Antibiotics--exam 1 Flashcards by Adam Killpack

Penicillin (prototype)

β lactam ring forms irreversible covalent acyl-bond w/ transpeptidase enzyme (PBP)
Prevent x-linking (transpeptidation)
-cell continues to degrade wall (remodel)→ osmotic lysis
time dependent killing
most rapidly excreted drug by normal kidney
-can be partially blocked → probenecid
-can exacerbate gout
one of the most NON-TOXIC and SAFEST drugs
can produce all 4 types of hypersensitivities
-**most allergenic of Abx, then Sulfa then cephalosporins
-all are cross-allergic & sensitizing
-procaine-penicillin combo is worst

Toxicities (mostly dose dependent)

1) tissue irritation
2) excess Na, K+ from large doses → cardiac & renal toxicity
3) Soft frothy stools & diarrhea → broader spectrum is worse
- overgrowth of staph, pseudomonas, proteus or yeast
4) Superinfection
5) Jarisch-Herxheimer Rxn → severe febrile reaction
- -occurs in syphilis or leptospirosis due to massive killing

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Penicillin G potassium (IV, IM)
Penicillin G benzathine (IM depot)
Penicillin G procaine (IM)
Penicillin V (acid resistant → oral)

Natural penicillin

Penicillin G benzathine → longest acting preparation
-Treat → Syphilis (DOC) & Rheumatic fever
-mild/mod infections
-prophylaxis
activity against gram positives→ **HIGHEST
spectrum→ some G-
activity against anaerobes→ some
activity against pseudomonas aeruginosa→ none
penicillinase resistance→ readily inactivated
acid resistance→ only penicillin V
main route of elimination→ active transport in kidney
-no metabolism → no drug interactions
CNS penetration→ poor penetration (↑ w/ inflammation)

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Nafcillin (parenteral)

Oxacillin (oral)
Dicloxacillin (oral)
Methicillin

Penicillinase resistant penicillins*
(Anti-staphylococcal penicillins)

-**DOC for penicillinase producing staph. auerus
Methicillin was most common cause of interstitial nephritis
activity against gram positives→ lower against certain
spectrum→ some
activity against anaerobes→ some
activity against pseudomonas aeruginosa→
penicillinase resistance→ resistant
acid resistance→ some & **highly protein bound
-loading dose → 2x usual dose
main route of elimination→ **hepatic & renal excretion

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Amoxicillin

–Ampicillin

Extended spectrum penicillins* (amino penicillins)

activity against gram positives→ lower
spectrum→ extended G- (PeSSkEy, H. influ)
activity against anaerobes→ yes; w/ penicillinase inhibitors
activity against pseudomonas aeruginosa→ none
penicillinase resistance→ susceptible
acid resistance→ resistant
main route of elimination→ urinary excretion
Ampicillin rash → not allergic or itchy
-can occur w/ EBV

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Piperacillin

–Ticarcillin

Antipseudomonal Penicillin

activity against gram positives→ lower
spectrum→ same as amoxicillin + some G- enteric bacilli
activity against anaerobes→ yes; w/ penicillinase inhibitors
activity against pseudomonas aeruginosa→ YES
penicillinase resistance→ susceptible
acid resistance→ sensitive
main route of elimination→ renal excretion

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Aztreonam

Monobactam (same mxn as penicillin)

relatively resistant to β-lactamases
Targets → Gram negative rods (including Pseudomonas & Serrate)
NO ACTIVITY → Gram+ or anaerobes
Safe in pts w/ Penicillin allergy

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Imipenem, Cilastatin

-meropenem
-ertapenem
-doripenem

Carbapenems (same mxn as penicillin)

broad spectrum → anaerobes, G+, G- rods
-Pseudomonas may develop res. → add amino glycoside
Imipenem → inactivated by renal dehydropeptivdases
-must be given w/ Cilastatin
-can cause seizures
Meropenem → resistant to dehydropeptidases
less likely to cause seizures
Ertapenem → highly stable against β-lactamases
particularly effective against Enterobacteriaceae

-Doripenem → good activity against pseudomonas

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Clavulanic acid

-sulbactam
-tazobactam

Beta-lactamase inhibitors

resemble beta-lactam molecule
weak antibacterial action
inhibit many, but not all BETA LACTAMASES
-most active against → plasmid encoded lactamases

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Vancomycin

–teicoplanin

Inhibitor of cell wall synthesis (glycopeptides)

binds terminal D-alanine D-alanine of nascent PG pentapeptide
→ inhibits transglycosylase → no chain elongation
-**inhibits transpeptidation (cross linking)
ONLY effective for Gram+
staph aureus & epidermidis
strep & enterococci, corynebacterium & clostridium
penicillin and methicillin resistant staphylococcal (DOC)
-patient w/ penicillin allergy
parenteral
-sometimes oral → GI infections (pseudomem. colitis)
poor CNS penetration → don’t use for meningitis

Resistance → D-Ala-D-Ala → D-Ala-D-LACTATE

excreted unchanged in kidney → marked accumulation
nephrotoxicity in presence of renal insufficiency
-uremia after high dose may be FATAL
ototoxic
red man syndrome → histamine release

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Telavancin

Inhibitor of cell wall synthesis (lipoglycopeptide)

binds terminal D-alanine D-alanine of nascent PG pentapeptide (no elongation or x-linking like vancomycin)
↑ membrane permeability (like daptomycin)
bactericidal → select Gram+, MRSA
complicated skin & skin structure infections
take 1x day
CI → pregnancy & renal insufficiency

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Fosfomycin

Inhibitor of cell wall synthesis

inhibits one of the key 1st steps of peptidoglycan synthesis
-irreversibly inactivates enolpyruvyl transferase
-nucleotide precursors accumulate → death & lysis
active against Gram+ & Gram-
-uncomplicated lower UTI in women

-taken orally → excreted by kidney

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Bacitracin

Inhibitor of cell wall synthesis

inhibits activation (dephosporylation) of the lipid carrier
-no transport of peptidoglycan subunits (water soluble) through cell membrane
accumulate in cytoplasm→ not added to growing PG chain

-mainly target Gram+
-topical or parenteral
–serious nephrotoxicity w/ PE admin
–most commonly use in combo w/ polymyxin B & Neomycin
topically→ prevent superficial skin and eye infection

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Cycloserine

Inhibitor of cell wall synthesis

analog of D-alanine
competes w/ D-alanine for 2 enzymes (incorporate alanine)
-inhibits both enzymes & peptidoglycan synthesis
→ weak cell wall & eventual cell lysis
2nd line against active pulmonary & extra-pulm TB
severe CNS toxicity (anxiety, confusion, memory loss, seizures, etc.)

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Cephalosporins

β lactam ring forms irreversible covalent acyl-bond w/ transpeptidase enzyme (PBP)
Prevent x-linking (transpeptidation)
-cell continues to degrade wall (remodel)→ osmotic lysis
has a 7-methyl group → ↑ resistance to β-lactamase
resistance mxn → same as w/ penicillin
most have some plasma protein binding
penetrate most tissues → not eye & CNS
most excreted unchanged by kidney
-Probenecid → ↓ excretion & ↑ 1/2 life
-adjust dosage w/ renal insufficiency

Adverse

pseudomembranous colitis → ↑ specturm ↑ chance
dose dependent renal tubular necrosis
synergistic nephrotoxicity w/ aminoglycosides (esp in elderly)

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Properties of ICWS

activity against gram positives→
spectrum→
activity against anaerobes→
activity against pseudomonas aeruginosa→
penicillinase resistance→
acid resistance→
main route of elimination→
CNS penetration→

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Mechanisms of Bacterial Resistance

Inactivation by penicillinase (may be inducible)
↓ permeability of outer membrane (only G-) → prevents reaching PBP
Alteration of PBP (mxn if resistant to Methicillin)
Autolytic enzymes not activated (Listeria & Staph)
Lack cell wall (Mycoplasma)
Non-peptidoglycan cell wall (Chlamydia)

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Daptomycin

Inhibitor of cell wall synthesis (lipopeptide)

binds to bacterial membranes → rapid depolarization
→ inhibits protein, DNA, and RNA synthesis → death
bactericidal → Gram+
NO MXN OF RESISTANCE

-IV → excreted unchanged by kidneys

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Cefazolin (IV)

Cefadroxil Monohydrate (oral)
Cephalexin (oral)

First Gen. Cephalosporin (narrow spectrum)

good activity → Gram + (EXCEPT enterococci)
-most G+ cocci except → enterocci, MRSA, MRSEpi
-NO β-lactam is effective against MRSA
moderate activity → Gram -
good activity → E. coli, Klebsiella pneum., Proteus marbles
-1st & 2nd gen. → DOC for E. coli

Cefazolin → surgical prophylaxis

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Cefoxitin (IM, IV)

Cefaclor (Oral)
Cefotetan (IM, IV)
Loracarbef (Oral)

Second Gen. Cephalosporin (intermediate spectrum)

good activity → Gram +
increased activity → Gram -
good activity → E. coli, Klebsiella pneum., Proteus marbles
-1st & 2nd gen. → DOC for E. coli

Cefaclor → serum sickness like SE
Cefotetan & Loracarbef → disulfiram like effect
–inhibits acetyladehyde deydrogenase

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Cefotaxime Sodium

Ceftizoxime
Ceftazidime
Ceftriaxone
Cefixime

Third Gen. Cephalosporin (broad-spectrum)

→ diff from 1st & 2nd gen

pretty good G+ and G- coverage
-↓ G+ cocci but ↑ enterobacteriaceae coverage
even more resistant to B-lactamase
some will get into CNS → Cefotaxime & Ceftriaxone
effective against → Pseudomonas
first line choice → Salmonella
mostly/half metabolized → liver
-if it is lipid soluble wont be excreted in kidney and must be conjugated in liver

Ceftriaxone → ↑ hepatic elimination
--DOC gonnorhea
--penicillin resistant strep. pneumoniae
Cefixime → ORAL
Ceftizoxime & Ceftazidime → antipseudomonal

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Cefepime

Fourth Gen. Cephalosporin

good G+ and G- (similar to 3rd gen)
more resistant to some β-lactamases
anti-pseudomonal (similar to Ceftazidime)
better activity → Enterobacter & Citrobacter
reserved for ICU and severe systemic infections
↑ penetrvity → Enterobacter & Citrobacter
reserved for ICU and severe systemic infections

-penetrates CSF

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Ceftarolime fosamil

Unnamed gen. Cephalosporin

effective against MSSA, MRSA, & VRSA

high affinity to → PBP 2A (responsible for resistance)
-encded by mega
no antipseudomonal

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Organisms not reliably covered by cephalosporins

Enterococci → Penicillin
List. Monocytogenes → Penicillin
MRSA
Atypicals → Chlamydia & Mycoplasma

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Cephalosporins are 1st choice for infections with:

Moraxella catarrhalis → 2nd or 3rd gen
Neisseria gonorrhoeae → ceftriaxone, cefixime (oral)
E. coli, Klebsiella, Proteus → 1st or 2nd gen.
Salmonella → 3rd gen
Penicillin resistant Strep. pneumonia → ceftriaxone

MAY be used:

Gram + infections in penicillin-sensitve patiens
mixed infections → cellulitis or skin ulcers in diabetic
surgical prophylaxis → cefazolin
UTI → excreted & concentrated in urine

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Sulfonamide mechanism & uses

Sulfonamide (bacteriostatic)

-competes w/ PABA at dihydropteroate synthase
→ blocks formation of DHF
–folic acid necessary for Purine & DNA synthesis
–susceptible bacteria can’t multiply, grow, or survive
–mammals do not synthesize folic acid like bacteria

-inhibit both Gram+ and Gram-

RESISTANCE

-↓ sensitivity of target enzyme
-↑ formation of PABA
-use of exogenous folate

USES

DOC→ UTI infections (1st attack & prophylaxis)
DOC→ Nocardiosis
Toxoplasmosis & Trachoma
Pneumocytstis carinii → children and AIDS patients

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Sulfonamide distribution, metabolism/excretion, interactions and Toxicity

good distribution
-cross placenta and BBB
Good degree of plasma protein binding → no neg. effect
***urine conc. → 10-20x plasma can be reached for UTI
-at high concentrations → bactericidal
Metabolized in liver → acetylated products
Excreted through kidney
-insoluble (esp. *acidic urine) → crystalluria & renal dmg
–drink more water or alkalize urine

TOXICITIES

every organ systems may be adversely affected
Kernicterus in nursing infant → displaces bound bilirubin →CI infants <2 months
Drug sensitivy (allergy 6%, 2nd to penicillin)
Blod dyscrasia, leukopenia, granulocytopenia,
-thrombocytopenia, agranulocytosis
Kidney & Liver damage
Stevens-Johnson syndrom (dermal toxic lysis → lose epi)
Microscopic hematuria→ crystals damage
PHOTOSENSITIVITY

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Sulfasalazine

Sulfonamide (bacteriostatic)

competes w/ PABA→ blocks formation of DHF
-prodrug cleaved GI bacteria→ sulfapyridine + mesalamine
-local actions of melamine → effectiveness of sulfasalazine
used to treat Ulcerative Colitis
oral

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Silver Sulfadiazine

Sulfonamide (bacteriostatic)

exact mechanism is unknown→ dent inhibit FA synthesis
-damages cell membrane and cell wall
Topical → prevent & treat infections → 2nd/3rdº burns
Activity against → Bacteria AND yeast
does not inhibit CA (Mafenide does)
doesn’t stain dressing or tissue

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Trimethoprimp

Folate Antagonist

inhibits DHF reductase → blocs formation of THF
-THF needed for carbon transfer → NA, protein synthesis
-therapeutic does → no human enzyme inhibition
activity against Gram+ and Gram-
commonly used systemically for treatment & prophylaxis:
-uncomplicated UTI
–alone may be as effective → recurrent UTI
-traveler’s diarrhea
- - SMX or dapsone → pneumocystis carinii
can be used w/ impaired renal function or if sulfa drugs can’t be tolerated
may be TERATOGENIC → don’t take during pregnancy

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Co-trimoxazole (Bactrim)

Sulfamethoxazole + Trimethoprim (TMP-SMX)

Sulfonamide Combo

Sulfamethxazole blocks PABA incorporation to DHF
Trimethoprim prevents reduction of DHF to THF
-selective for DHF reductase of lower organisms
fixed 1:5 ratio (TMP-SMX) → 1:20 serum concentrations
DOC for uncomplicated UTI (except for enterococci)
-Prostatitis (along w/ doxycycline & fluoroquinolones)
DOC for Moraxella catarrhalis
P. jiroveci pneumonia (also TMP + dapsone)
-respiratory tract pathogens → pneumococcus
–Haemophilus, Moraxella catarrhalis, Klebsiella pneumonia
Shigellosis & systemic salmonella infections
some non TB myco infections
MSSA & MRSA
otitis media
2nd line for Listeria

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Sulfadoxine + Pyrimethamine

Sulfonamide Combo

pyrimethamine → inhibits parasitic DHF reductase
sulfadoxine → antagonizes PABA
–synergistic activity on FA production

used in combo → malaria treatment
-not prophylaxis → fatal toxic epidermal necrolysis

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Sulfadiazine

Sulfonamide (bacteriostatic)

-competes w/ PABA→ blocks formation of DHF

oral, intermediate duration
used w/ Pyrimethamine → toxoplasmosis
POORLY SOLUBLE in urine → CRYSTALLURIA (most likely)
-limited use for serious infection

Macrolide Group

Protein Synthesis Inhibitor

bacteriostatic??
effective alternative to penicillin → allergy or kidney failure
among the SAFEST antibiotics
Clarithromycin & Azithromycin → respiratory, skin & skin structure infections

Eryhthromycin mechanism, uses, resistances

Macrolide

reversibly binds 50s subunit → blocks translocation (A→P)
-near binding site for Chloramphenicol → antagonistic
spectrum similiar to Penicillin G
most active against → G+ cocci
active against → G+ bacilli (clostridium
effective against → Mycoplasma pneumonia
majority of gram negative → resistant

USE

most commonly → mixed infections of skin, soft tissue, body cavities caused by Gram-positive organisms
alternative to penicillin
Group A strep pyogenes → cellulites, scarlet fever, pharyngitis, erysipelas
Acute diphtheria
1ry pneumonia → M. pneumoniae & chlamydia
DOC → Legionnaire’s disease (legionella pneumophila)
-atypical pneumonia ??

RESISTANCE (mostly plasmid encoded)

1) Drug efflux by active pump
2) **Methylase enzymes→ modify ribosomal target; ↓binding
- -cross resistance w/ all members of group
3) Hydrolysis by esterases from enterobacteriaceae
4) Chromosomal mutations → alter a 50s ribosomal proein

Eryhthromycin metabolism, toxicity, adverse reactions, and drug interactions

Gastric acid → rapidly destroy erythromycin base
crosses placenta, penetrates prostatic fluid
no CNS penetration
Primarily fecal excretions (large amounts lost)
-some in bile → reabsorbed
Intravenous → E. Gluceptate & E. Lactobionate when large doses needed

ADVERSE

GI disturbances
DIARRHEA → stimulates motilin
-may help constipation
QT prolongation, torsades de pointes
-worst in group, but all do it
transient hearing loss → ototoxicity

INTERACTIONS

inhibits CYP3A4 → ↑ serum [ ] of other drugs
-→ serious QT prolongation and cardiac arrhythmias w/
-Cispride, Pimozide, Sparfloxacin or Grepafloxacin
changes GI flora → ↓ estrogen enterohepatic circulation
ICWS are made ineffective → they need growth to work
statins -> rhabdomyolysis

Clarithromycin

Macrolide
-binds to 50s subunit → protein synthesis inhibition

most common use → infections of respiratory tract
penetrates lung tissue & macrophage > Erythromycin
-**effective against MAC
H. pylori-associated duodenal ulcer
community-acquired pneumonia in children
inhibition of CYP3A4 → ↑ serum [ ] of other drugs
less QT elongation than Erythromycin
well tolerated → no disabling nausea & vomiting
other adverse reactions similar to erythromycin
best oral of macrolides

Azithromycin

Macrolide
-binds to 50s subunit → protein synthesis inhibition

not metabolized by liver & excreted into bile
→ less interactions & inhibition of P450
can be dosed → 1 daily
less GI intolerance than Erythromycin
reaches higher intracellular concentrations
-↑ efficacy & duration of action

USES

active against same organisms as erythromycin
STD → Chlamydia & gonorrhea combine w/ Ceftriaxone
pediatric otitis media, pharyngitis, MAC prophylaxis
IV for initial treatment of CA pneumonia & PID

Telithromycin

Ketolide
-binds 50s subunit → inhibits protein synthesis

greater antibacterial killing than macrolides
good against respiratory pathogens
-**erythromycin & penicillin resistant pneumococci
activity → intracellular and atypical bacteria
metabolized by CYP3A4
diarrhea, nausea, vomiting → most common SE
serious hepatoxicity

Clindamycin

Inhibitor of Protein synthesis
-binds 50s subunit → inhibits protein synthesis

**effective anti-aerobic antibiotic
-MOST anaerobes → G+ & G-
w/ pyrimethamine → toxoplasmic encephalitis in AIDS
strep (not enterococci) & staph → very susceptible
topically for acne → inhibits lipase-producing organism
-↓ FFA in sebum → inflammatory lesion w/ acne
well absorbed orally → high [ ] **BONE, bile, and urine
-poor CSF concentrations
well know cause → pseudomembranous colitis (c. dificile)

Dalfopristin; Quinupristin (Synercid)

Streptogramin

irreversible block ribosome functioning
-Dalfopristin → 70s or 50s → inhibits early phase
-Quinupristin → 50s → inhibits late phase
combo has up to 16x activity of each agent alone

USE (IV infusion)

**Vancomycin resistant enterococcus faecium bacteremia
Complicated skin and skin structure due to staph aureus
nausea, vomiting, pain, puritis, rash
inhibits CYP 3A4 (↓ cyclosporin, midazolam, nifedipine)

CI → pregnancy, children, breast feeding, hepatic disease

Linezolid

Oxazolidinones

-binds 50s → prevents formation of functional 70s initiation complex → blocks translation

**-reversible, non-selective inhibition → MAO!!

predominant activity → aerobic gram positive
-bacterial pneumonia
-skin & skin structure infections
-Vanco resistant enterococcal infections
-MRSA

-CI → pheochromocytoma or hypersensitivity

Isoniazid

Primary Antimycobacterial agent

inhibits biosynthesis of Mycolic acid
can reach intracellular bacteria (streptomycin can’t)
prodrug activated by Mtb protein (KatG → resistance)
-develops quickly when given alone
ALWAYS combo w/ rifampin, streptomycin or ethambutol for ACTIVE TB
given SOLO for LATENT TB
bactericidal → actively growing bacilli
bacteriostatic → latent or dormant infection
combo w/ Rifampin → bacteriocidal
most atypical mycobacteria → resistant to INH

TOXICITY:

CNS stimulation (convulsions
peripheral neuritis → slow acetylators (↓ by Pyridoxine)
liver damage → fast acetylators (MUST test liver enzymes)
Hemolysis → G6PD
Lupus like syndrome

Rifampin

Primary Antimycobacterial agent

inhibits DNA-dependent RNA polymerase
-resistance → mutation rpoB gene
primarily used for TB in combo w/ other anti-TB drugs
effective against TB & some atypical in very low [ ]
inhibits growth → G+ cocci and some G-
**bactericidal → active, latent, intra-/extra-cellular bacilli
-can be used alone for latent TB
prophylaxis for TB → HIV pts (Rifabutin if taking protease inhibitors)
Asymtomatic carriers of N. meningitidis (not for usual infxn)
***strong bactericidal activity → Leprosy
excreted primarily through Bile
induces CYP3A4
↓↓ effectiveness of oral contraceptives
↑ requirement of methadone
make tears, urine, and sweat harmless ORANGE

Rifabutin

Primary Antimycobacterial agent

-inhibits DNA-dependent RNA polymerase

very lipophilic → wide dist. (5-10x [ ] in lungs than serum)
→ substantial intracellular accumulation
Alternative to Rifampin
-LESS potent inducer of CYP → HIV pts on HAART
alternative to Clarithromycin or Azithromycin for 1ry MAC prophylaxis in HIV pts.
alternative to Rifampin for TB/TB prophylaxis in HIV pts if resistant to isoniazid
discoloration → URINE, tears, sweat, feces, saliva, sputum
thrombocytopenia (not significant)

Pyrazinamide

Primary Antimycobacterial agent

requires conversion to active form
-resistance → mutation pncA
Mechanism not well understood
bacteriostatic/bacteriocidal
HIGH risk of hepatic injury
hyperuricemia
-CI if any degree of hepatic dysfunction

Ethambutol

Primary Antimycobacterial agent

inhibits arabinosyl transferases → cell wall synthesis
-inhibits arabinogalactan synthesis
-resistance → mutation in embCAB
bacteriostatic

-about 1/2 excreted in urine unchanged

↓ visual acuity
loss of green-red perception → retrobulbar neuritis
-not recommended for children < 13 yrs.

Streptomycin

Aminoglycoside (Primary Antimycobacterial agent)

-Protein synthesis inhibitor → 30s (bactericidal)

(para-)Aminosalocylic acid