antimicrobial drug chart

8/12/2019 Antimicrobial Drug Chart

1/286

Drug Mechanism of Action

Inhb cell wall synth

Cell wall peptidoglycancross-links

via peptide side-chains(transpeptidation )

PBP init enz actvy by binding to

terminal D-Ala-D-Alaof side-

chains.

PCNs & Cephs = structural analogs

of D-Ala-D-Ala substrate

PCN covalently binds to active

site of PBPs

irrev inhb of transpeptidation

& cell wall synth

cell lysis & death

not p.o. b/c acid labile

C;Penicillins (PCN) = -Lactams Time-dependent BACTERICIDAL (keep C

Route of Admin

Penicillin G

i.v.

cont i.v. infsn common


2/286

Route of Admin Mechanism of Actioni.m.


slow release (see PCN)

D-Ala-D-Ala analog irrev bind

to PBP active site

Drug Route of AdminMechanism of

Action Pharmacological Effects

i.v. (see above) NOT degraded by -Lactamase

Benzathine Penicillin G

-Lactamase (Penicillinase) Resistant PCN Broader spectrum PCN

Penicillins (PCN) = -Lactams (contd) Time-dependent BACTERICIDAL

Drug

Procaine Penicillin G


3/286

Designed spcfc

to kill -

lactamase

producing

Staph aureus

Inhb cell wall

synthesis

short t1/2:

D-Ala-D-Ala

analog irrev

bind to PBP

active site

dose q4h/q6h

Oxacillin


4/286

Nafcillin

Oxa, Naf, Diclox > Vancb/c kills

quickly

Dicloxacillin p.o.


ActionPharmacological Effects

Inhb cell wall

synthesisDestroyed by -lactamase!

Aminopenicillins = Extended Spectrum PCN


5/286

(see above)

Combine w/ -lactamase

inhibitors to Rx -lactamase

producing bugs

(e.g. staph aureus)

D-Ala-D-Ala

analog irrevbind to PBP

active site

Ampicillin i.v.


6/286

Combo poss:

Ampicillin + sulbactam(i.v.)

Destroyed by -lactamase!

Combine w/ -lactamase

inhibitors to Rx -lactamase

producing bugs

(e.g. staph aureus


7/286

Combo poss (2nd

line otitis

media):

Amoxicillin + clavulanate(p.o.)

aka Augmentin

p.o. Absorption NOT affected

by presence of food.



Amoxicillin p.o.

Anti-Pseudomonal PCN Kills Pseudomonas aeruginosa (& Enterobacteriacea)


8/286

i.v.Inhb cell wall

synthesisTicarcillin + clavulanate

(see above) (ticar/clav)

esp in ICU

D-Ala-D-Ala

analog irrev

bind to PBP

active site

Piperacillin + tazobactam

(pip/tazo)

broadest spectrum PCN


Action Pharmacological Effects

Ticarcillin

Piperacillin

-Lactamase InhibitorsBroadens spectrum of -lactamase-susceptible PCNs


9/286

Clavulanate

*Co-admin

w/suscep PCN:

protect them

from

inactivation by

-lactamases

&

cephalosporin

ases

aka

Clavulinic Acid

(All Cephs

more resistant

to degradation

by -

lactamases

than some

PCNs)

aka

clav

Tazobactam

Sulbactam


10/286

aka

tazo



Imipenem/

Cilastatin

Inhb cell wall

synth

Metabolized by renal dihydro-

peptidases (DHP)

(carbapenam) (same as PCN)Imipenem must be given in

combo w/ Cilastatin (DHP inhbtr)

D-Ala-D-Ala

analog irrevbind to PBP

active site

Good tissue penetration

Broadest

spectrum

(Must use in combo!!) -lactams

ErtapenemInhb cell wall

synthdoes NOT cover:

Carbapenems & Monobactams i.v. only!!!

i.v.


11/286

(same as PCN) pseudomonas

(carbapenam) acinetobacter

enterococci

Inhb cell wall

synth

Aztreonam (same as PCN)

(monobactam)

D-Ala-D-Ala

analog irrev

bind to PBP

active site

Spectrum

AGs

(e.g.

gentamicin)

i.v.

i.v.


12/286


ActionPharm Effects

1st

:Inhb cell wall

synth1

stgeneration

Cefazolin i.v. (same as PCN) Best against G(+)

D-Ala-D-Ala

analog irrev

bind to PBP

active site

Few G()

Spectrum

varies by gens

(Bactericidal

by gen)

~ Resist

hydrolysis by -lactamases

broader

spectrum >

PCNs

Good distrb in

most body

fluids but NOT

INTRACELLULAR

Cephalosporins

G(+) activity: 1st

gen > 2nd

gen > 3rd

gen G(-) activity: 3rd

gen > 2nd

gen >


13/286

1st

:

Renalelim

dose in pt

w/ poor renal

func (but

cetriaxone

liver)

Cephalexin

2nd

: 2nd

generation

Cefoxitin G() > 1stgen

G(+) < 1st

gen

Anaerobes!!!

2nd

:

Cefotetan

Route of Admin

i.v.

i.v.

p.o.

3rd

:

Ceftaroline

Cephalosporins (continued)

Drug

3rd

:

Ceftazidime


14/286

i.v.

i.m.

p.o.

i.v.

Drug

Doxycycline

(see p. 26)

3rd

:

Cefotaxime

3rd

:

Ceftriaxone

4th

:

Cefepime

3rd

:

Cefpodoxime

3rd

:

Cefixime

3rd

:

Cefdinir

i.v.

p.o.

F=100%

Tetracyclines BACTERIOSTATICRoute of Adm


15/286

Minocyclinep.o.

F=100%

Macrolides (ML)Does NOT cover Enterococcus (espVRE) orMRSA !Drug

(estolate ester= highest F)

Excreted in bile

Erythromycin

i.v. (hurts!)p.o.

(lim p.o. F b/c

acid labile)

Esters less acid labile better F

Azithromycin


16/286

i.v.

p.o.

(F ~ 0.5)

Long t1/2

Large Vd

Clarithromycin

p.o.

Excreted in bile

Ciprofloxacin

i.v.

p.o.

F = 90%

Fluoroquinolones (FQ) Does NOT cover Enterococcus (espVRE) orMRSA !Drug

(F ~ 0.5)

Metab by liver, excreted in urine

* 20% metab by CYP1A2 in liver

FQ chelate oral Fe++

& Ca++

supplements, and Al++

Dairy/food: not affect GI absorbofgemi & levo; d

Ciprofloxacin___________

* Ca++

-fortified milk, anatacids & yogurt F but n

Inhb DNA synth rapidly BACTERICIDAL

(conc-dependent)

Inhb bact topo II & IV

Topo II (DNA gyrase):

Catalyzes relaxn of () supercoiled DNA allows n

Topo IV: Required for separation of replicated DN


17/286

F = 90%

Fluoroquinolones (FQ) (contd) Does NOT cover Enterococcus (espVRE) orDrug

Renal elim no CYP450 interact

Levofloxacin*

i.v.

p.o.

Moxifloxacin*

i.v.

p.o.

F = 90%


18/286



Must giveInhb cell wall

synth G(+) incl anaerobes

Streptomycin

(see TB drugs)

Aminoglycosides (AG) BACTERICIDALDrug

Hepatic metab but no CYP450 drug interactions

Other Antibiotics: Vancomycin BACTERICIDAL

Neomycin

Gentamicin*

Tobramycin*

Amikacin*


19/286

Does NOT

involve PBPs! NO G()s!

i.v.

SLOW

BACTERICIDAL

Big molec penetrn probs (poor

CSF penetrn)

Always use -

lactam to Tx

MSSA instead

Elim by urinary excrtn monitor

renal func & adjust dose in pt w/

renal failure

Lg glycoprot

inhb cell wall

synth b/ccovalently

binds

D-ala-D-ala

terminus of

pentapeptide

side chains of

polysacch

backbone

Poor p.o. absorption!!!

Sterically

hinders action

of

peptidoglycan

polymerase &

transpeptidase

s

elongation of

peptidoglycan

polymerase

ceases

CANNOT use p.o. for systemic

infxns

Vancomycin


20/286

p.o. Vanc = 2nd

line:

C. diffpseudo-membranous

colitis

*DOC C. diff = metronidazole

Give 2 courses p.o. metronidz. Ifstill C. diff then p.o. Vanc

If still no response fidaxomicin



Clindamycin

(see p. 26) i.v.Inhb protein

synth Excellent G(+)!!

BACTERIOSTAT

IC

- SSTIs (staph aureus & -

hemolytic streps

p.o. - covers MRSA

(same as

macrolides!)

- outpatient Rx of MRSA

cellulitis in adults & children

Also topical

cream

binds 50S

subunit at P

site

Good coverage of G(+)

anaerobes

Other Antibiotics: Clindamycin BACTERIOSTATIC


21/286

(acne) inhb

translocation- aspiration pneumonia

amino acid

most recently

added to

peptide chain

does not move

from A site to

P site

peptide

elongation

stops &

protein synth

terminated

----------------------

Good p.o. F No G(-) coverage!

Penetrates

most body

fluids & tiss

(not CSF &

brain)

Good

intracellularconc

No VRE coverage!

Very hi

bone/serum

conc

Heptaic metab

(NO need to

adjust for

renal func)



Other Antibiotics: Linezolid, Daptomycin, Fidaxomicin


22/286

Excellent G(+) (incl MRSA, VRE

& PCN-resistant strep pnemo)

i.v.

Syntheitic

antiobiotic: 1st

oxazolidione

Min G() actvy

pts on i.v. Vancin hospital

sent home on p.o. linezolid

p.o.Inhb protein

synth

irreversible inhibitor of MAOI

serotonin syndrome if co-

admin w/ SSRI

F = 100%BACTERIOSTATICtho cidal

against some

Bind to unique

site on 23S

ribosomal RNAof 50Ssubunit

block

assembly of

70Sribosomal

complex

needed to init

prot synth

Do NOT need

to adjust dose

for renal func

600 mg dose

Linezolid


23/286

$$$ ($50/pill)

i.v.bind bact mb

depol

no mb

potential

$$$$ cell death

($250-500/d)

Fidaxomicin $$$$Inhibit RNA

synth no

RNA pol

As effective as vanc

Drug Route of Admin Mechanism ofAction

Pharm Effects

Trimethoprim/

Sulfa-methoxazolep.o.

Sulfonamides

= 1st

class

systemic

antibact drugs

Broad spectrum:

aka F = 90% S. aureus incl MRSA

Daptomycin

Other Antibiotics: Trim/Sulfa


24/286

trim/sulfa Synergy: Enterobacter in ICU

akap.o. even in

serious infxns

BacterioSTATI

C alone; E. coli & Klebsiella

BactrimBacterioCIDAL

combo

- drugs * + in urine Rx

uncomplicated UTI in healthy

* Sulfa:

comptv

antagonist of

PABA inhb

dihydropteroa

te synthetase

prevent

DHF synth

DOES NOT cover GAS

i.v. poss

(avoid huge

volumes of i.v.

fluid)

* Triminhb

dihydrofolate

reductase

prevent

conversion of

DHF to THF

* pref inhb

bact enz (w/

little effect on

mammalian

enz)


25/286



p.o.

Macrocrystalli

ne form:

slower absorb

& renal

excretion

* + in urine bactericidal

High F Most active in ACIDIC urine

BACTERIOSTAT

IC (low [ ]) Rx: UTI: G(+) & G(-)

duration

of action in

macro-

crystalline

form

- E. coli

BACTERICIDAL

(high [ ])- Klebsiella

- Enterococcus

Other Antibiotics: Nitrofurantoin

Nitrofurantoin


26/286

*Bact enz

rapidly reduce

nitrofto

reactv

intermed

damages DNA cell death

- some Proteus resistant

Bactericidal Bacteristatic

Aminoglycosides Tetracyclines

PCN Macrolides

Carbepenems Clindamycin

Monobactams

(aztreonam)Linezolid

Cephalosporins

Nitrofurantoi

n (may be

cidal w/ largedose)

Vancomycin Ethambutol

Fluoroquinolones

Nitrofurantion (static

at low [ ]; cidal at high

[ ])

Quinupristin/dalfoprist

in

Metronidazole

INHRifampin

Pyrazinamide

Systemic Antifungals: Polyenes


27/286



Amphotericin B* i.v.

Bind to

ergosterolin

fungal cell

membrane

*Extremely broad spectrum

create

porins

(polyene) topical cell

permeability**Gold standardanti-fungal drug

ions &

macromolec

leak out of cell

cell death

Fungal cell

membrane!

*Do NOT use after Rx w/ azole

b/c azoles take away site of action

of ampho B

Nystatin Oral suspen. Extremely broad spectrum


28/286

(polyene) Topical *Effective against C. albicans

*NOT effective against MET bugs

MET bugs (Dermatophytes)

1. Microsporum 2. Epidermophyton

Systemic Antifungal: Azoles cover: Candida albicans , MET fungi, Pityrosp


29/286



i.v. Most commonly used systemic

antifungal agent

AZOLES: Lacks major toxicity

p.o. p.o. F is excellent

FUNGISTATIC

b/c slow

Pt need patentimm systm

*inhb bact enz

CYP450

lanosterol 14-

demethylase

prevent

ergosterol

formation

accum of

14-

methylsterols

inhb enzy

actvy of

electron

transport

system

block cell

growth

Fluconazole*


30/286

Fungal cell

membrane!


Action

i.v. AZOLES:

topical

FUNGISTATIC

b/c slow

Pt need patent

imm systm

* inhb bact

enz CYP450

lanosterol 14-

demethylase

Systemic Antifungal: Azoles(contd)Candida albicans , MET fungi, Pityros

Pharmacologi


31/286

prevent

ergosterol

formation

accum of

14-

methylsterols

inhb enzy

actvy of

electron

transport

system

block cell

growth

topical

oral trocheFungal cell

membrane!

Clotrimazole Tastes > n

Miconazole


32/286

i.v.

Voriconazole

p.o.

F = 96%

DrugMechanism of

Action

Pharmacological

EffectsTherapeutic Uses

*probably replaced ampho B

Caspofungin

Inhb synth of

1,3--D-

glucan

Big molecule

(key

component

of fungal cell

wall in

Candida &

Aspergillus )

*salvage therapy in pts w/

invasive Aspergillosis who have

NOT responded to ampho B

(echinocandin) No p.o. avail

Systemic Antifungals: Echinocandin

Posaconazole p.o.erratic GI absorption

(need fat!)

* Extended spectrum

Can change from i.v. to p.o. w/o d


33/286

(Diff MOA

from azoles)

*rapidly cidal against Candida ,

even those resistant to

fluconazole

*limited spectrum:

-

Candida- Aspergillus

- Pneumocystis



Flucytosine p.o.(5-FC)

fluorinated

pyrimidine

(5-FC) converted

to 5-FU* rapid absorb

Must be

dosed QID

converted

to 5-FUMP

converted

to FdUMP

* extensive distrb (incl

penetration into CSF)

inhb

thymidylate

synthase

* Renal elim

Lack of

thymidine

inhb DNA

synthesis* Synergy:

5-FC w/ azoles & ampho B

(human cells

do not convert5-FC to 5-FU)



Systemic Antifungals: OTHER

Systemic Antifungals: OTHER (contd)


34/286

Drug accum in:

p.o.

Inhb enz

squalene

epoxidase

prev

ergosterol

synth

- skin

- nails

topical

Accum of

squalene kills

fungal cell.

- fat cells

p.o.

Bind

polymerized

microtubules

Terbinafine


35/286

Inhb fungal

mitosis

ingest w/

fatty foods to

F

Prevents

formation of

cytoplasmic

microtubules

necess forhyphae

growth

topical,

OTC

Drug

Antiprotozoal

Route of Admin

p.o.

Tolnaftate unknown

Griseofulvin


36/286

Metab by liver

Cleared by kidney


37/286


38/286

Route of Admin


ActionPharm Effects

Antiprotozoal(contd)

Drug

NitazoxanideInterferes w/ pyruvate:ferrodoxin

energy metab

Antimalarial Doxy & Clinda: Also Rx MDR malaria (all)

Pentamidine

Pyrimethamine Sulfadiazine

???

*S inhibits dihydropteroate synthe

*P inhibits dyhydrofolate reductas

*selectively inhibit two enzymatic


39/286

p.o.

Malaria

(Plasmodium

spp)

After parasites

w/in RBCs

digest Hb in

their food

vacuoles

released heme

rendered

nontoxic to

the parasite by

non-enz

polymerizn

into malarial

pigment

hemozoin

qWeek


40/286

Chloroq &

Mefloq

preventspolymerizn

free heme kills

parasite by

oxidative

damage of cell

membranes

Chloroquine


41/286

Drug Route of Admin Mechanism ofAction

Pharm Effects

p.o.MOA

unknown

Mefloquine

Antimalarial(contd) Doxy & Clinda: Also Rx MDR malaria (all)


42/286

(qd)

Gametocide

against ALL

Plasmodium

p.o.Atovaq:

ubiquinone

(qd)

Blocks

cytochrome-

medtd e

transport

destroys mito

mb potential

diff

Primaquine


43/286

Proguanil:

1. Enhances

ability of

Atovaqto

destroy mito

membr

potential

difference

2. Prevents

resistance

Doxycycline(see p. 8)

Clindamycin

(see p.14)

DrugMechanism of

Action

Pharmacological

EffectsTherapeutic Uses

*kills round & tape worms

Atovaquone/

Proguanil

Antihelminitic


44/286

Inhb synth of

microtubules

necess for

glucose

uptake

[glycogen] &

*ATP+

*pinworm (Rx whole family!)

*hookworm

Parasite:

1. Dies

2.

Immobiliz

ed &

cleared

from GI

tract

Also

larvacidal &

ovicidal.

safety

pinworms

bendBroad

spectrumKills all worms in mixed infections

*roundworm

p.o. (low F) *pinworm (Rx whole family!)

Mebendazole


45/286

butb/c

drug just goes

thru GI tract to

kill worms

*hookworm

*threadworm

*tapeworm (cestodes)*flukes (trematodes)

**DOC: mixed infxns

(roundworms & tapeworms)

**DOC:tapeworms

Kills all worms incl larval stage of

pork tapeworms

(cysticercosis calcified larval

cysts in brain focal neuro Sx,

intracran pressure, seizures)

Rx followed by laxatives expel

remaining eggs from GI tract

Ganglionic

nicotiniccholingergic

agonist

musc tetany

*kills round worms

Neuromuscul

ar paralysis

allows

peristaltic

clearance

from GI tract.

*pinworm (Rx whole family!)

*hookworm

Albendazole

Pyrantel pamoate


46/286

DrugMechanism of

ActionPharm Effects Therapeutic Uses

Ivermectin

Releases

GABA &

GABA

binding

facilitate

opening of Cl-

channelsin

NMJ

flaccid

muscle

paralysis in:

**DOC: threadworm

-

helminths

p.o. - insects * River Blindness (onchocerciasis):

-

ectoparasi

tes

Single dose 2/yr kills filarial infxn

Antihelminitic(contd)


47/286

Also poss

tonic

paralysis of

musc in

nematodes

(roundworms

) via Glu-

gated Cl-

channels

found only in

invertb.

*Livestock (e.g. cattle): singledose kills all roundworms &

arthropods (ticks, mites, other

insects) for 30 days

reVolution for benny

iVermectin

FDA has NOT approved ivermRx

scabies but p.o. admin very

effectv

*esp useful Rx scabies in:


48/286

- immunocompromised pts

- pts w/ severely encrusted

scabies

- pts who have failed therapy

w/ topical permethrin

1. Opens

Ca++

channels

musc

tetany

**DOC: Schistosomiasis

2. Spastic

paralysisFlukes (trematodes)

3.

Tegmental

damage Praziquantel


49/286

Activate

host

immune

system

Infxn cannot be transmitted in

US b/c no intermed host (a

snail)

DrugMechanism of

Action

Pharm Effects

Permethrin

1%

permethrin:

pelucidal

**DOC:Pediculosis (lice

infestations)

1% permethrin cream

topical

5%

permithrin:

scabicidal

Head: After shampoo & dry

saturate hair w/ soln for 10 min

rinse drug

Body: Rx clothes

Pubus: cream for 10 min

rinse

Ectoparasites

Therapeuti


50/286

Eyelashes: Rx w/ 1% yellow Hg

oxide ointment

**DOC: scabies (itch mite:

Sarcoptes sabiei)

5% permethrin to entire body

(avoid face, mucus membr &

eyes) for 8-14 h bathe & repeat

if necess

Ivermectin

Releases

GABA &

GABA

binding

facilitate

opening of Cl-

channelsinNMJ

flaccid

muscle

aral sis in:

**DOC: threadworm

-

helminths


51/286

p.o. - insects * River Blindness (onchocerciasis):

-

ectoparasi

tes

Single dose 2/yr kills filarial infxn

Also poss

tonic

paralysis of

musc in

nematodes

(roundworms

) via Glu-

gated Cl-

channels

found only in

invertb.

*Livestock (e.g. cattle): single

dose kills all roundworms &

arthropods (ticks, mites, other

insects) for 30 days

reVolution for benny

iVermectin

FDA has NOT approved ivermRx

scabies but p.o. admin veryeffectv

*esp useful Rx scabies in:


52/286

- immunocompromised pts

- pts w/ severely encrusted

scabies

pts who have failed therapy w/

topical permethrin



Inhb viral

neuraminidas

e Block

release of new

viral particles

Antivirals: Influenza


53/286



Trifluridine

Converted to

trifluridine

tri(PO4) by

host cell

enzymes:

active

metabolite

akaophthalmic

solution

inhibits viral

DNA synthesis

Trifluorothymidine

Antivirals: Herpes keratitis

Oseltamivir p.o.


54/286



p.o.

F = 15-20%Inhb viral DNA

polymeraseA guanosine derivative

Must be phosphorylated 3x

active metabolite: acyclovir

tri(PO4)

i.v.

Virus-specific

thymidine

kinase (found

ONLY in

infected cells)

dose in pts w/ renal failure

produces

acyclovir

mono(PO4)

incidence of resistance is low

topical

phosphorylase

enz of host cell

then produce

acyclovir di- &

tir(PO4)

Acyclovir

tri(PO4):

- Competes

w/ dGTP at

the viral DNA

polymerase

Antivirals: Herpes Simplex (HSV) & Varicella Zoster (VZV )

Acyclovir


55/286

p.o.

- Causes

chain

termination

when incorp

into viral

DNA

Prodrug converted to

acyclovir

F = 48% Rx Vanc (p.o.) *acyclovir+P 3-5x> Rx acyclovir (p.o.)

dose in pts w/ renal failure

inorganic

pyrophosphat

e

Acts directly

to inhibit:

1. viral DNA

polymerase

2. viral RNA

polymerase

Foscarnet i.v.

Valacyclovir


56/286

3. HIV

reverse

transcriptase

No activationvia virus or

host enz

required


ActionPharm Effects

p.o.Inhb viral DNA

polymerase

F = 6-9%

Virus-specific

thymidine

kinase (found

ONLY in

infected cells)

produces

acyclovir

mono(PO4)

i.v.

Antivirals: Cytomegalovirus (CMV)


57/286

phosphorylase

enz of host cell

then produce

acyclovir di- &tir(PO4)

ocular

implant

Acyclovir

tri(PO4):

- Competes

w/ dGTP at

the viral DNA

polymerase

p.o.

- Causes

chain

termination

when incorp

into viral

DNAF = 60%

F by hi fat

meal

inorganic

pyrophosphat

e

Acts directly

to inhibit:

Ganciclovir

Valganciclovir


58/286

1. viral

DNA

polymerase

2. viral RNA

polymerase

3. HIV

reverse

transcriptase

No activation

via virus or

host enz

required

Antisense

oligonucleotide

Binds to mRNA

prevents tsl

prevents

viral

replication

Antivirals: Treatment of HIV

Drug Mechanism of Action

Foscarnet i.v.

Fomivirisenintravitreal

injection


59/286

Fusion Inhibitors

Synthetic peptide binds gp41

Blocks viral/T-cell mb fusion

HIV cannot enter CD4 cell

Enfuvirtide(s.c.)

Maraviroc(p.o.)

Inhibit CCR5 receptor

Blocks gp120 binding to CD4 cell

Zidovudine(AZT, ZDV)

Lamivudine(3TC)

Abacavir(ABC)

NRTI

Nucleoside Rev TSCase Inhibitor

Intracellular kinases convert these nucleosides to

false nucleotides(triphosphates):

1. competitive inhb HIV rev tsc-ase

2. cause chain termination of viral DNA

NRTIs can be incorp into viral DNA


60/286

NNRTI

Non-Nucleoside

Rev TSCase Inhibitor

NO reqd phos to be active

Direct inhb rev tsc-ase stop rep

Bind diff site than NRTIs do NOT compete w/ nt for

binding to rev tsc-ase

NET effect blockage:

Emtricitabine

Tenofovir(TDF, a nt)

Protease Inhibitors

Nevirapine (NVP)

Efavirenz (EFV)

Integrase InhibitorsPrevents viral DNA insertion into human DNA

Raltegravir

1. RNA-dependent DNA pol

2. DNA-dependent DNA pol


61/286

Drug

Atazanavir

Ritonavir*

Lopinavir

Anti-TB (Mycobacterium tuberculosis )R-I-P-Eor R-I-P-SBACTERICIDA

Mechanism of Action Pharmacologi

Block viral protease prevent cleavage of viral

polyproteins into functional subunits necess for

assembly of new virus particles

Inhb cell wall synthesis

BACTERICIDAL for rapidly

dividing

BACTERIOSTATIC

for latent (non-dividing)

- INH antagonizes rxns where B6

- INH = struct sim to pyridoxine (

- Periph neuropathy neuropat


62/286

Active INH metabolite binds

covalently to acyl carrier

protein & -acyl carrier

protein synthetase

Prevents synth of mycolic

acid(a long chain fatty acid

needed to maintain integrity

of Mycobacterium cell wall

Isoniazid (INH)

A prodrug converted into

active form by mycobacterial

catalase-peroxidase


63/286

Drug Mechanism of Action Pharm Ef

Rifampin

Inhibit RNA synthesis

Bind to subunit of bact

DNA-dep RNA polymerase

Do NOT bind to human RNA

polymerase

Anti-TB(contd) R-I-P-Eor R-I-P-SBACTERICIDAL (dividing bacilli)

BACTERICIDAL

Easily penetrate tissues to kill

intracellular mycobact &bugs in abscesses


64/286

Drug

Ethambutol (EMB)

Mechanism of Action

Pyrazinamide

(PZA)Unknown MOA Kills semi-dormant intracellular ba

Rifabutin

Anti-TB(contd) R-I-P-Eor R-I-P-SBACTERICIDAL (dividing bacilli)


65/286

the PCN of TB

Streptomycin

(see AGs)

i.m.

i.v.

AG antibiotic

Inhb protein synth

Primarily against extracellular bacilli

Inhb of cell wall synthesis

Inhb arabinosyl transferase (enz which polymerizes

arabinoglycan)

Arabinoglycan = essential part of mycobacterial cell wall


66/286

Spectrum Drug/Class G() Coverage G(+) Coverage

N AminoPCN E. coli & H. flu

Carbapenem

s (except

ertapenem)

Good Good

Aztreonam Excellent

1st

gen ceph Little Good

Rx of Active TB: R-I-P-E or R-I-P-S

Gold Standard: INH-Rifampin-PZA

& either EMBor streptomycin for 9 months

All 4 drugs given until know susceptibility

(2 wks to culture)

Moxifloxacinshows the greatest activity

versus TB

MDR TB:

Rx for 18-12 mo w/ up to 6 drugs

(tho outcome still not good)

(see FQ)

Ciprofloxacin& levofloxacin

Rx MDR active TB

Rx Mycobacterium avium complex(MAC):

A macrolide (~HIV pts)

Cipro

Rifabutin

EMB


67/286

3rd

gen ceph Good Some (not ceftaxidime)

4th

gen ceph Excellent Moderate

Moderate

(> macrolides)

Little Good

(some w/

clarithromycin

&

azithromycin)

(except Enterococcus)

Fluoroquinol

ones

Vancomycin None Good

Clindamycin None Excellent

B()Aminoglycosi

desHigher doses

Lower doses (combo w/wall synth

inhibitor)

Linezolid None Excellent

B Trim-sulfa Good Good

Nitrofurantoi

n Excellent Excellent

N Macrolides

Definite differences in coverage within this class

2nd

gen ceph Some Good

MB Tetracyclines Moderate


68/286

Pharmacological Effects Therapeutic Uses Mechanism of Resistance

Pen Gt1/2= 30 min **DOC** 1. -lactamase *** (penicillinase)

Probenecid inhb renal transp

systm 1. -hemolytic strepdestroys PCN -lactam ring drug

inactive

Pen G secrtn Group A*, B, C, F, G strepsstaph aureus plasmid encodes -

lactamase

t1/2GAS killed quickly by

Pen G2. drug binding site(G(+))

MRSA/ORSA express an addl -

lactam binding site (bact gene mut)

resistant to ALL -lactams

2. suscep streppneumo

Strep pneumo PBP w/ aff for -

lactams

(but use p.o. amoxicillin)VREs terminus mut D-Ala-D-

lactate

Good distrb in ECFLg dose! If resist Pen G,

also resist 3rd

Ceph3. Drug efflux(G(-))

Will penetrate CSF ifmeninges inflammed

Pseudo & Acinetobacter

Does NOT enter cells3. meningococcalmeningitis (Hi doses!)

S. pneumo marcolides

Renal tubular secrtn ------------------------- 4. Prevent drug entry

Syphilis Pseudo # of porins carbapenams

Ghonorrhea

N. meningitides

NOT staph aureus

(resistant)

> MIC)


69/286

Pharmacological Effects Therapeutic Uses Mechanism of Resistance Good distrb in ECF Depot PCNs (see above)

Will penetrate CSF if

meninges inflammed

Does NOT enter cells prophylax: prev GAS

infxn in military recruits1. -lactamase (PCNase)

Renal tubular secrtn 2. drug binding site (G())

Syphillis 3. Drug efflux (G(-))

(But NOT neurosyph) 4. Prevent drug entry

Therapeutic Uses Adverse Effects/Toxicity

**DOC**

(keep CP> MIC)


70/286

Susceptible staph aureus(MSSA)orsuscep strep

cellulitis, abscesses,

endocarditis, meningitis &

others

(always prefd over broad,

e.g. FQ)


71/286

Cellulitis: always Staph/Strep

unless culture proves

otherwise

--------------------------------

PCNase-prod Staph

soft tissue infxn

Susceptible Strep

infxn


**DOC**

1. Enterococcus spp.


72/286

Also for Enterococcus:

Vanc, Doxy, tigecycline,

quinupristin/dalfopristin,

Linezolid, Dapto

2. Listeria spp.

----------------------------

* NOT active against MRSA!

* spectrum extended to cover

G(): E. coli & H. flu

p.o. diarrhea


73/286

b/c better penetration of outer

mb of G() bugs

**DOC**

1. 1st

line: otitis media

If NOT work, give

amox/clav

2. suscep strep pneumo

-------------------------


74/286

Strep Throat

* NOT active against MRSA!

* spectrum extended to cover

G(): E. coli & H. flu

b/c better penetration of outer

mb of G() bugs



75/286

**DOC**

Pseudomonas spp.

*excellent anaerobic actvy

*good vs MSSA, S. pneumo

*NEVER use just one drug for

pseudomonas!!!



76/286

*** 2ndline otitis media:Amox/clavaka Augmentin

when amox alone fails

**DOC Pseudomonas :

ticar/clav

Given i.v. in ICU

Combo poss:

Ampicillin + sulbactam(i.v.)

**DOC Pseudomonas :

pip/tazo

Diarrhea


77/286

Given i.v. in ICU


Cover many nosocomial G()

rods (incl Pseudomonas ),

anaerobes & G(+)

seizurecillin esp hi

doses in pts w/ poor renal

func & neurosurg pts

pt w/ PCN allergy:

BEWAREmore cross-

reactv than cephs

Multi-drug resistant bugs

Last resort drug after pt fails

pip/tazoor cefepime

pip/tazo, cefepime> carbap

for Pseudomonas

polymicrob, life-threat

infxns

e.g. intra-abdominal trauma

& nosocomial infxns by

Citrobacter, Enterobacter,

etc.

Use pip/tazoor cefepime

for febrile neutropenic pt

instead

Tx pts w/PCN allergy


78/286

Very good G() actvy (incl

Pseudo , actvy comparable to

ceftazidime)

Little allergic cross-

reactivity w/ other

-lactams

NOT clinically useful against

G(+) (incl MRSA) & anaerobes

Severe G() infxn in pt w/

PCN allergy


79/286

Mechanism of Resistance

(same as PCN)

1. PBP site!

2. Bugs begin to make cephalo-

sporinases

Cheap & good tissue penetration

1st

line: non-MRSA SSTIs

(better than vanc!)

1st line: mild PCN allergy

Rx: pyelonephritis in pregnant

MS-Staph Aureus & strep

1st

genNo activity against Enteroccocci, MRSA, Listeria, or PCN-resist

strep pneumo!

***DOC: Surgicalprophylaxis

Therapeutic Uses

Do NOT cover Enterococci orMRSA!!!!


80/286

MSSA SSTIs, strep

Safe for pregnant

Binds mutated PBP binding site in MRSA


Mechanism of Action

Spectrum varies by gens (cidal by gen)

(same as PCN)

D-Ala-D-Ala analog irrev bind to PBP active site

intra-abdominal infxns

pelvic inflamm disease (PID)

surgicalprophylaxis

**DOC: intra-abdominal

Not used much anymore, replaced by 3rd

gen

Do NOT cover Enterococci orMRSA!!!!


81/286

~ Resist hydrolysis by -lactamases spectrum > PCNs

Good distrb in most body fluids, but NOT INTRACELLULAR

Renalelim dose in poor renal func (cetriaxonehas liver elim)

Cefepime:

resist to degradtn by -lactamases

Good CNS penetr Rx bact meningitis

1. Ceftazidime

2. Cefotaxime

3. Ceftriaxone

4. Cefepime

in Mechanis

Inhb protein synth

BACTERIOSTATIC

Bind 30Ssubunit of bact ribosome blo

subunit

Oral bioavailb = 100%


82/286

- Albumin (in serum)

Long t1/2 & slow elim dosed bid

High [ ] in bile check liver func tests (L

-

alkaline phosphatase

- AST & ALT transaminases

BACTEROSTATIC

Mechanism of A

- Bilirubin

Inhb protein synth

BACTERIOSTATIC

Bind 50Ssubunit at peptidyltransferase

inhb translocation

(most recently added amino acid to peptide

to P site)

Peptide elongation stops, protein synth st

----------------

Good G(+) incl MSSA & strep pneumo

- Also CAP Rx: morax, H flu

- Intracellular: Legionella & Chlamydia

Some G(-)

(esp Clarith & Azith)

Good tissue penetration


83/286

(except brain & CSF)

BACTERICIDAL

Mechanism of Action

Mg++

antacids cations GI absorb

lay moxiabsorb

t dietary Ca++

ormal gene tsc & DNA replication

into daughter cells

--------------------


84/286

MRSA ! BACTERICIDAL

Mechanism of Action

Inhb DNA synth rapidly BACTERICIDAL

(conc-dependent)

Inhb bact topo II & IV

Topo II (DNA gyrase):

Catalyzes relaxn of () supercoiled DNA allows normal gene tsc &

Topo IV: Reqd for separation of replicated DNA into daughter cells

--------------------

FQ chelate oral Fe++

& Ca++

supplements, and Al++

& Mg++

antacids

absorb

Dairy/food: not affect GI absorbofgemi & levo; delay moxiabsorb


85/286


***DOC:severe MRSA infxns *ototoxicity deafness

Route of Admin

AG does NOT distrb in fat use adjusted body weight for obese pt

Elim by renal filtration

give i.v. for systemic infxns

Must

Poor GI absorb


86/286

* Amp-resistant enteroccoci:

(rare w/o excessive

plasma [ ] or prolonged

use

50% E. faecium resist to Vanc

E. faecalis ~always suscept to Amp *renal toxicity (overstated)

*PCN-resistant strep pneumo: poss renal func

Do NOT use Vanc.

FQ instead (if not meningitis)

Tox ~b/c co-Rx w/ other

nephrotox drugs

*G(+) MDR bugs

(!enterococci)

interstitial nephritis poss,

but very rare

MDR strep pneumo (FQ>Vanc)

* Hospital MRSA infxns

(min Rx: 14 days of i.v. Vanc)

red-man syndrome

* Empiric: bact meningitis(~strep pneumo)

NOT ALLERGIC RXN!

Ceftriaxone + Vanc(Vanc for PCN

resist); add i.v. Ampfor Listeria if pt

< 2 y.o. or elderly

1st

i.v. dose too rapid

massive histamine release

flushing in neck & head


87/286

*Empiric: febrile neutropenia

Prevent by slow infusion

(1-2h) or pre-Rx w/ Lg

dose antihistamine

(diphenhydramine)

Need bactericidal Rx G(): pip/tazo

or cefepime. Add Vancif evid ofG(+)/waiting for Cx results (esp if see

port wine skin)

*Empiric: G(+) bacteremia *allergic rxns & rashes

Init need Vanc b/c risk of MRSA.

Then do NOT use Vanc unless staph

in multiple blood Cx.#1 cultured from blood: coag(-)

staph epidermidis (90% skin

contaminant)


*reasonable choice for anyPCN or sulfonamide-allergic

pts who need G(+) coverage

*Rash

*excellent for SSTI infxn, esp

in pt w/ PCN or sulfonamide

allergy

*Diarrhea

due to change in

composition of bowel

flora

*Pulmonary anaerobic infxns

(e.g. aspiration pneumonia &

penetrating abdominal

wounds)

*C. dificile

pseudomembranous

colitis


88/286

*good for outpatient Rx of

comm-acq MRSA adults &

kids

Rx w/ p.o. metronidazole

*Cream (topical): Rx acne

* MDR malaria: RBC form of

ALL Plasmodium



89/286

*Rx MDR G(+) bugs ~well tolerated but N/V

*Reversible bone marrow

suppression 25%

platelet suppressionn in

25% pt when Rx 10 days

*Rx VRE, esp E. faecium (but

bacteriostatic)

(No prolonged Rx, Not in

bone marrow transpl pt)

Monitor platelets & CBC

Rx MRSA when pt cant tol

Vanc (but bacteriostatic)

* periph neuropathy

*Rx complicated SSTIs

* optic neuritis

(irreversible)

*Drug interactions:


90/286

*Does NOT work in deep

seated infxns (e.g.

endocarditis & osteomyelitis)

b/c bacteriostatic

irreversible inhbr of MAOI

serotonin syndrome if

co-admin w/ SSRI

* 2nd

line: MRSA N/V

(behind vanc) Sk mm tox

* NOT for MRSA pneumo

(inactivated by surfactant) or

SSTIs (too expensive)

(poss rhabdomyolysis)

* VRE

C. diffafter metronidazole &

vanc both fail


**DOC: Pneumocystis

jiroveci (PCP)

All S/E mainly occur w/

large doses & long term

use.


91/286

**DOC: Nocardia (esp

immune-compromised host)

HIV pt req larger dose

S/E more likely

*Stenotrophomonasmaltophilia : when ICU &

resist carbapenems

* Sulfonamide-inducedallergic rxn of skin

(hives)

- rash

*Staph aureus (incl MRSA) - fever

Outpatient MRSA: - photosensitivity

-clinda> trim/sulfaor doxy

b/c clinda covers GAS/GBS;

trim/sulfa not cover GAS

- urticaria

-

works well after abscessdrainage

-

erythemamultiforme

-MSSA: use -lactam p.o.

instead

- exfoliative

dermatitis

Inpatient MRSA:

- Stevens-Johnson

syndrome (bad rash

widespread skinsloughing)

-clinda, trim.sulfa, or doxy

-critical: i.v. Vanc 1st

line* blood dyscrasias (Lg

dose)

-Linez/Daptofor pt Vanc-intol

or Rx few days for uncomplic

MRSA infxn

- Thrombocytopenia


92/286

- Leukopenia

* Enterobacterin ICU

- Hemolytic anemia,

esp in pt w/ genetic

deficiency of G-6-P

dehydrogenase

* E. coli& Klebsiella* hyperkalemia: trim acts

as K+-sparing diuretic

Drugs * + in urine Rx un-

complicated UTIin healthy

* Toxoplasmosis (prophylaxis

in AIDS pt)


Effects lim to urine! urine brown

*UTI: G(+) & G(-) * Prolonged Rx:

- heptatitis

*uncomplicated UTIs - neuropathies

- pulm fibrosis


93/286

*safe in preg

(amox & cephalexinalso safe

for preg )

*Does NOT Rx: pyelonephritis

or prostatitis (cannot

penetrate tissue)


94/286


*Also interacts w/chol in

humans (massive IFN- &

IL-6 ):

*Do NOT use after Rx w/azole b/c azoles take away

site of action (ergosterol) of

ampho B

- arthralgia/myalgia

- fever

- malaise

*Nephrotoxic (dose-dep& transient)

Lipid Ampho B:Exacerbated by other

nephrotox drugs

- Enclosed in liposome Renal wasting of K

+&

Mg++

- Same MOA

No permanent renal

damage in pts w/ norm

renal func before Rx

- Still toxic but delayed

Renal damage

lessened by giving 1L

saline i.v. prior to

ampho B Rx

- $$$$$$$$$$$$$$*shake & bake

syndrome

- fevers & chills!

- caused by IL-1, IL-6,

TNF, IFN-

*oropharyngeal/esophageal

Candida (thrush):


95/286

Neonates, children, 90%

of HIV pts, asthmatics using

ICS

swish & swallow oral

suspension (3-4 days &

every other day for 2 wks)

Replaced by clotrimazole

(oral troche) b/c better taste

rum orbiculare ( tinea versicolor)


96/286

Mechanism of Resistance

1.Mut of binding to demythylase

Lanoesterol can still bind but azoles

cannot.

C. cruseiresist fluconazolebut notvorcionazole

* Candida vulvovaginitis (CVV) 150 mg tablet (p.o.)takes 48h to improve Sx tho few S/E

*If CVV ~ everytime, single p.o. dose after ABX Rx 48 hrs

Candida colonizes genital tract of 20-50% healthy

(70-75% of all healthy will 1 ep)

~ C. Albicans

Most common in :

-taking antibiotics

Therapeutic Uses

* very actv against C. albicans

* weakness: narrow spectrum

- Not C. crusei

- No anti-mold activity

- Not Aspergillus, etc.

-pregnant

-diabetes mellitus (DM)

symptoms:

-vaginal d/c


97/286

Therapeutic Uses Mechanism of Resistance

orum orbiculare ( tinea versicolor)

al Effects

-phys exam: white d/c & erythema

* tinea capitus

- (p.o. 2 wks) = efftv griseo& fewer S/E

- any azole: topical in very young pt

*Athletes foot & jock itch

Any azoletopical (or terbinaf)

-pruritus (severe itching)

-discomfort/pain during sex


98/286

*oropharyngeal/esopha

geal Candida (thrush):

Neonates, children, 90%

of HIV pts, asthmaticsusing ICS

1. Mut of binding to demythylase

swish & swallow oral

suspension (3-4 d & qod x

2 wks)

Oral troche replaced

nystatinb/c better taste

Lanoesterol can still bind but azoles

cannot.

* Candida vulvovaginitis(CVV)

200 mg suppository (3 d,

bedtime)

C. cruseiresist fluconazolebut not

vorcionazole500 mg vaginal tablet (1 d,

bedtime)

(see flucon)

statin

* Candida vulvovaginitis

(CVV) 200 mg suppository (3d, bedtime) (see flucon)


99/286

***DOC: systemic

Aspergillus infxns

(Voricon > ampho B)

*Fusarium spp. (pt needs

WBCs!)*Scedosporium

apiospermum

*Candida (incl C. crusei.

Otherwise use flucon,

cheaper)

Not effectv against C.

glabrata?

Adverse Effects/Toxicity Mechanism of Resistance

~None

No cross-resistance w/

azoles

*well tolerated w/ excellent

pharmokinetics

Covers voricon+

zygomycetes

se adjustment


100/286

*few drug-drug interactions

b/c it does NOT induce or

inhibit CYP450


* narrow spectrum:* bone marrow

suppression

- Cryptococcus neoformans - leukopenia

- some Candida - thrombocytopenia

(GI bact convert 5-FC 5-

FU)

* 5-FC+ ampho Bor itracon

in selected fungal infections

*Beware impaired renal

func

Therapeutic Uses


101/286

- age - Diabetes mellitus

- - Periph vascular Dz

- Nail trauma - Immunosuppression

- Tina pedis

- Chronic exposure of

nails to H2O Candida

infxn

-

Poor hygiene

toenails: qd x 12 wks but S/E

2x >

Risk factors:

*Athletes foot & jock itch : topical (or azole )

* tinea capitus (p.o. x 2 wks) = efftv griseo& fewer S/E

* Preg : category B

**DOC:nail fungus

(dematophyte, yeast, or mold)

Rx: 250mg/d same week each month for 3 consecutive

months (cure rate 80%)

fingernails: qd x 6 wks but S/E

***DOC:Covers all tineas


102/286

Mechanism of Action

Kills directly!!!

Pharmacological Effects

* MET fungi

* P. orbiculare

*safe for children

griseo use b/c replaced by terbinafine & itracon

(tinea capitus : ringworm of scalp & hair b/c

Trichophyton invades hair shaft & follicle)


103/286

Bugs electron transport chain

contains ferredoxins(donate

electrons to metronidazole

form a highly reactive nitro

radical

Nitro radical attacks protozoal

DNA

destroys helical struct

cell death

*pregnancy category B (but avoid during 1st

trimester)


104/286

Aerobic organisms do NOT

produce the toxic metabolite

from the prodrug

metronidazole


105/286


Mechanism of Action Therapeutic Uses

xidoreductase-dep e

transfer rxn, reqd for anaerobic

Giardiasis(Giardia lamblia ) = beaver fev

Pentamless efficacious & more toxic

**DOC: Toxoplasmosis (Toxoplasma go

immunocompetent pt

2nd

line for: Pneumocystis jiroveci (PCP)

Fungus but anti-protozoal drugs work

(trim/sulfa is DOC)

tase

teps in folate synth in Plasmodium spp.

Cryptosporidiosis(Cryptosporidium spp.

***DOC: Cryptospoidiosisin AIDS pts

combo w/ paromomycin & azithromycin


106/286

* Kills erythrocytic/RBC stage:

1. P. vivax*

2. P. ovale*

3. P. malariae (cure)


107/286

4. Senstv strains of P.

falciparum (cure)

* No effect on

exoerythrocytic (hepatic)

stage

* Prophylaxis in Chloriq-

senstv areas:

Rx 2 wk before travel &

continue 4 wk after leaving


108/286

Safe in children

*frequent (~difficult to

disting fr early stage ofPlasmodium fxn):

*~ Only drug able to suppress

& cure infxns by MDR P.

falciparum

- n/v

- diarrhea

* Prophylaxis in Chloriq-

resistant areas:- abdominal pain

Rx 2 wk before travel &

continue 4 wk after leaving

- dizziness

Safe in children - dysphoria

*50% of pts (~ mild & self-

lim):

- ataxia

- headache

- visual/auditory

hallucinations

- dizziness

*rare :

- disorientation

- seizures

- neurotic/psychotic Sx


*Rx ALL Plasmodium

*pts w/ genetic deficiency

of G-6-P dehydrogenase

(~Mediterannean/Asian):


109/286

w/o enz

RBCs cant synth

reducing eqv

(NADPH) to protect

cell membr fr

oxidative damage

*Only drug that kills hepatic

form (liver hypnozoites) of

P. vivax & P. ovale

hemolytic

anemia oxidatv

damage to RBC cell

membr

*Test pt for deficiency of G-6-

P dehydrogenase prior to

primaq Rx

*Normal pts:

methemoglobinemia

*Prophylaxis in Chloriq-

resistant areas:

*Avoid in preg : fetus

doesnt have well

developed G-6-P

dehydrogenase

Rx 2 wk before travel

& continue 4 wk after

leaving

Safe in children

*Rx of drug-resistant P.

falciparum


110/286

*Prophylaxis in Chloriq-

resistant areas:

Rx 2 wk before travel

& continue 4 wk after

leaving

Best tolerated

* active vs all erythrocytic

Plasmodium

* MDR malaria

Adverse Effects/Toxicity


111/286

*abdominal pain

*reversible alopecia


112/286

eased LFT

( AST & ALT)


113/286



114/286


115/286


116/286

Adverse Effects/Toxicityc Uses


117/286


118/286


119/286


Influenza A & B!

duration/severity of Sx

by 1 d


120/286

Rx NOT incidence of

complications

Avian H5N1still ~susceptible

to neuraminidase inhibitors


* herpes keratitis


121/286


* fever blister: Rx ASAP

* 1oor recurrent genital HSV * N/V

* suppressive Rx for recurrent

genital HSV

* HSV proctitis * diarrhea

* herpes zoster (VZV)

* prophylaxis of CMV retinitis

in pts w/ transplanted organs* headache

b/c inhb DNA synth NOT

effectv against non-

replicating, latent viruses


122/286

* HSV & VZV strains resistant

to acyclovir

* CMV strains resistant to

ganciclovir& cidofovir


123/286



124/286

* HSV & VZV strains resistantto acyclovir

* CMV

* CMV


125/286

* CMV strains resistant to

ganciclovir& cidofovir

Pharmacological Effects Therapeutic Uses

* CMV


126/286

CCR5-tropic pts (HIV tropism test needed

prior)

* Rx for sero(+) HIV pt offered when:

3.Prevent development of resistance to antiviral drugs

high viral loads despite contd Rx w/

other drugs

*** HAART ***

1. NNRTI-based (preferred)

Abacavir + lamivudine + zidovudine

Combo: (TZV) one log in 2-8wks

Not detectable (55,000 copies/ml

* Efficacy of Rx determ by viral load


127/286

MDR HIV infxns

*Many CYP450 interactions

PI (lopin) + PI (riton) + NRTI (lamiv) + NRTI (stavu, zido)

or

3. NRTI based regimen

Not effect if viral load >100,000)

Abacavir+ lamivudine+ zidovudine

(Trizivir)

NNRTI (efav) + NRTI (lamiv)+ NRTI (zido, stavu,

tenofovir)

or

2. PI-based

Often effectv when HIV resistant to NRTIs

affects CYP450 multiple drug

interactions

*Used w/ NRTI b/c diff MOA


128/286

(dividing bacilli)

al Effects Therapeutic Uses Adverse Effects/Toxicity

*1st

obligatory drug for Rx

TB

*NEVER used alone to Rx

active TB b/c rapid

development of

resistance

*Healthy people PPD(+) &

CXR(-): (Not active TB)

INHsingle agent Rx b/c

pt immun systm inhb

growth of bact (esp if

seroconvernsion w/in

previous 2 yrs)

is a cofactor

Vit B6)

* riton as pharmaco-kinetic enhancer inhb CYP450 hepatic clear of

lopin daily maintn dose

* riton = substrate & inhbtr of CYP3A4

(& CYP450)

y by B6 deficiency

*metabolized by hepatic N-acetylation

slow acetylator pt thought to be at

neuro- & hepatotoxicity

*hepatotoxicity

- Lower risk in younger adults

- ETOH hepatotox by INH

- 20% pt 3-4x AST & AGT but

necess to stop Rx

w/o Rx: ~5-15% lifetime

risk of developing TB

disease


129/286

- Rx: daily dose of B6 prevents & r

neuropathy

*neurotoxicity

- INH = struct sim topyridoxine (Vit B

- INH antagonizes rxns where B6 is a

- Periph neuropathy (axonal sensori

polyneuropathy) neuropathy by B6

- ~preceded by paresthesias of hand

If pt 35 y.o. &serconversion date

unknown: do NOT use

INH.

Use Rifampininstead

- ~1% pt severe hepatitis (jaundic

quad pain, n/v) STOP Rx else deat


130/286

ects Therapeutic Uses

*Rifampin + INH: preg category C Be

should > risk to fetus

*pt > 35 y.o. on INH: carefully monitor

*Drug regimens w/ rifampinclear mycobact fr sputum ~2wks

faster than regiments w/o rifampin

*NEVER used alone to Rx active TB b/c rapid development of

resistance

*2nd

obligatory drug for Rx TB

*TB prophylaxis: alternative to INH


131/286

Pharm Effects Therapeutic Uses Adverse Effects/Toxicit

*NEVER used alone to Rx active TB b/c rapid dev of resistance

illi in macrophages

*ocular damage

*Also Rx M. avium (MAC)

*Replacement for rifampinin HIV pts (b/c only 50% of CYP

induction caused by rifampin)

*NEVER used alone to Rx

active TB b/c rapid

development of

resistance

*50% resist INH-Rifampin also resistant to PZA

*Used as 3rd

drug w/ INH& Rifampin

*PCN-resistant strep pneumo

*MRSA

*Can elim meningococcal carrier state


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2. mycobact

disseminated infxn

1. mycobact

meningitis

*Given i.m. or i.v. Rx:

- poss serious retrobulbar neuritis

abnormal red/green vision

- Must obtain a basal vision exam be

- Visual exam q4-6 wks recommende

*No clin significant drug interactions

*Used as 4th

drug w/ INH-

Rifamp-PZA

Streptomycin-resist TB

poss susceptible to

Amikacin(see AGs)


*~80% resist INH-

Rifampin also

resistant to EMB

*~80% resist INH-

Rifampin also

resistant to streptomycin

*sometimes replaces

EMBin TB combo Rx: INH-

Rifamp-PZA

*greater vestibular toxicitythan the oth

loss of balance

*less auditory toxicity than the other AG

*less renal toxicity than the other AGs


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Anaerobic Coverage

Good

Twice/wkly INH& Rifampin

Directly Observed Therapy (DOT)

1st

2 weeks after actv disease detected:

Daily R-I-P-E@ home or hospital

Weeks 3-8 (pt should be smear (-) for b

Twice/wkly R-I-P-Ebut

INHdose & PZA-EMB

Weeks 9-26:


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Cefoxitin

Cefotetan

Good

Good


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Bactericidal bygeneration.


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ceftriaxone-resis strep pnuemo & MR

NOT for enterococcus

Pharm Effects

3rd

generation

Excellent G()

Moderate G(+)

Pseudomonas

(Always combo: e.g. -lactam & AG, gent)

No G(+) actvy (incl strep pneumo CAP)

Bactericidal bygeneration.


148/286

Cefotaxime & ceftriaxone:

Good G(+) actvy despite 3rd

gen

Ceftriaxone _

Single large i.m. dose for gonorrhea

**DOC: strep pneumo , effctv against PCN G-r

Meningitis (strep pneumo & Neisseria)

Strep: strep pn meng & - hemolytic stre

CAP(H flu, strep pneumo & Moraxella),

add ML (e.g. azithromycin) for atypical bugs

Cefotaxime _

Comm Acq Meningitis (H flu, Neisseria

Otitis media: After 2 fails w/ amoxor am

4th

generation

1st+ 3rd= 4thgen

Excellent G()

UTI by E. Coli

Pedi/adultUTI

1 p.o. dose for uncomplicated gonorrhea

of Action Pharmacological Effects

Moderate G(+)

> ceftazidime

Pseudo. aeruginosa & inpt strep pneu

G() meningitis (good CNS penetratio

Febrile neutropenic pt

Critically ill pts (ICU)

polymicrobial infxns & unknown infxn

ck aminoacyl tRNA access to A site of 30S

- do NOT use for infxns

- G(-) > macrolides

Moderately broad spectrum

Moderate G(+)

- 65% S. aureus suscept

- Strep (but not GBS)

- Avoid use in serious SSTI but can be used for co

Moderate G()


149/286

Ts )

(Borrelia burgdorferi)

Relapsing fever

(Borrelia recurrentis)

Plague (Yersinia pestis)

Malaria

(Entamoeba histolytica & Plastmodium falciparum)

- Good for outpt G(-) infxns

Good INTRACELLULAR

Mycoplasma, Chlamydia, Rickettsia

Lyme Disease

ction Pharmacological Effects

site (P site)

chain does not move from A site

ps

---

Erythpads topically Rx acne

***DOC: atypical outpt CAP


150/286

**DOC: outpt CAPb/c hi intracellular (atypical) & extracellula

(& low risk of MDR strep do not need to use FQ)

b/c intracellular [ ]

azith> clarith= eryth

**DOC: Cryptosporidiosis in AIDS pt

Combo Rx w/ paromomycin

Azith NOT good for extracellular pathogens


Anaerobes

moxi> levo= cipro

But use metronidazole or pip/tazoinstea

levo= cipro> moxi = gemi

Need culture for senstvy & need add pip/

Limited G(+)

moxi= gemi > levo> cipro

spectrum b/c overuse

Good G()

* Pseudomonas :

FQ only p.o. Rx for pseudo.


151/286

(e.g. atypical CAP)

Good Intracellular!


DNA replication

cations GI

***DOC:

***DOC: i

*** 1st lin

(clarith)

*** 1st lin

- urinary

- , preg

- Upper

Good Intracellular! (e.g. atypical CAP)

Anaerobes

moxi> levo= cipro

But use metronidazole or pip/tazoinstead of FQ

FQ only p.o. Rx for pseudo.

levo= cipro> moxi = gemi

Need culture for senstvy & need add pip/tazo

Limited G(+)

moxi= gemi > levo> cipro

spectrum b/c overuse

Good G()

* Pseudomonas :

- Bact m

* Diarrhea

* MDR TB

* greatest

***DOC:

***DOC: i

*** 1st lin

(clarith)

*Systemic

* Diarrhea:

Avoid fo


152/286

Mechanism of Action

Broad G(-) spectr

bactericidal

Will cover G(+) if

synthesis

G(-) = high doses

-

Add another dru

G(+) = low doses

Bind to 30Sbact ribosomal subunit:

1. Block init of peptide synth

2. misread mRNA codons incorrect amino acid added

nonfunc prot

3. prevent mRNA tsl b/c func polysomes broken into nonfunc

monosomes

Seldom used ALONE

~ Always combo w/ c

Synergy:

PCNs, cephs , & Vanc

penetrate G(-) cell

Irrev inhb of prot synth

but BACTERICIDAL

[ ]-dep & post-ABX effect

Cp rate & effic of killing large doses, less often

* Enter G(-)cell via aq porin chan in outer mb of cell wall

* Deeper penetration thru cell mb req actv Xport via O 2-dep

process involving H+grad

* Low O2tension (anaerobic cond) or low extracellular pH

cell wall Xport

- Never AG alone!

- Rx: endocarditis


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Therapeuti

c Uses

*Anaero

bic

bacteria :


*common:

- n/v


170/286

Bac

ter

oid

es

fragili

s

Clo

stri

diu

m

diff

icil

e

**DOC:

Trichom

oniasis(cure 80-

90%)

: p.o. &

topical

: p.o.

**DOC:

Giardiasis

(children

& adults)

Beaver

fever,

campers

fever

- dysguesia

-

xerostomia (dry mouth)

- abdominal pain

*uncommon:

- leukopenia

- dizziness

- headache

- metallic taste


171/286

**DOC:

Amebias

is

(b/c

metron =

mixed

amebicid

e kills

luminal &

systemic

organism

s)

Rx may

be

followed

w/

luminal

amebicid

e e.g.

paromo

mycin)- ataxia

- seizure

bleeding w/ warfarin

Ingestion of ETOH

- n/v

- abdominal pain

- flushing (disulfiram-like

rxn)

*Monitor CBC & LFT w/

prolonged Rx of chronic

recurrent trichomoniasis

*Avoid 1st

trimester of

pregnancy

*Drug interactions:

- urticaria

- vaginal candidiasis

- peripheral neuropathy,

- pancreatitis


172/286

Adverse

Effects/Tox

icity

Mechanism

of

Resistance

S/E

ab pain

diarrhea

headache

nausea

er, campers fever

Disulfiram inhb acetaldehyde

dehydrogenase (ADH)

acetaldehyde accum in blood

dii) in

)


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Mechanism

of

Resistance


193/286

*No cross

resistance

w/ other

antiretrovi

ral classes

pt can

have

dual/mixe

d CXCR4-

tropic HIV

*Some

cross

resistanc

e in this

class b/c

each

drug has

slightly

diff MOA


194/286

*Resistan

ce

quickly

develops

w/

monothe

rapy b/c

these

drugshave

same

MOA

*Resistan

ce to one

=resistanc

e to all


195/286

risk for

NOT


196/286

everses

6 )

cofactor

otor

deficiency

& feet

, upper rt


197/286

Adverse

Effects/Toxicity

nefit

- Skin

- Saliva

-

Tears

- Skin

*Flu-like syndrome

*Drug interactions

(many drugs):

Strong inducer ofCYP450

Enhances hepatic

clearance of HIV

drugs (NNRTIs &

protease inhibitors)

*turn ORANGE

(annoying but

harmless):

- Urine


198/286

Hepatitis: LFTs

are the norm but

disappear w/

continued Rx

*50% CYP450

induction of

Rifampin

Enhances hepatic

clearance of HIV

drugs (NNRTIs &

protease inhibitors)

*harmless yellow

discoloration of the

skin

*polymyalgias

*uveitis

*Rifampin + INH:

preg category C

Benefit should >risk to fetus

*N/V

*hepatoxicity (1-

5%)

*No clin significant

drug interactions


199/286

impaired vision &

fore Rx

d

r AGs vertigo &

s


200/286

Chemopro

phylaxis

Seroconve

rsion

(w/in 2

yrs):

300 mg

INHdaily

for 9

months

50%

probabilit

y of

developin

g active

TB

Avoid

ETOH b/c

risk of

hepatotox

.

cilli:


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A

Therapeutic Uses Adverse Eff

*thrombophlebitis: (uncommo

ceftoxitin

*superinfections esp w/ broad

*cross-reactv in pts w/ PCN alle

cross-reactv w/ later gen

1st

(5-10%)

3rd

/4th

(1-2%)


215/286

(regens reduced Vit K for synth

prolonged PT bleeding(rar

b/c cephs inhb Vit K epoxide re

(cervical, urethral, orophryg, rectal)

esist strep pneumo & potent (low MIC)

strep pneumo)

ox/clav

Therapeutic Uses

mo

n)

**DOC: Rickettsia infxns

Covers 95% of MRSA

CAP (esp doxy)

Cheap & effectv Rx

Typicals (extracellular) munity-acq MRSA b/c drugs

- Strep pneumo

- H flu

- Moraxella catarrhalis

GI pro

- N/V

Do NOT gi

- milk -

- MulVi

- Ca++

-


216/286

Partially metab by liver

MRSA & Actinobacter

-

Legionella

Very effectv against Chlamydia & Mycoplasma

pneumo

Rx: acne (esp Mino)

Doxycyline________

**DOC:pt w/ renal dysfunc b/c elim by fecal

excretion

Minocycline_________

Atypicals (intracellular)

- Mycoplasma pneumo

- Chlamydia

Superi- Disturb

- Oral, an

- C. diff p

Tetrac

- newly-f

- newly f

Photo

Hepat

Nephr

- Epiga

- Ab cr

- Diarr

GI prob

Therapeutic Uses

- Mycoplasma

- Chlamydia

Reasonable alt for PCN allergic pts w/ strep infxns (URI)

-----------------------

NOT good for staph & strep SSTIs b/c 7% staph susceptible

NOT for pedi otitis media

***DOC: atypical CAP

b/c excellent intracellular [ ] azith> clarith= eryth Gold standard: Legionella

Excellent for intracellular bugs, e.g.

- Mycobact. avium

- (NOT TB)


217/286

r (typical) drug [ ]


NEVER use cipro for G(+)!!!!

(incl strep pneumo)

*Cipro most effectv FQ for outpatient

UTI (E. coli) tho some strains resist FQ

still suscept to amox

*Rx: UTI

*Diarrhea: shigella, E. Coli, salmonella &

campylobacter

*MDR TB

of FQ

azo

Ciprofloxacin_______

Many CYP450 drug interactions (incl i

metab)

Phototoxicity

Gemifloxacin_______

50% pt develop rash after 7 days

Damage growing cartilage (tho short t

Tendon rupture

Q-T elongation:

- pt w/ congenital prolonged Q-T

- pt on other drugs that Q-T (sotal

Slow K+-medtd repolzn prolong Q-T

tachy (torsade de pointes)



218/286

Therapeutic Uses Adverse Eff

DR strep pneumo

pt RxCAP

e: Rx inpt CAP Alt Rx: ceph (ceftriaxone, cefotaxime) + ML

e: outpt complicated UTIs

tract w/ func & struct abnorm, (e.g. calculi or catheter)

, children & hospitlzd pts

rinary tract affected (pyelonephritis)

- pt w/ congenital prolonged

- pt on other drugs that Q-

re likely resist

: shigella, E. Coli, salmonella & campylobacter

Slows K+

-medtd repolzn proltachy (torsade de pointes)

Levo & moxilow risk unless fac

imbalance)

Damage to growing cartilag

Tendon rupture

Q-T elongation:

actvy vs TB

DR strep pneumo

pt RxCAP

e: Rx inpt CAP Alt Rx: ceph (ceftriaxone, cefotaxime) + ML

infxns: Salmonella (some resist b/c Rx chickens)

shigella, E. Coli, salmonella & campylobacter

UTI b/c p.o. only sm drug amt in urine


219/286

Pharmacological Effects Therapeutic Uses

m (incl enteric bact) & rapidly

in combo w/ an inhibitor of cell wall

class (e.g. gent -lactam)

!!!

ell wall synth inhbtr

inhb cell wall synth easier for AG to

S/E when *AG+p 5 d

Renal dysfunction ri

Furosemide(Rx: uri

*Can avoid nephroto

* Neuromuscular blo

blocking agents in O

Poss Very Toxic!

time & [ ] dep!

Longer CP> some cri

*Nephrotoxicity: (re

Damage to proximal tu

[creatinine]plasmaCo-Rx w/ other nephro

nephrotox

*Ototoxicity: (reversi

Vestibular ataxia, v

1 against extracellular bacilli

*TB (see TB drugs)

Ace in the hole for bact

resistant to gent& tobra

Given p.o. prior to surgery

decontaminate gut

Soley renalelim: dose in pt

w/ renal failure

Widely used in antibacterial

ear drops, eye drops &

ointments

Esp for Pseudo.

Add low dose -lactam or Vanc

(staph, strep or enterococcus)


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Mechanism of

Resistance

(same as PCN)

1. PBP site!

2.

Bugs begin tomake cephalo-

sporinases

cts/Toxicity

) poss esp w/ i.v. push

r spectrum cephs

rgy

s


282/286

of clot factors 2, 7, 9, 10)

, assocd w/ cefotetan)

uctase

Adverse Effects/ToxicityMechanism of

Resistance

helate cations prevent drub absorb fr GI tract

---------------------------

1.Mut protects

binding site

2.Pump efflux

(tho Doxymay still

work)

blems (common)

e p.o. with:

Mg++

it - Al++

Fe++


283/286

Widespread use in

livestock food

resistance of

Enterococci

nfections: b/c suppress fecal coliforms (C. diff & Candida grow)d GI func

al, vaginal candidiasis

seudomembranous colitis (Rx: metronidazole)

yclines bind to Ca++

rming teeth discoloration

rming bone deformity

sensitization: sunburn esp in fair people

otoxic (large do

antimicrobial drug chart

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