Drugs that destroy microbes, prevent multiplication or growth, or prevent their pathogenic action.
Types of Antimicrobials
Antibacterial, antiviral, antifungals, etc. Natrual or synthetic compounds that kill or suppress growth of microorganisms
Types of Antimicrobial therapy
Emperic,Documented, or Prophylaxis
1. Site of action 2. Chemical structure 3. Spectrum of activity 4. Static vs. Cidal
Principles of antimicrobial therapy
Evaluate infectious vs. non-infectious causes of fevers Have high suspicion for infection and source Obtain cultures Select likely organism, host factors, medication factors Verify presence of infection from site Choose narrowest spectrum of activity Monitor efficacy/toxicity of regimen
Antibiotic Tx. Risks
1. Direct tx toxicity: ototoxicity d/t aminoglycosides, lipodystrophy d/t HIV protease inhibitors. Hepatotoxicity d/t isoniazid and rifampin. 2. Allergic rxn 3. Superinfection via eradication of normal flora 4. Infectious disease therpay narrow spectrum.
How to select an Antibiotic Tx. Regimen
1. Host: Age, wt, organ fxn, sie, causative org, comobidities, pregnancy, genetic/metabolic abnormalities, allergies. 2. Med consideration: pharmakokinetic, dynamic, penetration, cost. 3. Route of admin: F, severity, location, organ
Gram positive vs. Gram negative Gram stain determines type of bacteria
1. Gram positive: purple or blue (absorbs the cyanocobalmin) 2. Gram negative: red or pink (does not absorb the dye)
1. Agents that destroy microbes, prevent replication or growth, prevent an organism's pathologic action. 2. Spectrum of activity: broad vs. narrow 3. Bacteriocidal: destroy vs. bacteriostatic: inhibit growth.
Effectiveness of Antibiotic
Via microbiology results: 1. Sensitive: org. should be eradicated by tx with the antibiotic recommended at the suggested dose. 2. Intermidiate: org. may/may not be eradicated dependent on achievable drug contectration and organism MIC. 3. Resistant: organism will not be inhibited by concentrations achievable by antibiotics.
Minimum Inhibitory Concetration (MIC)
The lowest concetration of antibicrobial that prevents VISIBLE bacteriocidal growth in the specified medium
Predicts bacteriological response to therapy in vitro.
* Machines can miss effectiveness ie. cannot tell diff b/t a urine or a plasma sample which may show different results in effectiveness of tx.
Microbiology Results and Spectrum of Activity
Determine MIX: lowest conc of drug that presents visible bacterial grwoth after 24 hours of incubation in a specified growth medium.
Susceptible , intermediate, or resistant.
Doses will always be doubles in vitro tubes to determine MIC: i.e. 0,2,4,6,8
Bacteriostatic vs. Bacteriocidal
Bacteriostatic: drugs will inhibit the growth of bacteria but do not kill them, need host's immune system to do some of the work.
Bacteriocidal: drugs kill organisms so that number of viable organisms decreases rapidly after exposure.
1. Increase bacterial killing as the drug concentrations exceed the MIC. 2. Higher peak concentrations increase killing 3. Peak MIC or AUC/MIC ratios are important ** Varies per patient and can admin more but decline will still happen according to drug's 1/2 life.
Drugs that are conc-dept= aminoglycosides, quinolones, daptomycin. A.Q.D.= A Quack Duck?
Mechanisms of Resistance Part 1
MIC: if a drug does not exceed the MIC adequately resistance can occur. 2 Types: 1. Intrinsic: lack of activity before antibiotic exposure 2. Acquired: develops during therapy due to mutations or transferred from one organism to another
Mechanisms of Resistance Part 2
3 Main Mechanisms 1. Inactivation of drug by microbial enzymes 2. Decreased accumulation of the drug: a. Increased efflux pumps to spit out drug b. Decreased uptake: site of action mutated 3. Reduced affinity by target for drug.
What you need to know to tx w/ antibiotics
1. Know the microbiology. 2. Know the patient. 3. Know the drugs.
PK factors: PO bioavailability Peak serum conc. Vd to site of infection Route of elimination 1/2 life
Site of infection
Very important factor to consider in tx. 1. Define the most likely organisms 2. Efficacy deter by conc of drug above MIC at site of infection. a. Does the antibiotic get there? b. In sufficient concentrations? c. Distribution: -diff in plasma vs. tissue conc -areas of compromised penetrations: CSF, bone, prostate, eye, abcesses. -e.g. UTI ueaseir than other sites. 3. Determine choice, dose, route.
General Concerns to Consider in Antibiotic Tx
1.Drug interactions w/ PO contraceptives + WARFARIN 2.Elimination: renal vs. liver 3.Dosing: loading doses, dose adjustments for renal (hepatic is much harder to do). time vs conc dep. -HD, CRRT, ECMO. 4.Pregnancy/lactation: does it cross? preg. catg. 5. CNS penetration, menigies, liphophilicty. 6. AE profile
Concomitant Drug Therapies
Combo therapy: 1. Used frequently in tx of infections to achieve broader spectrum of activity 2. Achieves better killing of bacteria: synergy 3. Minimizes development of bacteria
** Understand interaction potential: -Pharmakokinetic vs dynamic interactions. -AVOID using 2 agents with same mechanism -Monitor appropriately
Culture from infected site BEFORE giving drug~ -Sputum from non-intubated pts is tough -BAL/ET aspirate from intubated pts w/pneumonia -Mini-BAL for all? -Debride tissue first -CSF from meningitis pts. -Pus from aspiration -Additional blood cultures for endocarditis 3-5 samples.
2 blood cultures done at least 10 minutes APART should be drawn and a culture from the infected site should be taken prior to first dose. -Catheter tip + 2 peripheral cultures -Cultures for strict anerobes hsould be sent via anerobic transport.
Should not be done! Only body fluids, tissue, pus, and exudates should be cultured.
Renal impairment & dosing considerations
Always give aggressive first dose despite impairment, do not wait to receive lab results you are wasting time, you will not hurt the patient.
For antimicrobials that posses conc. dep. killing properties you should optimize the time above the MIC
Which of the following should be considered: 1. Site of infection 2. allergies 3. Spectrum of activity 4. Only A & C E. All of the above
3 Major Phases 1.Monomer synthesis: -Peptidoglycan monomers from aminos and sugars. -Precursor formation -Takes place in cytoplasm 2. Monomer polymerization -linkage to form long polymer -lipid-mediated and takes place at the cytoplasmic membrane 3. Cross-linking of polymers -mediated by transpedidases (extracellular periplasmic)
Thiazolindine ring attached to a beta-lactam ring. Side chain determines the pharmacologic properties. Nucleus is a structural requirement.
Interferes with the last step of cell wall syntheis (transpeptidation or cross-linkage) -Inactivate penicillin-binding proteins by binding to them. -Inhibit transpeptidase leased to autlysin-mediated autolysis and cell death. -Time-dependent kill. -Bactericidal against actively dividing bacteria. ** Dosed frequently!
Beta-Lactams: Mechanism of resistance
-Thickened cell-wall -Beta lactamase enzyme which hydrolyzes the beta lactam ring -Decreased permeability of the drug though the outer cell membrane -Altered PBP's with lower affinity for beta-lactam antibiotics -Efflyx of drug aross the outer membrane of the gram-negative organism.
Spectrum: staphylocci, PCN streptococcus, not active against enterocco, listeria spp, MRSA -Clinical use: infections caused by MSSA (Methilicillin-susceptible s. aureus) skin, soft tissue, endocarditis, osteomyelitis, etc.
Extended-Spectrum PCN (anti-psuedomonal) Spectrum of activity & Clinical Use
Actvity of aminopenicillins with expanded gram-negative activity. -Enterobacter sp, providencia, morganella, pseudomonas, aeruginosa. ** Hydrolyzed by beta-lactamase Clinical Use: Gram-neg infections caused by Enterobacteriaceae and P. aeruginosa -Bacteremias, respiratory tract infections, intra-abdominal infections. -Empiric therapy in patients with fever and neutropenia.
-Beta lactamases cleave the beta lactam RING that is required for activity. -Beta lactamase inhibitors mimic beta lactamase inhibitors to mimic the beta lactams and bind to the enzymes and inhibit their action. a. clauvalanic acid b. sulbactam c. tazobactam -Expand spectrum of parent beta lactam antibiotic
Beta-lactam & Beta-Lactamase inhibitors combo Spectrum of Actvity
Spectrum of activity: - largely depends on parent beta lactam (combo will not cover the organism if the PCN alone would not have) 1. amocillin/clavulanic acid and ampicillin/sulbactam have no activity against p. aeruginosa. -Gram positive, gram-negative, and anerobic organisms. -Adds activity against beta-lactamase producing organisms Does not improve activity vs MRSA, enterococci, streptococci.
Beta-lactam & Beta-Lactamase inhibitors combo Pharmakokinetics Part 1
Absorption: very variable, most incompletely absorbed - Dicloxacillin, ampicillin, amoxicillin more acid stable -PCN VK best absorbed on empty stomach.
Distribution: Very well, not god for eyes, brain, CSF, prostate (w/o inflammation). Ampicillin, oxacillin/nafcillin most useful in CNS infections. -HIgh URINARY Concentration excreted by KIDNEYS -Crosses placenta catg. B
Beta-lactam & Beta-Lactamase inhibitors combo Pharmakokinetics Part 2
Metabolism: only semisynthetic PCN are hepatically metabolized and excreted in the bile Excretion: Rapidly excreted by the kidney -Relatively short 1/2 life (.5-1.5 hrs) -Renal tubule secretion and glomerular filtration -Dose adjust in pts. with renal dysfunction *** Probenacid- increases conc b blocking renal tubular secretion. ****Nafcillin- Hepatically excreted vs all others are renal.
AE: 1.Hypersensitivity (anaphylaxis, rash) 2.Diarrhea, including pseudomembranous colitis Intersitial nephritis 3.CNS effects (SEIZURES at high doses) 4.Increased liver enzymes (most common with semi-synthetic) 5.High sodium load (PCN G, ticarcillin) 6.Thrombocytopenia; decreased plt aggregation 7.Throbophlebitis
Pharyngitis (usually viral) Otitis Media Sinusitis
Usually viral & consists of rhinorrha, cough, hoarsnes, conjunctivits, diarrha. -Most bacterial cases are self-limiting, but exception is group A strep. -streptococcus pyogenes (5-15%) -associated with rheumatic fever
TX: susceptible to penicillin- penicillin VK or amoxicillin suspension in children -Pen G benzathine IM x1 dose also an option.
Acute Otits Media
Most common indication for anibiotic RX -Streptococcus penumonia (30-35%) haemophilus influenzae (20-25%) Moraxella catarrhalis (10-15%) TX: 1st line = amoxacillin/clauvulanate, 2nd or 3rd gen cephalosporin -70% H. influenza and 100% M. catarrhalis produce beta-lactamase.
Amoxicillin and Amoxicillin Clavulanic Acid
Amoxicillin preferred at 90mg/kg/day in kidos with AOM -Amoxicillin/clavulanate is an option effective against beta lactamase producing strains of H. influenzae and m. catarrhalis -Multiple forms: a. Augmentin ES b. Augmentin 125 c. Augmentin 250 KEEP clavulanic acid dosage < 10mg/day d/t diarrhea AE.
Acute Bacterial Sinusitis
Inflammation from viruses, allergy, pollution, or other irritation. -Viral 20-200x more common than bacterial -Sx: fever, facial swelling, maxillary tooth or facial pain, prurulent nasal discharge.
S. pneumoniae, H. influenza, M. catarrhalis
Older generations more effective against Gram + and had narrow spectrum
Newer generations have broader spectrums with more Gram - ability.
First Generation Cephalosporin
Cefazolin IM/IV Cephalothin IM/IV Cephalexin PO Cefadroxil PO
Second Generation Cephalosporins
Cefaclor PO Cefprozil PO Cefuroxime axetil PO Cefuroxime IM/IV Cefamandole IM/IV Cefmetazole IV Cefotetan IM/IV Cefoxitin IM/IV
Third Generation Cephalosporins
Cefdinir PO Cefitoren pivoxil PO Cefixime PO Ceftibuten PO Cefpodoxime proxetil PO Cefoperazone IM/IV Cefotaxime IM/IV Ceftizoxime IM/IV Ceftazidime IM/IV Moxalactam IV
Fourth Generation Cephalosporin
5th gen sucked and rough on kidneys Now a 6th gen: ceftoraline
Cephalosporin Spectrum of Activity
NO activity against: -Enterococci -Listeria monocytogenes -Methicillin-resistant Staphylococcus aureus MRSA
Mechanism: destruction of beta-lactamases
Variable but well-absorbed (more acid-stable) -Vd variable and protein binding. -Only cefuroxime (IV), cefotaxime, ceftriaxone, ceftazidime, and cefepime achieve adequate CSF concentrations for meningitis tx. -Crosses placenta; catg. B Excretion: -Via glomerular filtration and tubular secretion -High urinary conc. -Ceftriaxone and cefoperazone are exceptions (biliary) -Probenacid- increase conc by blocking renal tubular secretion.
Cephalosporin tx use
1st gen: skin 2nd gen: URI 3rd & 4th gen: URI more severe
Ceftriaxone: longest 1/2 life take only 1 daily most are admined Q8
Hypersensitivty: anaphylaxis, rash IM admin painful Diarrhea, including pseudomembranous colitis Interstitial nephritis CNS effects: seizures Biliary sludge, pseudolithiasis *ceftriaxone 5-10% cross-allerginicity w/ PCN Avoid in severely allergic PCN pts. Minor reactions may be tx with newer generations
Community-acquired Pneumonia (CAP)
Leading cause of death and number one infectious death in the US -Outpatient mortality 1-5% -Inpatient mortality about 25%
4 million cases CAP annually
S.pneumonia leading cause (20-60%) H. influenza: staphylococcus aureus, gram-negative bacteria each about 3-10%
In patient (non-ICU) -Cefotaxime/ceftriaxone + macrolide/doxycycline -Respiratory quinolone Outpatient -Macrolide or doxycyline -If comorbidities > respiratory quinolone OR amoxicillin/augmentine/cefopodxime.cefuroxime + macrolide/doxycycline
Gram positive, alpha hemolytic streptococcus. -Pneumonia, sinusitis, AOM, meningitis, bacteremia, osteomyelitis, septic arthritis, endocarditis, peritonitis, brain abcess. -Normal flora of nasopharynx in 5-10% healthy adults, 20-40% in children -Increasingly resistant to PCN. -Alt in binding protein, no benefit of beta-lactamase inhibitor. -Need higher doses of PCN/Amoxicillin or alternative agents.
Inflammation of membranes surrounding the brain and spinal cord including the dura, arachnoid and pia matter.
Monocyclic beta lactam Only gram neagtive P.aeruginosa
NO gram positives
Azetreonam Kinetics and Use
IV only Distribution- widely distributed. Adequate CSF concentrations with inflamed meninges Excretion: primarily renal 1/2 2 hours Gram negative coverae in pts w/ PCN allergy Gram neg coverage for URI, abdominal, skin, meningitis, P. aeruginosa covered.
Preg cat B Adverse effects: Rash Adminesd to those with hypersenstivity to PCN or other beta-lactams. -Negligible cross-reactivity in rabbits and humans -Antibody response to side chain (same side chain as cetazidime)
Differ 5-membered ring structured. -Structurally related beta lactams FOUR of them: Imipenem (Primaxin) Meropenem (Merrem) Doripenem (Doripenem) Ertapenem (Invanz)
Carbabpenem Spectrum of Activity
Severe antibiotic resistance
Gram-positives, gram-negatives, anaerobes. Broadest activity/spectrum of all the beta-lactams: except ertapenem.
No activity against MRSA, enterococcus faecium, stenotrophomonas maltophilia
Lacks activity against P. aeruginosa, acinetobacter spp.
Carbapenems Kinetics #1
IV/IM only -Imepenim formulated w/ cistatin -Hydrolyzed by dehydropeptidase enzume in the kidney -Cilastatin= inhibitor of dehydropeptidase (=enzyme inhibitor) -Cilastatis has no activity of its own -Cilistatin is not a beta-lacatmase inhibitor
Polymicrobial infections Typically reserved for more resistant organisms Ertapenem is more narrow spectrum and may be useful for UTIs, skin/soft tissue infections, penumonia
Preg B 3:4 Preg C imipenem AE: Hypersensitivity -cross reactive in pts with PCN allergy estimated 10-50% -Avoid in pts with severe PCN allergy Seizure: Risk factors: CNS lesions, history of seizures, high doses, renal impairement. -Doripenem lowest risk< meropenem< imipenem
Carbapensm safety #2
Diarrhea + pseudomembranous colitis N/V > impipenem, admin rate related
Serious and life-threatening infections -very broad spectrum -bacteremia/sepsis, hospital -associated penumonia, intra-abdominal infections -febrile neutropenia -Gram negative meninigitis Polymicrobial infections -reserved for more resistant organisms -Ertapenems is more nearrow spectrum and may be useful for UTIs, skin/soft tissue infections, penumonia.
Which of the following has the most gram negative activity
Ceftriaxone (3rd gen)
Which of the following is most important AE w/ carbapenems
Which beta-lactam has the broadest spectrum
Which is safest to use in a pt. with PCN allergy?
Vancomycin Mechanism of Action
Glycopeptide antibiotic - Mechanism: inhibits cell wall synthesis in the peptidoglycan phase or elongation -Beta lactams different in that they inhibit the 3rd stage. -Bactericidal activity Spectrum of activity- Gram-positives only (staphyloccoci, streptococci, enterococci) Drug of choice for MRSA Broad spectrum gram positive agent
Vanco mechanisms of resistance
Alteration fo the d-alanyl-d-alanine target 1. Enteroccoci VRE -bind vanco poorly -mediated by the VAN gene -D-alanyn-d-lactate or d-alanyl-d-serine
2. Increased cell wall thickness -Staphylocci -Intermediate susceptibility to vanco
Absorption: -poorly absorbed after PO admin -PO admin high levels in gut not able to use for systemin infection -Distribution: distributes widely into various body fluids, CSF, and meninges -.7 L/kg (total body water) -Protein binding about 30-55%
Excreted primrily the kidney -Glom filtration, not dialize it.
1.Bactericidal 2.Time-dependent killing 3.Therapeutic drug monitoring: -Trough concentrations -Blood level prior to next dose -Peak levels not helpful 10-20mcg/mL is the optimal Vancomycin enema
Resistant Gram-positive infections -MRSA, MRSE -PCN resistant S. pneumonia Gram-positive coverage in pts. with allergy or intolerance. -Tx -Surgical prophylaxis Colstridium difficile associated diarrhea -PO only -IV does not achieve adequate gut concentrations -Alternative to metronidazole
Preg catg C -Red man syndrome -Erythematous rash with hypotension -Histamine-mediated r/t the rate of infusion -Usually admin 1g vanco over 1 hour Nephrotoxicity assicaited with early preps. Ototoxicity with high peak conc. Neutropenia Skin Rash
Skin and Toft Tissue Infections
Involve any or all layers of the skin, sub-q fat, fascia, or muscle Classified by site of inection and causative organism Outcomes: -Mild SSTIs are often self-limiting -Moderate to sever infections can progress if not treated appropriately
Acute inflammation of the skin and sub-q fat Local tenderness, swelling, pain, warmth, erythema -Often secondary to trauma or underlying skin lesion Insect bites, abrasions -Often caused by S. aureus and S. pyogenes
Mild= local tx cleaning irrigation with soap and water -More sever cellulitis: tx wiht po antibiotics targeting gram positive org: dicloxacillin, cephalexin, cefprozil, clindamycin, TMP/SMX * Immunocompromised pts, systemic signs and symptoms fever, increased pain, lymphadenopathy) Improvement should be seen within 2 days.
Gram-positive cocci (in clusters) -Skin infections, pnueumonia, meningitis, endocarditis, TSS, osteomyelitis. -Common in nonscomial infections too -20% colonized chronically in nares 1. Resistance: beta-lactamase Penecillin/ampcillin ineffective > semisynthetic PCN, beta-lactamase in combo 2. mecA gene- altered PCN binding protein= MRSA semisynthetic PCN ineffective > vancomycin, linezolid
RARELY USED -Binds reversibly to 50s ribosomal unit -Bacteriostatic -Gram +, neg, anaerobic bacteria -Good GI absorption, widely distributed, including CSF -HEPATICALLY metabolized -Preg C -Gray baby -Reversible bone marrow suppression -Rare potentially fatal aplastic anemia
Tetracycline, doxycycline, minocycline Bacteriostatic -Spectrum: some bacteria relatively narrow spectrum -Some gram-positives, some gram-negatives, S. pneumoniae, H. Influenza, gonocci, menincocci, E. Coli -Rickettsiae, chlamydiae, mycoplasma -Tick-borne illnesses
Rocky mountain spotted fever and others caused by ricketssiae (typhus too) Lyme disease Alternative to macrolides for Mycoplasma pneumoniae, Chlamydia pneumoniae, URI -Chlamydia trachomatis (STD) or pelvic inflammatory disease (doxy) -Select protozoal infections (plasmodium falciparum) -Acne -Option in PCN-allergic pts.
PO absorption incomplete except doxy and mino. -Watch out for other cations (aluminum, calcium, mg, irion, zinc-containing products) -Milk products -Distribution: widely distributed, including CSF (even without inflammation) Elimination Primary route of elimination -Tetracycline- renal (60% unchanged) -Minocycline- liver met, renal ex -Doxy inactivated in the GI and excreted feces
Doxy preferred in kidney dysf pts. -Tetra and mino accumulate in the kidneys
Pregnancy cat D AE: GI irritation, photosensitivity, liver toxicity, kidney toxicity. Fanconi syndrome: toxic effect on renal tubes esp outdated. N/V, polyuria, polydipsia, proteinuria, acidosis, glycosuria, aminoaciduria (outdated med) Permanent brown discoloration of teeth. - Depostition of drug in teeth and bones -Avoid in kids up to 8 yo Vestibular toxicity (mino > doxy)
Glycylcycline antibiotic: Derivative of minocycline Spectrum: gram-positives includin MRSA and VRE Gram neg including enterobacteriaceae, A. baumanni, S. maltophilia NO p. aeruginosa Anerobes including B. fragilis Mycobacteria
IV only Large Vd > 8L/kg -low mean blood levels .62 + .09 mcg/mL Eliminated through feces via biliary secretion Preg D Adverse effects -similar to tetracyclines -n/v hepatic toxicity
Erythromycin, clarithromycin, azithromycin -Mechanism of action: inhibit RNA dependent synthesis via binding to 50s ribosome. -Inhibit translocation of aminoacyl transfer-RNA and inhibit polypeptide synthesis. -BacterioSTATIC -High concentrations may be CIDAL
Associated with frequent use +/- high doses Alteration/mutation of ribosomal subunit (high-level) Active efflux pump (low-level) Possible cross-resistance w/clindamycin
Bacteriostatic Spectrum: gram +, some neg. -Erythromycin similar to PCN in spectrum against streptococci, not reliable against staphylococci. -Clarithro/azithro have improved activity aginst some gram-negatives. **H. influenza, Neisseria sp., M. catarrhalis, B. bugdorferi, H. pylori. -Added activity against chlamydia, my coplasma, legionella (atypicals) -Mycobacteria (MAC)
Absorption -Erythromycin base destroyed by gastric acid. Enteric coated or esterified. -Dist: widely distributed, except CSF -Hepatic metabolism
IV form avil, less GI intolerance, NO CYP450 drug interactions, Biliary/fecal excretion, yes on prolonged tissue levels
IV form avail, less GI intolerance, interacts with CYP450 drugs, CYP450/renal excretion, no prolonged tissue levels
IV form avail, GI intolerance exists, CYP450 drug interactions, Biliary excretion, no prolonged tissue levels.
Macrolide clinical uses
Respiratory infections: most are active against gram-positives like group A strept, S. pneumoniae, atypicals. -Clarithro and arithro have improved activity against some gram negatives> sinusitis, bronchitis, pneumonia -Hospitalized pts. erythromycin, azithromycin. -Chlamydia trachomatis urethritis= azithromycin -MAC mycobacteria in pts with HIV -H. pylori calarithromycin -PCN allergic pts.
Catg B (azithro/erythromycin) Catg C (clarithromycin) Adverse effects: GI intolerance: erythromycin is motilin-receptor agonist Cholestatic hep > risk erythromycin estolate form -Ototoxicity (erythromycin at high doses) -Cardiac arrhythmias including QT prolongation -erythromycin, clarithromycin >>> azithromycin -Erythromycin lactobionate inj: thromophlebits (use normal saline) conctration dependent. Sodium fluid overload Clarithromycin: metallic tatse, GI upset/diarrhea
Macrolides Safety #2
Drug interactions: ertyhro>clarithro> azithro -Erhtyromycin and clarthromycin -Potent inhibitors of CYP3A4 (and 1A2) -Warfarin, simvastn, carbamazepine, phenytoin, benzo, cyclosporine, tacrolimus.
Legionella pneumophila -Pneumonia Mycoplasma pneumoniae -Pharyngitis, bronchitis, pneumoniae Chlamydia pneumoniae -Pharyngitis, sinusitis, bronchitis, pneumonia Atypical: b/c may not produce classic symptoms -Elderly, smokers, chronic illness -Drugs of choice: macrolides, quinolones, tetracyclines.
Mechanism of action: Binds 50s unit and prevents traspeptidation. -Bacteriostatic -Spectrum: gram positive and anerobic organisms only -Streptococci, staphylococci, fusobacterium, peptostretococcus, peptococcus C. perfigines, B/ fragilis. NO ACTIVITY AGAINST GRAM NEGS -skin infections option for PCN allery pts. -ACNE
Oxazolidinone class Bacteriostatic Mechanism of action: binds to the 23S of 50S ribosome. Inhibits formation of the initiation complex. Mechanism of resistance: 23s rRNA mutation Kinetics: completely absorbed when admined orally (100% bioavailability) Widely distributed, including CSF.
Spectrum of activity: Gram-positive only -Streptococci, staphylococci, including MRSA, enterococci including VRE. -Listeria monocytogenes -Mycobacteria Uses: -Resistant gram + infections MRSA, VRW soft/tissue infections, respiratory infectins, bacteremia/sepsis.
Preg cat C Bone marrow suppression -thrombocytopenia low plts, anemia, leukopenia. -Weak MAO inhibitor. -Avoid tyramine containing foods wine/cheese -Potential for interaction with adrenergic and serotenergic agents. -can increase blood pressure. Seratonin syndrome and tyramine -w/in 10days thrombocytopenia.
Inhibit protein synthesis by binding to 30s ribosome -misread DNA producing nonfunctional proteins -Polyribos split apart, unable to synthesize protein -Result=increased AG transport increased disruption of bacterial cytoplasmic membranes = cell death. -Diffuse through porins of outer membrane, but transport across inner membrane depends on electron transport (energy-dependent process) -Rate-limiting and can be blocked or inhibited by divalent cations, reduced pH, and anerobic conditions -Transport may be facilitated by PCN and Vanco
inactivated by microbial enzymes -most common -genes that encode aminoglycoside-modifying enzymes -Amikacin is not inactivated in the same way- more stable. Failure to penetrate intracellularly. -Low affinity of the drug for the bacterial ribosome.
Aminoglycosides Spectrum of Activity
Aerobic gram-negative organisms only including p. aeruginosa. -Gram + activity limited to combo therapy -combined w/cell wall-active agent to achieve synergy.
Gram-neg coverage including p. aeruginosa -alternative for PCN allergy pts. -Respiratory tract infections, UTIs, skin/soft tissue infections bacterermia/sepsis, intra-abdominal infections. -Used in combo with other agents except UTIs. -Gram-positive infections at low doses for synergy ie. staphyloccoci, enteroccoci
Rapidly bactericidal CONCENTRATION dependent killing -peak/MIC ratios important -Post-antibiotic effect: bacterial will fail to grow despite concentrations below the MIC.
Linear kinetics -Absorption: primarily IV poorly absorbed from GI tract Rapidly absorbed after IM admin -Distribution: distribution limited 25% of lean body weight Low concentrations in respiratory secretions, CSF -Elimination Via kidneys Dose adjust in pts with kidney dysfunction
Preg D category -AE: Nephrotoxicity (8-26%) Cum dose, duration, elevated troughs, elderly usually reversible. -OTOTOXICITY: dose duration, concomitant ototoxins. USually not reversible!!!- high decible -Neuro blockade (rare): inhibits presynaptic release of Ach and blockage of postynaptic receptor sites of Ach resulting in anesthesia or the admin of other enuro blocking agents, rapid infusion. *** Troughs predict the toxicities.
Therapeutic monitoring: narrow index inter-patient variability in concentrations Therapeutic levels associated with improved response: peak = efficacy, troughs=toxicity Admin: dose based on lean or adjusted body weight. Infuse standard interval dose over 30mins and extended interval dose over 60mins -endotoxin like rxn (shaking, chills, fever) w EIA dose.
Aminoglycosides Extended Interval Rational
2 methods: -Conventional dosing -Extended interval dosing Rational for extended: concentration dependent killing Post antibiotic effect Tissue penetration Negligible troughs potentially reduce toxicity: renal accumulation is saturable. Little to no ototoxicity Easier to monitor
Which of the following protein synthesis inhibitors requires a dose adjustment in acute renal failure?
Gentamicin= renal adjustment Azithro, Clinda, Linezolid are all liver
Target DNA gyrase and topoisomerase IV Inhibits the activity of topoisomerases, which are enzymes responsible for the supercoiling of the DNA. -Inhibit topoisomerases IV, interfers wiht the replicated DNA separation into daughter cells.
Alteration in DNA gyrase or topoisomerase enzyme -alterations in membrane permeability -active efflux pump
Gram-negative organisms Enterobacteriaceae Cipro and levofloxacin active against p.aeruginosa Newer agents: levofloxacin and moxifloxacin active against strept pneumoniae -Moxi has SOME ANEROBIC activity -Atypicals
Concentration dependent Bactericidal
Well absorbed after PO admin > 95% Impaired absorption with multivalent cations Distribution is wide high tissue levels RENAL elimination Moxifloxacin is liver 1/2 lives: Cipro 4 hrs, Moxi 12 hrs, Levo 8 hrs.
UTIs (NOT MOXI), prostatitis, intra-abdominal infections, febrile neutropenia, often in combo with other agents. Traveler's diarrhea Skin/soft tissue infections (levofloxacin, moxifloxacin) TOO BROAD Not ideal agents (b/o broad spectrum) Can be used in PCN allergy pts. Respiratory tract infections: pneumonia, bronchitis, sinusitis 1. Hospital: cipro, levo 2. Community: levo, moxi
Category C AE: rashes, photosentivity, increased liver enzymes, QT prolongation, CNS side effects (dizzy hallucinations, delerium, seizures) GI: N/V/ associated w/ C.diff Allergic rxn: glottic angioedema (never again) Drug interactions: Al+, mg+, ca+, ca supplements, irion, sucrafalate, dairy, tube feeds. Separate by 2 hrs. *** Not used in kidos d/t bone and tissue development
Folic Acid Inhibitors
Sulfonamide strucutral analogs and competitive antagonists of PABA
Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate