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
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.
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.
Peak serum conc.
Vd to site of infection
Route of elimination
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?
-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
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
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
3. Spectrum of activity
4. Only A & C
E. All of the above
All of the above
Cell-Wall Synthesis Inhibitors
Cell Wall Synthesis
3 Major Phases
-Peptidoglycan monomers from aminos and sugars.
-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.
-Bactericidal against actively dividing bacteria.
** Dosed frequently!
Beta-Lactams: Mechanism of resistance
-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.
Extended spectrum penicillins
PCN G (Parenteral)
-K+ or Na_
-Procaine (IM) comp levels to IV for 24 hrs.
-Benzathine (IM) low levels for long period of time x weeks
PCN VK (PO)
Spectrum: gram +, anerobes, gram negative cocci
-hydrolyzed by penicillinase
Spirochetes (treponema pallidum - syphillis)
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.
Pennicilinase-resistant PCN Drugs
-methilcillin (not avail)
-Nafcillin, oxacillin (parenteral)
-cloxacillin, dicloxacillin (PO)
Aminopenicillins Drug Types
Ampicilin (parenteral, PO)
Aminopenicilin Spectrum & Clinical Use
Similar to PCN G > activity against Enterococcus sp, Listeria, some gram neg E.coli, haemophilis influenza, salmonella typhi.
** Hydrolyzed by beta-lactamase
Clinical use: Infections caused by Streptococcus sp. (pharyngitis, tonsilits, otitis media, sinusitis)
-Infections causes by enterococcus (endocarditis) Listeria (bacteremia/meningitis).
-Prophylaxis of neonatal group B streptococcal disease and rheumatic fever (dental prophylaxis)
Extended-Spectrum PCN (anti-psuedomonal)
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
-Expand spectrum of parent beta lactam antibiotic
Beta-lactam & Beta-Lactamase inhibitors combo
-Amoxicillin/clavulanic acid (Augmentin)
-Ampicillin/sulbactam (Unasyn) (IV)
-Ticarcillin/clavulanic acid (Timentin) (IV)
-Piperacillin/tazobactam (Zosyn) (IV)
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.
1.Hypersensitivity (anaphylaxis, rash)
2.Diarrhea, including pseudomembranous colitis
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
Pharyngitis (usually viral)
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%)
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
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
Second Generation Cephalosporins
Cefuroxime axetil PO
Third Generation Cephalosporins
Cefitoren pivoxil PO
Cefpodoxime proxetil PO
Fourth Generation Cephalosporin
5th gen sucked and rough on kidneys
Now a 6th gen: ceftoraline
Cephalosporin Spectrum of Activity
NO activity against:
-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
-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
Cephalosporin 1st Gen
skin soft/tissue infections, UTIs, surgical prophylaxis
Cephalosporin 2nd Gen
Skin soft/tissue infections, UTIs, respiratory tract infections
-only cefuroxime has reliable activity against s. pneumonia for respiratory infections.
-Cefoxitine, cefotetan: OB/GYN infections, intrabdominal/pelvic infections
Cephalosporin 3rd Gen
1. Respiratory tract infections (s.pneumoniae activity)
-cefotaxime, ceftriaxone, cefepime, cefopdoxime (PO)
2. Menigitis: (cefotaxime, ceftriaxone, cefepime, ceftazidime)
3. UTIs, intra-abdominal infections w/ anti-anaerobic drug.
4. Pseudomonal infections (ceftazidime, cefepime)
5. N.gonorrhea (ceftriaxone)
Hypersensitivty: anaphylaxis, rash
IM admin painful
Diarrhea, including pseudomembranous colitis
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
-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
NO gram positives
Azetreonam Kinetics and Use
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:
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
MOR: Carbapenemases, KPC, metallo-carbapenamase
Lacks activity against P. aeruginosa, acinetobacter spp.
Carbapenems Kinetics #1
-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
Dist: adequate penetration into inflamed meniges
Carbapenems Kinetics #2
Excretion: Primarily renal (need renal dose adjustment) seizure potential
Impenemen, meropenem, doripenem= 1 hour
Ertapenem: 4 hours
All admin 1x daily
Very broad spectrum
-Bacteremia/sepsis, hospital-associated pneumonia, intra-abdominal infections, febrile neutropenia, gram-negative meningitis (meropenem)
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
-cross reactive in pts with PCN allergy estimated 10-50%
-Avoid in pts with severe PCN allergy
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
Drug interactions: Eleptogenic agents (tramadol, quinolones, valproic acid) LOWERS seizure threshold.
Carbapenems clinical uses
Serious and life-threatening infections
-very broad spectrum
-bacteremia/sepsis, hospital -associated penumonia, intra-abdominal infections
-Gram negative meninigitis
-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
- Mechanism: inhibits cell wall synthesis in the peptidoglycan phase or elongation
-Beta lactams different in that they inhibit the 3rd stage.
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
-Intermediate susceptibility to vanco
-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.
3.Therapeutic drug monitoring:
-Blood level prior to next dose
-Peak levels not helpful
10-20mcg/mL is the optimal
Resistant Gram-positive infections
-PCN resistant S. pneumonia
Gram-positive coverage in pts. with allergy or intolerance.
Colstridium difficile associated diarrhea
-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.
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
-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
Protein Synthesis inhibitors
-Binds reversibly to 50s ribosomal unit
-Gram +, neg, anaerobic bacteria
-Good GI absorption, widely distributed, including CSF
-Reversible bone marrow suppression
-Rare potentially fatal aplastic anemia
Tetracycline, doxycycline, minocycline
-Spectrum: some bacteria relatively narrow spectrum
-Some gram-positives, some gram-negatives, S. pneumoniae, H. Influenza, gonocci, menincocci, E. Coli
-Rickettsiae, chlamydiae, mycoplasma
Rocky mountain spotted fever and others caused by ricketssiae (typhus too)
Alternative to macrolides for Mycoplasma pneumoniae, Chlamydia pneumoniae, URI
-Chlamydia trachomatis (STD) or pelvic inflammatory disease (doxy)
-Select protozoal infections (plasmodium falciparum)
-Option in PCN-allergic pts.
PO absorption incomplete except doxy and mino.
-Watch out for other cations (aluminum, calcium, mg, irion, zinc-containing products)
-Distribution: widely distributed, including CSF (even without inflammation)
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)
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
Large Vd > 8L/kg
-low mean blood levels .62 + .09 mcg/mL
Eliminated through feces via biliary secretion
-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.
-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
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)
-Erythromycin base destroyed by gastric acid. Enteric coated or esterified.
-Dist: widely distributed, except CSF
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
-Erhtyromycin and clarthromycin
-Potent inhibitors of CYP3A4 (and 1A2)
-Warfarin, simvastn, carbamazepine, phenytoin, benzo, cyclosporine, tacrolimus.
*** Erythromycin w/azole antifungals = prolonged QTC
-Pharyngitis, bronchitis, 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.
-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.
Nearly completely absorbed
Distributes well, except CSF
> 90% protein bound
Extensive liver metabolism
Preg Catg B
-Diarrhea, includng pseudomemranous colitis
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.
-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.
Gentamycin, Tobramycin, Amikacin, Neomycin, Streptomycin.
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
-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
CONCENTRATION dependent killing
-peak/MIC ratios important
-Post-antibiotic effect: bacterial will fail to grow despite concentrations below the MIC.
-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
Dose adjust in pts with kidney dysfunction
Preg D category
Cum dose, duration, elevated troughs, elderly
-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.
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
-Extended interval dosing
Rational for extended: concentration dependent killing
Post antibiotic effect
Negligible troughs potentially reduce toxicity: renal accumulation is saturable.
Little to no ototoxicity
Easier to monitor
Aminoglycosides EIR Safety
REnal dysfunction, pregnancy, elderly, dialysis, endocarditis, gram +, severe fluid overload states, burns
Aminoglycosides Conventional Dosing
Therapeutic monitoring very important:
Peaks 30 mins after end of infusion
Troughs prior to dose: gram neg 7-9mcg/mL
Peaks 20-30 mcg/ml
Higher end of range for life threatening infections:
Gram-negative aerobic ROD
-Sepsis, penumonia, UTI, lung infections chronic, endocartditis, dermatitis, otitis externa.
P. aeruginosa Drugs with Activity
Ticarcillin, pipercillin, ceftazidime, cefepime, carbapenems not ertapenem, axtreonam, aminoglycosides, cirpo, levofloxacin, polymyxins
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
Cipro and levofloxacin active against p.aeruginosa
Newer agents: levofloxacin and moxifloxacin active against strept pneumoniae
-Moxi has SOME ANEROBIC activity
Well absorbed after PO admin > 95%
Impaired absorption with multivalent cations
Distribution is wide
high tissue levels
Moxifloxacin is liver
Cipro 4 hrs, Moxi 12 hrs, Levo 8 hrs.
UTIs (NOT MOXI), prostatitis, intra-abdominal infections, febrile neutropenia, often in combo with other agents.
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
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