to multiple antibiotics • positive cultures may represent contamination (i.e. one positive blood culture bottle of one set) Staphylococcussaprophyticus(S.saprophyticus) o microbiology • coagulase-negative, urease-positive, novobiocin-resistant o clinical features • second most common cause of simple cystitis in sexually active women (after E. coli) o treatment • penicillin Streptococci o microbiology • cocci in chains or pairs • catalase-negative (vs. Staph. catalase-positive) • hemolytic patterns on sheep blood agar: alpha (green partially-hemolyzed), beta (clear-hemolyzed), or gamma (non-hemolytic) • also grouped based on cell-wall carbohydrates (Lancefield groups A, B, D, etc...) Group A Streptococci(GAS or S.pyogenes) o microbiology • beta-hemolytic • sensitive to bacitracin o mode of transmission • colonizes pharynx (15% of children are carriers) • person-to-person transmission o pathogenic mechanisms • pili for attachment to epithelial cells • M protein on cell wall resists phagocytosis • production of toxic enzymes such as DNAse, hyaluronidase, streptokinases, streptolysins o clinical features MILD INFECTIONS • tonsillo-pharyngitis • purulent exudate on tonsils, fever > 38ºC, tender swollen anterior cervical lymph nodes, and absence of cough • 40-60% of patients with all 4 criteria have GAS pharyngitis • diagnose with throat culture or rapid antigen test • follow-up: negative rapid test with culture • skin, soft tissue, and wound infections • erysipelas, impetigo, cellulitis, lymphangitis SEVERE INFECTIONS • scarlet fever (erythrogenic/pyrogenic toxin) • pharyngitis, fever, erythema, desquamation of palms and soles, “strawberry” tongue Infectious Diseases 4 MCCQE 2000 Review Notes and Lecture Series AEROBIC BACTERIA Notes . . . CONT. • necrotizing fasciitis • severe pain out of proportion to lesion in early stages • fever, well-demarcated expanding area of erythema, hemorrhages, blisters, bullous and gangrenous skin lesions • rapid progression • renal failure • streptococcal toxic shock syndrome (TSS toxin) • fever, shock, rash or bullous skin lesion • early renal failure, thrombocytopenia • risk factors: minor trauma, surgery, preceding viral illness (chicken pox) • bacteremia (rare) o complications SUPPURATIVE • local extension and invasion NON-SUPPURATIVE (ANTIBODY-MEDIATED) - specific to GAS • rheumatic fever • rare but recent resurgence • Jones major criteria: myocarditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules • 10-20 years after infection, may develop permanent heart valve damage • acute post-streptococcal glomerulonephritis (PSGN) • tea-colored urine following streptococcal skin or pharyngeal infection o diagnosis (applicable to all streptococcal strains) • specimens: throat swab, pus, blood for culture • smears from pus; smears from throat swabs are never helpful because Strep. viridanswhich are always present have the same appearance as GAS • antibody detection tests • serological tests; e.g. antibodies to GAS antigens - antistreptolysin O (ASO) o treatment • penicillin V or G • erythromycin if allergic to penicillin • treatment of pharyngitis reduces the chance of rheumatic fever but not PSGN Group B Streptococci(S.agalactiae) o microbiology • beta-hemolytic o mode of transmission • colonizes large intestine, vagina (25% of women) • person-to-person and vertical transmission o clinical features • perinatal infections (majority: think Group B for BABY) • puerperal sepsis • septic abortion, chorioamnionitis • neonatal sepsis (< 10 days old), neonatal meningitis (> 10 days old), neonatal pneumonia • bacteremia and soft tissue infections in the elderly and patients with chronic disease o diagnosis • routine vaginal/rectal cultures in late third trimester (36-37 weeks) • if positive culture, give prophylactic antibiotics to high-risk mothers o treatment • penicillin or ampicillin Group D Streptococci/Enterococci o microbiology • beta-, alpha-, or gamma-hemolytic • all Enterococciare Group D Streptococci • not all Group D Streptococciare Enterococci • major species: Enterococcus faecalisand Enterococcus faecium o reservoir/mode of transmission • colonize intestinal tract and genitourinary tract • person-to-person transmission o clinical features • subacute bacterial endocarditis • urinary tract, hepatobiliary tract, intra-abdominal infections • wound and decubitus ulcer infection MCCQE 2000 Review Notes and Lecture Series Infectious Diseases 5 AEROBIC BACTERIA Notes . . . CONT. o treatment • Enterococcionly inhibited, not killed by penicillin • inherently resistant to cephalosporins • for most urinary tract and minor soft tissue infections, use ampicillin or TMP/SMX • for more severe infections, use combination of ampicillin and aminoglycoside (for synergy) or vancomycin + aminoglycoside Vancomycin-Resistant Enterococci(VRE) • resistance via change in peptidoglycan component from D-alanine to D-lactate • drugs of choice still ampicillin and gentamycin • sensitivity to teicoplanin depends on phenotype • new streptogramin therapy under investigation Streptococcispecies ViridansStreptococci(S.mutans,S.mitis) o microbiology • non-Lancefield Group Streptococci • alpha-hemolytic (green on agar) o mode of transmission • normal oropharyngeal flora o pathogenic mechanisms • frequently seed the bloodstream during dental manipulation (tooth brushing) • produces sticky dextrans that help it adhere to surfaces and other adherent mechanisms - can cause dental plaques o clinical features • most common cause of subacute bacterial endocarditis • affects abnormal heart valves • S. mutanscauses dental caries o treatment • penicillin +/– aminoglycoside S.pneumoniae(pneumococcus) o microbiology • non-Lancefield Group Streptococci • alpha-hemolytic • Gram positive cocci in pairs • growth inhibited by optochin on agar (to differentiate from S. viridans) • 84 serotypes based on capsular antigen, all are pathogenic • immunity to one type not cross-protective o mode of transmission • colonizes nasopharynx, person-to-person, airborne o pathogenic mechanisms • polysaccharide capsule resists phagocytosis o risk factors • alcoholics, splenectomy, sickle-cell anemia, HIV, hypogammaglobulinemia, multiple myeloma, Hodgkin's Disease o clinical features • pneumonia • often preceded by upper respiratory tract infection (e.g. influenza virus) • sudden onset of shaking chills, pleuritic pain, rusty sputum, lobar involvement (dense consolidation on CXR) • sterile pleural effusion (50%) • meningitis • second most common cause of bacterial meningitis in adults • can occur after pneumonia, sinusitis, or skull fracture • bacteremia (25%) • otitis media (in children) o treatment • polysaccharide vaccine (“pneumovax”) • protective against the 23 most common capsular antigens o recommended for elderly, immunocompromised, splenectomized and those with cardiopulmonary, liver or kidney disease, or sickle-cell anemia • antibiotic treatment • penicillin or erythromycin • second generation cephalosporin (e.g. cefuroxime) Infectious Diseases 6 MCCQE 2000 Review Notes and Lecture Series AEROBIC BACTERIA Notes . . . CONT. Penicillin-Resistant S.pneumoniae • in Toronto 7% resistance in adults, 20% resistance in children • resistance via change in penicillin-binding proteins • for CNS infection: combine vancomycin and cefotaxime until sensitivities available GRAM POSITIVE BACILLI Corynebacteriumdiphtheriae o microbiology • club-shaped rods with beaded or barred appearance • non-spore-forming o mode of transmission • colonizes pharynx • person-to-person transmission via airborne respiratory droplets o pathogenic mechanisms • pseudomembrane forms in the upper respiratory tract which serves as a base from which organism secretes exotoxin • disease caused by airway obstruction or effect of exotoxin on heart and nervous system (not invasion) o clinical features • mild sore throat, fever, nasal discharge, hoarseness • tenacious gray membrane over the tonsils and pharynx • myocarditis (10%) • neural involvement (peripheral nerve palsies, Guillain-Barré-like syndrome) o diagnosis • immunity detected by Schick skin test o treatment (see Pediatrics Notes) • antitoxin + penicillin or erythromycin • prevent by immunization with diphtheria toxoid Listeriamonocytogenes o microbiology • non-spore-forming, tumbling motility • beta-hemolytic on blood agar o mode of transmission • ingestion of soft cheese (foodborne outbreaks) • from soil, decaying matter, feces • vertical transmission (vaginal delivery) o pathogenic mechanisms • facultative intracellular parasite o clinical features • usually < 1 or > 55 years of age ANTENATALLY • neonatal meningitis and bacteremia • infection is associated with abortions and premature deliveries IN THE ADULT POPULATION • meningitis in immunosuppressed patients (e.g. alcoholics, pregnancy, diabetics, steroid or immunosuppressive medication users) • 3rd most common cause of adult meningitis • bacteremia, gastroenteritis o treatment • ampicillin or TMP/SMX Bacilluscereus o microbiology • spore-forming, motile o mode of transmission • ubiquitous organism • transmission via endospores, usually from food such as fried rice o pathogenic mechanisms • enterotoxins and pyrogenic toxin o clinical features • food poisoning: nausea, vomiting, and diarrhea • opportunistic infections (rare) o diagnosis • culture specimen from suspected food source MCCQE 2000 Review Notes and Lecture Series Infectious Diseases 7 AEROBIC BACTERIA Notes . . . CONT. o treatment • resistant to beta-lactam antibiotics • clindamycin or vancomycin • no antibiotic treatment for food poisoning since caused by the pre-formed enterotoxin Nocardiaasteroides,Nocardiafarcinica o microbiology • elongated rods that branch at acute angles and often show irregular staining • weakly acid-fast o mode of transmission • commonly found in the environment (soil) • transmitted by inhalation • not person-to-person transmission o clinical features • pulmonary nocardiosis • ~50% have underlying disease or compromised immunity due to treatment (e.g. leukemia, lymphoma, COPD, chronic steroid use) • can disseminate to distant organs (e.g. brain) where multifocal abscesses are often produced o diagnosis • Gram stain, acid-fast stain, cultures o treatment • TMP/SMX and surgical drainage GRAM NEGATIVE COCCI Neisseriameningitidis(Meningococcus) o microbiology • diplococci resembling two kidney beans • 9 serogroups based on capsular polysaccharides (A, B, C, W, Y) • obligate human pathogen o mode of transmission • colonizes pharynx (15%) • droplet transmission • endemic in areas; periodic epidemics • risk factors: splenectomy, complement deficiency (C8, C9), hypogammaglobulinemia • high risk people: closed populations, e.g. army recruits (carrier rates > 40%) o pathogenic mechanisms • capsule is antiphagocytic • pili for attachment to epithelial cells • toxic effects of LPS o clinical features • asymptomatic colonization in the nasopharynx • meningitis • fever, vomiting, nuchal rigidity, lethargy • petechial rash, hemorrhages, thrombocytopenia • meningococcemia • fever, petechial rash, hemorrhages, thrombocytopenia • hypotension • fulminant meningococcemia (Waterhouse-Friedrichsen Syndrome) • bilateral adrenal hemorrhage • petechial rash, hemorrhages, thrombocytopenia, purpura, gangrene • hypotension o diagnosis • Gram stain and culture of CSF • antigen detection (latex agglutination in CSF) o treatment • polysaccharide vaccine (used in epidemics); A, C, Y, W, B135 covered • antibiotics • penicillin, third generation cephalosporins • rifampin, minocycline, ciprofloxacin used prophylactically for close contacts Neisseriagonorrhea(Gonococcus/GC) o microbiology • diplococci Infectious Diseases 8 MCCQE 2000 Review Notes and Lecture Series AEROBIC BACTERIA Notes . . . CONT. o mode of transmission • obligate human pathogen • transmitted sexually via contact with secretions, often by asymptomatic carriers, vertical transmission o pathogenic mechanisms • pili, antigenic variation • endotoxin, IgA protease o clinical features • asymptomatic (but still infectious) • local infection in men • urethritis, epididymitis, proctitis and pharyngeal infections • local infection in women • cervicitis most frequent (vaginal bleeding) • urethra, anus, and pharynx can be infected • can progress to pelvic inflammatory disease with complications including sterility, ectopic pregnancy, abscess, peritonitis, perihepatitis (Fitz-Hugh Curtis syndrome) • disseminated infection in both men and women • gonococcal bacteremia • pustular skin rash (dermatitis/arthritis syndrome) • tenosynovitis • septic arthritis: GC arthritis is the most common cause of septic arthritis in sexually active individuals • neonatal infection • ophthalmia neonatorum (usually within the first 5 days) • risk factors for disseminated disease • menstruation • complement deficiency (C8, C9) o diagnosis • Gram stain, culture • in smears of exudate, GC is typically found in PMN cells o treatment • neonatal GC and Chlamydiaconjunctivitis prophylaxis with erythromycin eye drops immediately following birth • antibiotic of choice: third generation cephalosporin (e.g. ceftriaxone IM or cefixime PO x 1 dose) • second line: spectinomycin, quinolone • single dose therapy unless disseminated • treat with doxycycline to cover coinfecting Chlamydiatrachomatis • report to public health • follow-up cultures to test for cure Moraxellacatarrhalis o Gram negative diplococci o recently recognized as an important human pathogen o upper respiratory tract acts as reservoir and portal of entry for infection o causes acute otitis media, sinusitis, bronchopneumonia o 75% of strains produce beta-lactamase o drugs of choice: amoxicillin-clavulanate, cephalosporins GRAM NEGATIVE BACILLI Enterobacteriaceae o reservoir in GI tract; fecal-oral transmission • ascending migration up the urethra • colonization of catheters in hospitalized patients o cause urinary tract infections, pneumonia, sepsis, nosocomial infections o diagnosis by culture o treatment • many become antibiotic-resistant • aminoglycosides, third generation cephalosporins, piperacillin, quinolones, TMP/SMX Escherichiacoli o microbiology • normal gut flora, lactose-fermenter o pathogenic mechanisms • capsule, flagella, pili, adhesins, enterotoxin MCCQE 2000 Review Notes and Lecture Series Infectious Diseases 9 AEROBIC BACTERIA Notes . . . CONT. o clinical features • gastroenteritis 1. enterotoxigenic • non-invasive, watery traveller's diarrhea • produces heat-labile and heat-stable enterotoxins 2. enterohemorrhagic • bloody diarrhea, no pus in stool, no fever • strain 0157:H7 causes hemorrhagic colitis, hemolytic uremic syndrome due to verocytotoxins 3. enteroinvasive - bloody diarrhea, pus in stool, fever • urinary tract infections (most common cause) • newborn meningitis • sepsis o treatment • invasive disease: cephalosporins, aminoglycosides, TMP/SMX, quinolones Klebsiellapneumoniae o microbiology • lactose-fermenter, mucoid colonies on culture o mode of transmission • inhabits gut of man/animals and in soil/water • infection either endogenous or acquired by contact spread o pathogenic mechanisms • encapsulated and resistant to phagocytosis o clinical features • pneumonia • significant lung necrosis, bloody sputum • risk factors: alcoholic, diabetes, elderly, underlying lung disease • hospital-acquired urinary tract infections • nosocomial sepsis and wound infections o treatment • third generation cephalosporin, ciprofloxacin, TMP/SMX Enterobacterspp. o lactose-fermenting, encapsulated, small Gram negative bacillus o part of normal human gut flora o also found free-living on plants o causes ICU infections o causes nosocomial UTI, sepsis o treatment • quinolones or imipenem, may be resistant to third-generation cephalosporins Proteusmirabilis o microbiology • indole-negative, non lactose-fermenting, urease-positive, swarming motility seen as concentric rings on culture plates o mode of transmission • endogenous infection, fecal contamination o clinical features • urinary tract infection • turns urine alkaline due to urease (splits urea into NH2and CO2) • associated with urinary calculi • sepsis o treatment • ampicillin, quinolones, TMP/SMX Shigella o microbiology • several species differing in pathogenicity • nonmotile, non lactose-fermenter o mode of transmission • obligate human pathogen, not part of normal human flora • small inoculum suffices (highly communicable) • fecal-oral contamination o pathogenic mechanisms • invasion of small intestine mucosa helped by Shiga toxin and adhesins o clinical features • bloody diarrhea with mucus, pus, tenesmus (similar to EIEC) Infectious Diseases 10 MCCQE 2000 Review Notes and Lecture Series