Pharm Block 4-2
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What are the 2 main penicillins?
- G which is given O or P(mostly P) and Pen V which is oral only
- Give Pen G every 4 hours for sever infections like meningiococcimea
- Procaine and benzathine penicillin G are repository forms with longer half lives
What is the spectrum of action for ampicillin and amoxicillin?
- E. coli(80%), Proteus mirabilis, Salmonella, Shigella, H influenzae, H.pylori(almost 100%)
- Strep pneumo,
- Listeria monocytogenes(100%) only sensitive to ampicillin can cause neonatal menenditis and puperal endometritis
- Moraxella catarrhalis
- Borellia bergdorfi
What are the penicillinase resistant penicillins?
- Nafcillin, oxacillin, Cloxacillin, Dicloxacillin
- Used for methicillin sensitive staph aureus and staph epidermitis
- Nafcillin no good for enterococcus or e coli
What is the spectrum of action of Penicillin G and V
- Narrow spectrum penicillins
- GAS- Strep pyo
- strep pneumo- 95% of bact pneumonia
- Some gram positives
- Treponema pallidum
- No good for Staph aureus Bacteroides Fragillis or ecoli
What mechanisms do bacteria use to resiste penicillin action?
- beta lactamase that destroy the antibacterial actions ( staph resistance to penicillin G)
- Mutation of the penicillin binding targets of penicillins ( staph resistance to methicillin)
- Alter porins to decrease penetration
What is the mechanism of action for penicillins?
- Interfere with cell wall synthesis by binding penicillin binding proteins located in the bacterial cytoplasmic membrane.
- inhibit transpeptidases that crosslink proteoglycan chains
- Also activate autolytic enzyes that cause cell wall lesions
- Best for acute infections
What are the general pharmacologic principles of penicillins?
- variable oral absorption
- Minimally metabolized and excreted in urine (blocked by probenecid)
- Ampicillin partly and nafcillin mostly are excreted into biliary tract
- Penicillin only has minimal access to CNS, eye, or prostate.
What are the extended range penicillins?
- Ampicillin P/O
- Amoxicillin O
- Ticarcillin P
- Piperacillin P
What are the different penicillins?
- Methicillin P
- oxacillin PNaficillin P
- Cloxacillin O
- Dicloxacillin O
What is Cefazolin and what organisms are sensitive to it?
- A first generation Cephalosporin administered Parenternally with a T1/2 of 1.8 hrs
- Strep/Staph- 4+ sensitive
- H flu- 1+
- Gram Negatives- 2+
What is Piperacillin and what can it treat?
- It is an extended range Penicillin, can be used to treat: Ecoli and mirabilis 3+ sensitivity
- Pseudomonas, Enterobacter, Indole + orgs, and Proteus are 4+ sensitive
- Bacteroides Fragilis is 3+ sensitive
What is Ticarillin?
- An extended range Penicillin Organisms that are sensitive to Ticarillin are- Ecoli and proteus Mirabilis 2+
- Pseudomonas, Enterobacter, and Indole+ proteus 2+
- Bacteroides Fragilis 2+
What is Ampicillin?
- An extended range penicillin.
- Only Ecoli and Proteus Mirabilis are sensitive 2+
What are some common clinical uses for Penicillin?
- Treatment of Step Pharyngitis
- Prophylaxis against Rheumatic fever
- Syphilis treatment
Some staph organisms are resistant to normal penicillins, need to use penicillinase resistant drug.
What are common clinical uses of Ampicillin and Amoocicillin?
- Otitis Media
- Lyme disease
- Can only use these drugs if sensitve strains of a given organism are causing the disease.
What Can Ticarcillin and Piperacillin be used to treat?
Gram negative organisms especially Pseudomonas infections. Also Mixed intra abdominal infections if caused by strains sensitive to these drugs.
Often replaced now with tazobactam (piper+beta lactamase inhibitor)
What are some side effects of Penicillin use?
- Diarrhea is common due to disruption of normal intestinal flora ( often with Amocicillin and augmentin)
- Seizures possible with high doses of penicillin
- Allergic hypersensitivity- anaphylactic rxns (rash and urticaria) 1 in 10,000 doses
What are some side effects of penicillin use?
- Elevated hepatic transaminases
- Drug fever
- Nephritis- usually methicillin related
- Penias, hemolytic anemia (coombs positive)
What is used to test for penicillin allergy?
- RAST blood test for screening
- then follow up skin tests for major and minor determinants
- life/health threatening rxns are rare
What are Cephalexin and Cefadroxil?
- First generation cephalosporins both given orally
- Cephalexin has a t1/2 of .8 hrs
- Cefadroxil has a t1/2 of 1.3 hours
What is Cefuroxime and what is it used for?
- A second generation Cephalosporin given Parenternally
- Mostly gram positive action, some gram neg
- Non MRSA staph and strep are 4+ sensitive
- H flu is 3+ sensitive, Gram Negatives are 3+ sensitive
What are Cefoxitin and Cefotetan
- Second generation cephalosporins that can treat both administered parenternally
- Non MRSA staph and strep 2+
- H. Flu 2+
- Gram Negative 3+
- Bacteroides 3+
What are Cefuroxime Axetil, Cefprozil, and Cefaclor?
- second generation cephalosporins, all administered orally
- Cefprozil is the best for gram negative coverage out of the second gens
What are the common clinical uses for first generation cephalosporins?
Surgical Prophylaxis and soft tissue infections
What are the common clinical uses for second generation cephalosporins?
Treatment of Intra abdominal infections
What are Cefotaxime and Ceftriaxone?
- third generation cephalosporins given parenternally. Can be used to treat- non MRSA staph and strep 3+
- H. Flu 4+
- Gram negatives 4+
- bacteroides 1+
- Ceftriaxone is the drug of choice for Borellia Bergdorfi
What is Ceftazidime?
- A third generation cephalosporin given parenternally. Can be used to treat non MRSA staph and strep 1+
- H. Flu 4+
- Gram Negatives 4+
- Pseudomonas 4+
- Bacteroides 1+
What is Cefepime?
- 4th generation cephalosporin given parenternally can be used to treat Non MRSA staph or strep 3+
- H. Flu 4+
- Gram Negatives 4+
- Pseudomonas 4+Bacteroides 2+
Which generation of cephalosporins work well in CNS?
Which cephalosporins are excreted into the biliary tract?
Cefoperazone and Ceftriaxone
Cefotaxime is metabolized in liver
What organisms are cephalosporins inable to treat?
Enterococci, Listeria, and MRSA
Which generation of Cephalosporins have the best activity on Gram Positive organisms?
What are the pharmacologic principles of cephalosporins?
- Variable oral absorption
- Renal elimination
- Cefoperazone and Ceftriaxone are well excreted into the biliary tractCefotaxime is metabolized in the liver
- Only cephalosporins that enter CNS effectively are Third gen (ceftriaxone)
Which 2 cephalosporins work well on anaerobic organisms?
Cefoxitin and Cefotetan
What are common clinical uses for 3rd and 4th generation cephalosporins?
- Ceftriaxone and Cefotaxime given for serious pediatric infections like meningitis, broad spectrum but no good for anaerobes, pseudomonas, enterococci, listeria and MRSA
- Ceftriaxone used in gram neg liver abscess
- Ceftazidime given for pseudomonas infections
- Cefepime has a very broad spectrum but no good on anaerobes, Enterococci, Listeria, or MRSA
What kind of allergic rxns are seen with cephalosporins?
- Rash/ urticaria
- not much cross allergy between penicillin and cephalosporin
- Disulfiram-like reaction – cefamandole or cefoperazone (ingestion with alcohol
- produced headache, nausea, vomiting, abdominal pain)
What are some side effects of cephalosporin use?
- Bleeding diathesis- cefamandole (no longer avail in US) or cefoperazone
- Phlebitis at infusion site
- Biliary ubstruction when rapidly infused-ceftriazone
What is Augmentin?
- Amoxicillin+ clavulanic acid(beta lactamase inhibitor)
- administered orally
- Drug of choice for animal bites
What is Timentin?
Ticarcillin+ Clavulanic acid- ad ministered parenternally
What is Unasyn?
Ampicillin + Sublactam ( beta lactamase inhibitors) given parenternally
What is Zosyn?
- Piperacillin+ Tazobactam (beta lactamase inhibitor)
- given parenternally
What is Clavulanate Potassium?
- A beta lactamase inhibitor that is isolated from Streptomyces Clavuligerus.
- Irreversibly binds beta lactamase
What is the reason for combining antibiotics with beta lactamase inhibitors.
- to broaden the spectrum of effectiveness against
- Staph Aureus, H. Flu, Bacteroides, Moraxella Catarrhalis, and Gram negative enteric bacteria.
What does Beta lactamase do to the MIC of an antibiotic?
Increases the MIC
What is Aztreonam?
- a monobactam beta lactam that is administered Parenternally and does not penetate the CNS
- used to treat gram negatives including pseudomonas, not effective on anaerobes.
What is Imipenem?
- A carbapenem beta lactam administered parenternally with no CNS action.
- Administered with cilastatin to inhibit renal inactivation by dehydropeptidase1
- Rarely causes neurologic rxns like seizures- usually assoc with high dose/renal failure
What is Meropenem?
A carbapenem beta lactam
What is Ertapenem?
A carbapenem beta lactam
Are carbapenem beta lactams susceptible to beta lactamase?
No but some organisms make extended spectrum beta lactamases that can inactivate carbapenems.
When are carbapenem beta lactam antibiotics traditionally used?
- As a last resort for resistant organisms, have a very broad spectrum.
- NOT used for listeria, MRSA, some enterococcus strains, some pseudomonas, and some anaerobes.
- can be used as empiric treatment of patients that "crash" secondary to suspected resistant organism
- also used for mixed infections
What is Vancomycin?
- A complex Gluco-polypeptide, unrelated to
- other antibiotics
- excreted renally, not well absorbed orally, and has inadequate CNS/Eye/Prostate penetration
How does vancomycin work?
- Irreversibly inhibits
- biosynthesis of peptidoglycan polymers in cell wall of
- dividing gram positive organisms
Blocks cell wall synthesis
What is vancomycin used to treat for?
Has a narrow spectrum works on resistant gram positive orgainsms including MRSA, enterococci and pneumococci
Clostridium Difficile also susceptible
What is the drug of choice for serious infections with resistant gram positive
- not as good for lung infections
- Drug of second choice for Pseudomembranous colitis caused by clostridium difficile (because of the concern about Vanco resistance, Metranidazole
What are potential side effects of vancomycin use?
- Renal toxicity
- Auditory toxicity
- Red man syndrome- fixed with slow infusion
What is daptomycin?
A lipopeptide antibiotic given Intravenously
- Bactericidal by disrupting multiple aspects of the bacterial plasma membrane function ,
- including peptidoglycan synthesis, lipoteichoic acid synthesis, and
- bacterial membrane potential.
What is the antimicrobial spectrum of daptomycin?
- Narrow, works on gram positive organisms including linazolide resistant MRSA, vancomycin resistant enterococcus (VRE)
- Usually has a low MIC
Common clinical uses for daptomycin?
- Skin and soft tissue
- infections #
- Sepsis #
- Endocarditis #
- # (With resistant gram positive infections)
NOT yet approved for children
What are the kinetics of daptomycin?
- Rapid concentration dependent activity
- concentration dependent post antibiotic effect.
- given once daily
- excreted via kidney
What are some side effects of daptomycin use?
- Transientmuscle weakness, myalgias after 6 - 11 days of Rx. CPK levels (MM isoenzyme) rose 2-3 days before and
- peaked at 10,000-20,000 U/L. CPK normal
- in 1 week
- Once daily dosing (4 mg/kg) may increase the
- therapeutic –toxicity ratio by increasing efficacy and decreasing skeletal muscle adverse effects associated with twice daily dosing
What are the classes of ribosomally active antibiotics?
What antibiotics are Aminoglycosides?
- kanamycin P/O, Neomycin O/Topical, Streptomycin P
- Tobramycin P, Netilmicin P, AmikacinP, and Gentamycin P/T
What is the mechanism of action of aminoglycosides
- Binds to 30 S subunit of Bacterial Ribosome
- Bacteriocidal Inhibitors of Protein Synthesis
- Blocks formation of initiation complex
- Causes misreading of mRNA template - cidal
- Inhibits translocation
- Prevents polysome formation
- Blocks subunit association
What are the pharmacologic properties of aminoglycosides?
- Polar compounds so not orally absorbed
- Excreted renally- dose adjustment in renal insufficiency
- Poor CNS/Sputum/Bile/ Prostate penetration
- pH dependent activity 7.4 best
What are some of the properties of aminoglycoside pharmacology
- Demonstrateconcentration dependent killing – high levels of antibiotic facilitate entry through cell wall and membrane
- Demonstrate post-antibiotic effect
- Therefore, administer one or two larger doses each day to achieve high peak levels
- Toxicity is related to trough levels and host tissue “recovery time”
What mechanisms do bacteria use to resist aminoglycosides?
- Inactivating enzymes called group transferases- confered by plasmids
- Inhibition of drug penetration into the organism
- Decrease affinity of the 30s subunit target for the antimicrobial
What is the spectrum of action of aminoglycosides?
E coli, Proteus, Klebsiella, Enterobacter, Serratia, Pseudomonas, and moderate gram positive coverage.
What are some common clinical uses for aminoglycoside antibiotics?
- often used in combo with cell wall active drugs like beta lactams
- used in serious gram negative infections of hospitalized patients
- Empiric treatment of neonatal infections
- Second line of drugs for mycobacterial infections
What are some side effects of aminoglycoside use?
- Significant renal toxicity – acute tubular necrosis, reversible and dose related
- Ototoxicity- auditory and vestibular damage could be irreversible- dose related
- Not to be used in pregnancy
- Neuromuscular blockade
What are the drugs that fall under the class tetracyclines?
What are the properties of tetracyclines?
- Variable oral absorbtion- impaired by food
- Moderate tissue distribution
- Enterohepatic cycling
- Tetracycline excreted in the urine, doxycycline in feces
- Antagonistic when used in combo with beta lactams
What mechanisms do bacteria use to become resistant to tetracyclines?
facillitate efflux of the drug from the bacteria or decrease the entry of the drug
What is the mechanism of action of tetracyclines?
- Bacteriostatic bind reversibly to the 30s subunit of bacterial ribosome
- Inhibits attachment of aminoacyl tRNA
What is the spectrum of action of tetracyclines?
- Gram positive Staph and strep
- Gram negative enterics
- Atypically- Mycoplasma, Chlamydia, Chancroid, Rickettsia, Borrelia, Entamoeba
Variable efficacy on top 3
What are some common clinical uses of tetracyclines?
- Treatment of subacute bronchitis secondary to H flu and strep pneumonia
- Atypical pneumonia
- STDs; Prostatitis (doxycycline)
- Rocky Mountain Spotted FeverLyme disease
What are some of the side effects of tetracycline use?
- GI- Nausea, abdominal pain, diarrhea
- Fetal and child effects on bones/teeth- CONTRAINDICATIONHepatic Necrosis (especially with doxycycline)
- Renal tubular acidosis
- Headache, vestibular (dose dependent), Pseudotumor CerebriJarisch Herxheimer rxn
What is Tigecycline?
- A derivative of minocycline only given via IV
- Binds 30s ribosomal subunit with high affinity blocking tRNA binding
- Bacteriostatic, good tissue distro, post antibiotic effect, metabolized in liver and excreted into billiary tract.
What are common clinical uses of Tigecycline?
- MRSA, MRSE, VRE, resistant pneumococci and enterococci
- Acinetobacter and other gram negative aerobes and anaerobes, some mycobacteria, and mycoplasma, NOT pseudomonas
- Synergistic with Rifampin
- Skin and skin structure infections
- Intra-abdominal infections
- Not approved for children (See tetracyclines
What are some side effects of Tigecycline use?
- Cross hypersensitivity to tetracyclines
- Nausea and vommiting
- Headache and pseudo tumor cerebri
- Possible bone and tooth discolorationTransaminase elevation
What is Chloramphenicol?
- Antibiotic that is rarely used due to feared toxicity
- Has excellent oral absorption but can be administered IV
- Best distribution b/c lipophillic
- Metabolized in the liver by glucuronyl transferase
- Inhibits cytochrome P450
What is the mechanism of action of Chloramphenicol?
Binds the 50s subunit of the bacterial ribosome and inhibits peptidyl transferase activity.
What mechanisms do bacteria use to resist chloramphenicol?
- Antibiotic inactivating enzyme production- conferred by plasmidReduction of permeability to drug.
What is the spectrum of action of chloramphenicol?
- Broad but no good for staph or pseudomonas
- Works for H. flu, Neisseria meningitides, salmonela, anaerobes, and rickettsia
what are the common clinical uses for chloramphenicol?
last drug used for brain abscess, typhoid fever, and rocky mountain spotted fever.
last due to toxicity
What are the side effects of chloramphenicol use?
- 1/40,000 irreversible aplastic anemiadose related aplastic anemia
- Gray baby syndrome- inability to conjugate chloramphenicol because of decreased levels/immature glucuronyltransferase
What are the Macrolides/ketolides?
What are the pharmacologic proterties of macrolides/ketolides?
- Used orally mostly but IV available
- Poor CNS and Eye penetration
- Concentrates in Respiratory secretions
- Azitromycin is concentrated in phagocytic cells and other tissues
- Mostly hepatic metabolism and excretion, some urinary excretion
What is the mechanism of action of Macrolides/ketolides?
- Bind 50s subunit of bacterial ribosome preventing ribosomal translocation.
- Bacteriostatic for the most part.
What mechanisms have bacteria evolved for macrolide/ketolide resistance?
- high level of resistance by alteration of the receptor on the ribosome (plasmid mediated) Strep pneumo is one
- Production of inactivating enzymes
- Increase efflux mediated by mef A (low level resistance
- Decrease in permeability to the drug
Levels of pneumococcal resistance to macrolides/ketolides?
- Penicillin V- 15%
- Erythyomycin- 35%
- Augmentin- 8%
- Azithromycin- 35%
What is the spectrum of action of Macrolides/Ketolides?
- Sensitive gram + but not entero coccus
- some anaerobes
- Salmonella (typhoid fever-azithromycin)
- Legionnaire's disease
- Bordetella Pertussis (azithromycin)Campylobacter
- Atypical Mycobacteria (claritromycin)
What are common clinical used for Macrolides/ketolides?
- Substitute for penicillin in respiratory bacterial infections
- Atypical pneumonia; whooping cough
- MAI (clarithromycin)
- Resistant Salmonella (Azithromycin)
- Contra indicated in pregnancy (except azithromycin)
What are side effects of macrolide toxicity.
- Abdominal pain and nausea
- Cholestatic hepatitis (erythromycin estolate)
- Associated with higher incidence of pyloric stenosis if used in infants
- Multiple drug interactions secondary to inhibiion of hepatic cytochromes (not azitryomycin)
What are the pharmacologic properties of Telithromycin?
Metabolized in the liver by CYP 450 and CYP 349
used on penicillin resistant pneumococci, H. Flu, Moraxella Catarrhalis, B pertussis, mycoplasma, legionella, and chlamydia
What are the effects seen in telithromycin toxicity?
- Blurred visionGi disturbance
- Prolonged QT interval
- Exacerbation of myasthenia gravisMultiple drug interactions
What is clindamycin?
- A Lincosamide antibiotic
- Similar to macrolides and as such there is some cross resistance.
- good oral absorption and tissue penetration but no CNS or Eye
- Resistance usually mediated by increased efflux
What is the spectrum of activity of Clindamycin?
- Good for Gram positives including Staph aureus and severe invasive strep. Not for enterococci
- Good for anaerobes
- High incidence of pseudomembranous colitis secondary to C difficile overgrowth
What is Synercid?
- A Streptogramin Combination
- quinupristin 30% and Dalfopristin 70%
- Metabolized and excreted by liver
- Only given IV
- Binds 50s subunits prevents ribosomal translocation- bacteriocidal
What is the spectrum of activity of Synercid?
Staph aureus and epidermidis, Strep pyo and aglaci, some enterococci
Causes drug interactions, phlebitis (most common), Jaundice, arthralgia and myalgia
What is Linezolid?
- An oxazolidione
- absorbed well orally 100%- not altered by food
- metabolized by liver but excreted by kidney
- Better penetration into lung than vancomycin (significant for pneumonia)
- has low serum protein binding independent of drug concentration
What is the mechanism of action of Linezolid?
- Binds the 50s subunit and inhibits initiation complex and translocation of tRNA
- BacteriostaticResistance from decreased affinity of target for the drug
What is the spectrum of Linezolid action?
- All aerobic gram positives, especially resistant staph strep and enterococci
- Toxicity causes thrombocytopenia, neutropenia, reversible marrow suppression
- Also a weak MAO inhibitor
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