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57 Cards in this Set
- Front
- Back
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MIC
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Minimal inhibitory concentration
-Concentration of antimicrobial that inhibits growth -Commonly used by clinical lab |
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MBC
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Minimal bacteriocidal concentration
-Concentration that kills bacteria -Used clinically only in special circumstances |
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Breakpoint
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The MIC that is used to designate between sensitive and resistant. Arbitrarily set by a committee
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Bacteriostatic
Bacteriocidal |
Antibiotic that reversibly inhibits growth. Host defenses usually complete killing and eradication
Antibiotic that kills microorganisms rapidly. Probably important for difficult to treat infections (e.g. endocarditis, immunocompromised, neutropenics) |
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Time above MIC
Resistance, Susceptibility |
50% of dosing interval
If MIC > Breakpoint, resistant If MIC < Breakpoint, susceptible |
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Beta-lactam antibiotics overview
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Penicillins, cephalosporins, carbapenems, monobactam (aztreonam)
Binds to penicillin binding proteins (PBPs) in cell wall Bactericidal Spectrum dependent on subclasses within classes -R groups change pharmacokinetics and spectrum of activity Generally good serum, urine, tissue levels; CSF level variable Time dependent pharmacodynamics |
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Mechanism of action of Beta-lactam antibiotics
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Multiple types of PBP (numbered)
PBP also called transpeptidases Beta-lactam antibiotics act on PBP to inhibit cross-linking of peptidoglycan via pentaglycine bridge Autolysins degrade peptidogylcan forming spheroplast Osmotic dysregulation causes lysis |
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B-lactam Resistance
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Beta-lactamases
-Gram positive organism with one cell membrane/wall --Beta-lactamase diffuses away thus “weak” concentrations -Gram-negative concentrates beta-lactamase between membranes and b-lactam antibiotic needs to get through porins in outer membrane to reach periplasm -inducible Altered PBPs Decreased permeability |
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Beta-lactamase inhibitors
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“Suicide” molecules that resemble beta-lactams
Bind to beta-lactamase irreversibly at active site -Major effect Bind to PBP on bacteria (acts like antibiotic) -Minor effect Given in combination with beta-lactam antibiotic Clavulanic acid, Sulbactam, Taxobactam |
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Penicillin class antibiotics
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Penicillin—IV and PO
Aminopenicillin -Ampicillin-IV (Ampicillin/sulbactam) -Amoxicillin-PO Antistaphylococcal penicillin -Methicillin -Oxacillin -Nafcillin -Dicloxacillin—PO Extended spectrum (Antipseudomonal penicillin) -Ticarcillin (Ticarcillin/clavulanate) -Piperacillin (Piperacillin/tazobactam) |
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Penicillin G Use
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Directed therapy:
-Streptococci, including Group A, B strep. -Enterococci -Spirochetes: syphilis, Lyme, leptospirosis Empiric therapy -Dental/periodontal Resistance an an issue with: -Pneumococcus -Enterococci -Viridans streptococcus -NOT a concern in Group A & B Streptococcus |
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Penicillin Preparations
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Aqueous IV crystalline PCN
Procaine PCN -IM only -Doesn’t see much clinical use Benzathine PCN -Depot prep. with LONG half-life -Useful in Syphilis |
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Anti-staphylococcal penicillins
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methicillin, nafcillin, oxacillin, and dicloxacillin
Bacteriocidal for Staphylococcus Short ½ life (dose frequently) Resistance through PBP alteration -Termed “Methicillin Resistant S. aureus -Resistant to ALL Beta-lactams, not just methicillin -Transferred via “MecA” operon |
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Aminopenicillins overview
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Ampicillin, amoxicillin
-Extend PCN spectrum to more GNR (e.g. Haemophilus influenza (H. flu), H. pylori) -Amoxicillin for most Outpatient BACTERIAL sinusitis, Otitis media; Peptic Ulcer Disease--H. pylori |
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Aminopenicillins with clavulinate/sulbactam
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Augmentin, Unasyn
B lactamase inhibitor Extends to all H. flu, MSSA Excellent for anaerobes (both mouth and most gut) Makes an excellent head and neck, respiratory tract infection drug, |
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Anti-pseudomonal penicillins
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Know ticarcillin, piperacillin
Extends activity to include more GNR’s e.g.: Pseudomonas aeruginosa and anaerobes No useful oral antipseudomonal penicillin |
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Anti-pseudomonal penicillins:Beta-lactamase inhibitor combinations
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ticarcillin + clavulanic acid (Timentin ®)
piperacillin + tazobactam (Zosyn ®) -Tazobactam does not add activity for PsA Mostly used in mixed aerobic/anaerobic infections (aspiration pneumonia, intraabdominal/pelvic, complex soft tissue-including diabetic foot) and some nosocomial infections, especially those involving pseudomonas |
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Beta-lactam Allergy
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Type 1: Immediate Hypersensitivity
-IGE/Mast Cell medicated -Urticaria/Anaphylaxis Type 2: Innocent bystander -Adherence of drug as a hapten to a cell -Hemolytic anemia Type 3: “Arthus” Immune Complex -Serum sickness: Fever, glomerulonephritis, arthritis, adenopathy. Not always all at same time Type 4: Delayed hypersensitivity -Most common -T cell mediated -Usually after 7-10 of antibiotic -Rash, usually with fever -Eosinophilia |
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Cephalosporins overview
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B- lactam: bind to penicillin binding proteins
more stable to B-lactamases than PCN and aminopenicillins Resistance through altered PBP’s (e.g. MRSA), B-lactamase (GNR’s); B-lactamase may be inducible high therapeutic to toxicity ration (i.e. safe) good CNS penetration only with 3rd generation agents (e.g. ceftriaxone, ceftazadime,) |
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Cephalosporins by class
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1st Generation (best against G positive)
-Cefazolin—IV -Cephalothin –IV & PO 2nd Generation (Haemophilus influenzae, Enterobacteriaceae, some anaerobes) -Cefoxitin--IV -Cefuroxime—IV and PO 3rd Generation (best against G. negative) -Broad spectrum --Ceftriaxone -Anti-pseudomonal --Ceftazidime 4th Generation (better against G. negative) -Cefepime |
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Cephalosporin Preparations
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1st generation cephalosporins
-Mostly gram positives (not MRSA, enterococcus) -Parenteral: e.g. cephalothin, cefazolin -Uses: Skin and soft tissue, bone and joint infections; surgical prophylaxis 2nd generation cephalosporins -parenteral: e.g. cefuroxime, cefoxitin, cefotetan -Oral: e.g. cefuroxime axetil (Ceftin ®) -Uses: Respiratory tract, intrabdominal infections (for those with anaerobic activity), skin and soft tissue, surgical prophylaxis 3rd generation cephalosporins -parenteral: e.g. ceftriaxone, ceftazidime -only ceftazidime with activity against Pseudomonas aeruginosa -ceftriaxone with decent gram positive activity (S. aureus [not MRSA], streptococcus, pneumococcus) -oral: cefixime, cefpodoxime, cefdinir --none of oral agents with anti-pseudomonal activity -Uses: Meningitis, gonorrhea, pneumonia, fever in neutropenic patients 4th generation cephalosporins -parenteral: cefepime -Think of as ceftriaxone + ceftazadime -Uses: pneumonia (particularly hospital acquired), hospital acquired infections |
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Aztreonam
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Monobactam
Activity ONLY against gram-negative aerobes but does include Pseudomonas aeruginosa Poor cross allergenicity with other beta-lactams major indication for usage is suspected or proven GNR infections in penicillin- or cephalosporin-allergic pts for whom other antibiotics are not a viable option |
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Carbapenems
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Binds to PCN binding proteins
broadest spectrum of available antibacterial drugs with gram-positive and gram-negative aerobic and anaerobic activity drug of choice for 3rd generation cephalosporin resistant (inducible b-lactamase producing) klebsiella, enterobacter. “Achilles heels” include MRSA, enterococci. Listeria, and some esoteric gram negative rods |
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Carbapenems: resistance, allergies, clinical utilities
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Resistance: Most important is reduced permeability of GNR outer membrane; usually through loss of outer membrane porins carbapenemases (a very broad spectrum beta-lactamase) are increasing in incidence
Hypersensitivity reactions do cross with penicillins clinical utility: -resistant pathogens, including ESBLs -mixed infections (monotherapy) -Monotherapy for Fever &Neutropenia (not ertapenem) |
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Carbapenem Preparations
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Imipenem
-combined with cilastatin, a renal dipeptidase inhibitor, extends half-life and protects against potential nephrotoxicity Meropenem -does not need cilastatin -Less likely to cause seizures -Less nausea Ertapenem -Once-a-day dosing makes it attractive for home care -Less activity then above for pseudomonas and acinetobacter |
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Vancomycin overview
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Complex glycopeptide
NOT RELATED TO AMINOGLYCOSIDE Interferes with cell wall synthesis Bacteriocidal Vancomycin less rapidly bactericidal than anti-staphylococcal and 1st generation cephalosporin beta-lactams for beta-lactam-susceptible staphylococci |
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Vancomycin mechanism of action
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Inhibits peptidoglycan synthesis
Binds to d-alanine-d-alanine of peptide precurser Doesn’t bind or work through PBP Thus works against Staph. with altered PBP. i.e. MRSA |
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Vancomycin spectrum, resistance, absorption
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Spectrum = gram-positive organisms incl. MRSA (large, can't get through porins)
Acquired Resistance -Enterococci; rarely staphylococci, corynebacteria -Change in one cell wall amino acid change (D-ala—D-ala to D-ala—D-lactate -Recently found in Staph. Aureus but rare Poor oral absorption (give orally and stays in GI tract) No significant stool concentration IV NOT removed by dialysis (Dose roughly q5 days or base on levels) |
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Vancomycin indications
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Treatment of infections
-Due to gram-positive organisms not susceptible to beta-lactams or in patients with serious allergy to beta-lactams Prophylaxis for major surgical procedures involving implantation of prosthetic materials or devices at institutions with a very high rate of infections due to MRSA or MRSE When antibiotic-associated colitis (AAC) due to Clostridium difficile fails to respond to metronidazole: Only time given orally |
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Macrolides overview
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inhibits protein synthesis by binding to 50s ribosome (bacteriostatic)
Time above MIC more important for killing (like beta-lactams) Resistance: -Ribosomal methylation -Drug efflux |
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Macrolides: Erythromycin Spectrum
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Gram positives: Staph, Streptococcus, pneumococcus
-Resistance becoming a problem Mycoplasma pneumoniae , Chlamydia pneumoniae, C. psittaci Chlamydia trachomatis Legionella Diphtheria Bordetella pertussis: Pertussis (whooping cough) Campylobacter |
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Macrolides: Clarithromycin/Azithromycin
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Spectrum same as erythromycin plus adds activity for H. flu & Moraxella catarrhalis
Better pharmacokinetics/pharmacodyanmics Better tolerated than erythromycin (especially GI) More expensive than erythromycin Both cross resistant to erythromycin resistant gram-positive cocci, including pneumococcus and group A strep. |
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Macrolides: Indications
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Upper and lower respiratory tract infections (excellent “atypical” coverage)
Some S. aureus skin and soft tissue infections Mycobacteria Helicobacter pylori Single dose therapy of cervicitis due to Chlamydia trachomatis STD (azithro) |
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Streptogramin
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Quinupristin/Dalfopristin (Synercid ®)
Acts on ribosome to inhibit protein synthesis. The “S” of “MLS” (Macrolide/lincomycin/streptogramin). Role currently limited to therapy of resistant gram positive infections including MRSA -NOT active against some enterococcus species |
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Aminoglycosides overview
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bactericidal by inhibiting protein synthesis (binding to 30S ribosomes)
concentration dependent bacterial killing and prolonged post-antibiotic effect vs GNRs Gentamicin/tobramycin Streptomycin Amikacin low therapeutic index (may be toxic) Need to monitor serum levels to limit toxicity -kidney and ear toxicity |
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Aminoglycosides spectrum of activity and resistance
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Spectrum of activity
-gram-negative aerobes -no activity against anaerobes -synergistic with penicillin, ampicillin or vancomycin vs susceptible enterococci, some streptococci, & Listeria -re-emerging as antimycobacterial agents (streptomycin vs TB) Resistance -enzymatic inactivation most common mechanism (eg. sulfation, acetylation, phosphorylation) |
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Aminoglycosides preparations
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Streptomycin
-IM traditionally but can be given IV -now primary tuberculosis drug -no antipseudomonal activity Amikacin -less susceptible to inactivating enzymes with widest spectrum -Has anti-pseudomonal activity -Has most predictable activity against gram-negatives at WFUBMC Tobramycin/Gentamicin -Cheap -Most commonly used -Has anti-pseudomonal activity |
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Aminoglycosides:Uses:
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selected unusual infections
-Plague -Tularemia -Brucellosis in combination therapy for severe nosocomial or community-acquired infections when resistant GNRs are a concern as synergistic therapy for selected GPC infections -enterococcal disease -Endocarditis due to various pathogens |
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Clindamycin overview and resistance
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Binds to 50s ribosome and inhibits protein synthesis (bacteriostatic)
Resistance -ribosomal methylation (MLS pattern) |
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Clindamycin Spectrum and uses
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Gram-positive cocci
-Staphylococcus aureus (including some MRSA)--useful oral agent -streptococcal infections including Group A streptococci --Because acts on ribosome shuts down toxin production as well as inhibiting growth (beta-lactams inhibit growth only) -Anaerobes--excellent anti-anaerobic agent for head and neck anaerobes and pulmonary abscesses (above the diaphragm anaerobes--not some enteric anaerobes) Alone in the respiratory tract (dental, head and neck or anaerobic lung abscess) Getting more use for skin and soft tissue infections Combined with aminoglycoside or quinolone for intraabdominal infections or diabetic foot infections Nonbacterial organisms: -Pneumocystis carinii pneumonia -Toxoplasmosis (with pyrimethamine) |
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Tetracyclines: Overview and cost
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Inhibition of protein synthesis via binding to 30s ribosome (bacteriostatic)
Resistance through altered ribosome or drug efflux Tetracycline—cheap Doxycycline—cheap Minocycline—Not cheap |
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Tetracyclines Spectrum
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Broad antibacterial: Gram positive, some gram-negatives (not pseudomonas), little anaerobic activity
Atypicals -Mycoplasma -Chlamydia -Rickettsia Malaria |
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Tetracyclines Indications
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Community-acquired pneumonia for ambulatory patients without comorbidity, including chlamydia pneumonia, mycoplasma
Skin and soft tissue infections Chlamydial infections (STD) Lyme borreliosis (Lyme disease) Vibrio sp. Rickettsial infections: RMSF, etc. Helicobacter pylori -Tetracycline NOT doxycycline Malaria |
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Glycylcycline: Tigecycline
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Structurally very similar to tetracyclines
Binds to 30s ribosome Spectrum is broader than tetracyclines -Gram positives: Streptococcus spp., Staphylococcus spp. (including MRSA), some enterococci (including some VRE) -Gram negatives: Neisseria, Haemophilus, Enterobacteriaceae (including ESBL producers), other GNRs: EXCLUDING PSEUDOMONAS, ACINETOBACTER -Anaerobes Resistance is through efflux pumps, not ribosomal mutations Intravenous Only Expensive Nausea and vomiting in up to 20% Used mostly in mixed pathogen skin and soft tissue and intraabdominal infections |
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Co-trimoxazole overview, mechanism, and resistance
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(Trimethoprim/sulfamethoxazole)
blocks two consecutive steps in the biosynthesis of nucleic acids -PABA to folic acid -folic acid to folinic acid Resistance occurs through increased production of dihydrofolate reductase |
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TMP/SXT Spectrum
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Broad spectrum: NOT Pseudomonas aeruginosa, anaerobes, mycoplasmas
Covers sensitive MRSA, has become especially useful for community-acquired MRSA as most are susceptible |
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TMP/SXT Indications
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Community acquired MRSA
UTI’s Respiratory infections (not Group A strep. Pharyngitis) Prevention and treatment of PCP Enteric fevers Traveler’s diarrhea Brucellosis Nocardiosis Some unusual gram negatives Listeria and some gram-negative bacillary meningitis (good CSF penetration) |
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Metronidazole
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“cidal” agent with ? mechanism of action (DNA strand breaking effect)
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Metronidazole Spectrum and uses
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Anaerobic bacterial infections (especially those below the diaphragm)
Protozoal infections -Vaginal Trichomoniasis -Intestinal Amebiasis -Intestinal Giardiasis (Giardia intestinalis) Bacterial vaginosis (gel or oral) C. difficile colitis: primary agent Helicobacter pylori in combination therapy |
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Fluoroquinolones mechanism and resistance
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Inhibit DNA gyrase and topoisomerase
Resistance: -DNA gyrase/topoisomerase mutation -Drug efflux Bactericidal Very bioavailable—give orally if gut working |
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Floroquinolone drugs
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Levofloxacin
-levo is l-isomer of Ofloxacin Gatifloxacin, moxifloxacin Ciprofloxacin Most rapidly increasing antimicrobial utilization |
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Fluoroquinolones:Spectrum of activity
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All have good gram-negative activity
-Cipro best against P. aeruginosa Gatifloxacin, moxifloxacin, levofloxacin > ciprofloxacin for gram-positives -Good Streptococcus pneumoniae activity -Some activity for MRSA -Enterococcus variable moxifloxacin>gatifloxacin for anaerobes (minimal with levo and cipro) All have coverage of “Atypicals” -mycoplasma, chlamydia, Legionella Mycobacteria including TB |
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Fluoroquinolones: Indications
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UTI’s (levo/cipro preferred)
-Cystitis (2nd line), Prostatitis (1st line), Pyelonephritis (1st line for oral therapy) GI infections(levo/cipro preferred) -Infectious diarrhea (if treatment desired) -Traveler’s diarrhea: 1-3 day course Sexually transmitted diseases -single dose treatment of gonorrhea (no longer recommended due to resistance) -Levofloxacin, gatifloxacin and moxifloxacin for Chlamydia trachomatis urethritis/cervicitis -Uterine/fallopian tube infections Respiratory tract infections -Community acquired pneumonia: Levofloxacin, gatifloxacin and moxifloxacin ( better pneumococcal coverage) -Sinusitis and Acute exacerbations of chronic bronchitis 1st line drugs cheaper and probably similar activity -Nosocomial pneumonia: levofloxacin or ciprofloxacin (the later perhaps better choice) in combination with beta-lactam -Take advantage of early IV to oral switch GNR Osteomyelitis (cipro) Skin/soft tissue infections Intraabdominal/pelvic infections (often in combination) Surgical prophylaxis: NO |
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Rifampin
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A rifamycin
Inhibits DNA dependent RNA polymerase Never use alone, always in combination with other drugs Resistance: Can rapidly occur due to mutations in this enzyme Spectrum: Gram Positives: Staph. aureus, Strep., Bacillus, Clostridium. Gram Negatives: Meningococcus, Legionella, Brucella. Mycobacteria including TB and Leprosy Clinical use: -In combination therapy for difficult to treat gram-positive infections such as osteomyelitis or those involving non-removable foreign bodies. Prevention of meningococcal meningitis. -TB, Leprosy |
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Lipopeptides: Daptomycin
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New class of antibiotic
Calcium dependent increase in membrane permeability to potassium Activity against all gram positives including resistant Staph aureus (MRSA), and vancomycin resistant enterococcus Resistance very rare and not well defined Expensive |
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Oxazolidine:Linezolid
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New class of antibiotic
Inhibits protein synthesis at level of ribosomal translation Resistance not well defined—probably ribosomal mutation Activity against gram positives including MRSA and vancomycin resistant enterococcus Can be given orally (one of few oral drugs that can be used against MRSA) Expensive |
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Polymyxins: Polymyxin B or colistin
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Old antibiotics brought back to treat multiple drug resistant gram-negatives such as pseudomonas and acinetobacter
Intercalates with LPS in gram negative membrane Resistance not well understood Toxic |
