antibiotic pharm

8/6/2019 Antibiotic Pharm

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Pharm

,

Matthew Greer

Fe Absorbed in duodenum / proximal jejunum

Deficient patient can absorb ~230mg/day

n y o sor e n errous orm

Vitamin C converts ferric to ferrous

PO4 and Ca reduce converting ability

Heme Fe is best absorbed (eat red meat)

Spleen recovers Fe from extravascular hemolysis

Oral drugs better then parenteral

Gulconate < sulfate < fumarate Order of concentration and side effects


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Fe

Parenteral Fe = Iron dextran Only for extensive chronic blood loss or if oral meds can not

Can cause anaphylaxis, bronchospasm

Monitor therapy by reticulocyte count

Improve in 1-2 weeks (Hb levels take months)

Overdose = abd pain, cyanosis, diarrhea / vomitting

Treat with deferoxamine if> 3.5 m /L

Excreted from kidney as feroxamine

Contraindicated in renal failure Chronic overload use deferasirox

Folate If deficient will see macrocytic anemia

Give leucovorin (bypass DHFR step)

ormo ast c ce s seen n rs


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Anti-microbial basics

Inhibitor vs bactericidal MIC = concentration which inhibits growth

= owest concentrat on w c s .

Killing potential

Bactericidal = can kill bacteria (during division)

Fast action, not dependent on immune system

Bacteriostatic = inhibit growth (prevent division)

Slow action, require immune system

Anti-microbial basics Specturm

Narrow = single species

son az myco ac er a

Extended = gram-pos and neg

Ampicillin

Broad = destroys many species

Can cause superinfections


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Anti-microbial Properties

CDK = greater bactericidal activity with conc Can be given fewer times a day at higher conc to kill more of

TDK = conc does not affect killing rate

Drug must stay above MIC levels

PAE = suppression of growth remains after drug falls

below the MIC

Dru s with PAE and CDK = once a da dosin

Aminoglycosides and FQs

Anti-microbial Basics Allery = penicillins, cephalosporins, sulfas

Age = tetracyclins cause bone/teeth damage

Not for children or pregnant women

Pregnancy

Do not give: Tetracycline, Aminoglycosides, Macrolides (-

mycins), FQs, or sulfas

Basically penacillins and cephalosporins are cool

Man antibiotics reduce efficac of HBCPs


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Prophylactic treatments

Rheumatic heart disease = pen G

Bac endocarditis = amox- / ampicillin

Vert HIV transmission = Zidovudine

Influenza type A = Amantadine or Rimantadine

TB = Isoniazid (INH)

Most Important Combination -lactam with aminoglycoside

Synergistic effect, both are bactericidal and -lactam uptake

All combinations are bactericidal with bactericidal

Do not have to both be CDK though


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Superinfections

After therapy normal flora is wiped out and C. difficle orcandida can take over

rugs a are roa specturm :

Tetracyclins

Chloramphenicol

Ampicillin

Cephalosporins

Clindam cin

-lactams Penicillins, cephalosporins, carbapenems, and monobactam

All have -lactam ring

Required for action / target for resistance

Analogs of D-ala-D-ala = Inhibit transpeptidase

No transpeptidase = cell wall breakdown / death

Bactericidal with TDK

Knock out enzyme, not direct action


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-lactam Resistance

-lactamase = enzyme which hydrolyzes ring Produced by staph (and many others)

ram-neg ave toug to reac ce wa

MRSA = PBP is altered so no -lactams work

Penicillins Renal excretion, high therapeutic index, safe for preg

Standards Pen G, Phenoxymethyl pen (V)

Renal excretion by probenecid

Used for syphilis, meningococcal infections, tetanus,perfringins,

actinomycosis

Antisaph Methicillin,Nafcillin, Dicloxacillin

Inherint -lactamase resistance


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Penicillins

Amino Ampicillin, Amoxicillin Often combined with lactamase inhibitors

mp = ster a monoctogenes

Broad specturm = superinfection

Amo = completely absorbed ( risk of PMC)

Anti-pseudomonal Carbenicllin, Ticarcillin, Pipercillin,

Mezlocillin

Combined with lactamase inhibitors

Pipercillin is DOC for anti-pseudomonas

-lactamase Inhibitors Clavulinic acid = ~60% oral BA

Combined with amoxicillin and ticrcillin

u actam com ne w t amp c n

Tazobactam w/ pipercillin


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Cephalosporins

More resistant to lactamase inhibitors still have -lactam ring though

o not cover

Listeria, Atypicals, MRSA, Enterococci

Each generation has better gram-neg effect

1st Generation Cephalosporins Cefazolin (parenteral) and cephalexin (oral)

Great for gram-pos, weak gram-neg

Gram-neg use = PEK

Proteus

E. coli

Klebsiella


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2nd Generation Cephalosporins

Parenteral = Cefuroxime, Cefoxitin, Cefotetan

Oral = Cefaclor

Gram-neg use: Pek +

H. influenzae

N. meningitidis Note: cefotetan and cefoxitin can handle Bacteroides fragilis (anaerobic)

3rd Generation Cephalosporins Parenteral = Cefotaxime, Ceftriaxone, Ceftazidime,

Cefoperazone

ra = e x me

Lactamase resistant

Uses = PEK-HN +

Pseudomonas

Enterbacteriacea

Neisseria = good, Listeria = Ampicillin


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Ceftriaxone (3rd gen)

Gonorrhea = single dose

Bacterial meningitis = great if not listeria

Typhoid Fever

Acute otitis media = broad spectrum

4th Generation Cephalosporin Parenteral only = Cefepime

Just like 3rd generation but better lactamase resistance


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Carbapenems

Imipenem = gram-(+), gram-(-), and anaerobes Only in ICU Severe enterobacter infections

y ro yze y e y ropept ase- se zures

Block with cilastatin

Meropenem = not degraded by DHP-1

Monobactam Azetreonam

Used for H. influenza and pseudomonas

o ac v y on gram-pos or anaero es

Can be used on penicillin sensative patients with pseudomonal

infection


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Non--lactam Cell Wall Inhibitors

Vancomycin = binds D-ala-D-ala to block glycosylation(before cross-linking)

n y or gram-pos ves

Enterococci, MRSA, C. difficle

Resistance by cell wall (intermediate) or change D-ala-D-ala

D-ala-D-lactate

Adverse Effect = RED MAN (flushing)

Nephrotoxic and ototoxic as well

Non--lactam Cell Wall Inhibitors Fosfomycin = prevents NAG NAM formation

First step of PG synthesis (inhibits transferase)

ot gram- an gram- - a ecte

Bacitracin = Inhibits recycling of C55

Nephrotoxic so only topical

Great for gram-(+)

Cycloserine = analog of D-ala

Secondary therapy for TB


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Nucleic acid synthesis inhibitors

Fluoroquinolones (-floxacin) = inhibit DNA gyrase Expanded gram-(-) with mycoplasma and chlamydia

=

Folate synthesis inhibitor

Cotrimoxazole = Sulfamethoxazole and trimethoprim

Used for P. jirovecipneumonia in AIDS = syn bactericidal

Metronidazole = binds DNA and proteins

First reduced to cytotoxic intermediate

or . i superin ections

Preg category X and disulfram like reaciton

Methenamine = becomes formaldehyde in acidic urine

Conversion in tissue in presence of sulfas (BAD)

FQs (-floxacins) Fluorinated analogs of nalidixic acid

Have CDK and PAE

DOC for anthrax

Typhoid fever (w/ penicillin allergy)

Gastroenteritis

Respiratory FQs (levofloxacin, gemifloxacin, moxifloxacin)

Better Gram-(+) effect

Levo is DOC for CAP

MAC

Adverse

Seizures (when combined with NSAIDs)

Cartilage damage, QT prolongation


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Sulfonamides

Analog of PABA = blocks dihydropterate synthesis

Bacteriostatic normally

Bactericidal in urine and w/ combination (pyrimethamine)

Adverse

Metabolic product crystalluria in acidic urine (so fluid)

Can cross placenta, bind to albumin kernicterus

Hemolysis in G6PD

Uses

Silver sulfadizaine = topically for burns

Sulfasalazine (sulfapyridine w/ 5-ASA) = UC and RA

Protein Synthesis Inhibitor Aminoglycosides (Bactericidal)

Binds 30S subunit, at high doses toxic peptides (pores) Metabolic inactivation

n y ero c organ sms transport requ res

Adverse = otoxicity, nephrotoxicity, no oral

Tetracycline (Bacteriostatic) Binds 30S subunit, blocks t-RNA from A site

Efflux pump, ribosome protection protein

Adverse = superinfections, bone / teeth, vestibulo-toxicity

Absorption impaired by dairy

acro es ac er os a c Binds 50S subunit preventing translocation

50S methylation = affinity

Adverse = binds motilin, inhibits Cyt-P450, transiet ototoxicity

Mostly alternative for pen allergy


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Aminoglycosides (parenteral only)

Streptomycin Least nephrogenic

ses: , p ague, tu arem a

Gentamicin

Broad specturm (kelbsiella, proteus, Ps. aeurginosa)

Serious gram-(-) infections, combined with -lactams

Amikacin

-

Tobramycin

Superior against pseudomona (w/ pipercillin = synergistic)

Tetracyclines Doxycycline

Post exposure prophylaxis for plague and tularemia

or many s c amy a, r c etts ae, cox e a,

Lyme disease

Tigecycline

Derivative from minocycline

Active against vanco resistant MRSA

No activity against proteus or pseudomonas

Demeclocycline

Causes DI (used to counter SIADH)


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Macrolides

Erythromycin DOC C. diptheriae, B. pertussis, M. pneumonia

Chlamydial infection in infants (tetrcyclines contraindicated)

Not active against MAC

Inhibits Cyt-P450

Azithromycin

Use:MAC, toxoplasma, H. influenzae, chlamydia, legionella

No effect on Cyt-P450

Clarithromycin Similar activity as azithromycin but inhibits Cyt-P450

Clindamycin Same binding site as macrolides

DOC for bacteroides fragilis (anaerobics)

Broad spectrum = leads to superinfection


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Protein Synthesis Inhibitors

Linezolid Binds 50S subunit to prevent ribosome assembly

Used for vanco resistant bugs

Adverse: Inhibits MAO, peripheral and optic neuropathy,myelosuppresion

Quinupristin / dalfopristin Quin binds macrolide site (methylase = resistant)

Dalf inhances quin binding (metabolic inactivation)

Used for vanco resistant bugs

Blocks Cyt-P450

oramp en ca Blocks peptidyl transferase (stops elongation)

Similar site as macrolides Alternate drug only (due to resistances and myelosuppression)

Gray-baby syndrome and blocks Cyt-P450

Anti-TB 1st line drugs (all are hepatotoxic)

Isoniazid (INH) Blocks mycolic acid synthesis (InhA and KasA)

Converted to active form in bacteria (KagG catalase)

Peripheral neuropathy (give B6)

Rifampin Transcription inhibitor

Binds -subunit of DNA-dep-RNA polymerase

Cyt-P450 inducer, red / orange secretions

Pyrazinamide Converted to pyrazinoic acid ( pH)

Hyperuricemia (gout)

Ethambutol inhibits arabino alactan s nthesis cell wall

Only bacteriostatic of 1st lines

Optic neuritis (red/green)

(Streptomycin)

Nephrotoxic and ototoxic


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Anti-TB

Second line Ethanionamide = INH analog

er p aera neuropa y an epa o ox c y

Capreomycin = protein synthesis inhibitor

Psychosis, seizures, peripheral neuropathy

Cycloserine = D-alanine analog (cell wall synthesis)

FQs, PABA analogs and Rifamycins are also used

MDR-TB = resistant to INH and rifampin

Leprosy Dapsone inhibits folate synthesis

Bacteriostatic

emo ys s n , per p era neuropat y, opt c neuropat y

Rifampin binds -subunit of RNA polymerase

Bactericidal for M. leprae

Clofazimine bacteriostatic

Active against MAC as well

-

Treatments

Multibacillary = all 3 for 2 years

Pausibacillary = Dapsone + Rifampin for 1 year


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Antivirals

Most are purine or pyrimadine analogs

HSV (and VZV)

Valacyclovir (DOC HSV encephalitis), Famciclovir/penciclovir

Guanine analogs

Activated by viral thymidine kinase (only in infected cells)

Virus mutates this to have resistance

Nephrotoxicity and neurotoxicity

Tirfluridine (thymidine analog)

ct vate n a ce s even non- n ecte

Topical only (for ocular keratoconjunctivitis)

Antivirals CMV

Valganciclovir

Guanine nucleoside analo

Activated by viral thymidine kinase (only infected cells

Can cause myelosuppression

Cidoforvir

Cytosine analog

Nephrotoxicity (give with probenecid to tubular secretion)

Foscarnet

norganic p osp ate ana og in i its poymerase Alternate for resistant strains only (and works against HIV)

Nephrotoxicity, neurotoxicity, hypocalcemia (chelates Ca)

Fomiversen (only for resistant strains)

Antisense gene therapy (CMV mRNA)


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Antivirals (Influenza)

Amantadine (crosses BBB) and Rimantadine Type A influenza only

n ts v ra uncoat ng y oc ng on c anne

Oseltamivir and Zanamirvir

Active against type A and type B

Neuraminidase inhibitors (prevents release of new virions)

Zanamivir is intra-nasal and can cause bronchospasm

Antivirals (Respiratory Sysctial Virus) Ribavirin

Guanine analog (inhibits RNA polymerase)

or , ronc o t s, an pneumon a pe s

Given with IFN- for HCV

Inhalational route so can cause transient wheezing

Teratogenic

Palivizumab

MAB against A antigen site of F-glycoprotein on surface of RSV

Prevents RSV infection in high risk children


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Antivirals (Hepatic)

IFNs Induce bodies natural anti-viral enzymes

eurotox c, car otox c, an cause mye osuppress on

Lamivudine = cytosine analog

Adefovir = AMP analog

Given for lamivudine resistant HBV

Enecavir = guanosine analog

Ribavirin = guanine analog

Combined with IFN- for HCV

Anti-HIV drugs Reverse transcriptase inhibitors (RTIs)

Activated by phosphorylation with cellular kinases Competative inhibit reverse transcriptase

ause m toc on r a tox c ty

Include: Thymidine analogs = Zidovudine (AZT) and Stavudine

Cytosine analogs = Lamivudine and Emtricitabine

Guanosine analog = abacavir, didanosine = dAdenosine analog

Tenofovir = AMP analog (nucleotide)

NNRTIs-

Active only against HIV-1 (enzyme specific)

Metabolized by Cyt-P450

Rashes are major side effect (CNS for efavirenz)

Nevirapine, Efavirenze, Delavirdine


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Anti-HIV drugs

Protease Inhibitors (-navirs) Affect post-translational processing = production of immature

HIV viral articles

Massive inhibitors for Cyt-P450 (Ritonavir)

Adverse effects

All have lipodystrophy besides atazanavir

Ritonvir = circumoral paresthesia

Idinavir = nephrolithiasis, indirect hyperbilirubinemia

Integrase inhibitor (Zitevir)

Prevents infection of new cells

Fusion inhibitors Enfuvirtide binds gp41 (the harpoon)

Given sub-cutaneous

Cocaine Blocks mono-amine reuptake transporter

CNS stimulant

Also HR and BP and vasoconstriction (sniffed)

Arrhythmias and respiratory depression are problematic

Becomes benzoylecgonine (test urine)

Will see crash withdrawal due to intermittant usage

Bradycardia and dysphoria

=


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Cocaine

Overdose = Cardiac abnormalities, BP, seizures Treatment = -blockers

car ac sc em a as occurre en n rog ycer ne

Withdrawal

Crash 15-30 mins after last dose, can last 3-6 days

Depression, insomnia, irritability, anxiety, suicidal

No treatment

Maintenance

Not usually successful

Desipramine = use and craving Flupenthixol = craving

Amphetamines Indirect-acting sympathomimetic

Displaces mono-amines

st mu ant

Delirium and panic with repeated high doses

Tachycardia, hypertension, and mydriasis

Necrotising arteritis

Can cause hypertensive crisis when combined with MAO-I

Withdrawal = in REM slee de ression and fati ue


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Methyl Xanthines

Methyl Xanthines (caffeine and theophylline) Block adenosine receptors

g oses can oc p osp o es erases c

Also stimulatory action to CO2

Causes cortical arousal

MDMA (ectasy)

Hallucinogen

MOA is unclear

Noted 5-HT pathology in frequent users ( 5-HT cotransporter)

Alters body water dynamics

Adverse effects are similar to acute heat stroke

MI and brain hemorrhage are most important

Other Drugs of Abuse LSD

Psychomimetic which causes sense to be transmuted

Limited abuse because of bad trips

Death trip = meditatio mortis

PCP

May act via opiate receptors

Also blocks NMDA receptors

Reduction in pain, touch, and position sense

Will note vertical and horizontal nystagmus

anna s Uncontrolled laughter, red conjunctiva, reduced fertility, diminished

goal-setting behavior (?? Seriously)

Horizontal only nystagmus


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GHB

Inhibitory to dopaminergic pathways

Used to treat all symptoms of narcolepsy

Increases non-REM sleep

Date-rape drug

Respiratory depressive (major COD)

Also abused by body-builders

Opioids Overdose

Decreased respiration, cyanosis, coma w/ BP

Treatment = naloxone (Carefully!!!)

If methadone must use naltrexone (longer -life)

Withdrawal

Drowsiness, sweating / chills, piloerection

Acute (2 mo) = BP, resp, hyperthermia, mydriasis

Longer = BP, HR, hypothermia, meiosis

Treatment = detox to methadone (or buprenophine)

Maintanence

Naltrexone in already detoxified cancels effects of new dose

Buprenophine is partial agonist at mu receptors


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Barbiturates

Overdose Profound CNS depression

reatment = support ve or resp ratory

CNS stimulents are contra-indicated

Withdrawal

12-24 hours after chronic ingestion

Hypotension, anxiety, seizure (after 72 hrs)

Treatment = pentobarbital or secobarbital

Dilantin (diphenylhydantoin) if history of seizure

Benzodiazepine Overdose

Problem when mixing with EtOH

reatment = umazen to antagon ze enzo tox c ty

Withdrawal

Anxiety, agitation, seizures,

Treatment = flurazepam (or other anti-anxiety med)


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EtOH

Overdose Slurred speech, nystagmus, disinhibited behavior,

=

ThiamineTHEN glucose if necessary

Withdrawal (4-12 hrs after last drink)

Coarse tremor, anxiety, BP, hallucination (tactile / visual)

Overactive ANS = HR, miosis, sweating, fever

Delirium tremens = gross delirium

Treatment = short-acting depressants for symptoms then ween

Maintenance

Disulfiram = blocks aldehyde reductase cuasing adverse effectswith drink

antibiotic pharm

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