PHARM_MSII_MOA_BUG_DRUGS

COVALENTLY BIND TO THE ENZYMATIC SITE OF PENICILLIN-BINDING PROTEIN (A TRANSPEPTIDASE)

-->PRODUCE AN IRREVERSIBLE INHIBITION OF PEPTIDOGLYCAN TRANSPEPTIDASE

-->THUS PREVENT PEPTIDOGLYCAN (CELL WALL) SYNTHESIS

• BACTERIOSTATIC
• ---------

ERYTHRO

CLARITHRO

&

AZITHROMYCIN

SAME AS THE PENs

SAME AS THE PENICILLANS

SAME AS THE PCNs

BROADER SPECTRUM THAN PCN

• GOOD CNS PENETRATION WITH
• --*CEFTAZIDIME
• --*CEFTRIAXONE
• --*CEFOTAXIME
• --^CEFEPIME

• *3rd GEN
• ^4th GEN

COVALENTLY BINDS TO THE D-ALA-D-ALA TERMINUS OF THE PEPTIDE SIDE CHAIN:

• THIS BINDING PREVENTS THE BINDING OF THE D-ALA-D-ALA TERMINUS TO THE
• ENZYMATIC SITE OF PEPTIDOGLYCAN TRANSPEPTIDASE.

CELL WALL SYNTHESIS IS INHIBITED

INHIBITS CELL WALL SYNTHESIS IN THE SAME WAY AS DOES VANCOMYCIN + RAPIDLY DEPOLARIZES THE BACTERIAL PLASMA MEMBRANE, THUS INCREASING PERMEABILITY AND CAUSING DEATH

BINDING TO THE A SITE OF THE 30S SUBUNIT OF THE BACTERIAL RIBOSOME

PREVENTS THE BINDING OF THE AMINOACYL TRNA:

PROTEIN SYNTHESIS IS INHIBITED

BINDING TO THE 50S SUBUNIT OF THE BACTERIAL RIBOSOME

INHIBITS TRANSLOCATION OF THE MOST RECENTLY ADDED AMINO ACID FROM THE A SITE TO THE P SITE:

PROTEIN SYNTHESIS IS INHIBITED

THE SAME AS THE MACROLIDES

BINDING TO THE 50S SUBUNIT OF THE BACTERIAL RIBOSOME

INHIBITS TRANSLOCATION OF THE MOST RECENTLY ADDED AMINO ACID FROM THE A SITE TO THE P SITE:

PROTEIN SYNTHESIS IS INHIBITED

INHIBITION OF TOPOISOMERASES II (DNA GYRASE) AND IV

• TOPO II INH:
• PREVENTS THE RELAXATION OF (+) SUPERCOILED DNA NEEDED FOR REPLICATION

• IV INH:
• SEPARATION OF REPLICATED CHROMOSOMAL DNA REQUIRED FOR CELL
• DIVISION

BIND TO 30S SUBUNIT TO BLOCK FORMATION OF THE INITIATION COMPLEX,

CAUSE MISREADING OF MRNA AND BREAK POLYSOMES INTO NON-FUNCTIONAL MONOSOMES.

BLOCKS PROT SYNTH

BINDING TO A SITE ON THE 23S RIBOSOMAL RNA OF THE 50S SUBUNIT

• BLOCKS THE ASSEMBLY OF
• THE 70 S BACTERIAL RIBOSOMAL COMPLEX

CAN'T INITIATE PROTEIN SYNTHESIS

DRUG OF LAST RESORT FOR G+ (MRSA, VRE)

"ZAP-TOMYCIN"

BINDING TO BACTERIAL MEMBRANES CAUSES DEPLOARIZATION,

• LOSS OF MEMBRANE POTENTIAL AND
• CELL DEATH

MRSA & VRE

INH RNA SYNTHESIS BY INH BAC RNA POLYMERASE

NARROW SPECTRUM C. DIFF

OTHER G+ BAC INCLUDING CLOS spp

SULFAMETHOXAZOLE INH DIHYDROPTEROATE SYNTHETASE,

SULFAMETHOXAZOLE TRIMETHOPRIM BLOCKS DIHYDROFOLATE REDUCTASE:

THE SYNTHESIS OF TETRAHYDROFOLATE IS BLOCKED

SULFADIAZINE INH DIHYDROPTEROATE SYNTHETASE, AND

• - SULFADIAZINE PYRIMETHAMINE BLOCKS
• DIHYDROFOLATE REDUCTASE: THE SYNTH OF TETRAHYDROFOLATE IS
• BLOCKED

• BACTERIAL ENZYMES REDUCE NITROFURANTOIN TO A HIGHLY-REACTIVE
• INTERMEDIATE

-->DAMAGES BACTERIAL DNA CAUSING CELL DEATH

UTIs (e.coli)

Tx TB -- INH CELL WALL SYNTH

• BIOACTIVATION BY MYCOBAC
• CATALASE-PEROXIDASE,

THE ACTIVE METABOLITE COVAL BINDS TO THE ACYL CARRIER PROTEIN AND THE b-KETOACYL CARRIER PROTEIN SYNTHETASE

• --> PREVENT THE SYNTH OF MYCOLIC
• ACID

• BINDING TO THE b-SUBUNIT OF BACTERIAL
• DNA-DEPENDENT RNA POL

POLYMERASE PREVENTS RNA SYNTHESIS

Tx TB

INTERFERES WITH THE SYNTHESIS OF MYCOLIC ACID

-->AFFECTING THE GENE FOR FATTY ACID SYNTHASE I

INH ARABINOSYL TRANSFERASE

PREVENT THE POLYMERIZATION OF ARABINOGLYCAN, AN ESSENTIAL COMPONENT OF THE MYCOBACTERIAL CELL WALL

BINDS TO 30S SUBUNIT TO IBLOCK FORMATION OF THE INITIATION COMPLEX

CAUSE MISREADING OF MRNA AND BREAK POLYSOMES INTO NON-FUNCTIONAL MONOSOMES.

BINDING TO ERGOSTEROL IN FUNGAL CELL MEMBRANES CREATES PORES

-->INC THE PERM OF THE CELL WALL: LOSS OF INTRACELLULAR MACROMOLs AND IONS CAUSES CELL DEATH

ANTI-FUNGAL

INHIBITION OF CYP450 LANOSTEROL 14a-DEMETHYLASE

BLOCKS THE SYNTHESIS OF ERGOSTEROL

ERGO -- CELL MEM OF FUNGI & YEAST. LIKE CHOLESTEROL OF ANIMALS

INHIBIT CELL WALL SYNTHESIS BY BLOCKING THE ENZYME 1,3-b-D-GLUCAN SYNTHETASE:

CALLED "PENICILLINS FOR FUNGI"

5-FC CONVERTED TO 5-FLUOROURACIL (5-FU) BY FUNGI;

5-FU CONVERTED TO FDUMP WHICH BLOCKS FUNGAL THYMIDYLATE SYNTHETASE;

LACK OF THYMIDINE PREVENTS DNA SYNTHESIS

FUNGISTATIC:

BINDS TO MICROTUBULES TO PREVENT FUNGAL MITOSIS

FUNGICIDAL:

BLOCK SQUALENE-2,3- EPOXIDASE TO BLOCK ERGOSTEROL SYNTHESIS

BLOCKS THE RELEASE OF NEW VIRAL PARTICLES FROM INFECTED CELLS

-->INH OF VIRAL NEURAMINIDASE

ALL ARE CONVERTED TO MONOPHOSPHATES BY HSV AND CMV KINASES

• HSV
• --ACYCLOVIR
• --PENCICLOVIR

• CMV
• --GANCICLOVIR

-->CONVERSION TO TRIPHOSPHATES BY HOST CELL KINASES:

TRIPHOSPHATES INHIBIT VIRAL DNA POLYMERASE

Tx CMV

ANTISENSE OLIGONUCLEOTIDE WHICH BINDS VIRAL MRNA

-->PREVENTS TRANSLATION

Tx HERPES KERATITIS

CONVERTED TO TRIFLURIDINE TRIPHOSPHATE BY HOST-CELL KINASES:

THE ACTIVE METABOLITE INH VIRAL DNA POLYMERASE

• Tx
• --HSV
• --HZV
• --CMV

DIRECTLY INHIBITS VIRAL DNA POLYMERASE

• CONVERTED TO TRIFLURIDINE TRIPHOSPHATE BY HOST-CELL
• KINASES:

-->ACTIVE METABOLITE INH VIRAL DNA POL

BLOCKS THE FUSION OF THE VIRAL AND T-CELL MEMBRANES

--> HIV CANNOT ENTER THE CD+4 CELL

HIV

BLOCKS FUSION OF VIRAL AND T-CELL MEMs BY BINDING TO CCR5 RECEPTOR OF THE T-CELL

Tx HIV

NRTIs - INH REVERSE TRANSCRIPTASE -- CHAIN TERMINATION BY BY NUCLEOSIDE INSERTION (HIV)

• AFTER CONVERSION TO "FALSE" NUCLEOTIDES (TRIPHOSPHATES) BY
• INTRACELLULAR KINASES

-->THESE "FALSE" NUCLEOTIDES COMPETITIVELY INH HIV REVERSE TRANSCRIPTASE AND THEIR INCORPORATION INTO DNA CHAIN

• -->CHAIN TERMINATION
• ------------------------

• ZIDOVUDINE
• --AZT = AZIDOTHYMIDINE
• --S/E BONE MARROW DEP AND ANEMIA

Tx HIV

NNRTIs -- DIRECTLY INHIBIT REVERSE TRANSCRIPTASE (HIV)

-->BLOCK RNA- AND DNA-DEPENDENT POLYMERASE

Tx HIV

BLOCKADE OF THE VIRAL INTEGRASE

-->PREVENTS THE INSERTION OF VIRAL DNA INTO HUMAN DNA

Tx HIV

BLOCKADE OF VIRAL PROTEASE

• -->PREVENTS THE CLEAVAGE OF VIRAL
• POLYPROTEINS INTO THE FUNCTIONAL SUBUNITS NEEDED TO
• ASSEMBLE NEW FUNCTIONAL, INF VIRAL PARTICLES

RITONAVIR INHIBITS CYP450 WHICH DEC HEPATIC CLEARANCE OF LOPINAVIR

PROTOZOAL AND BACTERIAL FERREDOXINS REDUCE THE NITRO GROUP

-->PRODUCE A HIGHLY-RECTIVE NITRO RADICAL WHICH ATTACKS DNA AND DESTROYS ITS HELICAL STRUCTURE;

ALSO CAUSES DNA MUTATIONS

ANTI-PROTOZOAL

CRYPTOSPORIDIOSIS

GIARDIA, BUT DOC IS METRONIDAZOLE

• INTERFERS WITH PYRUVATE:FERRODOXIN
• OXIDOREDUCTASE-DEPENDENT ELECTRON TRANSFER REACTION

MOA -- UNKNOWN

Tx Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii SEEN WITH HIV Pt.

ALSO Tx FOR stage I infection with Trypanosoma brucei gambiense

CIDAL EXCEPT ETHAMBUTOL

"PCC-Mon VIBE"

PCCM = b-LACs

• PEN
• CARBAPENEMS
• CEPHALOSPORINS
• MONOBACTAMS (aztreonam)
• VANCOMYCIN
• ISONIAZID
• ETHAMBUTOL (static)
• BACITRACIN

CIDAL

• FLUOROQUINOLONES (levofloxin)
• RIFAMPIN
• NITROFURANTOIN

CIDAL

POLYMIXIN b

COLISTIN (polymixin E)

INH PROT SYNTH = STATIC

"ACCLMaTe"

• AMINOGLYCOSIDES (exception - cidal)
• CLINDAMYCIN
• CHOLRAMPHENICOL
• LINEZOLID
• MACROLIDES (eryth)
• TETRACYCLINES

PROD PCNase (b-LACTAMASE) WHICH DEGRADES DRUG

OXACILLIN AND NAFCILLIN NOT DEGRADED (MSSA)

MRSA -- CHANGED BINDING SITE FOR b-LACTAM bc OF MUTATED BAC GENE

CEFTAROLINE ONLY DRUG THAT KILLS MRSA

HIGH MOLECULAR WEIGHT PBPs WITH DECREASED AFFINITY FOR b-LACs

"COCKROACH OF THE ICU"

VANC BINDS TO TERM D-ALA-D-ALA OF PEPTIDE SIDE CHAINS OF G+ CELL WALL

VRE HAS MUTATED D-ALA-D-LAC

RESISTANCE CARRIED BY PLASMID

G- BUGS LIKE PSEUDOMONAS AND ACINETOBACTER PUMP DRUGS OUT

PSEUDOMONAS MAY HAVE 20 PUMPS AND 3-4 b-LACs

ALSO, MUTATIONS IN PORINS (channels) MAY INHIBIT ENTRY OF CARBAPENEMS IN PSEUDOMONAS

STREP PNEUMO & STAPH AUREUS MAY PUMP OUT MACROLIDES

• STAPH
• --COAG+ AUREUS
• --COAG- EPIDERMIDIS, SAPRO, other

STREP PNEUMO & PYOGENES (A)

ENTEROCOCCUS FAECALIS -- #3 CAUSE OF UTI, MAY CAUSE ICU INFs

ENTEROCOCCUS FAECIUM -- ICU INF

NEISSERIA GONO

NEISSERIA MENINGITIDIS

MORAXELLA CATARRHALIS

MORAXELLA -- fastidious, nonmotile, Gram-negative, aerobic, oxidase-positive diplococcus that can cause infections of the respiratory system, middle ear, eye, central nervous system and joints of humans. GROWING IMPORTANCE DUE TO RESISTANCE

PEPTOCOCCUS

PEPTOSTREPTOCOCCUS

LISTERIA MONOCYTOGENES

• ENTERIC
• --E. COLI #1 UTI
• --KLEB PNEUMO #2 UTI
• --PROTEUS MIRABILIS - UTI
• --SALMONELLA
• --SHIGELLA
• --ENTEROBACTER - ICU
• --CITROBACTER - ICU

• CAP & ICU:
• --PSEUDOMONAS
• --H. FLU
• --LEGIONELLA
• --CAMPYLOBACTER
• --ACINETOBACTER BAUMANII
• --HELICOBACTER PYLORI

• --CLOS BOT
• --CLOS DIFF
• --CLOS TETANI
• --CLOS PERF

BACTEROIDES FRAGILIS

PENs

• IMIPENEM
• --RESISTANT TO b-LAC
• --METABOLIZED BY RENAL TUB DIHYDROPEPTIDASES

• CILASTATIN
• --INH RENAL PEPTIDASES TO DEC CLEARNACE OF IMIPENEM

CLAVULANATE

SULBACTAM

TAZOBACTAM (tazo)

--PROBENECID INH RENAL ACID TRANSPORT SYST --> INC T1/2

• DISTRIBUTION
• --GOOD IN ECF
• --NOT GOOD IN CSF, MORE PENETRATION IF MENINGES INFLAMED
• --POOR INTRACELLULAR; CANNOT USE FOR INTRACELLULAR BUGS

• ELIMINATION
• --RAPID RENAL TUBULAR SEC, PEN G T1/3 IS 30mins
• --PROBENECID INH RENAL ACID TRANSPORT SYST --> INC T1/2

• iv CEFAZOLIN - srgy prophyl, ssti mssr = oxa&naf
• *po CEPHALEXIN - ssti; safe for pregos
• *poCEPHRADINE

*WEAK

• *iv CEFOXITIN
• *iv CEFOTETAN
• ^po CEFUROXIME
• ^po CEFACLOR

• * only 2 cephamycins that cover anaerobes
• ^ tx pedi and fp outpatients

• iv CEFOTAXIME
• iv CETRIAXONE - can give im
• iv CEFTAZIDIME - kills pseudomonas
• po CEFPODOXIME - bitter; kids spit up
• po CEFDINIR - brick red feces in kids
• po CEFIXIME - not good for strep pneum or mssa

• ANTI-MRSA 3rd GEN
• --iv CEFTAROLINE
• covers ceftriaxone R strep pneumo also

iv CEFEPIME

INC RESISTANCE TO DEGRADATION BY b-LACs

GOOD PSEUDOMONAS COVERAGE

1st - BEST FOR G+

2nd - G+ AND SOME G- AND ANAEROBES (only cefoxitin & cefotetan)

3rd - INC G- AT EXPENSE OF G+ (mssa)

4th - MODERATE G+ AND EXCELLENT G- ACTIVITY. RESEMBLES 1ST + 3rd GEN (1+3=4)

• RESEMBLES THYMIDINE
• --IF RESISTANT TO ONE, ALSO THE OTHER

TOPICAL

TRIPHOSPHATE INH VIRAL DNA POL

Tx HSV KERATITIS

INFLU A AND RUBELLA

INH MEM COAT ION CHANNEL

ALLOWS ACID-MEDIATED DISSOCIATION OF RIBONUCLEOPROTEIN COMPLEX EARLY IN REPLICAITON

PROPHYLACTIC FOR INFLU A

Tx FLU

INH VIRAL NEURAMINIDASE

ANTIVIRAL

CAUSES PROT SYNTH

• 2,5 ADENINE SYNTHETASE
• --MAKES ADENYLATE OLIGOMERS
• --ACTIVATE RNAse TO DEGRADE VIRAL RNA

• PROT KINASE PHOSes EF2
• --INH PEPTIDE CHAIN INITIATION

• PDEase DEGRADES TERMINAL NUC OF tRNA
• --INH VIRAL PEPTIDE CHAIN ELONGATION

• NET EFFECTS
• --INTERFERES w VIRAL PNETRATION, UNCOATING, ASSEMBLE AND RELEASE
• --INH SYNTH OF VIRAL mRNA
• --INH TRANSLATION OF VIRAL mRNA