MOD6 Antibiotics

antimicrobial resistance AMR

resistance occurs naturally and can occur to any antibiotic to a certain degree

what causes antimicrobial resistance

• prescribing unneeded/incorrect abx

• taking abx in non-prescribed way — not finishing full course

• self-medicating or abx sharing

• taking abx for infection not caused by bacteria

• kills susceptible population but leaves resistant populations survive and proliferate

synergy

activity of the abx combination is substantially greater than activity of either drug alone 

indifference 

activity of abx combo is no better/worse than either drug alone 

antagonism

activity of ax combo is substantially less than either drug alone

combo to avoid in tx

antimicrobial 

therapeutic agent for tx of infectious diseases 

broad term encompassing agents against bacteria/virus/parasite/fungus 

most antimicrobials are antibiotics 

antibiotics

chemical substance produced by microorg that may inhibit or kill others

can be derived naturally, semi-synthetically, or synthetically

criteria for abx use

• should have selective toxicity — less damage to host cells

• should not cause allergic rxns

• should be soluble in body fluids and be capable of penetrating tissues

• microorg should not readily develop resistance to them

broad spectrum

abx affects wide variety of microorg

GPO and GNO

narrow spectrum

affects small number of org or groups of org

GPO or GNO — some spillover to small grp might occur (mostly GPO, but small grp of GNO)

bactericidal

antimicrobial agent that kills bacteria

bacteriostatic 

antimicrobial agents that prevent bacterial multiplication — must rely on hosts functioning immune system to fully clear infection

less toxic shock and more tolerable side effects, less extensive monitoring

would you use a bacteriostatic or bactericidal drug for an immunocompromised pt

bactericidal — pt immune system is deficient, cant clear infc on own

modes of action of antimicrobials

inhibits:

• cell wall synthesis

• protein synthesis

• DNA/RNA synthesis

• cell membrane function

• other metabolic processes

what is targeted during cell wall synthesis inhibition

target peptidoglycan in cell walls

final step of peptidoglycan synthesis needs penicillin binding protein PBP

how is the formation of cell wall linkage prevented

penicillin binding protein PBP has affinity to beta-lactam abx

combine tgh, stops cell wall synthesis

what abx inhibits cell wall synthesis 

beta-lactam abx 

what do beta-lactam abx inhibit

cell wall synthesis — death results from osmotic instability/autolysis

are beta-lactams bactericidal or bacteriostatic 

bactericidal 

groups of beta-lactam abx 

• penicillins

• cephalosporins

penicillin — spectrum

narrow spectrum — GPO

effective against few GNO — not enterobacterales

clinical uses of penicillin

penicillin G — acid labile (given IV, nor orally bcs stomach acid)

penicillin V — acid stable (can give orally)

class concept 

test results for one abx will apply to others in that group 

in pen. G is tested, susceptible or resistant — pen V will also be S or R

dont need to test both drugs 

susceptible S

microorg is killed or slowed down by drug

infc will cease and dead bacteria are cleared from infected area by immune system

intermediate I 

response rate/effect may e lower than for susceptible isolates 

resistance R

microorg is not killed or slowed down by drug

infc will continue unless immune system kills bacteria, conditions not optimal for growth, or pt dies

beta-lactamases

enzyme produced by bacteria with denatures b-lactam ring of penicillin molecule — renders abx ineffective

2nd generation penicillins

resistant to b-lactamase

have bulky side chain — protects ring from bacterial enzymes

b-lactamase resistant penicillin — spectrum

narrow GP spectrum 

mutation of penicillin binding protein to PBP2A

prevents abx from attaching to normal binding site in bacterial cell wall

now can resist these abx

mediated by mecA gene

how do aminopenicillins work

extended spectrum of penicillins to make also effective on GNO 

allows penetration through GNO lipid layer and target PBP

still susceptible to b-lactamase

anti-pseudomonal penicillins

increase activity against GNO

two main groups:

• carboxyl penicillins — carbenicillin, ticarcillin

• ureidopenicllins — azlocillin, mezlocillin, piperacillin

broad spec, less active against GPO

clinical use of b-lactamase resistant penicillin 

used primarily for staph infc

given orally/intramuscularly/intravenously 

b-lactamase resistant penicillin — class concept

applies

ex. oxacillin, cloxacillin, dicloxacillin, methicillin

aminopenicillin — spectrum

broad spec, both GNO and GPO

clinical use of aminopenicillin

clinical use — better absorption/excretion properties

aminopenicillin — class concept

applies

ex. ampicillin, amoxicillin

when are anti-pseudomonal penicillins not used 

infections/coinfections where staphylococcus spp is involved

more stable against other b-lactamases but inactivated by staph b-lactamase 

clinical use of anti-pseudomonal penicillin

reserved for very resistant bacteria

used with aminoglycosides for synergy

very expensive drug

anti-pseudomonal penicillin — class concept

does not apply

• carboxyl penicillins — carbenicillin, ticarcillin

• ureidopenicllins — azlocillin, mezlocillin, piperacillin

beta-lactamase inhibitors

compounds that have weak antibacterial activity on their own, but when combo w b-lactam drugs, deactivates b-lactamases and allows drug to work

• clavulanic acid + amoxicillin or ticarcillin

• sulbactum + ampicillin + tazobactum

extended spectrum beta-lactamase ESBL testing

paper discs of abx on plate

zone of susceptibility — greater than or equal to 5mm

cephalosporins

second major group of b-lactam abx

originally from fungus cephalosporium

bactericidal

first generation cephalosporins

broad spec

class concept applies

ex. cephalothin, cefazolin, cephalexin

second generation cephalosporins

broad spec — more effective against GNO

class concept doesnt apply

ex. cefaclor, cefamandole, cefoxitin, cefuroxime

third generation cephalosporins 

broad spec — more effective against GNO

class concept doesnt apply

ex. cefixime, cefotaxime, ceftizoxime, cefoperazone, ceftazidime, ceftriaxone

which generation of cephalosporins does class concept apply 

first generation

what are cephalosporins more effective against

successive generations will show increased activity against GNO

fourth generation cephalosporins

broad spec — expanded activity against GPO and GNO

class concept doesnt apply

ex. cefipime (cefepime), cefpirome

what cephalosporin is less likely to induce bacterial resistance

cefipime/cefepime

fourth generation

fifth generation cephalosporins

broad spec

used for MRSA infc, VRE, strep. pneumoniae

class concept doesnt apply

ex. ceftaroline, ceftolozane

what cephalosporin can be used for MRSA and VRE

fifth gen

ceftaroline, ceftolozane 

aztreonam

b-lactam for GNO only

narrow spec

resistant to some bacterial b-lactamase enzymes

selective media

used when mixed culture has both GPO and GNO

combo of aztreonam and other abx added to media to prevent growth of GNO

isolates GPO for testing

carbapenems

b-lactam core, unique side chain — resistance to most b-lactamase enzymes

bactericidal

effective against most anaerobes and GNB

widest spectrum — last resort

what abx is the last resort/widest spec

carbapenems

ex. imipenem, meropenem, ertapenem

carbapenamase producing organisms CPO

org resistant to carbapenems 

mutated to be resistant to carbapenem abx 

resistance may be transferred to other organisms

ex. KPC (klebsiella pneumoniae), NDM, VIM

vancomycin

inhibits cell wall synthesis

class: glycopeptide

non b-lactam

large molecule — cant pass through blood-brain barrier or GNO cell wall

used for MRSA treatment, clostridiodes difficile, enterococcus spp

can cause hearing loss

vancomycin — spectrum

narrow spec — GPO

is vancomycin bactericidal or bacteriostatic 

bactericidal — binds PBP causing cell to elongate and lyse 

which antimicrobials inhibit protein synthesis

MCAT

macrolides — erythromycin and clindamycin

chloramphenicol

aminoglycosides

tetracyclines

site of action of antimicrobials that inhibit protein synthesis 

where tRNA brings amino acids into place in ribosomes 

macrolides — bactericidal or bacteriostatic

bacteriostatic in low concentration

bactericidal in high concentration

erythromycin

a macrolide

narrow spectrum — mainly GPO, few GNO

absorbed well in body — too large to cross blood/brain

not used in tx for CNS infc

some destruction in acidic env — vomiting may occur if given orally

clindamycin

narrow spec

better absorption and penetration properties than erythromycin 

tx of anaerobes

restricted use of abx — 20% of pts develop pseudomembranous colitis 

chloramphenicol

from streptomyces — GPO, from soil

cheap and easy to make

class: phenicols

bacteriostatic — competes for same binding site on ribosome used by erythromycin

broad spec

small molecule — can cross blood/brain > treat CNS infc

chloramphenicol toxicity

can cause gray (baby) syndrome

children present w ashen grey cyanosis, blue lips, listlessness, and progressive weakness

immature newborn liver cant metabolize abx to excrete — toxic lvls accumulate, can be fatal

chloramphenicol contraindications

newborns

previous hypersensitivity/allergic rxn

adults w liver and kidney disease (may tolerate lower doses)

side effects of chloramphenicol

aplastic anemia — bone marrow stops production of all cells (RBC, WBC, PLT), irreversible and fatal

dose-related bone marrow depression — disappears if drug is discontinued

chloramphenicol uses

adult typhoid fever infections (salmonella typhi)

adult bacterial meningitis when other abx cant penetrate from blood to CNS

aminoglycosides 

amino sugars linked by glycosidic bonds

inhibit protein synthesis by binding into ribosome subunits 

• initial formation of protein synthesis complex

• accurate reading of mRNA

• formation of ribosomal-mRNA complex

bactericidal

large molecule — no CNS penetration

no class concept

what abx is ineffective in treating anaerobic infc

aminoglycosides — unable to penetrate bacterial cells in a reduced oxygen environment

what affects the uptake of aminoglycosides 

Ca and Mg ions — susceptibility test medium should have the same concentrations of those ions as in the body

Mueller Hinton agar recommended 

aminoglycosides toxicity

ototoxicity affects CN VII (vestibulocochlear) results in hearing loss

toxic to kidney tissue but will vary w specific antibiotic

aminoglycosides — spectrum

broad spec — effectiveness against enterobacterales and P.aeruginosoa

ex. kanamycin, gentamicin, tobramycin, amikacin & netilmicin, spectinomycin

aminoglycosides — synergy

combo w b-lactam abx

usually taken tgh to treat some infections

tetracyclines

yellow in colour

bacteriostatic

broad spec

ex. tetracycline, terramycin, aureomycin, doxycycline, minocycline, tigecycline

treatment using tetracyclines

tx of exotics — chlamydia, mycoplasma, rickettsial infc, acne, some protozoan parasites 

can be given orally

contraindications for tetracyclines

binds w Ca and Mg ions — shouldnt be taken w milk bcs prevents absorption of minerals; therefore not given to children bcs bone formation issues

pregnancy — risk of hepatotoxicity and permanent discolouration of teeth in fetus/adult, impairment of fetal long bone growth

some evidence of interference with birth control pills

fluoroquinolones

quinolone class

inhibits DNA/RNA synthesis — binds to and interferes w DNA gyrase enzymes preventing normal unwinding and replication of DNA

fluoroquinolones — bactericidal or bacteriostatic // spectrum

bactericidal

broad spec

ex. ciprofloxacin, norfloxacin, levofloxacin, nalidixic acid

fluoroquinolones toxicity

irreversible cartilage and skeletal damage in admials

contraindicated for pts under 18yo, pregnant or nursing

metronidazole (flagyl) 

nitromidazole grp

breaks up DNA strand

bactericidal used for protozoan infc and anaerobic infc

polymyxins

polypeptide class

inhibits cell membrane function

bactericidal — attach to cell membranes causing leakage of cell → death

polymyxins — spectrum

narrow GNO — some derivatives effective against GPO

ex. polymyxin B (polysporin) and polymyxin E (colistin)

colistin

polymyxin E

used in selective media, disc used to determine if G stain inconclusive — CNA media inhibits GNO growth (GNO is susceptible to abx, zone of inhibition)

sulfonamides

synthetic antimicrobials

interferes w folic acid synthesis — inhibits pathway

bacteriostatic

broad spec

used for UTIs

sulfonamides — synergy and contraindications

synergy w abx trimethoprim

contraindications — sulfa drug allergies, liver/kidney disorders, hematological disorders, children under 6m

nitrofurantoin

nitrofurans grp

bacterial nitroreductase converts nitrofurantoin → reactive electrophilic intermediates — attack ribosome, disrupts protein synthesis

bright yellow

broad spec

for UTI

nitrofurantoin — cidal or static

bacteriostatic in low concentrations

bactericidal in high concentrations; concentrates well in the bladder for abx to be effective