Pharmacology Antibiotics Exam 2

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Antimicrobials

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

Drug Classification

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

Bacteria themselves

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)

Antibiotics mechanism

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.

Concetration-Dependent

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.

Pharmakokinetics

ADME

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

Cultures

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.

Blood Cultures

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.

Swab Cultures

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

- FALSE

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

All of the above

Cell-Wall Synthesis Inhibitors

Beta-Lactams:
Penicillin
Cephalosporins
Monobactam (aztreonam)
Carbapenems

Glycopeptide: Vancomycin

Cell Wall Synthesis

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)

Beta-Lactam

Thiazolindine ring attached to a beta-lactam ring. Side chain determines the pharmacologic properties. Nucleus is a structural requirement.

Beta-Lactams mechanism

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.

Penicillins

Natural
Penicillinase-resistant penicillin
Aminopenicillin
Extended spectrum penicillins

Natural 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)

Pennicilinase-resistant PCN

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

Antistaphylococcal penicillins
-methilcillin (not avail)
-Nafcillin, oxacillin (parenteral)
-cloxacillin, dicloxacillin (PO)

Aminopenicillins Drug Types

Ampicilin (parenteral, PO)
Amoxicillin (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)
Drugs

Ticarcillin (parenteral)
Piperacillin (parenteral)

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-Lactamase Inhibitors

-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

-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.

PCN SAFETY

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

URI

Pharyngitis (usually viral)
Otitis Media
Sinusitis

Phyarngitis

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

Tx: Amoxicillin-amoxicillin/clavulanate

Cephalosporins

1-4 generations

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

Cefepime IM/IV

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

Cephalosporin Kinetics

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

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)

Cephalosporin AEs

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

CAP causes

S.pneumonia leading cause (20-60%)
H. influenza: staphylococcus aureus, gram-negative bacteria each about 3-10%

CAP tx

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

Strept pneumonia

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.

Meningitis

Inflammation of membranes surrounding the brain and spinal cord including the dura, arachnoid and pia matter.

Monobactam (Azetreonam)

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.

Azetreonam Safety

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)

Carbapenems

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

MOR: Carbapenemases, KPC, metallo-carbapenamase
-Porin changes
-Efflux pumps

Ertapenem

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

Dist: adequate penetration into inflamed meniges

Carbapenems Kinetics #2

Excretion: Primarily renal (need renal dose adjustment) seizure potential

1/2 lives:
Impenemen, meropenem, doripenem= 1 hour
Ertapenem: 4 hours
All admin 1x daily

Carpanems Use

Very broad spectrum
-Bacteremia/sepsis, hospital-associated pneumonia, intra-abdominal infections, febrile neutropenia, gram-negative meningitis (meropenem)

Polymicrobial infections
Typically reserved for more resistant organisms
Ertapenem is more narrow spectrum and may be useful for UTIs, skin/soft tissue infections, penumonia

Carbapenems Safety

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

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
-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

Seizures

Which beta-lactam has the broadest spectrum

Imipenem (carbapenem)

Which is safest to use in a pt. with PCN allergy?

Azetreonam

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

Vanco Pharmacokinetics

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.

Vanco kinetics/dynamics

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

Vanco Uses

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

Vancomycin safety

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

Cellulitis

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

Cellulitis Tx

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.

Staphylococcus aureaus

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

Chloramphenicol
Tetracyclines
Glycylcyline (tigecycline)
Macrolides
Clindamycin
Streptogramins
Oxazolidinones
Aminoglycosides

Chloramphenicol

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

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

Tetracyclines Uses

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.

Tetras Pharmakokinetics

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

Tetras Metabolism

Doxy preferred in kidney dysf pts.
-Tetra and mino accumulate in the kidneys

Tetras safety

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)

Tigecycline (Tygacil)

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

Tigecycline (Tygacil)

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

Macrolides

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

Macrolides MOR

Associated with frequent use +/- high doses
Alteration/mutation of ribosomal subunit (high-level)
Active efflux pump (low-level)
Possible cross-resistance w/clindamycin

Macrolides

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)

Macrolides Pharmacokinetics

Absorption
-Erythromycin base destroyed by gastric acid. Enteric coated or esterified.
-Dist: widely distributed, except CSF
-Hepatic metabolism

Macrolide Azithromycin

IV form avil, less GI intolerance, NO CYP450 drug interactions, Biliary/fecal excretion, yes on prolonged tissue levels

Macrolide Clarithromycin

IV form avail, less GI intolerance, interacts with CYP450 drugs, CYP450/renal excretion, no prolonged tissue levels

Macrolide Erythromycin

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.

Macrolides Safety

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.

*** Erythromycin w/azole antifungals = prolonged QTC

Atypical Pathogens

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.

Clindamycin

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

Clindamycin kinetics

Nearly completely absorbed
Distributes well, except CSF
> 90% protein bound
Extensive liver metabolism
Preg Catg B
ADVERSE EFFECTS
-Diarrhea, includng pseudomemranous colitis

Linezolid (Zyvox)

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.

Linezolid Zyvox

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.

Linzolid (Zyvox)

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.

Aminoglycosides Drugs

Gentamycin, Tobramycin, Amikacin, Neomycin, Streptomycin.

Aminoglycosides MOA

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

Aminoglycosides resistance

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.

Aminoglycosides Uses

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

Aminoglycosides dynamics

Rapidly bactericidal
CONCENTRATION dependent killing
-peak/MIC ratios important
-Post-antibiotic effect: bacterial will fail to grow despite concentrations below the MIC.

Aminoglycosides kinetics

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

Aminoglycosides Safety

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.

Aminoglycosides dosing

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

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

Amikacin Aminoglycoside

Peaks 20-30 mcg/ml
Troughs 5-10mcg
Higher end of range for life threatening infections:
Peaks 25-30mcg/mL

P. aeruginosa

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

Quinolones MOA

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.

Quinolones resistance

Alteration in DNA gyrase or topoisomerase enzyme
-alterations in membrane permeability
-active efflux pump

Quinolones Spectrum

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

Quinolones Dynamics

Concentration dependent
Bactericidal

Quinolones Kinetics

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.

Quinolones Uses

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

Quinolones Safety

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

Trimethoprim/Sulfamethoxazole BACTRIM

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