Pharmacology- Bacterial Cell Wall Inhibitors

Penicillins what are they made from? common root in name what are the structural parts of pencillins? (which part is reason for MOA/activity)

"cillin" natural: made form mold (penicillum) : TRUE ANTIBIOTIC (note: some in class are semi-syn form natural origin) contains 1)thiazolidine ring (5 member ring with S) 2) B lactam ring (cleavage/hydrolysis by nucleotide form covalent bond with PBP=activity) 3) R group (leads to differences in spectrum overall: water soluble- has to use porin channel in gram -

spectrum of extended-spectrum pen resistance

+/- and PSEUDOMONAS (gram- rod) sensitive to b-lactamase

4th gen spectrum and use

+/- (broad) empiric or serious infections cefepime-iv

3 mechanisms of cephalosporin resistance

1) b lactamase hydrolysis (more resistant then pen so broader spectrum) affected by extended spectrum beta lactamases (ESBL) 2) change in PBP (MRSA-most ceph) 3) inability to reach target (gram-; better than penicillins)

penicillin resistance mechanisms (4)

1) inactivated by B lactamase (open ring so no mechanism of action) higher in gram + but used by both (need to use with b lactamase inhibitors) Most common form of resistance 2) modify target PBP (both+/-) change protein structure so penicillin cannot bind; methicillin resistant staphylcoccus auerus-MRSA 3) impaired penetration (-) down regulated porin channel in outer membrane 4) presence of efflux pump (makes pumps in outer membrane that kicks what got in back out)

3 resistance mechanisms to carbapenems

1) low permeability in some gram - 2) change in PBP (MRSA DOES NOT RESPOND TO CARBAPENEMS) 3) enzyme degradation (CRE)

4 ADRs of carbapenems contra

1) seizures (imipenem has greatest risk) 2) hypersen (pot. cross w/ pen) 3) GI N/V D 4) infusion site rxn contra- eat disorders and seizures

use of extended spectrum pen

1) serious infections by gram - pseudomonas- use 2 antimicrobials to tx (tica works better than pipera) 2) empiric therapy

5 common ADRs for cephalosporins

1)hypersen (cross allergy 3-5% with pen) 2) GI : N/V D 3) inj site rxn (thrombophelbitis) Im is painful and irritating 4)** renal toxicity (interstial nephritis) 5)** CEFTOTETAN - has MTT side chain--> BLEEDING AND DISULFRAM RXN W/ ALCOHOL (do not use alcohol

what are the 7 common ADRS of penicillins

1)hypersensitivity-common: rash, urticara, fever, angioedema, anaphylaxix (varying responses) cross-allergy: (if allergic to one then considered allergic to all other penicillins; and 3-5% with cephalosporins)-always get pt hx and rxn 2) GI: N/V D (>in aminopen) 3) suprainfections (extended and amino) 1) pseudomembrane colitis(c.diff) 2) vaginal candidiasis 4) Na accum at high doses (ticarcillin)-leads to fluid retention so contra in CHF K accum in Pen G K- monitor 5) inj site rxn (thrombophelbitis) 6) seizures at high doses 7)impaired platelet fxn (increased bleeding with warfarin-extended pen)

what are the MOAs of Penicillins what types of microbes is it effective against(general) cidal (time/conc) or static

1)inhibit cell wall synthesis covalent bond to PBP at active site inhibit transpeptidation (no crosslinking) blocks synthesis of peptidoglycan -->bacterial cell death 2) AUTOLYSINS effective in bacteria that is GROWING and synthesizing CELL Wall Bactericidal - TIME dependent

uses of natural penicillins

1)syphyllis 2) susceptible streptococcal infection

what is the PK advantage that allows__gen cephalosporins to treat meningitis

3rd gen- all cross BBB

classes of cephalosporins

5 generations based on spectrum goes from narrow 1 to broad 5(less susceptible to b lactamase)

MRSA

5th gen ceph and vanco

Monobactams name and route structure

Aztreonam- IV/IM monocyclic beta lactam ring

1st gen names:

Kelflex, Droxil -oral zolin-IV

common ADRS with extended spectrum pen

Na accumulation -ticarcillin suprainfections more common (broader spectrum) impaired platelet fxn (increase bleeding with warfarin)

Natural Penicillins 2 types (examples and routes of admin)

Penicillin G 1) pen G (k, aqueous, regular)- IV solution 2)benzathine pen G and Procaine penicillin G - IM only Pen V - oral

vancomycin resistance mechanisms (2)

VRE - VAnco resistant ENTEROCOCCUS (gram + -alters d-ala d-ala and decreases binding) staphlococcus aureus (sub AA w/ another and leads to decreases binding)

can penicillins cross the BBB

all are hydrophilic so they have a decreased ability to cross the bbb however: ampicillin can cross if meninges are inflamed to tx meningitis

half lives of penicillins

all have short t1/2 this makes the TIME dependent killers (30m-1h) decrease in renal fxn may increase half live of drugs so doing would need adjusted (not antistaph meds)

Aminopenicillins examples and routes

amoxicillin-oral ampicillin-IV

which aminopen has a synergist effect: explain use

ampicillin with aminoglycosides use in menigitis and endocarditis

extended spectrum penicillins also called examples and route combo?

antipseudomonal penicillins ticaracillin (only w/ B lact inhibitor) pipercillin (alone or in combo) IV route

penicillinase-resistant penicillins also called examples and routes excretion route

antistaphylococcal penicillins Methicillin (not used in US-MRSA, low oral bioav) nafcillin, oxacillin, dicloxacillin (oral bioavailable) biliary excretion

pseudomonas

aztreonam (monobact) ceftazidime- 3rd gen Iv ceph peper/ticarcillin - extended spectrum pen

Cephalosporins what class common prefix in name what are the structural parts of cephalosporins? (which part is reason for MOA/activity)

bacteriocidal-time dependent CELL WALL SYNTHESIS INHIBITOR "cef" a)nucleus= 7-aminocephalosporanic acid (6 member ring) b) B lactam ring (Activity) c) R group- changes in spectrum and properties

what is the MOA of carbapenems

bind to PBP and interfere with cell wall syn bactericidal -time dependent killer

moa of vancomycin

bind to d-ala d-ala terminal of peptide to inhibit polymerization and formation cell wall bacteriocidal and time dependent killer

moa of monobactams

bind to pbp and inhibit cell wall syn bacteriocidal -time dependent killer

spectrum of aminopenicillins narrow or broad specific resistance

broader (+ and - (better than natural)) sensitive to b-lactamase (use with inihibitors)

spectrum and USES of carbapenems

brodest spectrum +/- and anaerobe/aerobe empiric, serious/mixed, resistant bact

what is CRE

carbapenem resistant ENTERBACTERIACAE carbapenimase- transfers easily and >50% mortality new beta lactamase that led to multi drug resistance Ex: e coli, salmanella, klebsiella (gram - rod in GIT)

causes seizures

carbapenems (some penicillin)

4th gen names:

cefepime -IV

5th gen names:

ceftaroline- IV

5th gen spectrum and use

ceftaroline-iv broadest +/- and some drug resistant bact- MRSA use- drug resistant strep pnemonia*** last choice due to increased resistance

carbapenems class structure names and routes

cell wall synthesis inhibitor- "penem" a) 5 member ring (different from pen) b) b lactam ring- activity c) r group imipenem/cilastatin meropenem ertapenem doripenem all IV

renal tox

cephalosporins

what are the B-lactamase inhibitors what combos are available and by which routes what do they do to the spectrum of penicillins

clavulanic acid, sulbactam, tazobactam amox/clav-oral amp/sul- iv tic/clav-iv piper/tazo-iv expands the spectrum of pen to micro that produce b-lactamase broader than when abx are used alone

describe the clearance, oral bio, of carbapenems

cleared by kid (monitor and dose adj) low oral bioav-IV (hydrophilic)

what are autolysins

enzyme in bacteria used to degrade old wall to use in new (cannot replace-->water enters cell and lysis

resistance to monobactams

extended spectrum B lactamase (ESBL)

2nd gen names:

fox, fur, tetan -IV fur ax, clor, prozil -oral fox and tetan -anaerobe coverage tetan- mtt side chain bleeding and no alcohol

spectrum of 2nd gen ceph

fox, fur, tetan-iv; clor, fur ax, prozil-oral + (strep/staph) and - (better than 1st) anaerobe- tetan and fox (but these have less gram +)

spectrum and use of vanco

gram + only (NARROW) serious infection (MRSA or pen resistant Pneumococal) if penicillin allergy orally- C. diff pseudomembranous colitis

Common ADRS associated with aminopen

greater N/V and Diarrhea than others Suprainfections pretty common do to broader spectrum

fosfomycin moa resistance spectrum use PK

inhibit early stage in cell wall syn resistance- inadequate enterance into cell spectrum BROAD +/- use- SINGLE DOSE UTI (umcomp) in women Pk- excreted in urine- exceed MIC for many UTI pathogens

ADRs of monobactams

inj site rxn- pretty well tolerated (N/V D-rare)

MOA of cephalosporins

interfere w cell wall syn and cross linking of peptidoglycan bactericidal -time dependent killer

what is cilastatin

it inhibits renal dehydropepidase (to increase PK so IMIPENEM is cleared more slowly)

spectrum of 3rd gen

iv-taxi, tazi, triax oral-pod, tibut, dinir, ditor, fixime gram + and - tazi- pseudomonas (but less gram +) triaxone-long half life biliary excretion

PK of monobactams (excretion)

kidney excretes (monitor and dose adj)

vancomycin structure Pk of vanco

large glycopeptide IV for systemic; ORAL- only for GI C. diff excreted in urine (dose adjust and monitor)

uses of 3rd gen ceph

lower resp tract-pneumonia meningitis- PK advantage pseudomonas- tazi

uses of antistaph pen

methicillin-sensitive staph streptococcus- not typically used because natural and amino work better

route of elimination of penicillins exception

most- unchanged in urine monitor renal fx and dose adjustments needed exception: antistaph(max, ox, diclox)- excreted in bile (not dose adjusted needed in renal impairment)

what is the spectrum for natural penicillins narrow or broad specific resistance seen in this class

narrow gram + cocci treponema pallidum (spirochete-syphyllis) resistance: sensitive to beta-lactamse (most staph and some strept)

spectrum of antistaph pen narrow or broad specific resistance seen/not seen in this class

narrow methicillin-sensitive staph streptococcus- not typically used because natural and amino work better RESISTANT to PENICILLINASE- so these abx are not broken down by beta lactamases

spectrum and use of monobactams

narrow** only gram - aerobes** CF patients inhale solution to Tx Pseudomonas aeroginosa gram- aerobe infections

list the classes of penicillins(4)

natural amino antistaph extended spectrum

ADR of vanco

ototoxicity red-man syndrome (rapid infusion - at least 60 min usually 90-->flush, rash, hypoten, urticara) hypersen (no cross allergy- can be used in patients with penicillin allergY)

which penicillins have a delayed absorption and why

pen G that are given by IM increase tissue and blood conc

uses of 2nd gen ceph

resp tract infections GI anaerobe bacteria

uses of aminopen

resp tract infections UTI

Telavancin moa spectrum pk adr

similar to vanco disrupts cell membrane potential and interferes with polymerization/crosslinking spectrum- gram + only pk- low oral , monitor renal adr- nephrotox, infusion rxn, GI, **TASTE disturb (1/3 of patients)

uses for 1st gen ceph

surgical prophylaxis (gram + on skin- ZOLIN) resp infections (oral)

t1/2 and elimination mechanisms for cephalosporins exception BBB

t1/2 vary (1-3 hrs) ceftriaxone- long t1/2 (8hr) most renally excreted exception: ceftriaxone-biliary) CROSS BBB- only 3rd gen

3rd gen names:

taxi, tazi, triaxi- IV podoxime,tibuten, dinir, fixime, ditoren- oral

taste disturbance

telavancin

liver tox

telavancin and bacitracin

no alcohol with which cell wall syn inhib

tetan

bacitracin moa spectrum route adr

topical inhibit late stage of cell wall syn gram + (narrow) ADR- nephrotox if systemic

ototox

vanco

red man

vanco

what is the F of penicillins

variable F variable resistance to gastric acid amoxicillin has the best F

spectrum for 1st gen ceph

zolin, kelflex, droxil most narrow: mainly gram + (staph/strep) and limited gram - (proteus, ecoli, klebsiella)