C;Penicillins (PCN) = -Lactams

Drug
Route of Admin

Time-dependent BACTERICIDAL (keep CP > MIC)

Mechanism of Action

i.v.

Inhb cell wall synth Cell wall peptidoglycan cross-links via peptide side-chains (transpeptidation ) PBP init enz actvy by binding to terminal D-Ala-D-Ala of sidechains.

cont i.v. infsn common

PCNs & Cephs = structural analogs of D-Ala-D-Ala substrate

Penicillin G
not p.o. b/c acid labile

PCN covalently binds to active site of PBPs

irrev inhb of transpeptidation & cell wall synth cell lysis & death

Penicillins (PCN) = -Lactams

Drug

(contd) Time-dependent BACTERICIDAL (keep CP > MIC)

Mechanism of Action

Route of Admin

i.m. Inhb cell wall synth slow release (see PCN)

Procaine Penicillin G
D-Ala-D-Ala analog irrev bind to PBP active site

Benzathine Penicillin G

-Lactamase (Penicillinase) Resistant PCN

Drug
Route of Admin

Broader spectrum PCN

Mechanism of Action

Pharmacological Effects

i.v.

(see above)

NOT degraded by -Lactamase

Oxacillin

Designed spcfc to kill Inhb cell wall lactamase synthesis producing Staph aureus

short t1/2:

D-Ala-D-Ala analog irrev dose q4h/q6h bind to PBP active site

Nafcillin

Oxa, Naf, Diclox > Vanc b/c kills quickly

Dicloxacillin

p.o.

Aminopenicillins = Extended Spectrum PCN

Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

Inhb cell wall synthesis

Destroyed by -lactamase!

(see above)

Combine w/ -lactamase inhibitors to Rx -lactamase producing bugs

(e.g. staph aureus)

Ampicillin

i.v. D-Ala-D-Ala analog irrev bind to PBP active site

Combo poss:

Ampicillin + sulbactam (i.v.) Destroyed by -lactamase!

Combine w/ -lactamase inhibitors to Rx -lactamase producing bugs

(e.g. staph aureus

Amoxicillin

p.o.

Combo poss (2 line otitis media):

nd

Amoxicillin

p.o.

Amoxicillin + clavulanate (p.o.)

aka Augmentin

p.o. Absorption NOT affected by presence of food.

Anti-Pseudomonal PCN
Drug
Route of Admin

Kills Pseudomonas aeruginosa (& Enterobacteriacea)

Mechanism of Action Pharmacological Effects

i.v.

Inhb cell wall synthesis

Ticarcillin + clavulanate

(see above) esp in ICU

(ticar/clav)

Ticarcillin

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

Piperacillin + tazobactam

Piperacillin

(pip/tazo) broadest spectrum PCN

-Lactamase Inhibitors Broadens spectrum of -lactamase-susceptible PCNs

Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

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

Sulbactam

Tazobactam

aka

tazo

Carbapenems & Monobactams

Drug
Route of Admin

i.v. only!!!
Pharmacological Effects

Mechanism of Action

Imipenem/ Cilastatin

Inhb cell wall synth

Metabolized by renal dihydropeptidases (DHP)

(carbapenam)

(same as PCN)

Imipenem must be given in combo w/ Cilastatin (DHP inhbtr)

i.v. D-Ala-D-Ala analog irrev bind to PBP active site

Good tissue penetration Broadest spectrum

(Must use in combo!!)

-lactams

Ertapenem

Inhb cell wall synth

does NOT cover:

i.v.

(same as PCN)

pseudomonas

i.v.
(carbapenam)

acinetobacter

enterococci Inhb cell wall synth

Aztreonam

(same as PCN)

i.v.
(monobactam)

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

Spectrum AGs (e.g. gentamicin)

Cephalosporins
G(+) activity: 1st gen > 2nd gen > 3rd gen
Mechanism of Action

G(-) activity:

3rd gen > 2nd gen > 1st gen

Drug

Route of Admin

Pharm Effects

1st:

Inhb cell wall synth i.v.

(same as PCN) D-Ala-D-Ala analog irrev bind to PBP active site

1 st generation Best against G(+)

Cefazolin

Few G()

Spectrum varies by gens (Bactericidal by gen)

~ Resist hydrolysis by lactamases broader spectrum > PCNs Good distrb in most body fluids but NOT INTRACELLULA R

1st: p.o.

Renal elim dose in pt w/ poor renal func (but cetriaxone liver)

Cephalexin
2nd: 2 nd generation G() > 1st gen st G(+) < 1 gen i.v. Anaerobes!!!

Cefoxitin

2nd:

Cefotetan

Cephalosporins (continued)
Drug 3rd:
Route of Admin

i.v.

Ceftaroline

3rd:

Ceftazidime

3rd:

Cefotaxime

3rd:

i.v. i.m. p.o.

Ceftriaxone
3 :
rd

Cefpodoxime
3rd:

Cefixime
3rd:

Cefdinir
4th:

i.v.

Cefepime

Tetracyclines
Drug

BACTERIOSTATIC
Route of Admin

Doxycycline
(see p. 26)

i.v.

p.o.
F=100%

Minocycline

p.o.
F=100%

Macrolides (ML) Does NOT cover Enterococcus ( esp VRE) or MRSA !

Drug

BACTEROSTATIC

Erythromycin
i.v. (hurts!) p.o.
(lim p.o. F b/c acid labile) Esters less acid labile better F (estolate ester = highest F) Excreted in bile

Azithromycin

i.v. p.o.
(F ~ 0.5)

Long t1/2 Large Vd Excreted in bile

Clarithromycin
p.o.
(F ~ 0.5)

Metab by liver, excreted in urine

Fluoroquinolones (FQ)
Drug

Does NOT cover Enterococcus ( esp VRE) or MRSA ! Inhb DNA synth rapidly BACTERICIDAL (conc-dependent )

BACTERIC

Ciprofloxacin
i.v.

Inhb bact topo II & IV p.o.

F = 90%

Topo II (DNA gyrase):

Catalyzes relaxn of (+) supercoiled DNA allows normal gene tsc & DNA rep Topo IV : Required for separation of replicated DNA into daughter cells

FQ chelate oral Fe++ & Ca++ supplements, and Al++ & Mg++ antacids cations Dairy/food: not affect GI absorb of gemi & levo; delay moxi absorb Ciprofloxacin___________ * Ca++-fortified milk, anatacids & yogurt F but not dietary Ca ++

* 20% metab by CYP1A2 in liver

Fluoroquinolones (FQ) (contd)

Levofloxacin*

Does NOT cover Enterococcus ( esp VRE) or MRSA !

Drug

i.v.

p.o.
F = 90%

Renal elim no CYP450 interact

Moxifloxacin*
i.v. p.o.
F = 90%

Hepatic metab but no CYP450 drug interactions

Aminoglycosides (AG)
Streptomycin

BACTERICIDAL
Drug

(see TB drugs)

Neomycin

Gentamicin*

Tobramycin* Amikacin*

Other Antibiotics: Vancomycin

Drug
Route of Admin

BACTERICIDAL
Pharmacological Effects

Mechanism of Action

Must give

Inhb cell wall synth

G(+) incl anaerobes

Does NOT involve PBPs! i.v.

NO G()s!

SLOW Big molec penetrn probs (poor BACTERICIDAL 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/c covalently 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

p.o. Vanc = 2nd line: C. diff pseudo-membranous colitis

*DOC C. diff = metronidazole Give 2 courses p.o. metronidz. If still C. diff then p.o. Vanc If still no response fidaxomicin

Other Antibiotics: Clindamycin

Drug
Route of Admin

BACTERIOSTATIC
Pharmacological Effects

Mechanism of Action

Clindamycin
(see p. 26)

i.v.

Inhb protein synth BACTERIOSTAT IC

Excellent G(+)!! - SSTIs (staph aureus & hemolytic streps - covers MRSA

p.o. (same as macrolides!)

- outpatient Rx of MRSA cellulitis in adults & children

binds 50S Also topical subunit at P cream site

Good coverage of G(+) anaerobes

(acne)

inhb translocation 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 Penetrates most body fluids & tiss (not CSF & brain) Good intracellular conc Very hi bone/serum conc Heptaic metab (NO need to adjust for renal func)

- aspiration pneumonia

No G(-) coverage!

No VRE coverage!

Other Antibiotics: Linezolid, Daptomycin, Fidaxomicin

Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

 Excellent G(+) (incl MRSA, VRE & PCN-resistant strep pnemo) Syntheitic antiobiotic: 1st oxazolidione

i.v.

Min G() actvy

pts on i.v. Vanc in hospital sent home on p.o. linezolid irreversible inhibitor of MAOI serotonin syndrome if coadmin w/ SSRI

p.o.

Inhb protein synth BACTERIOSTA TIC tho cidal against some

F = 100%

Linezolid

Bind to unique site on 23S ribosomal RNA of 50S subunit block assembly of 70S ribosomal complex needed to init prot synth

Do NOT need to adjust dose for renal func

600 mg dose

$$$ ($50/pill) bind bact mb depol no mb potential

i.v.

Daptomycin
$$$$ cell death

($250-500/d)

Fidaxomicin

$$$$

Inhibit RNA synth no RNA pol

As effective as vanc

Other Antibiotics: Trim/Sulfa

Drug
Route of Admin

Mechanism of Action

Pharm Effects

Trimethoprim/ Sulfa-methoxazole
aka

p.o.

Sulfonamides = 1st class Broad spectrum: systemic antibact drugs S. aureus incl MRSA

F = 90%

trim/sulfa
aka

Synergy: p.o. even in BacterioSTATI serious infxns C alone; BacterioCIDAL combo

Enterobacter in ICU

E. coli & Klebsiella - drugs * + in urine Rx uncomplicated UTI in healthy

Bactrim

* Sulfa: comptv antagonist of PABA inhb DOES NOT cover GAS dihydropteroa te synthetase prevent DHF synth i.v. poss * Trim inhb dihydrofolate (avoid huge reductase volumes of i.v. prevent fluid) conversion of DHF to THF

* pref inhb bact enz (w/ little effect on mammalian enz)

Other Antibiotics: Nitrofurantoin

Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

p.o.

Macrocrystalli ne form: slower absorb & renal excretion

* + in urine bactericidal

High F

Most active in ACIDIC urine BACTERIOSTAT Rx: UTI: G(+) & G(-) IC (low [ ])

duration of action in macrocrystalline form

- E. coli

Nitrofurantoin

BACTERICIDAL (high [ ])

- Klebsiella - Enterococcus

Nitrofurantoin
*Bact enz rapidly reduce nitrof to reactv intermed damages DNA cell death

- some Proteus resistant

Bactericidal Aminoglycosides PCN Carbepenems Monobactams (aztreonam) Cephalosporins Vancomycin Fluoroquinolones Nitrofurantion (static at low [ ]; cidal at high [ ]) Quinupristin/dalfoprist in Metronidazole INH Rifampin Pyrazinamide

Bacteristatic Tetracyclines Macrolides Clindamycin Linezolid Nitrofurantoi n (may be cidal w/ large dose) Ethambutol

Systemic Antifungals: Polyenes

Drug

Route of Admin

Mechanism of Action

Pharmacological Effects

Amphotericin B*

i.v.

Bind to ergosterol in fungal cell membrane create porins

*Extremely broad spectrum

(polyene)

topical

cell permeability ions & macromolec leak out of cell cell death

**Gold standard anti-fungal drug

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

(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 , Pityrosporum orbiculare ( tinea

Drug

Route of Admin

Mechanism of Action

Pharmacological Effects

i.v.

Most commonly used systemic antifungal agent

AZOLES:

Lacks major toxicity

p.o. FUNGISTATIC b/c slow

p.o. F is excellent

Pt need patent imm systm

*inhb bact enz CYP450 lanosterol 14demethylase prevent ergosterol formation accum of 14methylsterols inhb enzy actvy of electron transport system block cell growth

Fluconazole*

Fungal cell membrane!

Systemic Antifungal: Azoles (contd) Candida albicans , MET fungi , Pityrosporum orbiculare ( tinea
Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

i.v. topical

AZOLES: FUNGISTATIC b/c slow

Pt need patent imm systm

* inhb bact enz CYP450 lanosterol 14demethylase

Miconazole

Miconazole

prevent ergosterol formation

accum of 14methylsterols inhb enzy actvy of electron transport system block cell growth

topical

oral troche

Fungal cell membrane!

Clotrimazole

Tastes > nystatin

i.v.

Voriconazole
p.o.
F = 96%

* Extended spectrum

Can change from i.v. to p.o. w/o dose adjustment

Posaconazole

p.o.

erratic GI absorption (need fat!)

Systemic Antifungals: Echinocandin

Drug Mechanism of Action Pharmacological Effects Therapeutic Uses

*probably replaced ampho B

Caspofungin

(echinocandin)

Inhb synth of Big molecule 1,3--D glucan (key component of fungal cell wall in Candida & Aspergillus ) No p.o. avail

*salvage therapy in pts w/ invasive Aspergillosis who have NOT responded to ampho B

(Diff MOA from azoles)

*rapidly cidal against Candida , even those resistant to fluconazole *limited spectrum: - Candida - Aspergillus - Pneumocystis

Systemic Antifungals: OTHER

Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

Flucytosine (5-FC)

p.o.

Must be dosed QID

(5-FC) fluorinated pyrimidine converted to 5-FU converted to 5-FUMP converted to FdUMP inhb thymidylate synthase

* rapid absorb

* extensive distrb (incl penetration into CSF)

* Renal elim Lack of thymidine inhb DNA synthesis (human cells do not convert 5-FC to 5-FU)

* Synergy: 5-FC w/ azoles & ampho B

Systemic Antifungals: OTHER (contd)

Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

Drug accum in: Inhb enz squalene epoxidase prev ergosterol synth

p.o.

skin

nails

topical

Accum of squalene kills fungal cell.

fat cells

Terbinafine

p.o.

Bind polymerized microtubules

 Inhb fungal mitosis

Griseofulvin

ingest w/ fatty foods to F

Prevents formation of cytoplasmic microtubules necess for hyphae growth

Tolnaftate

topical, OTC

unknown

Antiprotozoal
Drug
Route of Admin

p.o.

Metab by liver

Cleared by kidney

Metronidazole

Metronidazole

Antiprotozoal (contd)
Drug
Route of Admin

Mechanism of Action

Nitazoxanide

Interferes w/ pyruvate:ferrodoxin oxidoreductase-dep e tra energy metab

???

*selectively inhibit two enzymatic steps in folate synth in Pla

Pyrimethamine Sulfadiazine
*P inhibits dyhydrofolate reductase

*S inhibits dihydropteroate synthetase

Pentamidine

Antimalarial
Drug

Doxy & Clinda: Also Rx MDR malaria (all)

Route of Admin

Mechanism of Action

Pharm Effects

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

Chloroquine

Chloroquine

Chloroq & Mefloq prevents polymerizn free heme kills parasite by oxidative damage of cell membranes

Mefloquine

Antimalarial (contd)
Drug

Doxy & Clinda: Also Rx MDR malaria (all)

Mechanism of Action Pharm Effects

Route of Admin

p.o.

MOA unknown

(qd)

Primaquine

Gametocide against ALL Plasmodium

p.o.

Atovaq: ubiquinone

(qd)

Blocks cytochromemedtd e transport destroys mito mb potential diff

Atovaquone/ Proguanil

Proguanil:

Atovaquone/ Proguanil

1. Enhances ability of Atovaq to destroy mito membr potential difference

2. Prevents resistance

Doxycycline
(see p. 8)

Clindamycin
(see p.14)

Antihelminitic
Drug Mechanism of Action Pharmacological Effects Therapeutic Uses

*kills round & tape worms

Inhb synth of microtubules necess for glucose uptake [glycogen] & *ATP+

*pinworm (Rx whole family!)

*hookworm

Mebendazole

Parasite: 1. Dies

2. Immobiliz ed & cleared from GI tract

Also larvacidal & ovicidal.

safety pinworms bend Broad spectrum p.o. (low F) Kills all worms in mixed infections *roundworm *pinworm (Rx whole family!)

but b/c drug just goes *hookworm thru GI tract to kill worms *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

Albendazole

Ganglionic nicotinic cholingergic agonist musc tetany

*kills round worms

Pyrantel pamoate
Neuromuscul ar paralysis allows peristaltic clearance from GI tract.

*pinworm (Rx whole family!)

*hookworm

Antihelminitic (contd)
Drug Mechanism of Action Pharm Effects Therapeutic Uses

Ivermectin

Releases GABA & GABA binding facilitate opening of Cl channels in NMJ flaccid muscle paralysis in:

**DOC: threadworm

helminths

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 Glugated Clchannels 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 iverm Rx scabies but p.o. admin very effectv

*esp useful Rx scabies in:

- immunocompromised pts

- pts w/ severely encrusted scabies

- pts who have failed therapy w/ topical permethrin

1. Opens Ca++ channels musc tetany 2. Spastic paralysis

**DOC: Schistosomiasis

Flukes (trematodes)

Praziquantel

3. Tegmental damage

Praziquantel

Activate host immune system

Infxn cannot be transmitted in US b/c no intermed host (a snail)

Ectoparasites
Drug Mechanism of Action Pharm Effects Therapeutic Uses

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

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 Clchannels in NMJ flaccid muscle paralysis in: helminths

**DOC: threadworm

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 Glugated Clchannels 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 iverm Rx scabies but p.o. admin very effectv

*esp useful Rx scabies in:

- immunocompromised pts

- pts w/ severely encrusted scabies

pts who have failed therapy w/ topical permethrin

Antivirals: Influenza
Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

Inhb viral neuraminidas e Block release of new viral particles

Oseltamivir

p.o.

Oseltamivir

p.o.

Antivirals: Herpes keratitis

Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

Trifluridine

Converted to trifluridine tri(PO4) by host cell enzymes: active metabolite

aka

ophthalmic inhibits viral solution DNA synthesis

Trifluorothymidine

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

Drug
Route of Admin

Mechanism of Action

Pharmacological Effects

p.o.
F = 15-20%

Inhb viral DNA A guanosine derivative polymerase Must be phosphorylated 3x active metabolite: acyclovir tri(PO4) Virus-specific thymidine kinase (found ONLY in infected cells) produces acyclovir mono(PO4)

i.v.

dose in pts w/ renal failure

incidence of resistance is low

topical Acyclovir phosphorylase enz of host cell then produce acyclovir di- & tir(PO4)

Acyclovir tri(PO4): - Competes w/ dGTP at the viral DNA polymerase

p.o. Valacyclovir
F = 48%

- Causes chain termination when incorp into viral DNA

Prodrug converted to acyclovir

Rx Vanc (p.o.) *acyclovir+P 3-5x > Rx acyclovir (p.o.) dose in pts w/ renal failure

inorganic pyrophosphat e

Foscarnet

i.v.

Acts directly to inhibit:

1. viral DNA polymerase

2. viral RNA polymerase

3. HIV reverse transcriptase

No activation via virus or host enz required

Antivirals: Cytomegalovirus (CMV)

Drug
Route of Admin

Mechanism of Action

Pharm 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.

Ganciclovir

Ganciclovir
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.

Valganciclovir
F = 60%

- Causes chain termination when incorp into viral DNA

F by hi fat meal inorganic pyrophosphat e Acts directly to inhibit:

1. viral DNA polymerase

Foscarnet

i.v. 2. viral RNA polymerase

3. HIV reverse transcriptas e

No activation via virus or host enz required Antisense oligonucleotid e

Fomivirisen

intravitreal Binds to mRNA injection prevents tsl prevents viral replication

Antivirals: Treatment of HIV

Drug Mechanism of Action

Synthetic peptide binds gp41

Blocks viral/T-cell mb fusion

Fusion Inhibitors

HIV cannot enter CD4 cell

Enfuvirtide (s.c.)
Inhibit CCR5 receptor

Maraviroc (p.o.)
Blocks gp120 binding to CD4 cell

NRTI

Intracellular kinases convert these nucleosides to false nucleotides (triphosphates):

Nucleoside Rev TSCase Inhibitor

1. competitive inhb HIV rev tsc-ase

Zidovudine (AZT, ZDV) Lamivudine (3TC) Abacavir (ABC)

2. cause chain termination of viral DNA

NRTIs can be incorp into viral DNA

Emtricitabine

Tenofovir (TDF, a nt)

NNRTI

NO reqd phos to be active

Non-Nucleoside

Direct inhb rev tsc-ase stop rep

Rev TSCase Inhibitor

Bind diff site than NRTIs do NOT compete w/ nt for binding to rev tsc-ase

NET effect blockage:

Nevirapine (NVP) Efavirenz (EFV)

Integrase Inhibitors

1. RNA-dependent DNA pol

2. DNA-dependent DNA pol

Prevents viral DNA insertion into human DNA

Raltegravir

Protease Inhibitors

Block viral protease prevent cleavage of viral polyproteins into functional subunits necess for

Atazanavir

Block viral protease prevent cleavage of viral polyproteins into functional subunits necess for assembly of new virus particles

Ritonavir*

Lopinavir

Anti-TB (Mycobacterium tuberculosis ) R-I-P-E or R-I-P-S BACTERICIDAL (dividing bacilli)

Drug Mechanism of Action Pharmacological Effects

Inhb cell wall synthesis

- INH = struct sim to pyridoxine (Vit B6)

- INH antagonizes rxns where B6 is a cofactor

BACTERICIDAL for rapidly dividing

- Periph neuropathy neuropathy by B6 deficiency

BACTERIOSTATIC for latent (non-dividing)

A prodrug converted into active form by mycobacterial catalase-peroxidase

Isoniazid (INH)

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

Anti-TB (contd)
Drug

R-I-P-E or R-I-P-S BACTERICIDAL (dividing bacilli)

Mechanism of Action Pharm Effects

Inhibit RNA synthesis

Bind to subunit of bact DNA-dep RNA polymerase

Do NOT bind to human RNA polymerase

BACTERICIDAL

Rifampin
Easily penetrate tissues to kill intracellular mycobact & bugs in abscesses

Rifabutin

Pyrazinamide (PZA)

Unknown MOA

Kills semi-dormant intracellular bacilli in macrophages

Anti-TB (contd)
Drug

R-I-P-E or R-I-P-S BACTERICIDAL (dividing bacilli)

Mechanism of Action

Ethambutol (EMB)

Inhb of cell wall synthesis

the PCN of TB Inhb arabinosyl transferase (enz which polymerizes arabinoglycan)

Arabinoglycan = essential part of mycobacterial cell wall

Streptomycin

AG antibiotic

(see AGs)

Inhb protein synth i.m. Primarily against extracellular bacilli i.v.

MDR TB:

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

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

Gold Standard : INH-Rifampin-PZA

(tho outcome still not good)

& either EMB or streptomycin for 9 months

(see FQ)

All 4 drugs given until know susceptibility

Ciprofloxacin & levofloxacin

(2 wks to culture)

Rx MDR active TB Moxifloxacin shows the greatest activity versus TB

Rx Mycobacterium avium complex (MAC): A macrolide Cipro Rifabutin EMB (~HIV pts)

Spectrum

Drug/Class AminoPCN

G() Coverage G(+) Coverage E. coli & H. flu Good Good

Carbapenem s (except Good ertapenem) Aztreonam Excellent 1st gen ceph Little

2nd gen ceph Some 3rd gen ceph Good 4th gen ceph Excellent Moderate MB Tetracyclines (> macrolides) Little

Good Some (not ceftaxidime) Moderate

Moderate

Good

Macrolides

(some w/ clarithromycin (except Enterococcus) & azithromycin) Definite differences in coverage within this class None None Higher doses None Good Excellent Good Excellent Lower doses (combo w/wall synth inhibitor) Excellent Good Excellent

B() B

Fluoroquinol ones Vancomycin Clindamycin Aminoglycosi des Linezolid Trim-sulfa Nitrofurantoi n

AL (keep CP > MIC)

Pharmacological Effects Therapeutic Uses Mechanism of Resistance

Pen G t1/2 = 30 min Probenecid inhb renal transp systm Pen G secrtn t1/2

**DOC** 1. -hemolytic strep

1. -lactamase *** (penicillinase) destroys PCN -lactam ring drug inactive staph aureus plasmid encodes lactamase 2. drug binding site (G(+)) MRSA/ORSA express an addl lactam binding site (bact gene mut) resistant to ALL -lactams

Group A*, B, C, F, G streps GAS killed quickly by Pen G

2. suscep strep pneumo

Strep pneumo PBP w/ aff for lactams

(but use p.o. amoxicillin) Lg dose! If resist Pen G, also resist 3rd Ceph

VREs terminus mut D-Ala-Dlactate 3. Drug efflux (G(-)) Pseudo & Acinetobacter

Good distrb in ECF Will penetrate CSF if meninges inflammed Does NOT enter cells Renal tubular secrtn

3. meningococcal meningitis (Hi doses!) ------------------------ Syphilis Ghonorrhea N. meningitides

S. pneumo marcolides 4. Prevent drug entry Pseudo # of porins carbapenams

NOT staph aureus (resistant)

TERICIDAL (keep CP > MIC)

Pharmacological Effects Therapeutic Uses Mechanism of Resistance

Good distrb in ECF Will penetrate CSF if meninges inflammed Does NOT enter cells Renal tubular secrtn

Depot PCNs

(see above)

prophylax : prev GAS infxn in military recruits

1. -lactamase (PCNase) 2. drug binding site (G(+))

Syphillis (But NOT neurosyph)

3. Drug efflux (G(-)) 4. Prevent drug entry

um PCN
Therapeutic Uses Adverse Effects/Toxicity

**DOC**

Susceptible staph aureus (MSSA) or suscep strep cellulitis, abscesses, endocarditis, meningitis & others

(always prefd over broad, e.g. FQ)

Cellulitis: always Staph/Strep unless culture proves otherwise

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

PCNase-prod Staph soft tissue infxn

Susceptible Strep infxn

Therapeutic Uses

Adverse Effects/Toxicity

**DOC**

1. Enterococcus spp.

Also for Enterococcus: Vanc, Doxy, tigecycline, quinupristin/dalfopristin, Linezolid, Dapto

2. Listeria spp. p.o. diarrhea

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

* NOT active against MRSA!

* spectrum extended to cover G(): E. coli & H. flu

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

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

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

acteriacea)
Therapeutic Uses Adverse Effects/Toxicity

**DOC**

Pseudomonas spp.

*excellent anaerobic actvy

*good vs MSSA, S. pneumo

*NEVER use just one drug for pseudomonas!!!

ble PCNs
Therapeutic Uses Adverse Effects/Toxicity

*** 2nd line otitis media: Amox/clav aka Augmentin

when amox alone fails Diarrhea

**DOC Pseudomonas : ticar/clav

Given i.v. in ICU Combo poss: Ampicillin + sulbactam (i.v.) **DOC Pseudomonas : pip/tazo

Given i.v. in ICU

Therapeutic Uses

Adverse Effects/Toxicity

Cover many nosocomial G() seizurecillin esp hi rods (incl Pseudomonas ), doses in pts w/ poor renal anaerobes & G(+) func & neurosurg pts pt w/ PCN allergy: BEWAREmore crossreactv than cephs Multi-drug resistant bugs

Last resort drug after pt fails pip/tazo or cefepime

pip/tazo, cefepime > carbap

for Pseudomonas polymicrob, life-threat infxns e.g. intra-abdominal trauma & nosocomial infxns by Citrobacter, Enterobacter, etc. Use pip/tazo or cefepime for febrile neutropenic pt instead Tx pts w/PCN allergy

Very good G() actvy (incl Little allergic crossPseudo , actvy comparable to reactivity w/ other ceftazidime) -lactams

NOT clinically useful against G(+) (incl MRSA) & anaerobes

* Severe G() infxn in pt w/ PCN allergy

Do NOT cover Enterococci or MRSA!!!!

No activity against Enteroccocci, MRSA, Listeria, or PCN-resist strep pneumo!
Therapeutic Uses Mechanism of Resistance

> 2nd gen > 1st gen

***DOC: Surgical prophylaxis Cheap & good tissue penetration (same as PCN)

1 line: non-MRSA SSTIs

st

(better than vanc!)

1. PBP site!

1st line: mild PCN allergy

Rx: pyelonephritis in pregnant

2. Bugs begin to make cephalosporinases

MS-Staph Aureus & strep

MSSA SSTIs, strep

Safe for pregnant

**DOC: intra-abdominal surgical prophylaxis pelvic inflamm disease (PID) intra-abdominal infxns

Not used much anymore, replaced by 3rd gen

Do NOT cover Enterococci or MRSA!!!!

Mechanism of Action

Binds mutated PBP binding site in MRSA

Inhb cell wall synth

(same as PCN) D-Ala-D-Ala analog irrev bind to PBP active site

Spectrum varies by gens (cidal by gen)

~ Resist hydrolysis by -lactamases spectrum > PCNs Good distrb in most body fluids, but NOT INTRACELLULAR Renal elim dose in poor renal func (cetriaxone has liver elim) Good CNS penetr Rx bact meningitis 1. Ceftazidime 2. Cefotaxime 3. Ceftriaxone 4. Cefepime Cefepime: resist to degradtn by -lactamases

Route of Admin

Mechanism of Action

i.v. Inhb protein synth p.o.

F=100%

BACTERIOSTATIC

Bind 30S subunit of bact ribosome block aminoacyl tR subunit Oral bioavailb = 100%

Long t1/2- & slow elim dosed bid

High [ ] in bile check liver func tests (LFTs ) - alkaline phosphatase - AST & ALT transaminases - Bilirubin - Albumin (in serum)

p.o.
F=100%

BACTEROSTATIC
Mechanism of Action

Inhb protein synth BACTERIOSTATIC Bind 50S subunit at peptidyltransferase site (P site)
inhb translocation

/c

better F

ghest F) ile

(most recently added amino acid to peptide chain does not m to P site) Peptide elongation stops, protein synth stops

------------------ Good G(+) incl MSSA & strep pneumo - Also CAP Rx: morax, H flu - Intracellular: Legionella & Chlamydia Some G(-) (esp Clarith & Azith) Good tissue penetration

(except brain & CSF)

ile

ed in urine

MRSA !

BACTERICIDAL
Mechanism of Action

allows normal gene tsc & DNA replication

licated DNA into daughter cells --------------------

, and Al++ & Mg++ antacids cations GI absorb

i & levo; delay moxi absorb

F but not dietary Ca ++

sp VRE) or 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 & DNA replication Topo IV : Reqd for separation of replicated DNA into daughter cells -------------------FQ chelate oral Fe++ & Ca++ supplements, and Al++ & Mg++ antacids cations GI absorb Dairy/food: not affect GI absorb of gemi & levo; delay moxi absorb

ctions
Route of Admin

Poor GI absorb

Must

give i.v. for systemic infxns

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

Elim by renal filtration

Therapeutic Uses

Adverse Effects/Toxicity

***DOC: severe MRSA infxns *ototoxicity deafness

(rare w/o excessive * Amp-resistant enteroccoci: 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. Amp for Listeria if pt < 2 y.o. or elderly

1 i.v. dose too rapid massive histamine release flushing in neck & head

st

Prevent by slow infusion (1-2h) or pre-Rx w/ Lg *Empiric: febrile neutropenia dose antihistamine (diphenhydramine)
Need bactericidal Rx G(): pip/tazo or cefepime. Add Vanc if evid of G(+)/waiting for Cx results (esp if see port wine skin)

*Empiric: G(+) bacteremia

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)

*allergic rxns & rashes

Therapeutic Uses

Adverse Effects/Toxicity

*reasonable choice for any PCN 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

*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

in
Therapeutic Uses Adverse Effects/Toxicity

*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:

*Does NOT work in deep irreversible inhbr of MAOI seated infxns (e.g. serotonin syndrome if endocarditis & osteomyelitis) co-admin w/ SSRI b/c bacteriostatic

* 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. diff after metronidazole & vanc both fail

Therapeutic Uses

Adverse Effects/Toxicity

**DOC: Pneumocystis jiroveci (PCP)

All S/E mainly occur w/ large doses & long term use.

**DOC: Nocardia (esp immune-compromised host)

HIV pt req larger dose S/E more likely

*Stenotrophomonas maltophilia : when ICU & resist carbapenems

* Sulfonamide-induced allergic rxn of skin (hives) - rash

*Staph aureus (incl MRSA)

- fever

Outpatient MRSA:
- clinda > trim/sulfa or doxy b/c clinda covers GAS/GBS; trim/sulfa not cover GAS

- photosensitivity

- urticaria

- works well after abscess drainage

- erythema multiforme

- MSSA: use -lactam p.o. instead

- exfoliative dermatitis

Inpatient MRSA:
- clinda, trim.sulfa, or doxy - critical: i.v. Vanc 1st line - Linez/Dapto for pt Vanc-intol or Rx few days for uncomplic MRSA infxn

- Stevens-Johnson syndrome (bad rash widespread skin sloughing) * blood dyscrasias (Lg dose) - Thrombocytopenia

* Enterobacter in ICU

- Leukopenia - Hemolytic anemia, esp in pt w/ genetic deficiency of G-6-P dehydrogenase * hyperkalemia: trim acts as K+-sparing diuretic

* E. coli & Klebsiella Drugs * + in urine Rx uncomplicated UTI in healthy * Toxoplasmosis (prophylaxis in AIDS pt)

Therapeutic Uses

Adverse Effects/Toxicity

Effects lim to urine!

* urine brown

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

* Prolonged Rx:

- heptatitis

*uncomplicated UTIs

- neuropathies - pulm fibrosis

*safe in preg

(amox & cephalexin also safe for preg ) *Does NOT Rx: pyelonephritis or prostatitis (cannot penetrate tissue)

Therapeutic Uses

Adverse Effects/Toxicity

*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) Exacerbated by other nephrotox drugs Renal wasting of K+ & Mg++ No permanent renal damage in pts w/ norm renal func before Rx 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-

Lipid Ampho B: - Enclosed in liposome

- Same MOA

- Still toxic but delayed

- $$$$$$$$$$$$$$

*oropharyngeal/esophageal Candida (thrush):

 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

, Pityrosporum orbiculare ( tinea versicolor)

Therapeutic Uses

Mechanism of Resistance

* very actv against C. albicans

* weakness: narrow spectrum

1. Mut of binding to demythylase

- Not C. crusei - No anti-mold activity - Not Aspergillus, etc.

Lanoesterol can still bind but azoles cannot.

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

C. crusei resist fluconazole but not vorcionazole

*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

- pregnant - diabetes mellitus (DM)

symptoms:
- vaginal d/c

- pruritus (severe itching) - discomfort/pain during sex - 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 azole topical (or terbinaf)

gi , Pityrosporum orbiculare ( tinea versicolor)

Therapeutic Uses Mechanism of Resistance

harmacological Effects

* Candida vulvovaginitis (CVV) 200 mg suppository (3

d, bedtime) (see flucon)

* Candida vulvovaginitis (CVV) 200 mg suppository (3

d, bedtime) (see flucon)

*oropharyngeal/esopha geal Candida (thrush):

Neonates, children, 90% of HIV pts, asthmatics using ICS swish & swallow oral suspension (3-4 d & qod x 2 wks) Oral troche replaced nystatin b/c better taste

1. Mut of binding to demythylase

Lanoesterol can still bind but azoles cannot.

Tastes > nystatin

* Candida vulvovaginitis (CVV)

200 mg suppository (3 d, bedtime) 500 mg vaginal tablet (1 d, bedtime) (see flucon)

C. crusei resist fluconazole but not vorcionazole

***DOC: systemic Aspergillus infxns (Voricon > ampho B)

p.o. w/o dose adjustment

*Fusarium spp. (pt needs WBCs!) *Scedosporium apiospermum *Candida (incl C. crusei . Otherwise use flucon, cheaper) Not effectv against C. glabrata? Covers voricon + zygomycetes

Adverse Effects/Toxicity

Mechanism of Resistance

~None No cross-resistance w/ azoles

*well tolerated w/ excellent pharmokinetics

*few drug-drug interactions b/c it does NOT induce or inhibit CYP450

Therapeutic Uses

Adverse Effects/Toxicity

* narrow spectrum: - Cryptococcus neoformans - some Candida

* bone marrow suppression - leukopenia - thrombocytopenia (GI bact convert 5-FC 5FU)

* 5-FC + ampho B or itracon in selected fungal infections *Beware impaired renal func

Therapeutic Uses

**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

toenails: qd x 12 wks but S/E 2x > Risk factors: - age - - Nail trauma - Tina pedis - Poor hygiene * Athletes foot & jock itch : topical (or azole )

- Diabetes mellitus - Periph vascular Dz - Immunosuppression - Chronic exposure of nails to H2O Candida infxn

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

* Preg : category B

***DOC: Covers all tineas

(tinea capitus : ringworm of scalp & hair b/c Trichophyton invades hair shaft & follicle)

griseo use b/c replaced by terbinafine & itracon

* MET fungi * P. orbiculare

Mechanism of Action

Pharmacological Effects

Kills directly!!!

*safe for children

*pregnancy category B (but avoid during 1st trimester)

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

Aerobic organisms do NOT produce the toxic metabolite from the prodrug metronidazole

Mechanism of Action

Therapeutic Uses

Giardiasis (Giardia lamblia ) = beaver fever, campers fev

errodoxin oxidoreductase-dep e transfer rxn, reqd for anaerobic

Cryptosporidiosis (Cryptosporidium spp. )

***DOC: Cryptospoidiosis in AIDS pts combo w/ paromomycin & azithromycin

enzymatic steps in folate synth in Plasmodium spp. **DOC: Toxoplasmosis (Toxoplasma gondii) in immunocompetent pt

e reductase

ate synthetase 2nd line for: Pneumocystis jiroveci (PCP) Fungus but anti-protozoal drugs work (trim/sulfa is DOC) Pentam less efficacious & more toxic

Therapeutic Uses

Adverse Effects/Toxicity

* Kills erythrocytic/RBC stage:

1. P. vivax*

2. P. ovale*

3. P. malariae (cure)

4. Senstv strains of P. falciparum (cure)

* No effect on exoerythrocytic (hepatic) stage

* Prophylaxis in Chloriqsenstv areas:

Rx 2 wk before travel & continue 4 wk after leaving

 Safe in children

*frequent (~difficult to disting fr early stage of Plasmodium fxn): *~ Only drug able to suppress & cure infxns by MDR P. falciparum * Prophylaxis in Chloriqresistant areas: Rx 2 wk before travel & continue 4 wk after leaving Safe in children
- n/v - diarrhea - abdominal pain - dizziness - dysphoria

*50% of pts (~ mild & selflim):

- ataxia - headache - visual/auditory hallucinations - dizziness

*rare :
- disorientation - seizures

- neurotic/psychotic Sx

Therapeutic Uses

Adverse Effects/Toxicity

*Rx ALL Plasmodium

*pts w/ genetic deficiency of G-6-P dehydrogenase (~Mediterannean/Asian):

 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*Normal pts: P dehydrogenase prior to methemoglobinemia primaq Rx *Avoid in preg : fetus doesnt have well developed G-6-P dehydrogenase

*Prophylaxis in Chloriqresistant areas: Rx 2 wk before travel & continue 4 wk after leaving Safe in children

*Rx of drug-resistant P. falciparum

*Prophylaxis in Chloriqresistant areas:

Rx 2 wk before travel & continue 4 wk after leaving

Best tolerated

* active vs all erythrocytic Plasmodium * MDR malaria

Adverse Effects/Toxicity

*abdominal pain *reversible alopecia

*eased LFT ( AST & ALT)

Adverse Effects/Toxicity

Therapeutic Uses

Adverse Effects/Toxicity

Therapeutic Uses

Adverse Effects/Toxicity

Influenza A & B!

duration/severity of Sx by 1 d

 Rx NOT incidence of complications

Avian H5N1 still ~susceptible to neuraminidase inhibitors

Therapeutic Uses

Adverse Effects/Toxicity

* herpes keratitis

VZV )
Therapeutic Uses Adverse Effects/Toxicity

* fever blister: Rx ASAP * 1o or recurrent genital HSV * suppressive Rx for recurrent genital HSV * N/V

* HSV proctitis

* diarrhea

* herpes zoster (VZV) * prophylaxis of CMV retinitis * headache in pts w/ transplanted organs

* b/c inhb DNA synth NOT effectv against nonreplicating, latent viruses

* HSV & VZV strains resistant to acyclovir

* CMV strains resistant to ganciclovir & cidofovir

Therapeutic Uses

Adverse Effects/Toxicity

* CMV

* CMV

* CMV

* HSV & VZV strains resistant to acyclovir

* CMV strains resistant to ganciclovir & cidofovir

* CMV

Pharmacological Effects

Therapeutic Uses

Goals of therapy:

1. Suppress viral RNA load to below undetectable values (< 50 copies/ml) for as long as possible

2. Restore & maintain immune func

* high viral loads despite contd Rx w/ other drugs

3. Prevent development of resistance to antiviral drugs

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

CD4 count < 200 cells/mm3 Viral load >55,000 copies/ml

CCR5-tropic pts (HIV tropism test needed prior) * Efficacy of Rx determ by viral load

one log in 2-8wks

Combo: (TZV)

Not detectable (<50 copies/ml) after 4-6 months

Abacavir + lamivudine + zidovudine

*** HAART *** 1. NNRTI-based (preferred)

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

or

Often effectv when HIV resistant to NRTIs

2. PI-based

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

*Used w/ NRTI b/c diff MOA

or

3. NRTI based regimen Not effect if viral load >100,000) Abacavir + lamivudine + zidovudine (Trizivir)

*Many CYP450 interactions

MDR HIV infxns

* affects CYP450 multiple drug interactions

* riton = substrate & inhbtr of CYP3A4 (& CYP450)

* riton as pharmaco-kinetic enhancer inhb CYP450 hepatic clear of lopin daily maintn dose

CTERICIDAL (dividing bacilli)

Therapeutic Uses Adverse Effects/Toxicity

harmacological Effects

pyridoxine (Vit B6)

*1st obligatory drug for Rx *metabolized by hepatic N-acetylation TB

s where B6 is a cofactor *NEVER used alone to Rx active TB b/c rapid *slow acetylator pt thought to be at risk for development of neuro- & hepatotoxicity resistance

neuropathy by B6 deficiency

*Healthy people PPD(+) & *hepatotoxicity CXR(-): (Not active TB) INH single agent Rx b/c pt immun systm inhb growth of bact (esp if seroconvernsion w/in previous 2 yrs) w/o Rx: ~5-15% lifetime risk of developing TB disease - Lower risk in younger adults

- ETOH hepatotox by INH

- 20% pt 3-4x AST & AGT but NOT necess to stop Rx

- ~1% pt severe hepatitis (jaundice, upper rt quad pain, n/v) STOP Rx else death

*If pt 35 y.o. & serconversion date unknown: do NOT use INH.

Use Rifampin instead

*neurotoxicity

- INH = struct sim to pyridoxine (Vit B6 )

- INH antagonizes rxns where B6 is a cofactor

- Periph neuropathy (axonal sensorimotor polyneuropathy ) neuropathy by B6 deficiency

- ~preceded by paresthesias of hands & feet

- Rx: daily dose of B6 prevents & reverses neuropathy

*Rifampin + INH: preg category C Benefit should > risk to fetus

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

Pharm Effects

Therapeutic Uses

*2nd obligatory drug for Rx TB

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

*TB prophylaxis: alternative to INH

*Drug regimens w/ rifampin clear mycobact fr sputum ~2wks faster than regiments w/o rifampin

*Can elim meningococcal carrier state *MRSA *PCN-resistant strep pneumo *Replacement for rifampin in HIV pts (b/c only 50% of CYP induction caused by rifampin)

*Also Rx M. avium (MAC)

*NEVER used alone to Rx active TB b/c rapid dev of resistance *Used as 3rd drug w/ INH & Rifampin *50% resist INH-Rifampin also resistant to PZA

cellular bacilli in macrophages

Pharm Effects

Therapeutic Uses

Adverse Effects/Toxicity

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

- poss serious retrobulbar neuritis impaired vision abnormal red/green vision *Used as 4th drug w/ INHRifamp-PZA - Must obtain a basal vision exam before Rx

- Visual exam q4-6 wks recommended *~80% resist INHRifampin also resistant to EMB *No clin significant drug interactions *Also Rx M. avium (MAC) Streptomycin-resist TB poss susceptible to Amikacin (see AGs)

*greater vestibular toxicity than the other AGs vertigo loss of balance *Given i.m. or i.v. Rx: 1. mycobact meningitis 2. mycobact disseminated infxn *less auditory toxicity than the other AGs

*less renal toxicity than the other AGs *~80% resist INHRifampin also resistant to streptomycin *sometimes replaces EMB in TB combo Rx: INHRifamp-PZA

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 bacilli: Twice/wkly R-I-P-E but

INH dose & PZA-EMB

Weeks 9-26: Twice/wkly INH & Rifampin

Anaerobic Coverage Good

Cefoxitin Cefotetan

his class Good Good

Bactericidal by generation.

Bactericidal by generation.
Pharm Effects Therapeutic Uses

ceftriaxone-resis strep pnuemo & MRSA NOT for enterococcus

Pseudomonas 3 rd generation Excellent G() Moderate G(+)

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

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

Cefotaxime & ceftriaxone: Good G(+) actvy despite 3rd gen

Meningitis (strep pneumo & Neisseria) Strep: strep pn meng & - hemolytic strep CAP (H flu, strep pneumo & Moraxella), add ML (e.g. azithromycin) for atypical bugs

**DOC: strep pneumo , effctv against PCN G-resist strep pneumo &

Cefotaxime Ceftriaxone

_ _

Comm Acq Meningitis (H flu, Neisseria & strep pneumo) Single large i.m. dose for gonorrhea

(cervical, urethral, o

UTI by E. Coli
Pedi/adult UTI

1 p.o. dose for uncomplicated gonorrhea Otitis media: After 2 fails w/ amox or amox/clav 4 th generation 1st + 3rd = 4th gen Excellent G() Moderate G(+) > ceftazidime Pseudo. aeruginosa & inpt strep pneumo G() meningitis (good CNS penetration) Febrile neutropenic pt Critically ill pts (ICU) polymicrobial infxns & unknown infxns

Mechanism of Action

Pharmacological Effects

Moderately broad spectrum Moderate G(+) - 65% S. aureus suscept - Strep (but not GBS) - Avoid use in serious SSTI but can be used for community-acq MRSA Moderate G() - do NOT use for infxns - G(-) > macrolides

ome block aminoacyl tRNA access to A site of 30S

d bid

- Good for outpt G(-) infxns Good INTRACELLULAR Mycoplasma, Chlamydia, Rickettsia Lyme Disease (Borrelia burgdorferi) Relapsing fever (Borrelia recurrentis) Plague (Yersinia pestis) Malaria (Entamoeba histolytica & Plastmodium falciparum)

unc tests (LFTs )

chanism of Action

Pharmacological Effects

Eryth pads topically Rx acne

ansferase site (P site)

to peptide chain does not move from A site

ein synth stops

-----------------ep pneumo

Chlamydia

***DOC: atypical outpt CAP

b/c intracellular [ ] azith > clarith = eryth **DOC: Cryptosporidiosis in AIDS pt Combo Rx w/ paromomycin Azith NOT good for extracellular pathogens

**DOC: outpt CAP b/c hi intracellular (atypical) & extracellular (typical) drug [ ] (& low risk of MDR strep do not need to use FQ)

Pharmacological Effects

spectrum b/c overuse Good G()

* Pseudomonas : 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 Anaerobes moxi > levo = cipro

But use metronidazole or pip/tazo instead of FQ

 Good Intracellular! (e.g. atypical CAP)

Pharmacological Effects

***DOC: MDR strep pneumo spectrum b/c overuse ***DOC: inpt Rx CAP

Good G()

*** 1st line: Rx inpt CAP Alt (clarith) *** 1st line: outpt complicate

gene tsc & DNA replication * Pseudomonas : FQ only p.o. Rx for pseudo. antacids cations GI levo = cipro > moxi = gemi Need culture for senstvy & need add pip/tazo

- urinary tract w/ func & struct

ghter cells

- , preg , children & hospitlz

- Upper urinary tract affected ( - Bact more likely resist

* Diarrhea: shigella, E. Coli, sal * MDR TB

oxi absorb Limited G(+) moxi = gemi > levo > cipro

Anaerobes moxi > levo = cipro

But use metronidazole or pip/tazo instead of FQ Good Intracellular! (e.g. atypical CAP)

***DOC: MDR strep pneumo ***DOC: inpt Rx CAP *** 1st line: Rx inpt CAP Alt (clarith) *Systemic infxns: Salmonella ( * Diarrhea: shigella, E. Coli, salmo * Avoid for UTI b/c p.o. onl * greatest actvy vs TB

Mechanism of Action

Pharmacological Effect

Irrev inhb of prot synth

Seldom used ALONE!!!

but BACTERICIDAL [ ]-dep & post-ABX effect Cp rate & effic of killing large doses, less often

~ Always combo w/ cell wall synth inhbtr

Synergy: PCNs, cephs , & Vanc inhb cell wall synth penetrate G(-) cell

* 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 O2 tension (anaerobic cond) or low extracellular pH cell wall Xport
+

Broad G(-) spectrum (incl enteric bact bactericidal

Will cover G(+) if in combo w/ an inhi synthesis G(-) = high doses

Bind to 30S bact 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

- Add another drug class (e.g. gent + G(+) = low doses

- Never AG alone! Add low dose -lact

- Rx: endocarditis (staph, strep or ente

Therapeuti c Uses

Adverse Effects/Toxicity

*common: *Anaero bic bacteria :

- n/v

 Bac ter oid es fra gili s Clo stri diu m diff icil e

- dizziness

- headache

- metallic taste

- dysguesia

**DOC: Trichom oniasis (cure 8090%) : p.o. & topical : p.o.

- xerostomia (dry mouth)

- abdominal pain

**DOC: Giardiasi *uncommon: s (children & adults) Beaver fever, campers fever

- leukopenia

- urticaria

**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)

- vaginal candidiasis

- peripheral neuropathy,

- pancreatitis

- ataxia - seizure

*Monitor CBC & LFT w/ prolonged Rx of chronic recurrent trichomoniasis *Avoid 1st trimester of pregnancy *Drug interactions: bleeding w/ warfarin Ingestion of ETOH - n/v - abdominal pain - flushing (disulfiram-like rxn)

Disulfiram inhb acetaldehyde dehydrogenase (ADH) acetaldehyde accum in blood

eutic Uses

Adverse Mechanism Effects/Tox of icity Resistance

beaver fever, campers fever

S/E ab pain diarrhea headache nausea

idium spp. )

AIDS pts

ithromycin

plasma gondii) in

veci (PCP)

ugs work

ore toxic

Mechanism of Resistance

*No cross resistance w/ other antiretrovi ral classes

pt can have dual/mixe d CXCR4tropic HIV

*Some cross resistanc e in this class b/c each drug has slightly diff MOA

each drug has slightly diff MOA

*Resistan ce quickly develops w/ monothe rapy b/c these drugs have same MOA

*Resistan ce to one = resistanc e to all

oxicity

etylation

to be at risk for

ults

& AGT but NOT

is (jaundice, upper rt else death

oxine (Vit B6 )

ere B6 is a cofactor

nal sensorimotor athy by B6 deficiency

as of hands & feet

revents & reverses

gory C Benefit

monitor

Adverse Effects/Toxicity

*Drug interactions (many drugs): Strong inducer of CYP450 Enhances hepatic clearance of HIV drugs (NNRTIs & protease inhibitors) *turn ORANGE (annoying but harmless):
- Urine - Skin - Saliva

- Tears

- Skin

*Flu-like syndrome

*Hepatitis: LFTs are the norm but disappear w/ continued Rx *Rifampin + INH: preg category C Benefit should > risk to fetus

*50% CYP450 induction of Rifampin Enhances hepatic clearance of HIV drugs (NNRTIs & protease inhibitors) *harmless yellow discoloration of the skin *polymyalgias *uveitis *N/V *hepatoxicity (15%) *No clin significant drug interactions

ects/Toxicity

neuritis impaired vision &

n exam before Rx

commended

actions

an the other AGs vertigo &

e other AGs

ther AGs

T)

Chemopro phylaxis Seroconve rsion (w/in 2 yrs): 300 mg INH daily for 9 months 50% probabilit y of developin g active TB Avoid ETOH b/c risk of hepatotox .

e detected:

al

ear (-) for bacilli:

Therapeutic Uses

Adverse Effects/Toxicity

emo & MRSA *cross-reactv in pts w/ PCN allergy cross-reactv w/ later gens 1st (5-10%) 3rd/4th (1-2%)

*thrombophlebitis: (uncommon) poss esp w/ i.v. p ceftoxitin *superinfections esp w/ broader spectrum cephs

AG, gent)

eumo CAP)

*prolonged PT bleeding (rare, assocd w/ cefotet b/c cephs inhb Vit K epoxide reductase

(regens reduced Vit K for synth of clot factors 2, 7, 9

inst PCN G-resist strep pneumo & potent (low MIC)

Neisseria)

molytic strep Moraxella), typical bugs

, Neisseria & strep pneumo) (cervical, urethral, orophryg, rectal)

norrhea

gonorrhea

mox or amox/clav

strep pneumo penetration)

nown infxns

gical Effects

Therapeutic Uses

**DOC: Rickettsia infxns Covers 95% of MRSA CAP (esp doxy) Cheap & effectv Rx
Typicals (extracellular) - Strep pneumo - H flu - Moraxella catarrhalis

Do NOT give p.o. with:

- milk - Mg++ - MulVit - Al++ - Ca++ - Fe++

sed for community-acq MRSA

b/c drugs chelate cations pr GI problems (common)

- N/V

Atypicals (intracellular)

- Epigastric distress

- Mycoplasma pneumo - Chlamydia - Legionella

- Ab cramping - Diarrhea

GI probs if take w/ food (bu Tetracyclines bind to Ca++

alciparum)

Very effectv against Chlamydia & Mycoplasma pneumo Rx: acne (esp Mino) Doxycyline________ **DOC: pt w/ renal dysfunc b/c elim by fecal excretion Minocycline_________ Partially metab by liver MRSA & Actinobacter

- newly-forming teeth discol - newly forming bone deform

Photosensitization: sunbu Hepatotoxic (large doses) Nephrotoxic (unlikely)

Superinfections: b/c suppr

- Disturbed GI func - Oral, anal, vaginal candidiasis

- C. diff pseudomembranous co

Therapeutic Uses

***DOC: atypical CAP

b/c excellent intracellular [ ] azith > clarith = eryth

Gold standard: Legionella Excellent for intracellular bugs, e.g. - Mycobact. avium - (NOT TB) - 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

extracellular (typical) drug [ ]

ffects

Therapeutic Uses

Adverse Effects/Toxicity

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

Damage growing cartilage (tho short term ~ ok for kids) Tendon rupture Q-T elongation: - pt w/ congenital prolonged Q-T - pt on other drugs that Q-T (sotalol, amiodarone) Slow K+-medtd repolzn prolong Q-T polymorphic vent. tachy (torsade de pointes)

d add pip/tazo

*Diarrhea: shigella, E. Coli, salmonella & Ciprofloxacin_______ campylobacter Many CYP450 drug interactions (incl inhb of caffeine *MDR TB metab) *Also Rx M. avium (MAC) Phototoxicity Gemifloxacin_______ 50% pt develop rash after 7 days

tazo instead of FQ

Therapeutic Uses

Adverse Effects/Toxicity

***DOC: MDR strep pneumo ***DOC: inpt Rx CAP *** 1st line: Rx inpt CAP Alt Rx: ceph (ceftriaxone, cefotaxime) + ML (clarith) *** 1st line: outpt complicated UTIs
- urinary tract w/ func & struct abnorm, (e.g. calculi or catheter) - , preg , children & hospitlzd pts - Upper urinary tract affected (pyelonephritis) - Bact more likely resist

Damage to growing cartilage (tho short term ~ Tendon rupture Q-T elongation: - pt w/ congenital prolonged Q-T

- pt on other drugs that Q-T (sotalol, amiodaro

Slows K+-medtd repolzn prolong Q-T polymor tachy (torsade de pointes) Levo & moxi low risk unless factors ( GFR or elect imbalance)

* Diarrhea: shigella, E. Coli, salmonella & campylobacter * MDR TB

***DOC: MDR strep pneumo ***DOC: inpt Rx CAP *** 1st line: Rx inpt CAP Alt Rx: ceph (ceftriaxone, cefotaxime) + ML (clarith) *Systemic infxns: Salmonella (some resist b/c Rx chickens) * Diarrhea: shigella, E. Coli, salmonella & campylobacter * Avoid for UTI b/c p.o. only sm drug amt in urine * greatest actvy vs TB

Pharmacological Effects

Therapeutic Uses

Adverse Effe

sed ALONE!!!

1 against extracellular bacilli

Poss Very Toxic!

combo w/ cell wall synth inhbtr *TB (see TB drugs)

time & [ ] dep!

Longer CP > some critical value likel

*Nephrotoxicity: (reversible) Prolonged R

Damage to proximal tubules (regenerate w/ [creatinine]plasma

hs , & Vanc inhb cell wall synth easier for AG to G(-) cell

Co-Rx w/ other nephrotox drugs (Vanc, Amp nephrotox

G(-) spectrum (incl enteric bact) & rapidly dal

*Ototoxicity: (reversible) Auditory hea

ver G(+) if in combo w/ an inhibitor of cell wall s

Vestibular ataxia, vertigo & loss of balanc

high doses

S/E when *AG+p 5 days large doses q12

nother drug class (e.g. gent + -lactam)

low doses AG alone! Add low dose -lactam or Vanc

docarditis (staph, strep or enterococcus)

Given p.o. prior to surgery Renal dysfunction risk decontaminate gut Soley renal elim: dose in pt Furosemide (Rx: urinary output in pt w/ re w/ renal failure Widely used in antibacterial *Can avoid nephrotox & ototox by monit ear drops, eye drops & ointments * Neuromuscular blockade esp when coEsp for Pseudo. blocking agents in OR/ICU Ace in the hole for bact resistant to gent & tobra

Adverse Effects/Toxicity

Mechanism of Resistance

w/ PCN allergy w/ later gens

(same as PCN) 1. PBP site! 2. Bugs begin to make cephalosporinases

uncommon) poss esp w/ i.v. push

w/ broader spectrum cephs

eeding (rare, assocd w/ cefotetan) epoxide reductase

K for synth of clot factors 2, 7, 9, 10)

Adverse Effects/Toxicity

Mechanism of Resistance

Do NOT give p.o. with:

- milk - Mg++ - MulVit - Al++ - Ca++ - Fe++

1. Mut protects binding site 2. Pump efflux (tho Doxy may still work)

b/c drugs chelate cations prevent drub absorb fr GI tract -------------------------- GI problems (common)
- N/V

- Epigastric distress

- Ab cramping - Diarrhea

Widespread use in livestock food resistance of Enterococci

GI probs if take w/ food (but cations can absorb) Tetracyclines bind to Ca++
- newly-forming teeth discoloration - newly forming bone deformity

Photosensitization: sunburn esp in fair people Hepatotoxic (large doses) Nephrotoxic (unlikely) Superinfections: b/c suppress fecal coliforms (C. diff & Candida grow)
- Disturbed GI func - Oral, anal, vaginal candidiasis

- C. diff pseudomembranous colitis (Rx: metronidazole)

Adverse Effects/Toxicity

Mechanism of Resistance

Stim gastric motilin receptors upset GI & cramping Cholesterol jaundice (rare) Drug interactions Inhb CYP450 prevents hepatic metab of other drugs

No cross resist w/tetracyclines 1. Ribosomal protection Binding site modified by bact methylase

2. Efflux pumps

NOT good for staph & strep SSTIs b/c 60% staph resist Large dose (2g) stim gastric motilin receptorrs emesis

Do NOT use lg dose to Rx gonorrhea! Drug interactions Least CYP450 < clarith

GI upset & metallic taste (10-20%) Drug interactions Fewer CYP450 < eryth
Mechanism of Resistance

ects/Toxicity

(tho short term ~ ok for kids)

*Mut change binding site on bact Topo 50% Pseudo resist cipro

ed Q-T Enterococcus (esp VRE) Enterobacter, Klebsiella & E. coli ~ soon resistant

Q-T (sotalol, amiodarone) ong Q-T polymorphic vent.

tions (incl inhb of caffeine

NOT to Rx SSTI. Do NOT use FQ for MRSA!!! Instead: - p.o. Clinda, trim/sulfa, doxy - i.v. Vanc (serious) Nursing home: strep pneumo resistant Do NOT use FQ! Rx like nosocomial w/ antipseudo/strep -lactam (pip/tazo or cefepime). Critically ill pt add AG ( gent) or antipseudo FQ (beware resist)

7 days

*Still effectv for outpt UTI (E. coli) tho some strains resist FQ still suscept to amox

Adverse Effects/Toxicity

Mechanism of Resistance

ing cartilage (tho short term ~ ok for kids) * Mut change binding site on bact Topo

Enterococcus (esp VRE) Enterobacter, Klebsiella & E. coli ~ soon resistant

prolonged Q-T that Q-T (sotalol, amiodarone)

olzn prolong Q-T polymorphic vent. NOT to Rx SSTI. intes) unless factors ( GFR or electrolyte Do NOT use FQ for MRSA!!! Instead: - p.o. Clinda, trim/sulfa, doxy - i.v. Vanc (serious)

* Nursing home: strep pneumo resistant Do NOT use FQ! Rx like nosocomial w/ antipseudo/strep -lactam (pip/tazo or cefepime). Critically ill pt add AG ( gent) or antipseudo FQ (beware resist) * Still effectv for outpt UTI (E. coli) tho some strains resist FQ still suscept to amox

Adverse Effects/Toxicity

Mech of Resistance

Toxic! 1. Bact transferase enz (most common) inactv AG by adding a phosphate, adenyl, or acetyl group to the drug 2. drug transport into cell mut alter struct of porins/ transport proteins which pump AG across cell wall

dep!

> some critical value likelihood of toxicity

oxicity: (reversible) Prolonged Rx (2 wks)

proximal tubules (regenerate w/ time) (reversible) renal func ]plasma

ther nephrotox drugs (Vanc, Ampho B, cyclocporine, & NSAIDs) risk of

Pseudomonas: 40 diff efflux pumps

ity: (reversible) Auditory hearing loss & tinnitus 3. binding site on 30S subunit

ataxia, vertigo & loss of balance (esp gent)

*AG+p 5 days large doses q12 or q24 instead of const i.v. infusion

unction risk

e (Rx: urinary output in pt w/ renal impair) also toxic to CN VIII

d nephrotox & ototox by monitor [gent]P

uscular blockade esp when co-admin w/ conventional neuromusc gents in OR/ICU