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218 Cards in this Set
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Probability of Disease
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inoculum size x growth rate x virulence/
host resitance |
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virulence factors
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properties that enable a microoranism to establish itself on or w/in a host and enhance its potential to cause disease
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host resistance
nonimmunological |
normal skin
mucous membranes- allow small #s bacteria to pass through to induce immunity constant flow in body tubes lungs protected w/ cilia and cough reflex |
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Host resistance
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Innate: Aquired:
PMNs B cells macrophages T cells NK cells Complement Interferons |
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Defects!
- Phagocytes - T-cells - Complement - Antibody |
Increased Susceptibility to:
- bacteria (staph) and fungi - mycobaceria (TB), facultative intracellular bac, some fungi and protozoa - encapsulated bacteria (Neisseria), some viruses - encapuslated Gm+ and Gm- bac |
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Consequences of general clinical responses to infection and inflammation:
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FEVER- enz. rxns accel, better survival at mod increases
ANOREXIA- benefit in healing proc? LETHARGY- rest, metabolic support MYALGIA- aa, heat for body temp |
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Commensals
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colonization of endogenous flora
-nutrient aquisition -differentiation of mucosal surfaces - stim. immune system -provides accessory GFs -impedes pathogenic org multiplication |
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Facultative pathogens
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Present in body
-can cause disease - can not cause disease |
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Obligate pathogens
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Disease causing
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Gram stain
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- Crystal violet- all purple
- Iodine- all purple - Alcohol (destroys relationships)- Gm+ purple, Gm- colorless - Safranin- Gm+ purple, Gm- red *** Bacterial ID, Early ID of good Ab |
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Gram Positives
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Teichoic acids- antigenic, anchoring, adherence
Peptidoglycan- cross-linked NAG-NAM, chains cross-linked by transpeptidase |
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Gram Negatives
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LPS
-core polysaccharide -O-specific antigen -Lipoid A- conserved endotoxin! |
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Bio activities of Lipid A
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- febrile response (IL-1, prostaglandins)
- act. of complement, granulocytes, macrophages - induction of interferon prod. - induction of TNF--> shock - colony stim. factor prod. - B-cell mitogen |
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Spores
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Clostridium and Bacillus genera produce them
HIGHLY resistant to heat and chemicals |
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-Obligate Aerobes
-Facultative Anaerobes -Obligate anaerobes |
-Cannot grow w/o O2 (ATP generation)
-CAN use O2, and anaerobic ferm. -CANNOT generate ATP via resp. |
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Transfer of DNA within bacterial cells
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Transposons
Programmed rearrangements |
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Transfer of DNA between cells
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Conjugation
Transduction Transformation |
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Bacteria and Iron
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free-living bac use siderophores (Fe chelator)
bac in host prod special siderophores, or direct uptake by stealing from transferrin/lactoferrin, or use of heme from breakdown of tissues |
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Enteric non-immunological and immunological factors controlling microbial flora
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Non-Imm: Gastric acid*, normal peristalsis, bile
Imm: IgA Ab produced mucosal immune sys, cell mediated imm in gut |
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DIARRHEA DEFINITIONS
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Acute: <14 days, mostly infectious
Chronic: >14 days, infectious or non-; usually parasite All bac diarrhea spread by fecal-oral route *inoculum size important Incubation period short Virulence: colonization factors, enterotoxins |
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V. cholerae
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SECRETORY DIARRHEA
-V. cholerae O1 & O139 -lg. inoculum size -colonize via fimbria -Enterotoxin CT produced, -B subunits attach to GM1 ganglioside receptors - A subunits activate AC-->cAMP--> dec. absorption, inc. secretion CL- RX = fluid replacement, antibiotics- tet, ery, cipro |
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Enterotoxigenic E. coli (ETEC)
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SECRETORY DIARRHEA
-most common bac cause of diarrhea in developing world, travelers' diarrhea -lg. inoculum size - colonize via fimbria -B subunits of LT attach to GM1 ganglioside receptors, ST attach to GC -A subunit of LT-->AC-->cAMP-->decreased absorption, increased secretion -ST-->GC -RX- ORT |
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Oral Rehydration Therapy
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Na, Cl, K, Citrate, carbohydrate
Na+, glucose transporter DOES NOT decrease duration, severity of diarrhea |
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Vibrio parahaemolyticus
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SECRETORY DIARRHEA
-Gram-negative rod, halophilic -Eating undercooked shellfish -Diarrhea mild, nausea, vomiting, low-grade fever -Illness is self-limiting in 2-3 days, no evi for Ab -Dx requires TCBS agar |
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Vibrio vulnificus
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SECRETORY DIARRHEA
-Halophilic -Undercooked seafood, wounds from injury in salt water -ALMOST ONLY in person with underlying liver disease, or compromised persons -Sepsis occurs -Difficult to treat |
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Shigella
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INVASIVE DIARRHEA
-prototype- Shigellosis (4 species)--> S dystereria (Shiga bacillis) most severe -Inoculum size low (person to person spread) - invasion of lg bowel, inflammatory changes of mucosa, diarrhea with blood, pus, fever, abdominal pain -Dx by stool culture -Rx Ciprofloxacin, ORS when necessary |
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Campylobacter jejuni
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INVASIVE DIARRHEA
-Gram-negative, slightly curved rods - acute diarrhea in US, kids in developing world - pus cells, blood in stool, fever, ab pain -growth requirement- 42C, microaerophilic cond. -Reservoir: primarily poultry - Association w/ Guillain-Barre syndrome. Serotype O19 most common - Rx Antimicrobial therapy: erythromycin, fluoroquinolones *Azithromycin drug of choice |
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Enterohemorrhagic E. coli
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INVASIVE DIARRHEA
- bloody diarrhea-- can lead to Hemolytic Uremic Syndrome -food industry failures - O157:H7 most common serogroup -Inoculum size low, attaching and effacing microvili of mucosal cells in lg bowel -SLT-1, SLT-2 (Shiga-like enterotoxins), controlled by bacteriophages -Dx stool cultures, Sorbitol MacConkey agar; ID toxin in stool, serological responses - 1-2 days, hemorrhagic colitis; 6 days HUS -Antimicrobials may inc. prod/release of toxins -Reservoir- young cattle |
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Enteropathogenic E. coli (EPEC)
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INVASIVE DIARRHEA
-Diarrhea limited to children <2 yrs - Hallmark: attachment of bug to SI by "attaching and effacing" of microvilli -No enterotoxins -Dx- ID serotype of E. coli in stool |
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Non-typhoid Salmonella
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INVASIVE DIARRHEA
-Gram negative, non-lactose fermenting rods - 2000 serotypes - Fecal-oral route, contaminated food -Reservoirs: chickens (eggs: shell, transovarial) - GI tracts of all animal, esp chx, amph, reptiles -Inflammatory changes; sepsis in children and elderly -Dx- culture of stool, blood -Rx- antimicrobials- Fluoroquinolones, Ceftriaxone |
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Enteric Fever (Typhoid fever)
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INVASIVE DIARRHEA
-Salmonella enterica -Gram negative intracellular -Only infect humans -Fecal-oral route, carriage in gall bladder -Large infection dose -Invade SI, transported by lymph and blood -Fever, constipation, hepatomegaly, splenomegaly, rose spots on abd -Dx- cultures of blood, bone marrow, stool, duodenal fluid -Rx- antimicrobials- fluoroquinolones, azithromycin, ceftriaxone - Two effective vaccines- live oral vaccine and Vi injectable vaccine - |
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Clostridium difficile
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INVASIVE DIARRHEA
-Anaerobic Gram positive, spore-forming bacillus -Broad-spectrum antibiotic-related, allow growth of organisms to high conc'n -Produce toxins- TxA, TxB -Sole cause of pseudomembranous enterocolitis -Diarrhea, colitis (fever, pain, cramping), elevated WBC, hypoalbumin, pseudomembranous colitis -Dx- ID of Toxins A or A+B in stool; EIA, tissue culture assay; endoscopy **Isolation procedures in hospitals |
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Listeria monocytogenes
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INVASIVE DIARRHEA
-Gram positive intracellular rods -contaminated foods (cheese, pork, milk) -Invade intestinal mucosa, may cause acute meningitis -pregnant women susceptible -Dx- culture of sterile body fluids (CSF, blood) Rx- Ampicilin +/- gentamicin Intracellular survival, "molecular mimicry" Grows well at refrigerator temp Disease: bacteremia, meningitis, meningoencephalitis |
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Yersinia enterocolitica
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INVASIVE DIARRHEA
Gram-negative coccobacillus, intracellular -Grows at refrigerator temp -contaminated foods -Self-limited mild gastroenterities...or pseudo-appendicitis -Dx- culture of stool, blood Rx- not needed |
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Helicobacter pylori
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-small microaerophilic gram negative rods
- colonize stomach -NO DIARRHEA, but dyspepsia -Dx- serology, hydrogen breath test - Peptic ulcer disease, gastric cancer - Eliminated w/ combo of 2+ Ab and proton-pump inhibitor |
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First Highly Effective and relatively nontoxic antibacterial agent
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Prontosil
Active principle = Sulfanilamide |
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Folic Acid Metabolism in Bacteria
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Pterin Pyrophospho Kinase (7,8-Dihydropterin---> 7,8-Dihydropterin pyrophophate)
DHP Synthase (7,8-Dihydropterin pyrophosphate + PABA--> 7,8-DHP) 7,8-DHP + glutamates ---> FH2 FH2 Reductase w/NADPH (FH2--->FH4) |
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Sulfonamides
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Structure: Molecular resemblance to PABA
Mechanism: Competitive Inhibition of DHP Synthase Selective Toxicity: - Bacteria have DHP Synthase, must make folic acids -Humans do NOT have DHP Synthase, must import folic acids Mech of Resistance: -Dec bacterial perm. -Mutation of DHP Synthase -Inc. in DHP Synthase -Increase in PABA Uses: -UTIs due to Gm- -Nocardia Toxicity: Rxns in pts. w/ AIDS; Idiosyncratic Rxns: Drug fever, skin rashes, joint pain, lymphadenopathy, implication in Stevens-Johnson syndrome Mech of Idiosyncratic Tox: Acetyation Polymorphism NEONATES: CAUSES KERNICTERUS (sulfonamides bind albumen, bump bilirubin off and into brain) |
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Sulfamethoxazole
Sulfisoxazole |
Sulfonamides with short Plasma t1/2
SKIN RASH NEONATE TOXICITY |
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Diaminopyrimidines
TRIMETHOPRIM |
Inhibits DHFR (like methotrexate)
Selective toxicity: only bacterial DHFR affected Resistance: Mutation in FH2 so TMP inhibits less; Increase in DHFR Toxicity: Rare; Rash nausea; folate deficiency in "deprived" |
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Cotrimoxazole
(TMP-SMX) |
Trimethoprim-Sulfamethoxazole
-Synergism -Broadened spectrum of activity -Dec likelihood of resistance -Dec dosage favors lower tox -Bacericidal, rather than bacteriostatic |
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Principles of Treatment
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Empiric Therapy- Begins broad
(Probability of organism in given clinical syndrome) Definitive Therapy- Becomes narrow (organism specific options, best antibiotic informed by pt characteristics) |
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Time vs. Concentration Dependent Killing
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Increased killing rate as conc'n rises above MIC (minimum inhibitory concentration)
ex. Aminoglycoside, Quinolones |
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Time-Dependent Killing
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Correlates
% time > MIC No Correlates -Drug Peak/ MIC -Drug AUC/MIC |
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Post-Antibiotic Effect (PAE)
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Suppression of bacterial growth that persists after short exposure of organisms to antibiotic agents.
Effect-time relationship (PD) may differ from drug-time relationship (PK) |
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B-lactam antibiotics and PAE
AG & Quinolones and PAE |
B-lactam antibiotics exhibit PAE against Gm+
B-lactam antibiotics DO NOT exhibit PAE against Gm- Aminoglycosides and Quinolones show PAE vs. Gm- |
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Penicillin
Mech Selective Toxicity PK Toxicity Antibacterial Resistance |
Beta-lactam
Homology to D-ala-D-ala Mech: Transpeptidase acylates at CO-N bond in penicillin covalently- suicide substrate Selecive Tox: Bacteria have cell walls, D-ala-D-ala, transpeptidase Spectrum: Gram Positive (strep) Anaerobes (oral) Absorption- acid unstable Dist- 50% body weight, OAT pump in spinal cord Metab- 10% metabolized Elim- renal excretion; t1/2 45 min Bacericidal Time-Dependent Kiling PAE for GRAM POSITIVES Alter PBP, Reduce Perm, Beta-lactamase Hypersensitivity; Toxic (GI, Na+overload) |
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Beta-lactams
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Inhibit cross-linking of peptidoglycan strands catalyzed by transpeptidase
-Bind covalently w/ enzyme -PCN = structural analogue of D-ala-D-ala -Beta-lactam in same position as peptide bond |
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Penicillin Binding Proteins
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-Located in bacterial cell membrane
-Transpeptidases -Transglycosylases -Localization specific to fxn |
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Beta-lactamase
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Hydrolyzes (opens) beta-lactam ring on PCN
Inactivated PCN= Penicilloic acid |
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Clavulanate
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Beta-lactamase Inhibitor
Competes w/ PCN for access to beta-lactamase active site |
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Augmentin
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Amoxicillin-Clavulanate
low concentrations inhibit strains compared to Amoxicillin alone |
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Beta-lactamase Inhibitor limitations
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Degraded by beta-lactamase after binding
Clavulanate induces Beta-lactamase expression |
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Streptococci pyogenes
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Group A Strep
Restricted to humans Causes pharyngitis, skin infections, systemic disease Local infection- heat, erythmena, pain, edema Post infection: Rheumatic fever, actue glomerulonephritis Beta-hemolytic Capsule- inhibits phagocytosis M-protein required for virulence (inhibits phagocytosis in absence of antibody, highly antigenic) LTA = key attachment factor Protein F- adhesion Cell-bound peptidase- Inactivaes C5a' Exogenic Toxins-Hemolysin O and S, Pyrogenic Exotoxins- scarlet fever, Endonucleases, Hyaluronidase, Streptokinase Pyogenic Disease: Pharyngitis, Skin infec, Necrotizing faciitis, Toxin-assoc: Scarlet Fever, TSS NON-Pyogenic: Acute Rheumatic Fever, Post Strep Glomerulonephritis |
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Streptococci agalactiae
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Group B Strep
Colonize GI tract Colonizes vaginal tract in sexually active women Newborn septicemia, meningitis (early or late) (immunocompromised pt too!) Beta-hemolytic |
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Streptococci pneumoniae
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The pneumococcus
#1 cause of bacterial pneumonia worldwide #1 cause of bacterial meningitis worldwide #1 cause of sinusitis and otitis media alpha-hemolytic IDed by inhibitory optochin, and bile solubility Key virulence: polysaccharide capsule, also pneumolysin -Pneumonia- follows acute viral URI, fever, cough, sputum, PMNs -Meningitis Resistance to penicilins Iintermediate and total) |
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Genus Streptococci
Description |
Gram positive
Spherical or ovoid bacteria Occur in pairs or chains Non-motile Cell division in single plane Most unencapsulated Fastidious Facultative anaerobes Fermentation Non-spore bearing Lack a cytochrome oxidase system (incuding catalase) |
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VIridans Group of Streptocooci
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alpha-hemolysis on blood agar
lack of virulence typical streptococci normal flora (protective) dental plaque, gingiva, tongue, salivary sec Importance: Endocarditis SPecies-associated abscess formers- *primary liver abscess Lethal septicemia in susceptible populations- *prophylactic Ab Dental caries- Str. mutans high acid prod |
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Enterococci
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Commensal normal flora of GI tract
2 cause majority of human infections: Enterococcus faecalis Enterococcus faecium Less fastidious than strept, resistant to heat, dry, acid, disinfectant usually non- or alpha-hemolytic Fermentive, facultative anaerobes lack cytochrome sys, catalase neg Virulence:microbial prop |
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E. faecalis
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Enterococcus
Virulenc Factors:adherence factors, cytolysins, "aggregation factor," LTA exhibits endotoxin-like features of sepsis, biofilm form. Disease: enterococcal infections Septicemia, bac endocarditis- elderly male obst. uropathy |
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E. faecium
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Virulence factors: resistance to almost all antibiotics and ease of spread in hospital and nursing home settings.
Disease: enterococcal infections- intra-ab abscesses, colonic diverticulitis, URI, gall bladder VRE- Vancomycin Resistant Enterococci |
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VRE
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E. faecium
Antibiotic inhibiting normal flora permits amplification of resistant E. faecium- nosocomial can transmit resistant genes to S. aureus |
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Extracellular bacteria
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Incite acute inflammation with edema- exudative
May cause necrosis- suppuration or abscess Increasing chronic inflammation over time ex: Str pneumoniae, S. aureus, Pseudomonas aeruginosa |
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Facultative and Obligate Intracellular Bacteria
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Incite chronic inflammation +/- acute
granulomas or granulomatous May cause necrosis- caseous, microabscesses w/in granulomatous, host cell-specific Ex: mycobacterium tuberclosis, Rickettsia rickettsii, chlamydia trachomatis |
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Exudative Inflammation
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Vascular Perm
Neutrophils Pus Caused by Pyogenic, extracellular bac Localized Group A strep pharyngitis, Str. pneumonia pneumonia and meningitis |
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Necrotizing Inflammation
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Exudative inflammation w/ necrosis
(suppration) Host damage caused by bac virulence factors Ex: pseudomonas aeruginosa pneumonia Clostridium perfringens myonecrosis (gas gangrene) |
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Granulomatous Inflammation and Granulomas
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epitheliod histiocytes (activated macs)
Dependent on cytokine response (IL-1B, IFN-gamma, CXCL, CCL; not IL-4, IL-10) Ex: Mycobacterium tuberculosis Mycobacterium leprae |
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Interstitial Inflammation
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nonspecific morphology
suggestive of virus, Mycoplasma, rickettsia, spirochete |
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Cytopathic/ Cytoproliferative changes
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Typical of viral infections
Seen with intracellular bac infection angioproliferative response caused by Bartonella spp.(blood vessels overgrow) |
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Procaine Penicillin
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equimolar salt of procaine and PCN G
Very slowly absorbed IM |
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Benzathine PCN
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Salt of two molecules of PCN G plus 1 molecule of dibenzylethylene
Very, very slowly absorbed IM |
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Penicillin V
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Orally available
Acid stable |
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Ampicillin
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An Aminopenicillin
Spectrum: Gm+ pneumococcus, streptococcus, Enterococcus includes some Gm- rods, H. influenza, E. coli, Salmonella Orally bioavailable Toxicity- Diarrhea, skin rash- macular and evanescent Ampicillin + sulbactam IV (Unasyn) = B-lactamase inhib combo Increase spectrum to include B-lactamase prod. S.aureas, H.influenzae, M catarrhalis, many GNR |
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Amoxicillin
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An Aminopenicillin
100% bioavailability Differs from ampicillin by -OH group Amoxicilin + clavulanate (Augmentin) = B-lactamase inhibitor combo |
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Piperacillin
Piperacilin/tazobactam |
An Aminoacylpenicillin
Spectrum: More nosocomial (Class II GNRs), Pseudomonas aeruginosa, Bacteroides fragilis PCN/Tazo- covers B-lactamase prod. strains of staphylococci and many GNR; no better against pseudomonas PAE in GPC |
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Methicillin (historic)
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Penicillinase-Resistant Penicillin
MRSA resistant due to altered PBP, extends to all othe beta-lactams Now use Oxacillin |
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Cephalosporins
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B-lactam ring
Broad antibacterial spectrum: GPC, GNR, pseudomonas Resistance to b-lactamases Safety > PCN 4 generations (increase Gm- coverage 1-->4) PAE vs Gm+ TIme-dep Killing Cont. Infusion more efficient |
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Cefepime
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4th generation Cephalosporin
Anti-pseudomonal *Best |
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Carbapenem
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Broad Spectrum: Gm+, including enterococcus; Gm-, including pseudomonas, anaerobes
Resistance rare PAE for Gm+ and Gm- Cilastatin inhibits renal deydropeptidase I (which forms renal tubular toxin metabolite) |
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Aztreonam
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Monobactam
Non-aminoglycoside "aminoglycoside" (means it treats Gm- rods) ONLY Gm- coverage |
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Vancomycin
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H-bonding with D-ala-D-ala
Prevents dipeptide access of transpeptidase Peptidoglycan cross-linking blocked S.aureus 100% suceptible No absorption- treats gut infections Toxicity: Allergenicity (skin rash, eosinophilia, drug fever) Phlebitis, "Red Man" flushing w/ IV |
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Bacillis anthracis
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-Aerobic, gram positive, spore-forming, rod-shaped
-causes anthrax -Humans get infections by inhalation, ingestion, trauma Virulence: capsule, 3-part toxin: protective antigen, edema factor- AC, lethal factor- zinc dependent protease 3 forms of anthrax: cutaneous: black eschar, ulcer, regional lymphadenitis Inhalation: hallmark = hemorrhagic mediastinitis GI- ingestion of vegetative bacilli, ulcers in GI tarct Rx: Penicillin, doxycycline, ciprofloxacin Zoonotic endemic in Middle East- potential agen of bioterrorism |
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Corynebacterium
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Aerobic
Non-spore forming irregularly shaped Catalase positive Normal flora of skin, mucous membranes *corynebacterium diphtheriae most important |
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Bacillus cereus
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-Aerobic, gram positive, spore-forming, rod-shaped
Bacillus cereus causes bacteremia, endocarditis, would infections, eye disease, food poisoning Diarrheal type- caused by heat-labile enterotoxin emetic type- caused by heat-stable enterotoxin Dx: Culture, gram stain, B-hemolytic, motile Rx: Vancomycin, clindamycin |
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Corynebacterium Diphtheriae
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Aerobic, non-spore forming
catalase positive non-invasive Humans only known reservoir Respiratory droplets, direct contact Colder months Virulence: Toxin: B segment, A segment; encoded by bacteriophages Disease: Respiratory tract disease (pharyngeal disease most common; membrane on tonsils- distorts lower airway causing "bull's neck") Systemic Complications: myocarditis, neurologic tox; Cutaneous- punched out ulcers Dx: Culture w/ special media Rx: Diphtheria antitoxin (horse serum) no longer licensed; penicillin or erythromycin Vaccine: DTaP series Reportable disease |
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Staphylococcus aureus
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On blood agar: golden yellow colonies, Beta hemolysis
Coagulase positive Virulence: Protein A- binds Fc region of Ab, antiphagocytic; coagulase- staphylothrombin catalyzes fibrinogen-->fibrin; A&B clumping factors; Toxins- exoenzymes, hemolysins; Panton-Valentine Leucocidin- lyses PMNs Superantigens- Enterotoxins A-D (food poisoning); Exfoliatins A,B- scalded skin syndrome; TSST-1 Acquires genetic elements-->pathogenicity Colonizes the NOSE, also skin, hair follicles, sweat glands, GI, vagina Transmission: person-to-person, environmental PMNS most important defense Antibiotic resistance- never choose penicillin for empiric treatment of S. aureus |
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Staphylococcus saprophyticus
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Gm+ cocci
UTIs in young women |
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Staphylococcus epidermidis
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On blood agar: white colonies,
no hemolysis Coagulase Negative Forms biofilm Less virulent, more abx resistant Infections: Hardware/Foreign material Neonatal septicemia, NEC, endocarditis |
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MSRA
VRSA |
Chromosomal mecA on staphylococcal cassette chromosome (SCCmec)
Resistant to all beta-lactam antibiotics 2 types: Hospital aquired (HA-MRSA) Community acquired (CA-MSRA)- more susceptible; produce PVL Vancomycin Resistant S. aureus exists, not common |
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Toxin
Toxoids |
Molecules produced by microbes that can produce disease.
Toxins are membrane damaging (pore-forming toxins, cytotoxins Toxoids are detoxified toxins that retain their antigenicity. |
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Exotoxin
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A molecule produced and released by a microorganism to affect target cells at a distance.
Structure: Most have Active "A" domain: enzymatic Binding "B" domain Mechanisms: 1. ADP-ribosylating toxins 2. Adenylate cyclase toxins 3. RNA glycosidase toxins 4. Metaloprotease oxins |
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Endotoxin
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Intracellular structural component of Gram-negative bacteria
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Anthrax Toxin
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B. anthracis produces three toxin components; none active alone:
A: Edema factor A: Lethal factor B: Protective antigen Receptor Mediated Endocytosis of toxin complex LF- protease induces cytokine release and is cytotoxic to cells EF: adenylate cyclase that increases cAMP levels in phagocytes and forms ion-permeable pore |
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Diphtheria Toxin
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A: catalytic domain
B: binding domain T: hydrophobic domain (insertion into endosome membrane to secure release of A) A domain catalyzes attachment of ADP-ribose of NAD to EF-2 Causes systemic toxicity; most severe- heart, nervous system |
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LPS/Lipid A and Virulence
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Febrile response
-hypothalamus -induction of endogenous pyrogens Activation of Macrophages Coagulation cascade Complement cascade Induction TNF-a induces vasodilation |
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Scarlet Fever
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Complication of Group A Streptococcus
Caused by pyrogenic exotoxin of GAS Causes "sandpaper" rash |
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Superantigens
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Toxins that stimulate T-cell proliferation through non-specific interaction with the class II MHC complex o APCs and specific Vb chains of the TCR of T lymphocytes
- Overstimulation of immune system, pyrogenicity, shock -Detrimental cytokine release |
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Endogenous Pyrogens
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IL-1
TNF IL-6 IFN Main source of endogenous pyrogens = macrophages- secrete IL-1, TNF, IL-6. |
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Is Fever a bad thing? (Yes)
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Basal metabolic rate rises about 10% for ever 1degC rise in temp.
Excessmetabolic demands-->malnutrition--> infection |
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Is Fever a bad thing? (No)
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Closely, regulated purposive response which evolved for a reason.
Stimulates immune response - 1degC rise in temp amps stimulatory effect of IL-1 on T cells by factor of10. Makes environment inhospitable for organism. |
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Why do we give antipyretics?
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Short courses relatively nontoxic
ANALGESIC EFFECTS Reduce metabolic demands If you are going to give antipyretic medications, GIVE IT CONSISTENTLY AND CONTINUOUSLY- Tylenol every 6 hours for 48 hours. |
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Acute Phase Response
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Numerous physiologic reactions mediated by pyrogenic cytokines that activate thermal response of fever (IL-6)
Stimuli: bac inf, viral inf, trauma, cancer, burns, strenuous exercise, childbirth Liver stops prod albumin, makes other proteins: C reactive protein and serum amyloid A associated protein are not present in normal plasma but are secreted during APR **changes induced by IL-6 Major falls in serum iron and zinc, rises in neutrophils and bands **changes induced by IL-1 |
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CRP
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crp binds phosphocholine on microorganism and damaged host cells; activates complement, promotes phagocytic adherence, promotes clearance of organism
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Serum Amyloid A
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Potentiates adhesiveness and chemotaxis of phagocytic cells and lymphocytes
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SIRS
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Systemic Inflammatory Response Syndrome: abnormal, generalized inflammatory reaction in organs remote from initial insult
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Sepsis
Severe Sepsis Septic Shock |
When SIRS occurs in pt. with suspected or proven infection
Severe sepsis= sepsis + hypotension Septic Shock = severe sepsis + organ dysfunction not reversed by fluids |
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Mechanism of Sepsis
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Host reaction to agents
Macrophages secrete TNF, IL-1, which produce inflammation in capillaries Endothelial cells lose contact Cellls secrete prostaglandins, leukotrienes Inf causes vasodilatation, vessels become dilated and leaky, blood vessel walls destroyed Tissues bypassed BP falls steady loss of fluid and protein from blood,BP falls further Lungs filled with fluid Acidotic ischemic heart fails Rx: FLUIDS, and Ab |
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Protein C
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Activated by thrombin bound to thrombomodulin
Inhibits thrombosis and promotes fibrinolysis Most septic pts exhaust protein C |
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Clinical Features of Sepsis
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High CO
Low SVR A-V shunting Acidosis and elevated lactate Increased gut perm |
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Enterobacteriacea
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-Gm- rod-shaped bacteria
-Found in GI tracts of humans, animals, fish, insects -Facultative anaerobes -Ferment glucose -Reduce nitrates to nitrites -Catalase POSITIVE -Cytochrome oxidase NEGATIVE -Disease assoc: UTI, Gastroenteritis/colitis, Meningitis, Bacteremia, Pneumonia Wounds |
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Urinary Tract Infections
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-Urethritis- ureter
-Cystitis- bladder -Pyelonephritis- kidney E. coli causes 80% CAI, followed by Proteus, Klebsiella E. coli main cause of HAI (bladder catheters) |
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E. coli
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-Gm- rod-shaped bacteria
-Found in GI tracts of humans, animals, fish, insects -Facultative anaerobes -Ferment glucose -Lactose Fermenter -Reduce nitrates to nitrites -Catalase POSITIVE -Cytochrome oxidase NEGATIVE -B-heymolytic -Rapid indole positive -Disease assoc: UTI -Virulence factors in UTI: Type 1 fimbriae (colonization); P pili (adherence); Toxins (endotoxin, alpha hemolysin) |
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Proteus sp.
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-Gm- rod-shaped bacteria
-Found in GI tracts of humans, animals, fish, insects -Facultative anaerobes -Ferment glucose -Reduce nitrates to nitrites -Catalase POSITIVE -Cytochrome oxidase NEGATIVE -Disease assoc: UTI, urolithiasis "SWARM" over surface of agar NON-LACTOSE FERMENTERS; produce urease, which can lead to crystallization and stones |
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Klebsiella pneumoniae
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-Gm- rod-shaped bacteria
-Found in GI tracts of humans, animals, fish, insects -Facultative anaerobes -Ferment glucose -Lactose Fermenting -Non-motile -Reduce nitrates to nitrites -Catalase POSITIVE -Cytochrome oxidase NEGATIVE -Virulence: Mucoid Capsule -Disease assoc: UTIs, Pneumonia (Klebsiella pneumoniae pneumonia), HAI |
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Aerobic Gram Negative Rod Meningitis
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Most common pathogens: E. coli, Klebsiella sp., Salmonella sp., Pseudomonas aeruginosa
-Neonates, neurosurg pts. -75% E. coli meningitis caused by capsular type K1 |
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Intestinal Infections Caused by Enterobaceriaceae
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Salmonella, Shigella, E. coli, Yersinia
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Salmonella
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-Gm-
-Motil bacillus -H2S positive -Can spread to blood stream -Virulence Factors: *Vi antigen (Salmonella typhi) -Infections: Gastroenteritis (nausea, vomiting, ab pain, diarrhea, fever); Bacteremia (non-typhoidal); Typhoid fever (MOS Infection, fever, diarrhea) |
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Shigella
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-Gm-
-Non-motile bacillus -Four serotypes -Mechanism: INVASION -Confined to mucosal layer of colon - Virulence Factors located on plasmid Disease: fever, severe cramping, bloody diarrhea |
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Shiga toxin producing E. coli (Enterohemorrhagic)
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-Gm-
-Diarrheagenic - Toxins: SLT-1, SLT-2 |
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Haemophilus sp.
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-Gm- rods, Pleomorphic
-Fastidious -Normal resp flora of humans, animals -Invasive strains encapsulated -In vitro growth requires: X factor-hemin; V factor- NAD; chocolate agar -H. influenzae type b- penetrates nasopharynx-> bloodstream->CNS->meningitis; Virulence: capsule, IgA protease -H. influenzae non-typeable- Non-typeable major cause of otitis media Plasmid-mediated B-lactamase -Rx: (invasive) 3rd gen cephalosporin; (non-invasive) amoxicillin/clavulanic acid |
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Bordetella pertussis
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-Gm- coccobacill
-Singly, pairs -Strict aerobe -Slow- growing, special media -ADULTS reservoir -Most severe disease- children < 1yr -SECRETES TOXINS; NO invasion- adherence to resp epi-> production of local damage-> Systemic disease via pertussis toxin Pertussis syndrome: Incubation->Catarrhal stage(most contagious)-> Paroxysmal state (whooping cough) Complications: pulmonary hemorrhage, seizures Dx: NP aspirates, NP swabs- culture, nucleic acid detection Rx: Erythromycicn, acellular vaccine |
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Legionellaceae
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-Gm-, thin rods
-Growth requirement- L-cysteine -Utilize aa for growth -Biochem inert: weak oxidase rxn, catalase pos, -motile -Aquatic settings -Survive in free-living amoebase -Form biofilms -Adherence to resp epi- intracellular survival- Phagosomes DO NOT fuse w/ lysosomes; cell ruptures -Many risk factors (cigs, alc, Immunosupp) -Legionella pneumonia; Legionnaire's disease- failure to respond to B-lactams; -Gold standard culture- buffered charcoal yeast extract agar w/ Ab, dyes -Urinary antigen- detects lipopolysaccharide -Rx: Newer macrolides: Azithromycin, Clarithromycin; Quinolones- levofloxacin |
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The Non-Lactose-Fermenters
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Pseudomonas aeruginosa, Acinetobacter baumanii, Burkholderia cepecia, Stenotrophomonas maltophilia
Gm- bacilli Aerobic Non-spore-forming Catalase positive Cytochrome oxidase positive (most) Do not ferment carbs May oxidatively metab. sugars Motile (most) Grow on MacConkey's aga |
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Pseudomonas aeruginosa
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-Gm- rod
-Non-lactose fermentation -Aerobic -Non-spore-forming -Motile -Cytochrome oxidase positive -Hospital environment - Simple growth requirements -Fluorescent- Produces PYOVERDIN -Produces Pyocyanin -Many Virulence factors: Structural: LPS, Pili, Capsule, Pyocyanin- hydroxyl radicals; Toxins&Enzymes: Exotoxin A, Exotoxin S, leukocidin, elastase Diseases: Bacteremia, Pneumonia Colonizes resp tract *CF pts Predisposing: Chronic Illness, Broad-spectrum Ab, tracheostomy, immunocomp Pulm Infections, Skin infections- burn wounds "CA" infections: corneal ulcers, endophthalmitis, otitis externa Rx: Antipseudomonal B-lactam antimicrobials (Piperacillin +/- Tazobactam); rth gen cephalosporin (cefepime); Carbapenems (meropenem); Combo w/ AG Intrinsic Resistance: Inducible B-lactamase; Efflux Pump Systems Use Colistin if needed?? (bad profile) |
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Acinetobacter
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-Gm- coccobacillary rods
-aerboic -NLF -Non-motile -Oxidase-Negative -Hospital environments, nature -Immunocompromised, debilitated pts -HA infections: URI, UTI, wound, bacteremia, NosoPneumo, VAP Risk factors: ICU, Ab Rx, surg, mech vent -CA infections: CAP w/ fatal outcome assoc w/ inapprop antimicrobial rx -wound infections, osteomyelitis -Intrinsic Resistance to cephalosporins -Carbapanem resistance 20% -Rx: Ampicillin-Sulbactam; Ticarcillin-Clavulanate; Imipenem, Trimethoprim-Sulfamethoxazole; Quinolones, Doxycycline Combo w/ AG for serious inf Colistin for MDR infections |
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Stenotrophomonas MALTOPHILIA
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-Gm- rod
-NLF -Motile -Oxidase negative -Use maltose faster than glucose -Intrinsic resistance to almost all antimicrobrials -Rx: TMP-SMX primary choice -Opportunistic human pathogen -Nosocomial pathogen- bacteremia- pneumonia- UTI-wound |
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Burkholderia cepacia
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Complex of 9 genomovars
-Not normal human flora, can colonize resp tract -Resistant to most antimicrobials -Rx: TMP-SMX, ceftazidime, imipenem, meropenem, some fluoroquinolones -Occasionally opportunistic- pts w/ CGD highly susceptible -Nosocomial (contaminated equip, albuterol, blood culture systems) -**CF pts -Contraindication for Lung tx |
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Burkholderia pseudomallei
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-Gm-
-NLF -Wrinkled colonies -Causative agent of melioidosis -SE Asia, N. Australia -Pneumonia is most common manifestation -Potential agent of bioterrorism |
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Melioidosis
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Caused by Burkholderia pseudomallei
Protean manifestation Asymptomatic-Cutaneous infection- Pulmonary disease Pneumonia most common manifestation, abscess formation, cavitation Rx: TMP/SMX + broad specrum cephalosporin |
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Gentamicin
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Ribosomal Inhibitor
Aminoglycoside Mech: Blocks initiation, terminates, misreads Site of Action: 30S, A Bacteriocidal |
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Tetracycline
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Ribosomal Inhibitor
Mech: Blocks tRNA binding (A/T to A/A) Site of Action: 30S A Bacteriostatic |
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Chloramphenicol
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Ribosomal Inhibitor
Mech: Blocks peptidyl transferase Site of Action: 50S A Bacteriostatic |
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Clindamycin
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Ribosomal Inhibitor
Mech: Blocks peptidyl transferase Site of Action: 50S A,P Bacteriostatic |
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Linezolid
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Ribosomal Inhibitor
Oxazolidinone Mech: Blocks fMet tRNA initiation complex Site of Action: 50S P |
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Erythromycin
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Ribosomal Inhibitor
Macrolide Mech: Blocks peptide exit tunnel Site of Action: 50S Exit Bacteriostatic |
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Aminoglycosides
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Gentamicin, Tobramycin, Amikacin
Mech: Blocks initiation of protein sythesis, Blocks further translation, Premature termination, Incorporation of incorrect aa Active transport into bacteria Inhibited by chloramphenicol, anaerobic environ, acidic environ PAE against Gm- and Gm+ Concentration-dependent killing Synergism (B-lactams) Antagonism (Chloramphenicol) Selective Tox: We have 80S ribosomes; don't bind AGs **Only cells w/ megalin membrane transporter transport AGs (prox tube, inner ear) Uses: Severe infections by Gm- bacilli; only used against Gm+ in synergistic combos Tox: Nephrotoxicity (reversible); Ototoxicity (irreversible) AG Nephrotox Risk factors: Age, Normal renal fnx, +72 hrs, concomitant meds (loop diuretics, Abs) Ototoxicity: high freq lost first, progression after sensation of drug Ototox risk factors: Age, Ehacrynic acid, genetic mutation PK: Absorption: poor oral bioavail; IV mostly D: Good into interstitial, poor into cells and CSF E:Glomerular filtration Dosing: 1 big dose daily, achieve high AG peak, then drug free interval to reverse adaptive post exposure resistance and toxicity AG TDM- decreases nephrotoxicity *Gentamicin as standard |
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Tetracycline Class
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Ribosomal Inhibitors
Mech: -Contact w/ A-site 16S rRNA away from codon-anticodon complex -Allows decoding, but no A/T to A/A transition -Potential interactions w/ rRNA -Bind to smaller 30S A site rRNA, inhibit shift from A/T to A/A Selective Tox: Enter eukaryotic cells passively and DO NOT accumulate Resistance: altered active transport system Uses: Chlamydial infections, Borrelia burdorferi (Lyme disease); Helicobater pyori PK: D-orally available, doxycycline 100% Tox: chelated w/ Ca2+, dark bands on teeth |
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Glycylcycline Class: Tigecycline
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Large sterically limiting side chain on minocycline core
Overcomes 2 tetracycline resistance mech: 1. active efflux 2. protection of ribosomes Broad spectrum of activity: GPCs MRSA, VREs; GNRs Acinetobacter, not pseudomonas; Anaerobic Bacteroides Efficacy: intra-ab, skin/skin, pneumonia |
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Chloramphenicol
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Ribosome Inhibitor
Inhibits 50S peptidyl transferase at A site Inhibits peptide bond formation Binding site overlaps w/ Linezolid, Clindamycin, Macrolide Selective Tox: Does NOT bind our ribosomal unit; Does NOT inhibit our PT; Does bind and inhibit our mt PT Resistance: acetylation Spectrum: cidal- Strep. Pneumoniae, Neisseria meningitidis, H. influenzae; static- many GNRs, many anaerobes PK: A- Excellent D- Wide, intracellular, CSF excellent M- Glucuronidation in liver E- renal Tox- Bone marrow suppression Aplastic anemia- Not dose, plasma level, or time related, irreversible Gray Baby Syndrome: Inefficient glucuronidation- high blood levels |
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Clindamycin
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Ribosomal Inhibitor
Inhibits 50S PT at A & P site 23rRNA Inhibits peptide bond form. Binding site overlap w/ Linezolid, Chloramphenicol, Macrolides Selective Tox: Does NOT bind to our ribosomal subunit; NO inhibition of our PT Spectrum: Gm+ cocci (S. pneumoniae, Group A Strep, S. aureus); Most anaerobes PK: A- orally Tox- Pseudomembranous Colitis; C. difficile secondary overgrowth |
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Linezolid
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Ribosomal Inhibitor
Blocks movement of fMet-tRNA into 50S P Site Inhibits formation of 70S initiation complex Inhibits EF-G mediated A to P translocation Inhibits EF-P mediated peptidyl transfer Overlaps Chloramphenicol and Clindamycin binding site (only additive effects) Selective Tox: Does NOT bind our 80S ribosomal subunit Bacteriostatic, except S. pneumoniae (cidal) PAE 1-2 hrs TIme-Dependent killing Spectrum: "WORST OF THE WORST" RESISTANT GM+ (VRE E. faecium, MRSA, PCN-resistant Strep. pneumo) |
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Macrolides
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Ribosomal Inhibitor
14 or 15 member ring Interaction w/ PTC, but no effect on PT Azithro/Erythro (one sugar)- occupies only exit tunnel, allows up to tetrapeptide Carbomycin (2 sugars & isobuyrate)- reaches PT center and occupies A site Bind in opening btwn PT center and peptide exit tunnel H-bonding via lactone ring and desosamine sugar Overlaps binding site w/ Clindamycin & Chloramphenico Selective Tox: Do NOT bind our larger ribosomal subunit; NO inhibition of our protein synthesis Spectrum: Atypical organisms & in PCN allergy for Strep. Pneumoniae, GAS PK: A- oral ery- q6h; clar q24h; azi q24h Macrophage penetration: AZI>ERY Toxicity: Safest!! nausea, vomiting |
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Neisseria Species
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Multiple nonpathogenic inhabitants of upper respiratory tract
Strict pathogens: Neisseria gonorrhoeae, Neisseria meningitidis General: inhabit mucous membrane surfaces Gm- diplococci Aerboic, stim by CO2 Grow best on choc agar Non-motile Non-spore forming Oxidase, Catalase POSITIVE Can survive extra- and intracellularly |
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Neisseria gonorrhoeae
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Share common char of other Neisseria sp.
More fastidious- require cysteine Pathogenesis: Adherence, Cell entry, evasion of immune sys, stim of neutrophilic response->pyogenic infection Pili- attch to CD46 Peptidoglycan- Toxic to fallopian tubes Membrane proteins- bactericidal resistance, promote invasion Lipo-oligosac- endotoxin, ciliary loss, cell death Disease: Gonorrhea Social & Behavioral risk factors Clinical Syndromes: Women mucopurulent cervicitis; Neonates- ophthalmia neonatorum, Men- urethrits, epididymitis Others: pharyngeal infections, eye, disseminated, gonococcal tenosynovitis Dx: Test of choice = PCR (certain cases TOC= culture) Gm stain more sensitive w/ males Isolation- selective media w/ growth factors, Ab agents inhibiting natural growth flora Uses GLUCOSE (all yellow slant) Rx: Uncomplicated- Ceftriaxone IM OR CEFIXIME PO REPORTABLE DISEASE |
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Neisseria meningitidis
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Share char of Neisseria sp.
Important cause of meningitis- all age grps 13 serogroups Asymptomatic nasopharyngeal carriage Colonization in closed pop. Groups B, C, Y most severe Recurrent assoc w/ complement deficiencies C5, C6, C7, C8. C9 Most cases sporadic Pathogenesis: Important** Polysaccharide capsule, Lipo-oliogsaccharide- endotoxin (gets in blood->brain) Bacteria proliferates, replicates, evades host immunity, intense host cell cytokine response Syndromes: Bacteremia w/o sepsis; Meningitis-neurologic sequelae; Meningococcemia (Waterhouse-Frederichsen Syndrome w/ adrenals) Meningococcal Meningitis (fever, chills, myalgias, arthralgias, headache, confusion, nuchal rigidity, meningococcemia rash, perpipheral gangrene from vasculitis, complete hemorrhage in adrenal glands-WFS) Dx: exam CSP via LP; on culture demonstrate glucose, maltose use Rx: Meningitis/Meningococcemia- PCN (alt: Ceftriaxone OR Chloramphenicol) Prophylaxis: Rifampin, Ciprofloxacin, Ceftriaxone Vaccines: Polysaccharide tetravalent vaccine (only given to at risk groups, >55) Tetravalent conjugate vaccine- 2-55 yrs., polsac conjugated to diphtheria toxoid; T-cell dependent response induced; MCV4 recommended for most Only general pop group- 11-19 yrs. Indications for vaccine: asplenia, complement deficiencies, taveling to endemic areas, closed populations |
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Anaerobes
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DO NOT grow in presence of oxygen
Two major groups: Obligate anaerobes Aerotolerant anaerobes Habitats: widespread (environment, animals/humans- oral cavity around teeth, GI tract, skin, orifices of GU tract) Low oxygen tension and reduced oxidation reduction potential Pathogenesis: Disruption of normal mucosal barriers Synergy w/ aerobes, anaerobes Virulence: capsules, adhesins, enzymes, toxins Common anaerobic infections: Brain abscess, empyema Clinical dx: foul smelling discharge, gas in tissues, inf in proximity to mucosal surface, neg aerobic cultures Lab dx: non-sterile specimens BAD, Swabs BAD, Aspirates & Tissue biopsies BEST, anaerobe transport media! Growth: Brucella agar (w/ blood, hemin, vit K1, antibiotics) Identification: Gm stain, morphology, pigmentation, fluorescence |
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Peptostreptococcus
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Anaeorbic Gm+ cocci
Variable size/shape Found on skin, mucous membranes Cause of bacteremia, mixed inf |
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Propionibacterium Species
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Anaerobic Gm+ rods, pleomorphic
Normal flora of skin, mucous membranes Non-spore forming Pathogenesis of Acne Infections of medical devides Blood culture contaminant |
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Actinomyces
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Anaerobic Gm+ rods
Slow growing "molar tooth" colonies Clinical Signif: Actinomycosis Progressive infection Purulent foci surrounded by dense fibrotic tissue Late stages: dev of sinus tract w/ drainage- sulfur granules |
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Clostridium Species
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Obligately Anaerobic Gm+ bacilli
Spore forming Pleomorphic Motile Inhabitants of GI tract of humans Broad range of disease: Tissue inf-food poisoning- septicemia |
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Clostridium perfringes
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Most important Clostridium species!
Obligate anaerobe gm+ bacilli Disease: Clostridial myonecrosis "gas gangrene"- Prod of potent alpha toxin, PLC Food poisoning- Elaboration of enterotoxin after ingestion of contaminated food Clostridial myonecrosis- septic appearance, gas in tissues Rx: Surgical debridement, PCN G plus clindamycin, Supportive care |
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Clostridium difficile
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Obligate anaerobic Gm+ bacili
Major cause of Ab assoc diarrhea and pseudomembranous colitis Pathogenesis: 2 potent toxins: Toxin A- enterotoxin- diarrhea Toxin B- cytotoxin- destroys cells (blood in stool) Dx: **Direct detection of toxin in stool (enzyme immunoassays, cell culture cytotoxicity assay, PCR) Rx: withdrawal of Ab agents; rx w/ oral metronidazole or vancomycin |
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Clostridium botulinum
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Obligate anaerobe Gm+ bacilli
Causes botulism Major types: Foodborne- preformed toxin Infant- prod of toxin in vivo by C. bot in GI tract, most common in US Pathogenesis: Toxin prod., neuro toxin blocks release of Ach in NMJ Clinical Pres: Incubation 18-36hrs-Afebrile, alert, oriented, normal sensory exam-Cranial nerve symptoms Motor symptoms (progressive)- bilateral descending flaccid paralysis->resp paralysis Dx: Demonstration of toxin in serum, gastric fluid, stool by mouse bioassay (Public Health Lab) Rx: Supportive Care (Airway); Trivalent equine serum; Infant- human botulism immune globulin |
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Clostridium tetani
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Obligate anaerobe Gm+
Widespread dist of C. tetani spores in soil, aquatic Pathogenesis: spore contamination of wounds Spores germinate under low redox potential created by poor vascular flow Vegetative cells multiply and release tetanospasmin Tetanospsmin attaches to peripheral motor nerve endings and travels along nerves to CNS Toxin binds gangliosides in CNS, blocks inhib impulses- prolonged muscle spasms Vaccine preventable Rx: Supportive care (Airway, antispasmodics); Administer human tetanus IgG, adsorbed tetanus toxoid, Ab (metronidazole) |
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Clostridium septicum
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Obligate anaerobe Gm+
Bacteremia assoc w/ malignancy Path mech: translocation of organisms at site of mucosal damage Rx: PCNG, supportive care |
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Zoonosis
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Any infectious disease that may be transmitted from other animals, both wild and domestic, to humans or from humans to animals
Bacterial zoonoses- via direct contact w/ animals/infected materials, animal bites/scratches, arthropod vectors, contaminated food |
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Leptospirosis
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Bacterial Zoonosis
Leptospira- spirochete Abundant in tropical regions Zoonosis aquired via contaminated animal/rodent urine- water/soil, skin abrasians/conjunctivae, domestic pets/livestock Disease: Leptospirosis Clinical Pres: fever, headache, myalgia, abd pain, conjunctival suffusion; 5-10% develop icteric form (Weil's disease) that can precede: renal failure pulm hemorrhage cardiac arryth uveitis death Pathogenesis: Non-immuno: motility, hemolysins, adhesins, hemostasis and coag genes Immuno: Proinflammatory response to bac LPS thru TLR2; MOF;Pulm hemorrhage (IgG and complement fixation on host cells); uveitis during "immune" phase only Dx: culture useful during acute spirochetemia (1st wk); microagglutination test Rx: doxycycline, penicillin, cefotaxime |
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Brucellosis
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Bacterial Zoonosis
alpha-2 proteobacteria Gm- coccobacilli Facultative intracellular bacterium - B. melitensis - B. abortus Human transmission: oral contamination from domestic farm animals, consumption of unpasteurized dairy products Clinical Manifestations: classical febrile brucellosis- acute infection, fever sweating, malaise, headache weight loss, arthralgias, myalgia Relapsing or undulant brucellosis (Malta fever)- occurs >2 mo after classical if untreated, liver involvement, uveitis, may be chronic Complications: peripheral arthritis, sacroilitis, spondylitis (lumbar spine, potential genetic mutation) Epididymoorchitis, abortion, granulomatous hepatitis, meningitis, endocarditis, relapse Dx: Blood/bone marrow culture; detection of Ab Rx: doxycycline + rifampin or streptomycin/netilomycin 4-6 wks |
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Bartonella henselae
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Bacterial Zoonosis
Small Gm- rods Mammalian, arthropod reservoirs alpha-2 proteobacteria Facultative itnracellular Infect erythrocytes or endothelial cells Disease: Cat scratch disease Clinical Dx: regional lymphadenophy, cat/kitten scratch/bite, inoculation papule Pathogenesis: inoculation, spread by lymph nodes, resolves spon. Histo: stellate microabscess in granuloma Episcleritis Parinaud's oculoglandular syndrome, Cat-Scratch neuroentitis Flea vector in animals Bacillary angiomatosis, peliosis, endocarditis in immune comp hosts- prolif of capillaries and blood vessels Pathogenesis: infection-binding-invasion-replication/persistence- spread to humans or transmission by blood-sucking arthropods |
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Chlamydia
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Obligate intracellular
Contain DNA, RNA, ribosomes- "True Bacteria" No peptidoglycan layer Unique BIPHASIC lifecycle (EB, RB) EBs are small infectious forms of chlamydia Rx: Tetracyclines (doxycycline) and macrolides (azithromycin) |
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Chlamydia trachomatis
D-K |
D-K serovars- common genital infections & conjunctivitis
Infects non-ciliated columnar epithelial cells Disease: scarring trachoma (from body's rxn); blinding trachoma; PID; cervicitis Perinatal transmission- neonatal conjunctivitis 30-50% Untreated infections- PID, infertility, ectopic preg D-K: male- urethritis, epididymitis; women- urethritis, cervicitis, PID, ectopic preg both: pharyngitis, pneumonia, conjunctivitis, proctitis NOTIFIABLE disease; reinfection very high Dx: PCR |
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Chlamydia trachomatis L1-L3
LGV Lymphogranuloma venereum |
Aggressive, systemic disease
3 stages: Primary- genital lesion Secondary- regional lymphadenopathy + systemic symptoms Tertiary- genital elephantiasis, strictures, fistulas Cause thrombolymphangitis Dx: PCR |
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Chlamydia trachomatis
Trachoma: Serovars A, B, Ba, C |
Chronic keratoconjnctivitis
Leading cause of preventable blindness Transmission hand to eye, via fomites, flies Repeated episodes of reinfection w/in family cause chronic follicular conjunctival inflammation (active trachoma)-> tarsal conjunctival scarring- distorts tarsal plate- corneal scarring, blindness Clinical Dx |
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Chlamydia pneumoniae
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Common cause of URI, LRI
bacterial cause of "atypical pneumonia" |
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Chlamydia psittaci
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Common in birds
Risk factors: pet owners, poultry farmer Most common manifestation: severe "atypical pneumonia" Dx: PCR, no culture |
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Mycoplasma
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Prokaryotes that lack a cell wall
Cell membrane w/ sterols RNA, DNA TINY Mycoplasma pneumoniae- URTI, atypical pneumonia Mycoplasma genitalium Associated w/ urethritis, cervicitis Smallest prokaryote bac capable of self-rep Rx: Doxycycline, macrolides, fluroquinolones |
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Leprosy
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M. Leprae- obligate intracellular parasite
Cannot be cultivated in lab Armadillos = natural reservoir Distribution in cooler parts of body Muscular and sensory nerve damage Tuberculoid v. Lepromatous Lepromatatous:: weak immune response, numerous bacilli, sheets of macrophages, non-reactive Lepromin test Tubercculoid: strong immune response, few bacilli, granulomatous reaction, reactive Lepromin test Bacteria multiply in tissue macs and Schwann cells Reversal Rxn: Treatment of BB may -> immune reconstitution Erythema nodosum leprosum- pts w/ BB or LL- fever, eruption of tender red nodules Examine for erythematous or hypo-pig skin lesions w/ sensory loss; enlarged peripheral nerves Skin biopsy |
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Tuberculosis
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2nd main killer among infectious disease
Epi: poverty, overcrowded housing, undernourishment Rapid dx of TB: Nucleic acid amplification Positive test strongly supports dx Negative test does NOT exclude TB Micro: Mycobacterium tuberculosis Acid-fast; high lipid content Obligate aerobes Capacity to survive intracellulary Person-person small droplets |
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Primary TB
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Middle or lower lung fiends receive greatest volumen of air
Nuclei implant on resp bronchioles/alveoli Bacilli elicit non-specific PMN response (not seen) Alveolar macs engulf mycobacteria Bacilli remain viable and multiply WITHIN macs Somes macs process/present antigens to T-helpers T-helpers release lymphokines- activate/attract macs Blood born monocytes enter lesion, macs activated and form granuloma Ghon focus= initial site of implantation Ghon complex= Ghon focus + lymph node Simon Foci- bacilli can travel to lung apices (higher oxygen tension) Apical scars harbor more bacilli Progressive Primary TB- primary infection progresses (esp in immunocomp) Miliary TB- Spread by bloodstream; numerous small lesions TB Bronchopneumonia- Spread by airways; nodules cluster/vary in size |
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Post-Primary TB
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Infections that develop in individuals w/ immunity to bacillus
REACTIVATION (Simon Foci) or REINFECTION of previously infected ** Cavitation= hallmark Progressive Post Primary: Enlarging cavity erodes into: Airway = TB bronchopneumonia Vein = Miliary TB Pleura = TB empyema Artery = Massive hemorrhage Cavity heals = Aspergilloma Prevention: Treat TB-positive pts w/ upper lobe fibrotic lesions w/ (INH) |
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Non-TB Mycobacteria
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Atypical mycobacteria
Free-living Opportunistic pathogens Acquired from environment Infect individuals w/ underlying lung dis. or immunocomp 4 Grps based on pigmentation, colony growth, morphology Clinical scenarios: Lymphadenitis, Inhalational pulmonary disease, Disseminated disease, Skin/skin structure infection |
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HIV & TB
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HIV depletes CD4+ cells, decreases monocyte/macrophage fxn
TB usually dx 6mo before opportunistic infections Often extrapulmonary Poorly dev granuloma Drug resistant TB Negative PPD (like lepramatous leprosy) |
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HIV and Non-TB Mycobacteria
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Non-TB mycobacteria common in pts w/ AIDS
Enters GI tract Occurs late in disease course No granulomas Histiocytes packed w/ bacilli |
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Mycobacteria
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Acid-fast
Grow slowly, may be over grown -Use sterile specimens -Non-sterile specimens require decontamination Culture- more sensitive than smear, weeks to grow, importance: species ID, drug susceptibility, monitoring Rx response DNA probes for speciation |
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Mycobacterium avium complex
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NTM
Selected Slow Grower Environmental organism 3 main clinical syndromes: Lymphadenitis Pulmonary Disease Disseminated infection in AIDS NTM lung dz: Underlying lung dz common Dx: Clinical- typical symptoms, radiographic appearance + exclusion other dx Microbiologic- Pos culture 2 sep sputa OR Pos culture 1 bronchoscopy OR biopsy evidence of granulomas + pos culture Hot Tub Lung |
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Mycobacterium marinum
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NTM
Selected Slow Grower Inhabits aquatic, marine environ Natural pathogen of fish Chronic ulceronodular skin disease = occupational hazard "Fish tank granuloma" |
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Mycobacterium ulcerans
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NTM
Selected Slow Grower Aquatic? Only toxin-prod mycobacterium Etiologic agent of Buruli ulcer |
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M abscessus
M. chelonae M. fortuitum |
NTMs
Rapidly-growing Form colonies <7days Home, hospital environ- fluids, devices Opportunistic- surgical site, implant-assoc Dx: AFB (more susceptible to decolorization, so notify lab) |
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Nocardia
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Aerobic
Gm+ FILAMENTOUS Rod Soil, decaying vegetation Inoculation or Inhalation NO PERSON-PERSON Cutaneous: cellulitis, abscess, lymphocutaneous, mycetoma Pulmonary & Disseminated: assoc w/ reduced cell-mediated immunity Nodular and/or cavitary infiltrates Disseminates to brain, skin Cultured on blood agar |
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Special metabolic features of MYCOBACTERIA
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Replicate intra- and extracellularly
Capable of prolonged metabolic inactiviy/dormancy Dormant organisms less susceptible to killling Need for prolonged therapy to completely eradicate Antimycobacterial drug resistance: Primary: Mutation rate CANNOT treat TB w/ single drug if pt has clinically apparent dz! Secondary: Acquired due to Noncompliance, MDR TB- resistance to isoniazid and rifampin EXceptionally drug resistant- XDR TB- combined resistance to all first-line drugs All suspected/proven cases of TB- Rx = 4 drugs for first 2 mo, followed by 4 mo of 2 drugs org is sensitive to Mycobacteria ALWAYS acquire resistance to drugs thru chromosomal mutation MDR facilitated by noncompliance |
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Isoniazid
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Mycobacterial drug
INH Nicotinamide analog- IsoNicotinic acid Hydrazine Mech: Bactericidal, inhibits synthesis of mycolic acids, inhibits NRG-requiring pathways, accumulates inside mycobacteria, FORMS OXYGEN FREE RADICALS Resistance: katG (catalase-peroxidase enzyme); inhA (enzyme for mycolic acid syn) PK: metab by hepatic N-acetyltransferase Tox: Hepatitis (reversible, prob never fatal if transaminases monitored) Neurotoxicity (prevented w/ VitB6) Hypesens, Drug-Induced Lupus |
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Rifampin
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Mycobacterial drug
Semi-synthethic macrocyclin Broad Spectrum inhibitor of bacterial DNA-dependent RNAP BacteriCIDAL against most Gm+, some Gm- Eradicates nasal carriage of NeissMen Resistance rapid PK: metab by deacetylation; biliary excretion, enterohepatic recirculation; non-linear - can accumulate Potent inducer of CYP450 Resistance: RNAP gene mut Tox: Orange disc of body fluids, Hepatitis, Hypersensitivity Rifabutin & Rifapentene are similar to rifampin, approved in US, but not commonly used |
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Pyrazinamide
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Mycobacterial drug
PZA Mech: sructural analong of nicotinamide Highly bacteriCIDAL Active at acidic pH *useful at killing intracellular myco Not effective against dormant org. PK: metab to pyrazinoic acid, renally excreted Toxicity: hepatotoxicity; hyperuricemia (can precipitate gout); photosensitivity (so give drug at night) |
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Ethambutol
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Mycobacterial drug
Mech: bacterioSTATIC; inhibits both RNA sy and mycolic acid metab Tox: can induce peripheral neuropathy, esp retrobulbar optic neuritis w/ color blindness -> loss of peripheral vision MONITOR W/ EYE EXAMS |
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Para-Aminosalicyclic Acid
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Para-Aminosalicyclic Acid (PAS)
Analog of para-aminobenzoic acid Folate antagonist (probably) Used in children in US GI TOXICITY! Hypersensitivity Drug-induced lupus |
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Dapsone
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Leprosy drug
A sulfone (sulfonilamide analog) Inhibits folate synthesis Resistance common b/c use as monotherapy for leprosy Toxicity: Hemolytic anemia (esp in G6PD deficiency) Hypersensitivity rxns Reversal reaction & erythema nodosum leprosum may occur during initiation of Rx (kills bac so quickly, cells lyse- severe inflammatory response- skin lesions on limbs esp lower legs) PK: metab by n-acetylation genetic polymorphismin dapsone metab Other leprosy drugs: Clofazimine Rifampin Ethionamide (INH analog) Use 2-3 drugs for <6mo Regimens: Pauci-bacillary leprosy: Rifampin and Dapsone for 6 mo Multi-bacillary leprosy:Rifampin, Clofazimine, Dapsone for 12 mo |
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Rifabutin
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Structural analog of rifampin
More potent in vitro Longer half-life FDA approved for prophylaxis of Myco avium in AIDS pts w/ CD4< 100 Resistance: RNAP gene mu Cross-resistance btwn rifampin and rifabutin Toxicity: orange-brown discoloration of urine etc., Uveitis (infl of anterior chamer of eye) Dose dependent |
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Yersinia pestis
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Plague
Transmission -Flea bite- bubonic -Aerosol- pneumonic plague -Either- septicemic plague Africa, Asia, N. & S. America Rapid spread, growth in tissues, blood HIgh case fatality rate Extensive tissue necrosis w/o extensive inflammation -Bacterium suppresses leukocyte fxn (Yops, LcrV) -LPS activates systemic inflammatoy responses, coagulation, fibrinolytic pathways (sepsis) -Pla protease permits tissue destruction, complement degradation Dx- clinical suspicion, blood culture, bipolar staining Rx- streptomycin, doxycycline, sulfonamides |
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Borrelia burgdorferi
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Lyme Disease
Tick bite transmitted N. America, Europe, Asia Early localized infection- erythema migrans Early disseminated- mult. erythema migrans, CNVII palsy, carditis (arrhythmias), oligoarticular arthritis, meningitis Late infection arthritis, encephalopathy Post-Lyme disease syndrome- no response to antibiotics Clinical manifestations- from infl response to spirochetal lipoproteins Dx- clinical, culture, SEROLOGY Rx- amoxicillin, doxycycline, ceftriaxone (CNS infections) |
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Rickettsia rickettsii
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Rocky Mountain spotted fever
Tick-bite transmitted N., C., S., America High fever, headache, maculopapular-petechial rash after 3-5 days Normal WBC count w/ left shift; thrombocytopenia Underlying pathology- lymphohistiocytic vasculitis results in loss of intravascular fluid -hypotension, end-organ ischemic injury -cerebral edema -pulmonary edema HIGH case fatality rate Dx- clinical, Serology to confirm Rx- DOXYCYCLINE |
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Quinolones
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Mechanism: Inhibition of prokaryote type II topoisomerase, DNA gyrase, and topoisomerase IV
Stabilize DNA-topoisomerase intermediate, the "cleavable complex" KILLING IS NOT DUE TO ENZYME INHIBITION BUT RATHER TO THE PRESENCE OF CLEAVABLE COMPLEXES, WHICH LEAD TO IRREVERSIBLE BREAKS IN DNA Selective Tox: Fluoroquinolones bind selectively to DNA-gyrase or DNA-topo IV complexes Resistance: mut in gyrase, topoIV at DNA-binding subunit Gm- Gyrase DNA-binding subunit GM+ TopoIV DNA-binding subunit Spectrum: 1st gen- only Gm-; 4th gen extends to Gm+ and anaerobes PK: Absorption- rapid, complete, bioavailability 85%, reduced by coadmin w/ Mg2+, iron Dist- widely Metab- Ciprofloxacin- phase I enzymes (oxidation) (interferes w/ theophyline metab) Moxifloxacin- phase II enzymes (conjugation) Elimination0 Renal, some biliary Tox: Some GI, CNS, skin Postmarketing surveillance has taken three drugs off market |
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Reproductive Number, R
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Ratio of new infectious organisms (or infected cells) produced after some arbitrary time period during with the organism is replicating.
Ratio After: Before R >1; organism will gro and reporduce. R <1; organism will expire (in indiv.) or become extinct (in population) R is always < 1 in presence of effective antimicrobial rx R is > 1 in drug resistant organism in presence of antimicrobial drug |
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Primary drug resistance
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Pre-dates drug therapy
Most primary drug resistance exists because of improper use (or overuse) of antibiotics |
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Secondary drug resistance
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Occurs during drug therapy.
Non-adherence to a prescribed drug regimen is the cause of most infections exhibiting secondary resistance. |
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Inactivation of antibiotic
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B-lactamase-catalyzed inactivation of B-lactams
Acetylation, adenylation, phosphorylation of AGs Acetylation of chloramphenicol |
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Modification of antibacerial target
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Alteration of D-ala-D-ala to D-ala-D-lac in peptidoglycan pentapeptide target of vancomycin
Alteration of PBPs Methylation of rRNA to block macrolide bonding Point mutation in RNAP to block rifampin binding Point mut in DNA gyrase to block quinolone binding |
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Efflux of antibiotic
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Resistance to tetracyclines
Resistance to macrolides Resistance to quinolones |
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Key Resistance points
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Resistance mech in clinical pathogens are reminiscent of self-resistance mech in antibiotic producing organisms
Resistance determinants are clustered with biosynthetic genes for production of antibiotic in producing organism *Practical implications: combination therapy, selective removal/restriction of Ab classes |
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Genital ulcer diseases
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Syphilis
Herpes Chancroid Lymphogranuloma venereum- LGV |
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Syphilis
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Treponema pallidum
Spirochetes Cannot be cultured in vitro Paucity of proteins on outer membrane Little genetic diversity Path: Spirochete penetrates abraded skin; disseminates thru lymph/blood to ANY organ Incubation period about 3 weeks |
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Stages of Syphilis
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Primary Syphilis: Chancre- single papule at site of inoculation which develops into an ulcer; ulcer is painless, well demarcated, edges heaped up, smooth base (women often unaware of primary stage)
Secondary: Occurs 2-8 weeks after appearance of chancre if untreated Skin manifestation most common (palms, soles rash) fever, lymphadenopathy, early neurosyphlis, meningitis Latent Syphilis: Pts become asymptomatic Early latency- 1st year; pt can relapse into secondary syphilis, still infectious Late latency- follows early latency; host is immune to relapse and to reinfection VERTICAL TRANSMISSION AT ALL STAGES SEXUAL TRANSMISSION IN EARLY STAGES Late Syphilis- Gummas & Cardiovascular syphilis Gummatous- benign, granulomatous-like lesions; affect skin, bones; local destruction Cardiovascular- endarteritis obliterans of vasa vasorum of aorta leading to aortitis and saacular aneurysms Late neurosyphilis- symptomatic- 10 yrs after primary infection; 2 grps Meningovascular- medcerebal artery stroke Prechymatous- Tabes Dorsalis; General Paresis Pathophys: T. pallidum produced MMP-1; Treponemes disseminate; induces endothelial cells to express ICAM-1, VCAM-1, E-selectin (signal inflam cells); PMNS respond first |
Dx: DARKFIELD MICROSCOPY
Serology: Non treponemal tests: RPR, VDRL (nonspecific tests) FIRST TEST, CHEAP If positive- confirm w/ TREPONEMAL TEST **Abs haven't formed yet in Primary Stage **Gives Ab titer- 4 fold reduction = successful Rx **Usually if you see ulcer, treat empirically Congenital Syphilis: Infection of fetus in utero CAN OCCUR AT ANY STAGE Infection in fetus occurs AFTER 4th month gestation Manifestations: rhinitis, rash, anemia, jaundice, Late: neurosyphilis, deafness, keartitis, arthropathy, Hutchinson's teeth Rx: PCN; ALL Sex partners preceeding 60 days must be treated; always test pts who have syphilis for other STIs Early stages: 2 shots benz PCN-G in bum (2.4 million units) 3X in late phase! TREPONEMAL TESTS (MHA-TP, FTA-ABS-Test for Abs that are treponemal-specific; EXPENSIVE. Once positive, ALWAYS Positive |
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Granuloma Inguinal Donovanosis
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Klebsiella granulomatis
Painless progressive ulcerative lesions w/o regional lymphadenopathy; beefy red, highly vascular Dx: tissue biopsy Rx; Doxycycline 100mg po BID X 3 weeks |
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Chanchroid
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Haemophilus ducreyi
Symptoms: painful genital ulcer, tener suppurative inguinal adenopathy Dx: culture Rx: Azithromycin 1g PO X1 OR Ceftriaxone 250 mg IM X1 |
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Pain & GUD Lesions
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Syphilis, LGV, GI- PAINLESS ULCERS
Herpes, Chancroid- PAINFUL ULCERS |
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PID Pelvic Inflammatory Disease
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Infection spreading to upper genital tract in women
Symptoms: abdominal pain, fever Signs: Uterine tenderness, cervical motion tenderness Complications: infertility, chronic pelvic pain, ectopic pregnancy |
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Proctitis
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Neisseria gonorrhoeae
Chlamydia trachomatis HSV 1 & 2 Pts may be infected buy asymptomatic Symptoms: pain on defecation, rectal discharge (blood, mucus) |
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Urethral, vaginal, cervical inflammation
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Neisseria gonorrhoeae
Chlamydia trachomatis Trichomonas vaginalis Symptoms: pain w/ urination, increased frequency of urination, a urethral/cervical/vaginal discharge and in men, testicular pain (epididymitis/orchitis) |
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Prophylaxis
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Use of antimicrobial agents to prevent the development of an infection
-Pre-exposure (surgical) -Post-exposure (N.meningitidis) |
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Empiric treatment
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Use of antimicrobial agents when infection is suspected and patient is ill enough to require treatment (pt w/ possible sepis)
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Pathogen-directed treatment
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Use of antimicrobial agents to treat a proven infection
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Principles of Antibiotic Treatment
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Develop a differential diagnosis
Determine if Abs are necessary Choose an antibiotic Refine Ab choice Have a plan for length of Rx |
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Abs DO NOT have an effect on mild bacterial infections like:
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Acute bronchitis
Most acute sinusitis Most acute otitis media Most infectious disarrhea |
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When to Give Antibiotics
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Known focus of infection that requires antibiotic treatment to prevent the pt from getting sicker
(Acute meningitis, pneumonia, acute endocarditis, epidural abscess w/ evidence of cord compromise) W/O a known focus of infection and -Neutropenia and cancer w/ fever -Asplenic or functionally asplenic patients w/ fever -Highly immunosuppressed pts w/ fever -Toxic-appearing pts or those w/ unstable vital signs |
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When to Wait w/ Antibiotics
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Stable pateitn w/ subacute process in whom culture data may be hard to obtain but is critical to management
-Pt admitted w/ fever of unknown origin -Pt admitted w/ suspected vertebral osteomyelitis w/ o neurological symptoms -Pt admitted w/ weight loss and mass-like lesion in right middle loe of lung |
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Urine culture
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Source?
Symptoms? Urinalysis? Culture? -positive > 10^5 colonies -common: E.coli K. pneumoniae |
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Wound Culture
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Cx taken from newly incised and/or drained abscesses more reliable
-Signif pathogens usually result in heavy growth (S. aureus, Gram- rods) |
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Sputum Cultures
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Type 1: discarded, many squamous cells
Type 2: adequate, equal numbers of PMNs and squamous Type 3: good, moderate or many PMNs and rare or no squamous epithelia cells Type 4: spit |
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When to Stop Abs
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Started empirically:
Trust culture results MRSA and Pseudomonas grow easily; if not isolated, coverage can be stopped -No requirement to complete a course just b/c you started them empirically For specific pathogens: Length of most courses of Rx are artitrary and tend to be in multiples of 7 days |
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