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Pathogenicity and VirulencePathogen: organism capable of causing disease Viruses, bacteria, fungi, unicellular organisms, etc. To infect humans, pathogens must bypass a number of elaborate body
defenses Entrance may include broken skin, ingestion, inhalation or contact with
mucous membranes such as nasal, urinary or vaginal mucosaPathogenicity: ability of an organism to cause infection Only a few dozen pathogens cause disease in humansVirulence: microbe that can produce disease when present in minute numbersPathogens cause disease by one of two basic mechanisms:1. Invasiveness: ability to grow rapidly & cause damage by sheer number2. Production of toxins
Acquired Resistance Microorganisms have the ability to replicate rapidly
During cell division, bacteria make frequent errors in duplicating their genetic code (mutations)
Mutations occur spontaneously and randomly throughout the ribosomal chromosome
Although most mutations are harmful to the organism, mutations occasionally result in a bacterial cell that has reproductive advantages over its neighbors
The mutated bacterium may be able to survive in harsher conditions or perhaps grow faster than other cells
Mutations that are of particular importance to medicine are those that confer drug resistance to a microorganism
Acquired Resistance Antibiotics promote the development of drug-resistant bacterial
strains
Killing populations of bacteria that are sensitive to the drug leaves behind those microbes that possess mutations that made them insensitive to the effects of the antibiotic
Drug-resistant bacteria are then free to grow, unrestrained by their neighbors that were killed by the antibiotic, and the patient develops an infection that is resistant to conventional drug therapy = acquired resistance
Natural PenicillinsAgents: Penicillin G, Penicillin V (Pen V, Pen-VK)
MOA: Binds to receptors (penicillin-binding proteins) on the bacteria’s cell wall which results in cell lysis
Spectrum: Against gram positive, less active against gram negative, limited anaerobic activity
Adverse
Effects:
Hypersensitivity reactions, rash, phlebitis, diarrhea, GI upset, sodium/potassium overload, renal dysfunction, C. difficile, seizures, fever, thrombocytopenia
Comments: Anaphylaxis: 0.04% to 2%Streptococcal, meningococcal infections and neurosyphilisUsed infrequently due to resistanceShould be given 1-2 hours before or after meals
MOA: Binds to receptors (penicillin-binding proteins) on the bacteria’s cell wall which results in cell lysis
Spectrum: Beta-lactamase producing Staph (usually limited to treatment of these bacteria); less active than natural penicillins against gram positive, no gram negative or anaerobic activity
Adverse
Effects:
Hypersensitivity reactions, rash, phlebitis, diarrhea, GI upset, sodium/potassium overload, renal dysfunction, C. difficile, seizures, fever, thrombocytopenia
Comments: Anaphylaxis: 0.04% to 2%DOC for MSSA infectionsEmpirical use has decreased due to resistance
MOA: Binds to receptors (penicillin-binding proteins) on the bacteria’s cell wall which results in cell lysis
Spectrum: Extended-spectrum; active against anaerobes in addition to gram negative and gram positive bacteria
AdverseEffects:
Hypersensitivity reactions, rash, phlebitis, diarrhea, GI upset, sodium/potassium overload, renal dysfunction, C. difficile, seizures, fever, thrombocytopenia
Comments: Anaphylaxis: 0.04% to 2%Pip/tazo: diabetic foot infection, HAPAmp/sulb: animal/human bites, pyelonephritisTicar/clav: second line for Stenotrophomonas
MOA: Binds to receptors (penicillin-binding proteins) on the bacteria’s cell wall which results in cell lysis
Spectrum: Active against anaerobes, some gram positive, gram negative as well as Pseudomonas
Adverse
Effects:
Hypersensitivity reactions, rash, phlebitis, diarrhea, GI upset, sodium/potassium overload, renal dysfunction, C. difficile, seizures, fever, thrombocytopenia
Comments: Anaphylaxis: 0.04% to 2%Adjust dose for renal impairmentPiperacillin: on drug shortage listRarely used if availableRequires frequent dosing (q4h)
MOA: Binds to receptors (penicillin-binding proteins) on the bacteria’s cell wall which results in cell lysis
Spectrum: Very active against gram positive cocci, inactive against enterococci and MRSA; limited activity against gram negative (E. coli, Klebsiella, & Proteus)
Adverse
Effects:
Phlebitis, diarrhea, allergic reactions, rash, C. difficile, seizures, fever, thrombocytopenia
Comments: Cross-reactivity with PCN allergy: 10%Adjust dose for renal impairmentDOC for antibiotic prophylaxis, cellulitisNot for CNS infections
Comments: Cross-reactivity with PCN allergy: 10%DOC for antibiotic prophylaxis (GI procedures), CAP, abdominal and pelvic infectionsNot for CNS infections
MOA: Binds to receptors (penicillin-binding proteins) on the bacteria’s cell wall which results in cell lysis
Spectrum: Most of these agents are active against gram positive but less than the first generation cephalosporins; major advantage is their expanded gram negative coverage
Adverse
Effects:
Phlebitis, diarrhea, allergic reactions, rash, C. difficile, seizures, fever, thrombocytopenia
Comments: Cross-reactivity with PCN allergy: 10%DOC for CAP, UTI, meningitis, endocarditisCeftazidime effective vs. Pseudomonal infections
MOA: Binds to receptors (penicillin-binding proteins) on the bacteria’s cell wall which results in cell lysis
Spectrum: Broad spectrum; active against gram positive and gram negative bacteria
Adverse
Effects:
Phlebitis, diarrhea, allergic reactions, rash, C. difficile, seizures, fever, thrombocytopenia
Comments: Cross-reactivity with PCN allergy: 10%Adjust dose for renal impairmentDOC for HAP, neutropenic feverCan be used for CAP, skin/soft tissue infectionsRole in therapy still to be definedGenerally not considered first line agent
Comments: Cross-reactivity with PCN allergy: thought to be fairly high (up to 40%)Not active vs. MRSA,VRE, atypical pathogens or StenotrophomonasErtapenem does NOT cover Pseudomonas, but does still cover ESBLShould NOT be used routinely
(Biaxin), fidaxomicin (Dificid)MOA: Inhibit protein synthesis by reversibly binding to the 50S
ribosomal subunit of the bacteria resulting in cell deathSpectrum: Limited gram positive activity, little gram negative activity,
active against Chlamydia and MycoplasmaAdverseEffects:
GI intolerance: diarrhea, nausea, metallic taste (possibly less with azithromycin & clarithromycin), cholestatic hepatitis, rash
Comments: Many drug-drug interactionsDOC for atypical PNA coverageAzithromycin: MAC prophylaxis & treatment, chlamydial infectionsFidaxomicin: Clostridium difficile infection only
Telithromycin (Ketek) MOA: Similar to that of macrolides, and is related to 50S-ribosomal
subunit binding with inhibition of bacterial protein synthesis
Spectrum: Similar to macrolides, with additional activity against multi-resistant S. pneumoniae (including erythromycin-resistant and penicillin-resistant strains), methicillin-resistant Staphylococcus aureus, H. influenzae, and enterococci
MOA: Inhibits protein synthesis of bacteria (does not produce cell death, but halts cell reproduction)
Spectrum: Active against gram positive and gram negative as well as anaerobes, mycoplasma, rickettsia, chlamydia
AdverseEffects:
GI intolerance, stains and deforms teeth in children, vertigo, affects bone growth, phlebitis, photo-sensitivity, hepatotoxicity
Comments: Many drug-drug & drug-food (Ca, Fe) interactions DOC for atypical PNA coverage, acneDue to the emergence of resistance these agents have lost most of their usefulnessNOT for CNS infections
Tetracyclines – continued Contraindicated in children < 8 years of age yellow-brown discoloration
of the teeth
Pregnancy category D effect linear skeletal growth of the fetus and child
Decrease the effectiveness of oral contraceptives
Toxic effects may occur if taken past the expiration date (do not save medication)
Do not take with milk products, Fe supplements, Mg-containing laxatives or antacids
o Wait 1-3 hours before taking antacids; Wait at least 2 hours before taking lipid-lowering drugs such as colestipol (Colestid) and cholestyramine (Questran)
May increase the risk of oral/perineal Candida (?)
MOA: Inhibits protein synthesis (irreversibly binds to 30S ribosomes) resulting in cell death
Spectrum: Active against gram negative organisms; given in combination with beta-lactam for gram positive synergy (never use alone for the treatment of gram positive infections)
MOA: Inhibits the conversion of dihydrofolic acid in the bacteria halting reproduction
Spectrum: Inhibits gram positive and gram negative organisms; active against toxoplasma and PCP
Adverse Effects:
Pruritus, photosensitivity, GI intolerance, renal failure, hyperkalemia, bone marrow suppression, SJS
Comments: Combination of trimethoprim and sulfamethoxazole results in bacteria cell deathAdjust dose for renal impairmentPrimary use: UTI, MRSA skin infections, PCP treatment and prophylaxis
Comments: Drug of last resort!Primary use: VRE, VRSA, alternative to vancomycin for MRSAResistance can occur during treatmentSeveral drug-drug interactionsReduce dose in hepatic impairmentIncompatible with saline solutions
MOA: Binds to the 30s subunit on the ribosome and interferes with bacterial synthesis (bacteriostatic) glycylcycline, is a derivative of minocycline (tetracyclines)
Spectrum: Broad spectrum: active against gram positive, gram negative, anaerobes and atypical organisms
Comments: Uses: Traveler's diarrhea, hepatic encephalopathyResistance is a concernHepatic encephalopathy: rifaximin may suppress gastrointestinal floraDo not use for infectious diarrhea due to pathogens other than Escherichia coli
Comments: Not an agent of first choiceAdjust dose in renal impairmentAvoid use during pregnancy; women of childbearing potential should have a serum pregnancy test prior to administrationBBW: may increase mortality in patients with pre-existing moderate or severe renal impairmentREMS program: avoid exposure during pregnancy
Differences in TB Drug Therapy3 Differences in Treating TB vs. Other Infections:
1. Mycobacteria have a cell wall that is resistant to penetration by anti-infective drugs For medication to reach the organisms in tubercles, therapy must be for 6
to 12 months2. Pharmacotherapy requires at least three and sometimes four or more
antibiotics administered concurrently Mycobacterium grow slowly and resistance is common Using multiple drugs in different combinations for long periods of time
lowers the potential for resistance and increases the success of therapyo Two broad categories of antitubercular drugs:
First-line agents: safer and generally, the most effective Second-line agents: more toxic, less safe and reserved for when
resistance develops3. TB drugs are used extensively for chemoprophylaxis
Comments: Approved only for MDR TB w/ 3 other agentsShould be used only when other effective treatment regimens cannot be offeredNot recommended for drug-sensitive tuberculosis, latent TB or for extra-pulmonary tuberculosisBBW: QT prolongation