CELL WALL SYNTHESIS INHIBITORS Flashcards Preview

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Flashcards in CELL WALL SYNTHESIS INHIBITORS Deck (49):
1

Why do CW synthesis inhibitors work? 

-mammalian cells DO NOT have a cell well

--> these drugs require actively proliferating bacteria (CW synthesis must be occuring) in order for them to be effective

2

CELL WALL SYNTHESIS INHIBITORS

1) B-LACTAM ANTIBIOTICS = MP CC 

--> PENICILLINS, CEPHALOSPORINS, CARBAPENEMS, MONOBACTAMS

MISCELLANEOS:

1) VANCOMYCIN

2) DAPTOMYCIN

3) BACITRACIN

4) FOSFOMYCIN

 

3

PENICILLINS: B-LACTAM

B-LACTAM

-is widely effective, has little toxicity, but there has been to shown to be increasing levels of resistance 

-structure includes a B-lactam ring 

MOA: is BACTERICIDAL: --> inhibit the lAST STEP in peptidoglycan synthesis through binding to PBPs

Note: is INACTIVE against organisms w/o peptidoglycan CW (eg mycoplasma, protozoa, fungi, viruses)

4

PENICILLIN MOA

 

What are autolysins? 

-are BACTERICIDAL

--> inhibit last step in peptidoglycan synthesis through binding to PBPs

--> inactive against organisms w/o peptidoglycna CW

PBPs: 

--> are bacterial enzymes that get inactivated by penicillins

--> includes transpeptidases

--> number varies with type of organism

--> RESISTANCE CAN DEVELOP WITH PBP MUTATIONS

--> AUTOLYSIN PRODUCTION: is produced by bacteria and mediates cell lysis --> penicillins activate autolysins to initiate cell death --> BACTERIA EVENTUALLY LYSE D/T ACTIVITY OF AUTOLYSINS + INHIBITION OF CW ASSEMBLY!!! 

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PENICILLIN G

IS AN IM DRUG!!! (T1/2 = 3-4 weeks)

 

-Benzylpenicillin

• Active against:

• most Gram-positive cocci (not staph)
• Gram-positive rods (eg, Listeria, C.perfringens) • Gram-negative cocci (eg, Neisseria sp)
• most anaerobes (not bacteroides)

DOC FOR

1) SYPHILLIS (benzathine penicllin G)

2) STREP INFECTIONS (especially in prevention of rheumatic fever) 

3) SUSCEPTIBLE PNEUMOCOCCI

 

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PENICILLIN G PROCAINE

REPOSITORY PENICILLIN

IM, not IV (risk of procaine toxicity)

--> t1/2 = 12-24 hours

-is SELDOM USED (increased resistance) 

 

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PENICILLIN G BENZATHINE

-IM

-t1/2 = 3-4 weeks

DOC FOR

1) SYPHILLUS

2) RHEUMATIC FEVER PROPHYLAXIS

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PENICILLIN V

 

-similar antibacterial spectrum to Penicillin G (less active against Gram -ve bacteria)

-most are ACID STABLE than G (CAN GIVE ORALLY

DOC: for STREP THROAT

"like swallowing a sharp KniVe" when have strep throat --> give penicillin V 

--> employed mostly orally for mild-moderate infections eg) pharyngitis, tonsilitis, skin infectious (caused by Strep) 

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ANTISTAPHYLOCOCCAL PENICILLINS

"NOD" that you know what to do with the STaff" --> used for Staph endocarditis and patients with artificial valves

1) METHICILLIN --> only used in the lab now (not in humans)

2) NAFCILLIN

3) OXACILLIN

4) DICLOXACILLIN

they are ALL B-LACTAMASE RESISTANT (inactive against MRSA)

--> is restricted to treatment of B-lactamase-producing staphylocci

DOC for 

1) STAPH ENDOCARDITIS

2) PTS WITH ARTIFICIAL HEART VALVES

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EXTENDED SPECTRUM PENICILLINS

USE AMPS (blasting music, travels far) and AMO (can shoot far) for EXTENDED spectrum

1) AMPICILLIN:

2) AMOXICILLIN: has a HIGHER ORAL BIOAVAILABILITY than other penicillins (including ampicillin) 

--> is a common antibiotic prescribed for children and in pregancy 

 

-are both similar to penicilin G, but also ahve gram -ve activity

-susceptible to B-lactamases

-activity enhanced with B-lactamase inhibitor 

USES: 

1) ACUTE OTITIS MEDIA

2) STREP PHARYNGITIS

3) PNEUMONIA

4) SKIN INFECTIONS

5) UTIs, etc... 

6) WIDELY USED TO TREAT UPPER RESP INFECTIONS (H. influenza + Strep pneumonia)

7) AMOXICILLIN = STANDARD FOR ENDOCARDITIS PROPHYLAXIS during DENTAL/RESP TRACT PROCEDURES

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ENDOCARDITIS PROPHYLAXIS during DENTAL PROCEDURES

AMOXICILLIN

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TX OF ENTEROCOCCI + LISTERIA INFECTIONS

-AMPICILLIN is used in COMBO with AMINOGLYCOSIDES to treat 

1) ENTEROCOCCI

2) LISTERIA 

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ANTIPSEUDOMONAL PENICILLINS

she's eating grapes, so those are CARBS, she has a pet TIGER (dalmation), and the PIPERACILLIN piper player on the left

1) CARBENICILLIN

2) TICARCILLIN

3) PIPERACILLIN

-is effective against MANY gram -ve and gram +ve BACILLI

-is often combined with a B-LACTAMASE INHIBITOR

-is active against Pseudomonas Aeruginosa 

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1) CARBENICILLIN

2) TICARCILLIN

3) PIPERACILLIN

-commonly used to treat PSUEDOMONAS AERUGINOSA

-main clincial use = an INJECTABLE TREATMENT of GRAM -VEs

-Treatment of moderate-severe infections of susceptible organisms (eg, uncomplicated & complicated skin, gynecologic and intra-abdominal infections, febrile neutropenia)

15

 

EFFECTIVE EMPIRIC TX FOR INFECTIVE ENDOCARDITIS

PENICILLIN + AMINOGLYCOSIDE

are SYNERGISTIC

-penicillins facilitate the movement of aminoglycosides through cell wall

--> should never be placed in same IV (form inactive complex) 

--> is an EFFECTIVE EMPIRIC TX FOR INFECTIVE ENDOCARDITIS

 

16

PENICILLINS - RESISTANCE

-one of 4 general mechanisms (primary or acquired):

1) INACTIVATION by B-lactamase

2) MODIFICATION of TARGET PBPs

3) IMPAIRED PENETRATINO of drug to target PBPs

4) INCREASED EFFLUX

Note: MRSA --> have altered target PBPs (low affinity for B lactam antibiotics) 

17

PENICILLIN HALF LIFE AND ABSORPTION

Half-life

~30-60 min (except repository penicillins)

Oral absorption

• Absorption impaired by food

-EXCEPTIONS: amoxicillin --> high oral bioavailability)

Nafcillin = erratic (not suitable for oral admin.)

18

PENICILLINS = DISTRIBUTION

• All achieve therapeutic levels in pleural, pericardial, peritoneal, synovial fluids & urine

Nafcillin, ampicillin & piperacillin achieve high levels in bile, (PAN = high in the bile)

• Levels in prostate & eye = insufficient***


• CSF penetration = poor (except in meningitis)

19

PENICILLIN - ADVERSE EFFECTS:

 

1) HYPERSENSITIVITY: penicilloic acid = major antigenic determinant 

--> ~5% of patients claim to have some reaction (maculopapular rash --> anaphylaxis) 

--> • Cross-allergic reactions between B-lactam antibiotics can occur

2) GI disturbances (eg, diarrhea)
3) Pseudomembranous colitis (ampicillin)
4) Maculopapular rash (ampicillin, amoxicillin)

5) Interstitial nephritis (particularly methicillin)

6) Neurotoxicity (epileptic patients at risk)
7) Hematologic toxicities (ticarcillin)
8) Neutropenia (nafcillin)

9) Hepatitis (oxacillin)
10) Secondary infections (eg, vaginal candidiasis)

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PENICILLIN - EXCRETION

-most excreted primarily via KIDNEY (beware of kidney failur)

NAFCILLIN = EXCEPTION --> is primarily excreted in the BILE 

OXACILLIN + DICLOXACILLIN = renal + biliary excretion

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CLAVULANIC ACID

SULBACTAM

TAZOBACTAM

B-LACTAMASE INHIBITORS

-contain B-lactam ring but do not have signif antimicrobial activity 

--> bind to and inactivate most B-lactamases 

--> available only in fixed combinations with specific penicillins

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WHAT ARE THE 3 B-LACTAMASE INHIBITORS?

 

1) CLAVULANIC ACID

2) SULBACTAM

3) TAZOBACTAM

23

CEPHALOSPORINS

• B-lactam antibiotics
• Bactericidal
• Same MOA as penicillin's
• Affected by similar resistance mechanisms

• Classified into generations

1ST GEN = "LIN is EXIN" us up 

CEFAZOLIN

CEPHALEXIN

2ND GEN = DOLE... TIN OR TAN?

1) CEFOXITIN

2) CEFACLOR

3) CEFOTETAN

4) CEFAMANDOLE

3RD GEN: "DIME ZONE XIME" with the TRI-AX-ONE dude

1) CEFTRIAXONE

2) CEFOPERAZONE

3) CEFTAZIDIME

4) CEFIXIME

 

4) 4th GEN: "4th line rides the PINE" 

1) CEFEPIME

 

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CEPHALOSPORIN ACTIBACTERIAL SPECTRUM

1st, 2nd, 3rd, 4th, and 5th generations based on: 

• 1) Order of introduction into clinical use

• 2) Spectrum of activity

CLASS 1 -----------------> CLASS 3

GRAM +VE GRAM -VE

In general, Gram positive activity diminishes while Gram- negative activity increases moving from the first-to third generations

4th generation demonstrate similar activity to first- generation agents against Gram-positive cocci and are also active against most Gram-negative bacilli. = BROAD SPECTRUM --> ie we should probably save this drug so we can use it when we have no damn clue what kind of bacteria is causing the illness

5th generation have a similar spectrum to the 3rd generation. They are unique in that they have activity against MRSA.

NOTE: 

-All 1st-4th generation cephalosporins are considered inactive against MRSA,

All cephalosporins are considered inactive against enterococci, Listeria, Legionella, Chlamydia, mycoplasma, and acinetobacter species. 

 

25

PENICILLIN used when kidney problems? 

NAFCILLIN

(b/c is excreted via BILE, not by kidney) 

26

ALL CEPHALOSPORINS ARE CONSIDERED INACTIVE AGAINST WHICH BACTERIA? 

"LA MEAL"

L= Legionella

A = actinomyces

 

M = MRSA

E = Enterococci

A = atypical bact (Chlamydia, Mycoplasma)

L = Listeria

 

 

 

Class notes: also include Legionella + Actinetobacter

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CEFAZOLIN

CEPHALEXIN

1ST GENERATOIN CEPHALOSPORIN

are penicillin G substitutes

-are resistant to staphylococcal penicillinase

--> activity against gram +ve COCCI + P. mirabilis, E. coli, and K. pneumoniae

-is RARELY DOC FOR ANY INFECTIONS

CEFAZOLIN = DOC FOR SURGICAL PROPHYLAXIS

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DRUG FOR SURGICAL PROPHYLAXIS AGINAST GRAM +VE INFECTION

CEFAZOLIN

 

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CEFACLOR

CEFOXITIN

CEFOTETAN

CEFAMANDOLE

2nd GENERATION CEPHALOSPORINS

-extended gram -ve coverage

-greater activity against H. Influenze, Enterobacter aerogens, and some Neisseria species

"HEN PEcKS"

Haemophilus influenzae, Enterobacter aerogenes, Neisseria spp., Proteus mirabilis, E. coli, Klebsiella pneumoniae, Serratia marcescens.

--> Weaker activity against Gram + ve organisms than 1st gen 

CLINICAL APPLICATIONS: 

1) Primarily used to treat sinusitis, otitis & LOWER respiratory tract infections

2) Cefotetan & cefoxitin = prophylaxis & therapy of abdominal and pelvic cavity infections

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CEFTRIAXONE

CEFOPERAZONE

CEFOTAXIME

CEFTAZIDIME

CEFIXIME

3RD GENERATION CEPHALOSPORINS

• Enhanced activity against Gram-negative cocci
Highly active against enterobacteriacae, Neisseria, &

H.influenzae

• Less active against most Gram-positive organisms

• Cefotaxime & ceftriaxone = usually active against pneumococci

 

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CEFTRIAXONE DOC

3rd GENERATION CEPHALOSPORIN

1) DOC FOR GONORRHEA

2) DOC FOR MENINGITIS d/t AMPICILLIN RESISTANT H. INFLUENZA

3) PROPHYLAXIS OF MENINGITIS IN EXPOSED INDIVIDUALS

4) TREATMENT OF LYME'S DISEASE (CNS or Joint infection) 

32

CEFAPERAZONE

CEFTAZIDIME

3RD GENERATION CEPHALOSPORIN

 

-Has activity against Pseudomonas aeruginosa 

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CEFIPIME

4TH GENERATION CEPHALOSPORIN

• Parenteral admin. Only (ie NOT orally)

• Wide antibacterial spectrum

• Gram +ve activity of 1st generation + Gram -ve activity of 3rd generation

• eg, enterobacter, Haemophilis, Neisseria, E.coli, pneumococci, P.mirabilis & P.aeruginosa

34

CEFIPIME CLINICAL APPLICATIONS:

4th generation cephalosporin

-Treatment of infections with susceptible organisms

eg, UTI’s, complicated intra-abdominal infections, febrile neutropenia

35

CEFTAROLINE

5TH GENERATION CEPHALOSPORIN

-PARENTERAL ADMIN. ONLY

-HAS ACTIVITY AGAINST MRSA 

-similar to spectrum of actiivty of 3rd generation 

CLINICAL APPLICATIONS: 

1) Skin and soft tissue infection due to MRSA, particularly if gram-negative pathogens are coinfecting

2) Community-acquired pneumonia (when first-line agents are unsuccessful)

36

PHARMACOKINETICS OF CEPHALOSPORINS

-most administered PARENTERALLY 

--> exceptions = cephalexin, cefaclor, cefixime

ONLY 3RD GENERATIONS reach adequate levels in CSF 

-mainly eliminated via KIDNEYS

--> exceptions = CEFTRIAXONE + CEFOPERAZONE (excreted in bile)

37

CEPHALOSPORIN ADVERSE EFFECTS

• Allergic reactions (cross-sensitivity with penicillins can occur)

However, minor***** penicillin allergic patients often treated successfully with a cephalosporin

• Pain at infection site (IM), thrombophlebitis (IV)

• Superinfections (eg, C.difficile)

Cefamandole, cefoperazone & cefotetan contain methyl-thiotetrazole group, all can cause:

1) hypoprothrombinemia (Vit. K1 admin can prevent) &
2) disulfiram-like reactions (avoid alcohol)

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IMIPENEM

MEROPENEM

CARBAPENEMS

-Resist hydrolysis by most B-lactamases

• Very broad spectrum of activity

• Active against penicillinase-producing Gram-positive &

negative organisms; aerobes & anaerobes; P.aeruginosa

Not active against carbapenemase producing organisms

eg, carbapenem-resistant enterobacteriaceae, carbapenem-resistant klebsiella

• Not active against MRSA

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CARBAPENEM CLINICAL APPLICATIONS

DOC FOR:

1) ENTEROBACTER INFECTIONS

2) EXTENDED-SPECTRUM B-LACTAMASE PRODUCING GRAM -VES

 

40

CARBAPENEM PHARMACOKINETICS + ADVERSE EFFECTS

-administered via IV

"imiPEN" IN ME --> produces SEIZURES, can be potentially NEPHROTOXIC, combine with CIALstatin (like cialsis is good right?) and this makes things better

Imipenem forms potentially nephrotoxic metabolite. Combining with enzyme inhibitor Cilastatin prevents metabolism thus prevents toxicity & increases availability.

NOTE: Meropenem is not metabolized by same enzyme (no need

for Cilastatin)

ADVERSE EFFECTS:

• GI distress (nausea, vomiting, diarrhea)

• High levels of imipenem can provoke seizures

Allergic reactions (partial cross-reactivity with penicillin’s)

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AZTREONAM

MONOBACTAM

-used for AEROBIC GRAM -VE RODS ONLY!!! (including pseudomonas) 

-has NO activity vs gram +ve bacteria or anaerobes

-is resistant to action of B-lactamases

CLINICAL APPLICATIONS: --> look out for CF (Pseudomonas aeruginosa) 

UTI’s, lower respiratory tract infections, septicemia, skin/structure infections, intraabdominal infections, gynecological infections caused by susceptible Gram- negative bacteri

42

AZTREONAM PK AND AE

MONOBACTAM

• Mainly IV or IM

• Can be given by inhalation in CF patients

• Penetrates CSF when inflamed
• Excreted primarily via urine

 

AE: 

• Relatively nontoxic

Little cross-hypersensitivity with other B-lactam antibiotics --> can be used in patients with penicillin anaphylaxis

• Occasional skin rashes / elevation of serum aminotransferases

• GI upset, vertigo, headache
• Phlebitis or thrombophlebitis reported with IV use

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VANCOMYCIN

MOA + resistance

If you have a VAN you know you're always +1 (having kids) D-ALA-D-ALA (looks like the windows of the long van) 

 

Bacterial glycoprotein

• Bactericidal

• Active against Gram-positive bacteria only

• Virtually all Gram-negative organisms are intrinsically resistant

Effective against multi-drug resistant organisms (eg, MRSA, enterococci, PRSP)

MOA: Binds to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide--> INHIBITIS CELL WALL SYNTHESIS and PEPTIDOGLYCAN POLYMERIZATION

Resistance: 

• Plasmid-mediated changes in drug permeability

Modification of the D-Ala-D-Ala binding site (D-Ala replaced by D-lactate)

 

44

VANCOMYCIN 

CLINICAL APPLICATIONS

1) Treatment of serious infections caused by B-lactam resistant Gram +ve organisms eg, MRSA

2) Treatment of Gram +ve infections in patients severely allergic to B-lactams

3) In combination with an aminoglycoside for empirical treatment of infective endocarditis

4)  In combination with an aminoglycoside for treatment of enterococcal endocarditis or PRSP

5) Given orally for the treatment of staphylococcal enterocolitis or antibiotic-associated pseudomembranous colitis (C.difficile)

45

VANCOMYCIN PK + AE

PK

• Poor oral absorption
Requires slow IV infusion (60-90 min)

• Penetrates CSF when inflamed
• 90-100% excreted via kidneys

AEs: KNOW THESE 

• Mostly minor eg, fever, chills, phlebitis at infusion site

‘Red man’ or ‘red neck’ syndrome (infusion-related

flushing over face and upper torso)

Ototoxicity (drug accumulation)
Nephrotoxicity (drug accumulation)

46

DAPTOMYCIN

DAPTOMYCIN "DEPOLARIZES" --> K+ depolarization of bacteria leads to death

 

• Bactericidal
• Effective against resistant Gram-positive organisms (eg,

MRSA (ORSA), enterococci, VRE & VRSA) • Inactive against Gram-negative bacteria
Not effective in treatment of pneumonia

MOA: 

• Novel mechanism of action --> useful against multi-drug resistant bacteria

Binds to cell membrane via calcium-dependent insertion of lipid tail

• Results in depolarization of cell membrane with K+ efflux

--> cell death

47

DAPTOMYCIN

CLINICAL APPLICATIONS, PK, AE

1) Recommended for treatment of severe infections caused by MRSA*** or VRE***

2) Treatment of complicated skin/structure infections caused by susceptible S.aureus

PK: IV ONLY!!! can accumulate in renal insufficiency

AE: 

• Constipation, nausea, headache, insomnia

Elevated creatine phosphokinases (recommended to discontinue coadmin. of statins)

 

48

BACITRACIN

-Unique mechanisms --> no cross resistance

• Interferes in late stage cell wall synthesis
• Effective against Gram-positive organisms
• Marked nephrotoxicity --> mainly topical use

49

FOSFOMYCIN

Inhibits cytoplasmic enzyme enolpyruvate transferase in early stage of cell wall synthesis

• Active against Gram-positive and negative organisms

• Oral
• Used for treatment of uncomplicated lower UTI’s, but is NOT first line