Penicillins (list)

• IV aqueous penicillin G
• Procaine penicillin G
• Benzathine penicillin G (bicillin)
• Penicillin V

Penicillin - Class of Antibiotics

-All penicillins have beta lactam ring

-All beta lactam drugs interfere with the final cross-linking steps during synthesis of peptidoglycan

-Penicillin binds to penicillin binding proteins, promoting lysis of the bacteria by interfering with final cross linking steps during synthesis of peptidoglycan

Distribution of Penicillin

-Reasonably good

-poor CNS penetration, need high dose IV penicillin to be able to work

-poor prostate penetration

How is penicillin metabolized and excreted?

• Renally Excreted

Penicillin Activity

-Drug of Choice for Group A Strep and Veridans Strep

-Active against oral anaerobes, Treponema pallidum, and gram negative Neisseria gonorrhea

IV aqueous Penicillin G

• use a high dose for serious infections like meningitis

• use an intermediate dose for strep pyogenes skin infections

• low dose is not useful

IV Aqueous Penicillin G + Gentamycin

• Used in synergy for Enterococci Endocarditis

IM Penicillin Formulations

• Procaine Penicillin G (procaine increases half-life)
• Benzathine Penicillin G (bicllin)

Benzathine Penicillin G (bicillin)

-Long lasting IM penicillin that gives very low serums for 3-4 weeks

-Used in syphillis regiments

-1 dose only for group A strep

-Can be used prophylactically for Rheumatic Fever

Oral Penicillin Preps (Penicillin V)

-Resists gastric acid breakdown

-DOC for group A strep pharyngitis (strep pyogenes)

Side Effects of Penicillin

-Delayed Rash

-Anaphylaxis (not common)

-interstitial nephritis (IV)

-Mycolonic twitching/seizures (rare, unless giving high IV doses to a patient with renal failure)

-drug fever

-Remember to adjust dose for those with renal failure

Anti-Staphylococcal Penicillins (list)

• methicillin
• oxacillin
• dicloxacillin
• naficillin

Activity of Anti-staphylococcal Penicillins

-Active against Staph aureus and Staph aureus penicillinase (DOC for MSSA)

-Group A Strep

-Do not work for gram negatives

-Do not work for anaerobes

Pharmacokinetics of Anti-Staphylococcal Penicllins

-Oral forms poorly absorbed, give IV

-Dicloxacillin may be absorbed orally but has a bad taste and may cause GI upset

Methicillin

-No longer used in adults

-Causes interstitial nephritis

Oxacillin

-Anti-staphylococcal penicillin

-Can cause mild hepatitis that goes away when the drug is stopped

Naficillin

-anti-staphylococcal penicillin

-can cause leukopenia

Extended Spectrum Penicillin (list)

• Ampicillin
• Amoxacillin

Amoxicillin

• Active against:
  
  • Gram Positive: Enterococci, group A strep, viridans strep, Strep pneumoniae Treponema pallidum (syphillis)
  • Gram neg: Neisseria gonnorhea, Hemophilus influenzae
• Modest activity against CA gram neg bacilli (E.coli, Klebsiella, Campylobacter)
• Oral prep: useful for routine, uncomplicated otitis media and sinusitis

Ampicillin

-IV prep

-Active against enterococci, group A strep, Treponema pallidum, gram negative Neisseria gonorrhea

-Used for pyelonephritis

-Ampicllin+gentamycin for enterococcus + gram negative (such as Pseudomonas)

-Renally excreted

Anti-Pseudomonas Penicillins (list)

• Carbenicllin
• piperacillin
• ticarcillin
• mezocillin

Carbenicllin

-No longer used because of high sodium load

-Results in heart failure and fluid load

Activity of Anti-pseudomonas Penicillins

• (carbenicllin, piperacillin, ticarcillin, mezocillin)
• aimed at Hospital Acquired gram negatives
• active against bowel anaerobes
• piperacillin+aminoglycoside = synergy against pseudomonas

Anti-Pseudomonas Penicillins Pharmacokinetics/Excretion

-Renally excreted

-high amount of sodium -- may result in hypokalemia

Beta lactams/Beta lactamase inhibitors (list)

• Amoxicillin-clavulanate (Augmentin)
• Piperacillin-tazobactam
• Ticarcillin-clavulanate
• Ampicillin-sulbactam

Amoxicillin-clavulanate

-Oral prep -- Augmentin

-active against Beta lactamase producing MSSA, H. influenzae, but not against S. pneumoniae

-useful against resp. infections, otitis media, sinusitis -DOC for dog bite wounds (against dog and cat mouth flora)

Augmentin Excretion

• Renal

Side effects of augmentin

• GI Upset (the big one)
• drug fever
• rash
• anaphylaxis

How much creatinine clearance is lost per year as you age?

• After the age of 25 you use 1 mL of creatinine clearance per year

Bedside Creatinine Clearance Calculation

(140-age) x ideal weight in kg

72 x serum creatinine

Cephalosporins

-Beat lactam drug

-inhibit cell wall synthesis

-some are very broad spectrum

-DOC's for surgical prophylaxis

Cefazolin

• First generation cephalosporin
• Most active cephalosporin against MSSA
• Use for group A strep and surgical prophylaxis
• CA gram positive like penicillin susceptible strep (strep veridans)
• Common CA gram negatives: Klebsiella, E. Coli
• Combine with good anaerobic drug for intra-abdominal infections (cefazolin + metronidazole)

Second Generation Parenteral Cephalosporins

• cefuroxime, cefoxitin
• Activity against Hemophilus influenza and Bacteroides fragilis
• (plus first generation activity - MSSA, Group A Strep, Strep Veridans, Klebsiella, E. Coli)

2nd Generation Parenteral Cephalsporins (list)

• cefamandole (no longer used, thinned blood)
• cefuroxime (not used much)
• cefoxitin

• Active against: B. fragilis, E.coli, Klebsiella, penicillin susceptible staph, strep pyogenes, H. influenzae, strep veridans

cefuroxime

-parenteral

-active against H. influenzae, including ampicillin resistant

-former DOC for CA pneumonia, then abx resistance became a problem

-probably will not see used

cefoxitin

-parenteral second generation

-1st cephalosporin active against Bacteroides fragilis and N. gonorrhea

-Was used in intra-abdominal infections

-now only used for certain gonacoccal infections and PID (cefazolin-metronidazole is more cost effective)

3rd Generation Parenteral Cephalosporins (list)

-Ceftriaxone

-Cefatazidime

-Cefepime

3rd Gen. Parenteral Cephalosporins

-When first out, very active against gram negative bacteria

-renally excreted

Ceftriaxone

-3rd generation parenteral

-Long half-life, give once a day

-essentially active against all CA gram negatives and some HA gram negatives

-NOT ACTIVE against pseudomonas

-Good against gram positive (pneumococci, Group A & B strep)

-broad spectrum, safe-this has lead to resistance, may need to use other drugs especially for HA infections

Ceftriaxone - distribution

• Penetrates CSF (but may need to give every 12 hours)
• Favorite agent for meningitis

Ceftriaxone - excretion

• renal, but don't usually have to adjust unless there is profound renal failure

Cefotaxime

Cefatazidime

-3rd generation parenteral

-less gram positive activity, but more gram negative activity

-active against Pseudomonas and HA gram negative infections

-can be used with an aminoglycoside for Pseudomonas infections

-used in treating fever of unknown etiology in a patient with no WBC's

Cefepime

"4th generation" - combines gram positive activity of ceftriaxone with gram negative activity of cefatazidime

-very potent, very broad; use carefully

-used mostly for nosocomial infections

-given every 12 hours

Oral Cephalosporins (list)

-Cephalexin

-Cefprozil

-Cefixime

Cephalexin

-first generation oral cephalosporin

-used for minor soft tissue infections due to GAS or MSSA

-also used for susceptible gram negative UTI

Cefprozil

-2nd Generation oral cephalosporin

-bubble gum flavor, given 2 times a day

-active against H. influenza

-used in acute otitis media or used in pts allergic to amoxicillin

-sinusitis, flare ups of bronchitis, CA pneuomonia

Cefixime

-3rd generation cephalosporin (good gram negative activity, seldom used)

-used for soft tissue out patient infections

Side Effects of Cephalosporins

-rash, hives,generally well tolerated

-anaphylaxis is rare

-C. diff diarrhea

-OK to administer to a patient with delayed penicillin allergy, but not to a patient with anaphylactic rxn

Other beta-lactams

Monobactam

     aztreonam

Carbapenem

     imipenem

     meropenem

     ertapenem (not important)

Aztreonam

-monobactam, binds PBP interfering with cell wall synthesis

-inpatient drug, works only against gram negatives (CA enterobacteriaceae and many HA infections)

-IV use only

-KNOW: used for HA gram neg. infections, safe in pregnancy and safe for patient allergic to penicillin, negligible side effects

imipenem

-broad spectrum potent carbapenem

-not active against MRSA, VRE, and some gram negative HA infections

-poor bioavailability, renal excretion

-use for severe nosocomial infection or polymicrobial infection

Imipenem - concerns

-toxic levels may cause seizures; probably not good to use imipenem for meningitis

imipenem - DOC for what?

-Enterobacter spp.

-Acinetobacter spp.

-Citrobacter spp.

(Hospital aquired gram negatives, broad spectrum)

Meropenem

-me-too carbapenem

-same indications as imipenem

-IV use only, less likely to cause seizures

Macrolides

• Inhibit RNA-dependent protein synthesis by binding the 50s ribosomal sub-unit

• Erythromycin

• Azythromycin

• Clarithromycin

Erythromycin

• Macrolide, binds 50S ribosomal subunit
• Uses:
  
  • group A strep
  • penicillin susceptible pneumococci (CA pneumonia)
  • Bordatella pertussis (DOC)
  • Legionella, mycoplasma
  • not good for UTI bugs

Erythromycin - toxicity

• GI upset
• allergies uncommon, ok for pt allergic to cillins or cephalosporins
• erythromycin estolate is contraindicated in pregnancy
• may see problems with drug-drug interactions; interferes with cytochrome P450 oxidase
  • can increase levels of theophylline, warfarin, cyclosporin

Erythromycin - excretion

• Erythromycin is excreted biliarily.

Azithromycin

• Uses: group A strep, Pneumococci, Mycoplasma, H. influenza, non-gonococcal urethritis
• High sustained tissue levels because it is concentrated in PMN's and alveolar macrophages
  • 5 day pack = 10 day dose
• no drug-drug interactions
• no side effects

Clarithromycin

-Macrolide, binds 50s ribosomal subunit

-Similar to erythromycin but less GI effects

-used often in H. pylori infections (with bismuth and amoxicillin)

Sulfanomides

-not used often anymore

-sulfadiazine active against Toxoplasma gondii and Norcardia asteroides

Sulfa Side Effects

• Competes for binding sites on plasma albumin and can increase blood levels of unconjugated bilirubin resulting in hyperbilirubinemia or kernicterus (like ceftriaxone in neonates)
• Can displace protein bound drugs like coumadin
• Can cause diffuse erythrodermas due to hypersensitivity
• Avoid sulfa use in late pregnancy and neonates due to side effects

Trimethoprim-Sulfamethoxazole (TMP-SMX)

-good bioavailability

-distributes into spinal fluid and prostate*

-Used for UTI's, prostatitis

-DOC for pneumocystis carinii

Trimethoprim-sulfamethoxazole MOA

-Inhibits steps leading to formation of tetrahydrofolic acid and interferes with cell replication

-SMX (sulfamethoxazole) competitively inhibits reduction of para-aminobenzoic acid to dihydrofolic acid, TMP then inhibits dihydrofolate reductase, preventing reduction to tetrahydrofolic acid and subsequent nucleic acid synthesis

Chloramphenicol

-IV form only, but not longer available in the US due to association with fatal bone marrow suppression (aplastic anemia)

-Broad-spectrum, why use? Multi-allergic patient with severe infection -- monitor CBC, WBC count -contrandicated in neonates because they cannot metabolize resulting in metabolic acidosis, hypotension -GRAY BABY SYNDROME

Aminoglycosides (list)

• gentamycin
• tobramycin
• amikacin
• streptomycin

Aminoglycosides MOA

• Bind irreversibly to the 30s ribosomal subunit prevent protein synthesis

Aminoglycoside Use

• gram negative hospital acquired infections (rarely used for CA gram neg)
• May see used in combo with a cillin for synergistic activity against enterococci
• Piperacillin-tazobactam + gentamycin is used for Psuedomonas aeruginosa
• Also used for febrile leukopenic patient post-chemotherapy

Aminoglycoside Pharmacokinetics

-bad bioavailability, give IM or IV

-good distribution to tissue, penetration to kidney/urinary tract

-NO penetration of CNS or eyes

Aminoglycosides - Excretion and Toxicity

-renally excreted

-risk of ototoxicity, nephrotoxicity

Aminoglycoside precautions

-Difficult to dose, consult pharmacokinetics team or guess based on weight

-common to order peaks and troughs

Aminoglycoside Summary

-use aminoglcycosides only when indicated for gram negative hospital acquired infection

-be aware of renal and otoxicity

-difficult to dose

Tetracyclines

-oral, out-patient drugs

-MOA: 30S ribosomoal subunit inhibitor

Pharmacokinetics of Tetracycline

-better absorbed in fasting patient, take two hours before or two hours after meal

-Calcium, antacids, iron interfere with absorption and combine with tetracyclines resulting in decreased serum levels (chelation)

Distribution of tetracycline

-good to tissues

Tetracycline Activity (uses)

-Strep pneumoniae

-H. influenza, Moraxella catarrhalis

-mycoplasma

-respiratory pathogens; used for mild/moderate out patient pneuomnias

Tetracycline Toxicity

-dental deformities/discoloration in children -contraindicated in pregnancy

-GI upset

-photosensitivity

Fluoroquinilones (LIST)

• Ciprofloxacin
• Levofloxacin
• Moxifloxacin
• Ofloxacin

Fluoroquinilones MOA

Ciprofloxacin

• Inhibits DNA Gyrase
• very good against gram negatives, but not gram positives
• active against most community acquired gram negatives and many hospital acquired, including Pseudomonas aeruginosa

Levofloxacin

• "Respiratory Quinolone," inhibits DNA gyrase
• works well against S. pneumoniae (gram positive, so cipro doesn't work well) including penicillin resistant
• also active against gram negatives (CA and some HA) including Hemophilus and Mycoplasma, but not as good for pseudomonas as cipro

Ofloxacin

-fluoroquinolones

-use for certain STD's like C. trachomatis

Fluoroquinolones Pharmacokinetics/dynamics

-Excellent bioavailability

-take fasting with water (antacids, iron, sulcraphate can decrease absorption)

-penetrate tissue well, including prostate! (as does TMP-SMX)

-adjust in renal failure

-avoid in pregnant patient, nursing mom, children under 17 because they may affect cartilage formation

Fluoroquinolone Side Effects

• Mostly well tolerated
• May see:
  • GI upset
  • prolongation of Q-T interval (cardiac arythmia risk)
  • tendon rupture with protracted use
  • hepatotoxicity
  • blood sugar may be affected

Vancomycin

• DOC for MRSA, works against MSSA

• also gram positive streptococci, pneumococci, enterococci

• Inhibits cell wall mucopeptide formation by binding D-ala D-ala portion of cell wall precursors.  Bactericidal.

Vancomycin Pharmacokinetics

-give via IV, gets into tissues and CNS

-can give to cillin and cephalosporin allergic patient

Vancomycin Toxicity

-Well tolerated, if infused to quickly may see Red Man Syndrome (not an allergy)

-rare to see a true allergic reaction with angioedema and difficulty breathing

-neutropenia can occur if on vanco for an extended period of time

Antivirals (cyclovirs)

-Acyclovir

-Famciclovir

-Valacyclovir

Acyclovir Absorption

-Topically poor

-Orally, provides slow variable absorption with short half life

-IV provides much higher levels

Acyclovir distribution

• Excellent, modest levels in CSF

Acyclovir elimination

• Renal, drug interaction not a major problem

Acyclovir clinical uses

• Immunocompromised: HSV prophylaxis and treatment, Herpes zoster

• Immunocompetent: HSV, neonatal herpes, HSE, varicella zoster

Acyclovir toxicity

-minor, wide therapeutic window

-renal dysfunction if patient is not hydrated

-with overdose may see neurotoxicity

Acyclovir MOA

• Susceptible herpes virus like HSV produces thymidine kinase which helps to convert acyclovir to a mono-phosphate that can be further metabolized to acyclo-GTP

• The acyclo-GTP is a variant building block that competes with further viral DNA synthesis and is incorporated into replication viral DNA

• Causes DNA disruption and cell death, "terminal chain disruption"

Antivirals for Influenza A & B (list)

-Amantadine

-Rimantadine

-Osteltamivir

-Zanamivir

Amantadine

-blocks viral uncoating

-not used anymore, too many side effects

-only useful for influenza A

Rimantadine

-anti-viral for influenza

-blocks viral uncoating

-replaced amantadine, but viral influenza A strains became resistant

Osteltamivir (tamiflu)

-neuraminidase inhibitor (blocks packaging and assembly of virus)

-take one tablet twice a day, reduces duration of symptoms

-particularly useful for fragile pt but expensive and we are starting to see resistance

Zanamivir

-neuraminidase inhibitor

-inhaled

-may cause bronchospasms in asthmatic

Ribaviron

-May use aerosol form for kids with RSV, but seek consultation

-can cost 1000 dollars a day -oral form used in select cases of Hep C Virus - costs $16,000/year

Antifungals (list)

-Amphotercin B

-Flucytosin

-Flucanazole diflucan

-liquid prep Amphotercin B

Amphotercin B

-big gun, gold standard

-MOA: binds ergosterol in membrane of susceptible fungi and forms a pore

-cellular contents leak out resulting in fungal death

Amphotercin B Pharmacokinetics

-Poorly understood, but:

-Poorly absorbed, give IV

-does go to tissues - CNS, kidney, lung

Amphotercin B Toxicity

• nephrotoxicity; almost everyone who gets amphotercin has a little kidney damage
  • keep patient hydrated and monitor kidney function

• hypokalemia--can prevent by giving potassium

• fever and chills--pretreat with acetominophem, demerol or NSAID
• IV phlebitis
• anorexia nausea vomiting

Amphotercin B Dosing

• Complex, one dose per day in slow infusion

Flucytosine

-antifungal; inhibits DNA synthesis by conversion to 5-fluorouracil

-use only with ID consult

-if not properly dosed leukopenia can result

Flucanazole diflucan

-Inhibits ergosterol synthesis (contrast with Amphotercin B which binds to ergosterol, makes a pore for contents to leak out)

-used in AIDS patients to suppress candida and cryptococcus

-hospitalized patient with candidemia

-candida infections, UTI, Balanitis (inflammation of glans penis)

-single dose for yeast infections/vaginitis

Flucanazole toxicities and MOA

• well tolerated; GI upset, rashes
• safer, oral alternative to IV amphotercin
• MOA: inhibits ergosterol synthesis

Drugs for invasive Aspergillosis

• Voriconazole - oral azole metabolized by cytochrome P-450

• Caspofungin - IV prep only

Flumazenil

• Antidote for benzodiazepine (Xanax, Ativan, Valium, Ambien) poisoning

• OD of benzodiazepine = drowsiness, possibly stop breathing

• DO NOT use if person may have taken something that could cause seizures or something that is excitatory because benzodiazepines may be the only thing that is keeping them from being sicker

Physostigmine

  -rarely indicated

-used as an antedote for anticholinergics (atropine, Jimson Weed, scopolamine)

-with Jimson weed/atropine anticholinergics you will be red as a beet, dry as a bone, mad as hatter, hot as a stone

-absolutely contraindicated with tri-cyclic antidepresents

Naloxone (narcan)

-used for heroin/opioid overdose

-fast onset (1-2 minutes)

-blocks opioid receptors

(heroin reduces the inhibitory effect of GABA when it binds to the opioid receptors thus creating a euphoric effect -- in overdose inhibitory effect is reduced too much)

Acetominophen Overdose

-excessive doses of acetominophen overwhelm good metabolism and bad metabolism increases and toxic metabolite (N-acetyl-p-benzoquinoneimine) accumulates

-results in liver toxicity

N-acetylcysteine

Aspirin Overdose

-should be taken very seriously; excessive doses of Aspirin overwhelm metabolism and you can see toxicity.

-GI: nausea, vomiting, diarrhea

-Metabolic: ion gap metabolic acidosis, respiratory alkalosis

-CNS: confusion, agitation, seizures

-Pulmonary: edema (possible, not common)

Aspirin Overdose Interventions

-treat with bicarb or dialysis (if very high levels, renal dysfunction and heart failure)

Don't Use in the Elderly

-1st generation antihistamines

-anti-cholinergics

-long lasting dizapines

-tric-cyclic antidepressants

DOC for Group A Strep

• Penicillin
• Erythromycin if penicillin allergy
• Can use amoxicillin

Enterococci endocarditis

• IV penicillin G +gentamycin

Ampicillin +Gentamycin

• Useful for enterococcus plus a gram negative

Pneumocystis carinii

• Trimethoprim-Sulfamethoxazole

Doxycycline

• Used to treat chlamydia