Antibiotics Flashcards
resistant worries for Vancomycin
resistant gene on plasmid(means very mobile gene) being picked up by MRSA
Vancomycin
MRSA
penicilin resistant S. pneumo
susceptible enterococcal infections
Drug for vancomycin resistant Enterococci
Dancomycin
Target of beta lactam antibiotics
Peptidoglycan synthesis
Aerobic gram +
staph
strep
enterococci
listeria
anaerobes
clostridium actinomyces peptostreptococcus propionibacterium bacteroides fusobacterium prevotella
aerobic (facultative) gram negative
enterobacteriaceae
neisseria
pseudomonas
haemophilus
Atypical/intracellular bacteria
mycoplasma chlamydia legionella mycobacterium rickettsia spirochetes
Examples of Aminoglycosides
streptomycin
gentamicin
amikacin
toxicities of aminoglycosides
nephrotoxicity - see elevated creatinine
ototoxicity
Macrolides and Ketolides
Broad spectrum but not deep Erythomycin Clarithromycin Azithromycin (known as z pack) Telithromycin - ketolide
mechanism of Macrolides
bind 23S rRNA of the 50s ribosome
prevents protein elongation
Telithromycin
binds at 2 sites
ketolides
Erythromycin
can cause GI upset - makes pt nauseous
Azithromycin
longer half life
clinical uses for Macrolides
empiric therapy for community aquired pneumonia (CAP)
DOC for legionella, mycoplamsa, and chlamydia
Macrolides
Most aerobic gram neg rods are resistant to
Macrolides
Resistance to Macrolides
Efflux pump
Enzyme mediated methylation of binding site on 23S ribosome
Examples of Lincosamide
Clindamycin
Clidamycin active against
generally anaerobic drug
aerobic gram + including MRSA and s. pneumo
gram + and - anaerobes
some protozoans
mechanism of Tetracyclines
bind reversibly to 30s subunit
blocks binding of tRNA
What is clindamycin not useful for?
aerobic gram negatives
Tetracycline
broad range many aerobic gram pos and neg
anaerobes
Atypicals - especially useful
some protozoa
Adverse reactions to Tetracyclines
Not given to childern under 8
Not used in pregnancy
Cause photosensitization - bad sunburn
Fluoroquniolones
Ciprofloxacin - below the waist Gatifloxacin levofloxacin oflaxacin moxifloxacin
DNA gyrase inhibitor
Fluoroquinolones
clinical uses of fluoroquinolones
broad spectrum
aerobic, gram neg bacteria
active against strains of staph and strept and many atypical
toxicities of Fluoroquinolones
may damage growing cartilage - so no childern under 18 or pregnant women
Black box warning of tendon rupture
Anti folate drugs
TMP/SMX
sulfonamides
trimethoprim
anerobic drug
metronidazole
clindamycin
TMP/SMX mechanism and activity
broad spectrum interferes with folate synthesis by bacteria which is needed for nucleic acid synthesis aerobic gm pos (CA-MRSA) some aerobic gm neg non bacterial organisms
Clinical uses of TMP/SMX
UTI
RTI
prostate and vaginal infections
Toxicities of TMP/SMX
skin rash
GI upset
bacteriocidal antibiotics
antibiotics that target cell wall causing lysis of bacteria
beta lactams
vancomycin
daptomycin - cell membrane
Antibiotics that block protein synthesis
aminoglycosides 30s macrolides 50s tetracyclines 30s clindamycin 50s chloramphenical 50s linezolid 50s
Bacterostatic
antibiotics that inhibit growth and/or replication
Antibiotics that inhibit RNA synthesis
Rifamycin
Rifabutin
Antibiotics that target DNA or DNA synthesis
Quniolones
metronidazole
clofazimine
Antimetabolite antibiotics
Trimethoprimsuflamethoxazole (TMP/SMX)
dapsone
para-aminosalicylic acid
Empirical
treatment before receiving the test/cultures back
Beta lactams
Effective for certain Gr+ or Gr- Penicillins cephalosporins carbapenems monobactams
Antibiotics for Gram + cocci
Vancomycin
Daptomycin
TB drugs
Isonizad
Ethambutol
Pyrazinamide
Peptidoglycan synthesis and structure
Composed of alternating NAG and NAM units linked by transpeptidases (PBP) via D-Ala D-Ala units
Cyloserine
inhibits reactions involved in incorporation of alanine into cell wall percusor
Glycopeptides
bind to terminal D-ala-D-ala residues prevents incorporation of subunit into growing peptidoglycan
Bacitracin
prevents dephosphorylation of phospholipid carrier which prevents regeneration of carrier necessary for synthesis to continue in building peptidoglycan walls
Beta lactams
bind to end inhibit enzymes which catalyze this link
Mechanism of action of beta lactam antibiotics
transpeptidases catalyse crosslinking of peptidoglycan residues
beta lactam antibiotics bind transpep. and block this reaction resulting in weak cell walls and bacterial lysis if bacteria are actively growing
Bacteriocidal
Types of Penicillins
natural
anti-staph penicillins
aminopenicillins
extended spectrum
what is unique about the structure of Penicillin
B lactam ring
Thiazolidine ring - essential for activity
Natural penicillins
5 is oral G is IV or IM limited spectrum Most strept - GAS, GBS, viridians group NOT s. pneum Most gram + anaerobes N. meningitidis Treponema pallidum
Poor activity against aerobic and anaerobic gram neg rods and not active for intracellular bacteria
natural penicillin
Anti Staph Penicillin
Many staph make beta lactamases
this antibiotic have large side groups making resistant to lactamases
Naficillin and Oxacillin (IV)
Dicloxacillin (oral)
Anti Staph penicillin activity
MSSA
MSSE - methicillin resistant staph epidermidis
Not active against
MRSA
MRSE
How is methicillin resistance confered?
due to altered PBP
Aminopenicillin
Ampicillin
Amoxicillin
amino group is R group - allows penetration through porins of some gram neg (esp. enteric rods)
better absorption through GI than natural penicillins
Aminopenicillins activity against
limited spectrum similiar to natural PLUS E.coli Shigella Salmonella enterica AND borrelia burgdorferi
Extended spectrum penicillins
Piperacillin
Ticarcillin
Carbenicillin
better able to penetrate gram neg porins than aminopencillins
spectrum of extended spectrum penicillins
same as natural PLUS
more enterobacteriaceae
some strains of pneumonia aeruginosa
AKA anti pseudomonal penicillins
What is used in combination with aminopenicillins and extended spectrum penicillins?
B lactamase inhibitors
Some bacteria that contain beta lactamases
Staph. Aureus H. Inf N. gonorrhoeae Many enterobacteriaceae certain anaerobes
B lactamase inhibitors
can contain b lactam ring to act as decoy or inhibit lactamases following binding
Clavulanic acid
sulbactam
tazobactam
Extended spectrum penicillin (ESP) and b lactamase inhibitors
Big guns
some of most potent available
Piperacillin/Tazobactam (Zosyn)
Ticarcillin/clavulanate (Timentin)
gives ESP spectrum PLUS S. Aureus S. pneumo Most enterobacteriacae Most pseudomonas
Major toxicity of penicillins
Hypersensitivity rxns
acts as hapten but immunogenic when binds RBC
Type 1 response - skin rash, Anaphylaxis
Type 2 response - Drug induced hemolytic anemia
What is more resistant to Beta lactamases than natural penicillins?
Cephalosporins and cephamycins
On cephalosporins R1 and R2 side chains affect
R1 - antibiotic activity
R2 - affect change in PK properties
First generation cephalosporins
cefazolin
cephalexin
Second generation
Cefotetan
cefoxitin
cefuroxime
Third generation cephalosporin
ceftriaxone
fourth generation cephalosporin
cefepime
Cephalosporins and cephamycins
beta lactam antiobiotics
more active against gram neg than natural penicillins
More stable too against many beta lactamases
in general:
increasing generation - aerobic gm + decreases and aerobic gm - increase
generally not useful against anaerobes or intracellular organisms
Clinical First generation cephalsporin
spect: GAS, viridians, s. pneumo, PLUS some E. coli, klebsiella, proteus
Minor skin and soft tissue infections (alt to anti staph pen)
UTIs (E.coli)
Second generation cephalosporins
same spect as first generation PLUS
H. Inf
Neisseria species
Third generation cephalosporins
moderate against aerobic gram + bacteria - MSSA PLUS
increased activity against aerobic gram -
b/c modification of R side chains allow increased penetration through porins
some can cross the BBB - cefotaxime and ceftriaxone
activity against anaerobes - ceftizoxime
activity against pseudomonas - ceftazidime
aerobic gram positive think ….
Staph
strept
N. gonorrhae
resistant to a lot of antibiotics
becoming more and more of a problem
N. meningitidis
not usually problem
can treat with penicillin
Fourth generation
cefepime
Spectrum 3rd gen PLUS
MSSA
activity against pseudomonas - increased penetration thru porins and affinity to PBP
increased against Enterobacteriaceae - increased resistance to beta lactamases
Fourth generation poor against
anaerobes
Carbapemems
Use for very serious infections - Big guns Imipenem, meropenem, ertapenem Among MOST broad spectrum among LAST LINE of defense against resistant bacteria improved penetration of porins enhanced binding to PBP increased resistance to beta lactamases USEFUL for pseudomonas
LAST LINE antibiotic
carbapemems
some Ecoli and klebsiella developed resistance
Carbapenems NOT active against
enterococcus
MRSA
C. Diff
Burkholdreia cepacia
Hail Mary - last resort antibiotic
Imipenem
used with cilastatin (combo called Primaxin)
to inhibit renal dihydropeptidase
Monobactams
Aztreonam
side groups give ability to penetrate porins and bind to gram neg PBP
CANNOT bind gram + PBP
Excellent safety profile
Monobactams
safe for pts with penicillin allergies and renal disease
Useful for pseudomonas
Spectrum of Monobactams
Narrow spectrum
Aerobic gram neg
Moraxella, neisseria, enterobacteriaceae, pseudomonas, haemophilus, burkholderia
* some strains developed resistance
Bacterial Mechanisms of resistance to Beta lactams
penetration - poor thus intracellular bacteria not affected
Porins - beta lactams must be able to pass through pores - mutations of porins can alter acessibility
Pumps - efflux pumps
Penicillinases - beta lactamases
Penicillin binding proteins - mutation prevents binding
Peptidoglycan - lacking cell wall intrinsically gives resistance
Intrinsic resistance to beta lactams
intracellular growth
lack of cell wall
porin that excludes antibiotics
Acquired resistance to beta lactams
mutation
genes from phage - transduction
genes from another bacteria - transformation and conjugation
altered penicillin binding proteins - methicillin resistant
efflux pumps (pseudmonas have mutli drug resist pumps)
decreased permeability of gram neg porins
Mechanism of resistance to Cephalosporins
production of beta lactamases
Vancomycin
Laser guided missile
Huge, wont fit through porin
spectrum very narrow
Gram positive only
Mechanism of Vancomycin
cell wall inhibitor - binds to D-Ala-D-Ala
Resistance to Vancomycin
Enterococci change to D-Ala-D-lac
resistance gene on plasmid thus concern could transfer to MRSA
Clinical app of Vancomycin
reserve use for MRSA
penicillin resistant S. pneumo
susceptible enterococcal infection
Daptomycin
Laser guided missile - narrow spectrum cyclic lipopeptide antibiotic lipid portion inserts forming channel in membrane induces bacterial lysis active against aerobic gram + not useful for gram neg bacteria
for Vancomycin resistant enterococci
Daptomycin
Reserve for MRSA, penicillin resistant S. pneumonae, vancomycin resistant enterococci
Daptomycin
No Alcohol with this drug
Metronidazole
Metronidazole
acts as free radical causing strain breaks bacterial DNA
Active against gram neg anaerobes and most gram pos anaerobes including C. Diff
Latent TB treated with
Isoniazid
Penicillin sensitive S. Pneum
Penicillin G
Ampicillin
Penicillian resistant S. Pneumo
can overcome intermediate resistance by increasing dosage otherwise cefuroxime ceftriaxone vancomycin macolides or telithromycin
Staph. Aureus
aerobic and gram + cocci
causes what illnesses
skin and wound infections septicemia Endocarditis Pneumonia septic arthritis and osteomyelitis
All MSSA strains have what mechanism
Beta lactamase production
MRSA resistance confers resistance from
altered PBP
Antibiotics for MSSA
Anti staph penicillins - Nafcillin, oxacillin
Cephalosporins - 1-3rd generation - cefazolin, cefuroxime, ceftriaxone
Antibiotic for Staph Aureus (not MSSA or MRSA)
beta lactam plus beta lactamase inhibitor
Ampicillin-sulbactam
Piperacillin-tazobactam
Ticarcillin-clavulanate
Antibiotics for MRSA (hospital acquired)
Vancomycin
Antibiotics MRSA (community acquired)
clindamycin
Antibiotics for MRSA
Linezolid
Quinupristin-dalfopristin
Daptomycin
Tigecycline (like tetracycline)
culture and sensitivity tests should guide therapy
MRSA isolates may be susceptible to other non beta lactam antibiotics including
clindamycin
doxycycline
minocycline
Pseudomonas Aeruginosa
causes serious infections in compromised hosts
bacteremia
pneumonia
UTIs
wound infection
lungs of CF patients chronically infected
Always base therapy on culture and sensitivity results for this organism
P. Aeruginosa
Resistance mechanisms of P. Aeruginosa
multidrug efflux pump
beta lactamase production
altered porin proteins
aminoglycoside-modifying enzymes
Combination therapy for Pseudomonas
ceftazidime and tobroamycin (beta lactam and aminoglycan)
Piperacillin and ciprofloxacin (extend spectrum and Fluoro)
Treatment for pseudomonas
Extended spectrum penicillins (piperacilin and ticarcilin)
Cephalosporins (ceftazidime 3rd and cefepime 4th)
Carbapenems
Aztreonam
Quinolones - some strains
Aminoglycosides
enterobacteriaceae
aerobic (facultative) gram neg rods
many produce bet lactamases some with broad activity - extended spectrum beta lactamases
E coli can cause
diarrhea intrabdominal infections sepsis UTIs meningitis in infants
shigella
diarrhea
person to person transmission
salmonella
diarrhea
animal to person
klebsiella
pneumonia
Proteus
UTIs
Yersinia
diarrhea
plague
E coli, klebsiella and Proteus
ampicillin
cefazolin
TMP/SMX
fluroquinolones
If enterobacteriaceae is resistant, use bigger guns
3rd gen - cephalosporins, aztreonam, piperacillin-tazobactam, ticarcillin-clavulanate, carbapenems
can add aminoglycans for synergy
N. Gonorrhoeae DOC
problem organisms, lots of resistance
Ceftriaxone (3rd gen)
cefixime
many resistance mechanisms -efflux pumps, beta lactamases, altered PBP, altered porins
N. meningitidis. Treat with?
penicillin
if resistant,
use ceftriaxone or cefotaxime (3rd)
Gram positive anerobes
clostridium
actinomyces
peptostreptococcus
propionibacterium
Gram negative anerobes
bacteriodes
fusobacterium
prevotella
Antibiotics active against at least some Anaerobes
penicillin
clindamycin
metronidazole
some second and third generation cephalosporins
beta lactam/beta lactamase inhibitor combinations
C. Diff causes
antibiotic resistant associated colitis
causes diarrhea and pseudomembranous
C Diff treatment
metronidazole - given first
Vancomycin
Tetracyclines, Macrolides and quinolones are effective for
mycoplasma (intracellular)
chlamydia (intracellular)
Legionella (intracellular)
Rickettsia (intracellular) - no macrolide
B. burgdorferi - treat with?
doxycycline
BUT if kid under 18 use aminopenicillin
T pallidum treat with?
penicillin
what is the second line of drugs for M.tb
streptomycin para-aminosalicylic acid cycloserine ethionamide amikacin levofloxacin capreomycin
MDR-TB is resistant to ?
Isoniazid
Rifampcin
XDR-TB is resistant to?
Isoniazid
Rif
fluoroquinolone
and one of three injectable second line drugs (capre, kana, amik)
What anti Tb drugs acts through inhibiting cell wall synthesis?
Isoniazid
Ethambutol
What Tb drug acts through disrupting the membrane?
Pyrazinamide
What drug for TB inhibits RNA synthesis?
Rifampin