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Flashcards in Antibacterial Drugs Deck (135):

What are the four main antibiotic antimetabolites and nucleic acid inhibitors ?

1. Sulfonamides
2. Fluoroquinolones
3. Other (for UTI)
4. Rifamycins


What are the 2 major sulfonamides?

1. Sulfisoxazole
2. sulfamethoxazole-trimethoprim (co-trimoxazole)


What are the 2 major fluoroquinolones?

1. ciprofloxacin
2. levofloxacin


What drugs are used as antimetabolite/nucleic acid inhibitors for UTI?

1. nitrofurantoin
2. metronidazole


What rifamycin drugs are we responsible for?

1. rifampin
2. rifabutin


What are the major categories of antibiotics used as cell wall inhibitors?

1. B-lactams
2. glyopeptides
3. "Other"- bacitracin, cycloserine, fosfomycin


What are 3 categories of B- lactams we are responsible for?

1. penecillins
2. cephalosporin
3. "other"


What are the major penecillins? (8)

1. Pen G
2. Pen G- benzathine
3. nafcillin
4. oxacillin
5. ampicillin
6. amoxicillin
7. ticarcillin
8. piperacillin


What are the major cephalosporins?

1. cefazolin
2. cephalexin
3. cefuroxime
4. cefoxitin
5. cefotaxime
6. ceftriaxone
7. ceftazidime
8. cefepime


What two b-lactams are NOT penecillins or cephalosporins?

Clavulanic acid
imipenem (+cilastatin)


What is the major glycopeptide bacterial cell wall inhibitor?



What are the four types of ribosome binder antibiotics?

1. aminoglycosides
2. tetracyclines
3. MLSK drugs
4. Linezolid


What are the major aminoglycosides?

1. streptomycin
2. gentamycin
3. tobramycin
4. amikacin


What are the major tetracyclines?

1. tetracycline
2. doxycycline
3. minocycline


What are the three classes of MSLK drugs we are responsible for?

1. Macrolides (erythromycin, clarithromycin, azithromycin)
2. Lincosamide (clindamycin)
3. Streptogramin (Quinupristin-dalfopristin)


What are the three macrolides we are responsible for?

1. erythromycin
2. clarithromycin
3. azithromycin


What is the major lincosamide we are responsible for?



What is the major streptogramin we are responsible for?



What antimicrobial drug is a lipopeptide?



What antimicrobials are anti-leprosy drugs?

1. dapsone
2. rifampin


Are sulfonamide drugs bacteria static or bactericidal?



All cells require ______ acid to grow, divide and sustain metabolism.
The active form is ____________ which must transfer carbons to synthesize purines, pyrimidines and several AA.

folic acid.
The active form is tetrahydrofolate


What is different about mammalian cells and microbes in regard to folic acid acquisition?

Mammalian cells take folic acid in as a vitamin through folic acid receptors
Microbes synthesize folic acid


What are the three moieties of folic acid?

1. pABA
2. dihydropteridine
3. glutamate


What is the first step in the microbial synthesis of folate?

pABA and dihydropteridine condense to make dihydropteroic acid.


What is the mchanism of action of sulfonamide drugs?

They are pABA analogs and act as competitive inhibitors for dihydropteroic acid synthase


What antagonizes the function of sulfonamide drugs?

Tissue break down products because microbes can import purines, pyrimidines and AA from the pus bypassing the need to synthesize their own


What are the steps of folic acid synthesis in microbes?

What drugs inhibit steps in this pathway?

1. pABA + dihydropteredine-->DAS--> dihydropteroic acid
2. dihydropteroic acid + 1 to 6 glutamic acids--> dihydrofolate
3. dihydrofolate--> DHFR--> tetrafolate

Sulfonamides are competitive inhibitors for DAS by mimicking pABA

Trimethaprim inhibits DHFR


What are two mechanisms of resistance to sulfonamides?

1. excess pABA concentration in the microbe cytoplasm
2. altered DAS that does not bind sulfonamides


How are sulfonamides:
1. absorbed
2. distributed
3. Metabolized
4. excreted

1. orally
2. distribute to all tissues including CNS
3. metabolized via acetylation in the liver
4. glomerular filtration


In a patient with what deficiency would the use of sulfonamide be contraindicated?

In patients with G6PD deficiency (lacking G6phosphate dehydrogenase).
If they lack G6PD they will not make glutathione reductase which is necessary to reduce oxidative substances.

Sulfonamides make a lot of oxidized species


What are the therapeutic uses for sulfonamides alone?

1. Nocardia infections
2. Minor UTI because G- and chlamydia respond


What are the therapeutic uses for sulfamethoxazole-trimethaprim (cotrimoxazole)?

What bacterial species is it effective against?
What bacterial species is it ineffective against?

This would inhibit two steps in folic acid biosythesis and act synergistically --> bactericidal

-Shigella, typhoid fever, salmonella, p. jirovecii
- ear infections

This gives protection against G+, G-, MRSA and fungi.
NOT protective against anaerobes


What is the most popular sulfonamide for single-drug therapy? Why?

1. free and acetylated are both soluble
2. practically no side effects
3. good CNS distribution


Which sulfonamide is typically used with trimethaprim? Why?

sulfamethoxazole because it has a longer half life than sulfisoxazole so it is more matched to the half life of trimethaprim


What bacteria are fluoroquinolones used against?
What bacteria are they not effective against?
Are they bactericidal or bacteristatic?

G+, G- and other infections (broad spectrum)
They are only effective against aerobes
They are bactericidal


What is the mechanism of fluroquinolone action?

They bind prokaryotic topoisomeraseIV or gyrase-DNA complexes inactivating the enzymes.
This makes them no longer able to relieve supercoil of the DNA and inhibits transcription and replication


_____________________ is the major target for fluoroquinolones in G+ bacteria while ________ is the target in G- bacteria.

Topoisomerase IV= G+ target
Gyrase = G- target


Describe the pharmokinetics of fluoroquinolines.
1. Absorption
2. distribution
3. metabolism
4. excretion

1. absorbed orally (but inhibited by cations like milk, antacids, Fe and Ca)
2. NO CNS penetration
3/4- depends. some enter bile and enterohepatic circulation while others are eliminated by the kidney


Who would the use of fluoroquinolines be contraindicated in?

1. children under 18 and women because it weakens cartilage
2. Skin sensitive because it causes phototoxicity


How is resistance to fluoroquinolines achieved?

due to its widespread use in animal feed, resistance is now due to
1.altered topoisomerase target
2. increased efflux and decreased influx mechanisms


What are the two major fluoroquinolones and what is the difference between the two?

1. Ciprofloxacin- used widespread but not respiratory because it is weakly active against Strep pneumonia
2. Levofloxacin- Active against strep pneumonia, staph, G+ and G-


What is nitrofurantoin used to treat?
What is the mechanism of action?
Is it static or cidal?
Who cannot use it?

It is used to treat UTI
It is reduced within bacterial cells and makes toxic intermediates to damage DNA
It is both static and cidal.
Pregnant women can't use it because it causes hemolytic anemia in newborns


What is metronidazole used to treat?
How is it different from the other anti-metabolite/nucleic acid inhibitor drugs?

UTI and is active against protozoal and anaerobic bacteria


What is the mechanism of action of rifamycin?
Is this class of drugs bacteriostatic or bactericidal?

They bind to DNA-directed RNA polymerase to inhibit it. This blocks initiation of transcription.



What are the two main rifamycin drugs?
What infections are they used against?

1. Rifampin- TB, prophylaxis of meningococcal meningitis, Legionella,hat leprosy in dapsone-resistant populations
2. Rifabutin- TB and Mycobacterium avium (MAC infection common in AIDs patients)


How do b-lactams inhibit bacterial growth in general?

They inhibit cell wall production and remodelling and activate autolysin.


What are the steps in bacterial cell wall synthesis?

1. disaccharide pentapeptide is synthesized
2. It binds to an isoprenoid lipid and flips across the membrane
3. Attachment of the disaccharide to the growing polysaccharide chain is established
4. Pentapeptides are crosslinked by transpeptidase which binds to the terminal D-ala-D-ala


What is different structurally between penecillins, cephalosporins and carbopenems (imipenem)

They all have the same b-lactam structure (cyclic structure with 4 sides and a nitrogen amide in the ring)
They differ in the second ring adjacent to the b-lactam.
Penicillin- five member ring with a S group
Cephalosporin- six member ring with a S group
Carbopenem- five member ring with no sulfur


What is the mechanism of action that B-lactams work?
Is the effect bacteriostatic or bactericidal?

1. They resemble D-ala-D-ala so transpeptidase will bind irreversible to the b-lactam and will be inactivated.
The bacteria will not be able to synthesize the cell wall (or remodel it) and thus will cease growing.
This effect is bacteriostatic.
2. Once cell wall synthesis is stopped by B-lactam, autolysins will degrade the cell wall and the cell will lyse
This is bactericidal


What must the cell be doing for a b-lactam to be an effective drug?

The cell must be growing to be killed by penicillin. The more vigorous the growth, the stronger the effect


What are the two main mechanisms of bacterial resistance to beta-lactams?

1. Inherent resistance-
*porins of G- and b-lactamase concentration in G- periplasm
2. Acquired resistance
*beta-lactamases break the unstable 90 degree bonds of the b-lactam
*transpeptidases have altered structure


B- lactams are great drugs for ________ infections but are less effective against ______ because______.

They are great with G+ but are less good at G- due to inability to come through porins and b-lactamase concentrated in the periplasm


What drug is a suicide inhibitor of b-lactamases, encouraging its use with penicillin or cephalosporin resistant bacteria?

Clavulanic acid


Describe the pharmacokinetics of beta-lactams.
1. absorption
2. distribution
3. elimination

1. They are acid labile so NOT delivered orally (exceptions: PenV, ampicillin/amoxicillin)
2. Widely distributed but not CNS or eyes unless there is meningitis. Low half life (hours, penG 30min)
3. Renal- glom filtration and organic acid pump


Why is penicillin able to be used for meningitis?

Because inflamed tissue allow penicillin past the BBB.
Drawback- relapses can occur one the BBB reseals


Why is the half life of penicillins so short?
What drug can lengthen the half life?

PenG (30min) to a few hours for the others.
The half life is short because renal elimination uses glomerular filtration and an organic acid pump in the kidney secreting it in the urine.

Probenecid is used blocks the organic acid pump in the kidneys


What is the function of probenecid?
What is the drawback of using it?

It is used to block the organic acid pump in the kidney that excretes penicillin so it prolongs the half life.
The drawback is that it inhibits the organic pump in the choroid plexus that eliminates the drug from the brain. This can lead to build up and seizure


When referring to penicillin allergies, what is meant by major and minor?
What causes the sensitivity in each?
Which is more severe?

The frequency of the allergy NOT the severity

Major- penicillin molecules covalently linked to lysine of serum proteins. Determined with a skin test. Seldom life threatening

Minor- breakdown products of penicillin and penicillin itself that can lead to life-threatening reactions.


If a patient is mildly allergic to a penicillin, administering a ____________ would probably be safe and vice versa.



How can you elicit a subclinical mast cell response when a patient has a penicillin allergy?

Give minute doses and slowly increase. This may desensitize but is also very dangerous and usually avoided


Aside from allergies, what are the adverse effects of using beta lactams?

1. large amount of sodium
2. seizures when accumulated in the brain (exacerbated by probenecid)
3. broad spectrum (cephalosporin) can lead to superinfections


What type of infection would you use a B-lactam against?

Most effective against G+ and spirochetes

Antipseudomonal b-lactams (ticarcillin and piperacillin)

3rd and 4th generation cephalosporins G- (but then become less good at G+ so its a trade off)


What are the two major narrow spectrum penicillins and what is the difference?

Pen G= acid labile but more potent
Pen V= acid stable (oral) but less potent


What is Pen G-benzathine?

a form of penicillin G that has a 1 to 2 week half life (much much longer than the normal 30-60 minutes)
It has a much lower serum concentration though


______________________ are inversely related to the half life when discussion penicillins.

Serum concentrations


What are the therapeutic uses for Pen G?
Which strains are usually resistant

G+ cocci and bacilli (but not enterococcus)
N. gonorrhea

S aureus and N. gonnorhea are mostly resistant
Strep faecalis is less sensitive


What are oxacillin and nafcillin used against?
What is the difference?

Nafcillin is the new "methicillin" and is used on staph that is resistant to pen G. ACID LABILE

Oxacillin is for less severe staph. ACID STABLE


What have MRSA strains acquired that make them resistant ?

MecA transpeptidase that is resistant to binding of beta-lactams


What are the broader spectrum penicillins?

Both are acid stable and orally prescribed
They are broader spectrum because in addition to G+, they are effective against:
1. H infleunza
2. E coli
3. proteus


Ticarcillin and piperacillin are used against what pathogens?
Why are they often prescribed with aminoglycosides?

They are anti-pseudomonal against P. aeruginosa as well as G- like Klebsiella and Serratia

They are frequently prescribed with aminoglycosides (that are effective against G-) because MIC for ticarcillin and piperacillin are too close to the therapeutic index


What are 4 reasons that cephalosporins are considered to be improved over some penicillins?

1. They can be used in pen allergic patients
2. Less sensitive to b-lactamases (including S aureus lactamase)
3. 2nd to 4th generation can penetrate CSF
4. Prophylaxis for surgery bc some can be useful against G- and anaerobes


What is the spectrum for first generation cephalosporin?
What are 2 examples of a first generation?

Similar to ampicillin. It covers G+, and a few G- (klebsiella, e coli, proteus)
Great against penicillinase staph strains

Parenteral = cefazolihat
Oral= cephalexin


What is the spectrum for 2nd generation cephalosporin?
What are 2 examples and what is the benefit of each?

Increased G- spread to include H influenza, enterobacter, neisseria
More effective at anaerobes

Cefuroxime- crosses BBB

Cefoxitin- good at anaerobes


What is the spectrum of 3rd generation cephalosporin?
What problem is encountered with third generation?
What are 3 examples?

Broader spectrum G-, pseudomonas, gets into CSF.
Problem is this increases superinfection risk.
1. cefotaxime
2. ceftriaxone
3. ceftazidime


What are the three 3rd generation cephalosporin and what is unique to each?

1. Cefotaxime- resistant to beta-lactamases, good for meningitis

2. Ceftriaxone- longest half life; gonorrhea (1st choice), meningitis, lyme disease

3. Ceftazidime- antipseudomonal


What is the difference between third and fourth/fifth spectrum cephalosporins?

Broader spectrum, greater resistance to beta-lactamases, greatest potency


What is the major 4th/5th generation cephalosporin?

Cefepime- better against staph, more b-lactamase resistant, great CSF penetration


What is the spectrum of Imipenem?

EXTREMELY broad spectrum
1. G+
2. G-
3. aerobes AND anaerobes

Resistant to most b-lactamases BUT in the last few years carbopenem-resistant enterobacteriacaeae have been developing


What is CRE?

carbopenem resistant enterobacteriaceae that is resistant to all drugs and the broadest spectrum drug imipenem


What is imipenem usually given in combination with? Why?

It is usually inactivated in the renal tubules by dihydropeptidases.

Cilastatin inactivates these enzymes


What does clavulanic acid do?

Inactivates beta-lactamases
Usual combos:
1. amoxacillin-clavulanic acid
2. piperacillin-tazobactam


What is the mechanism of action of vancomycin? What is the spectrum?
Is it bactericidal or bacteriostatic?

Instead of resembling D-ala-D-ala and binding to the transpeptidase like B-lactam drugs do, Vanco binds to the D-ala-D-ala shielding it from the transpeptidase

It works on G+ only
It is bactericidal (for the same reason as b-lactams. disrupt cell wall-> autolysin)


Vancomycin is the drug of last resort for what bacteria?
What bacteria has been gaining vanco-resistance?

It is a drug of last resort for MRSA

It is also used for E. faecalis, C. dificil and S. viridians (endocarditis)

Enterococci have been gaining resistance by substituting D-ala-D-lactate


What is the pharmacokinetics of Vanco?
1. absorption
2. distribution
3. excretion

1. poorly absorbed orally
2. good penetration, not CSF unless meninges are inflamed
3. glom filtration


What are the three major adverse effects of vanco?

1. red neck syndrome b/c it releases histamine
2. ototoxic- hearing AND balance
3. nephrotoxic (usually due to impurities in old preparations)


What should you NEVER give vancomycin with?

Aminoglycosides because they are both ototoxic and nephrotoxic


Vancomycin can be used to treat C. dificil, but what drug is preferred for this superinfection?



What are the ribosome binding drug classes?
Which bind 30S and which bind 50S?

1. Aminoglycosides (30S)
2. Tetracycline (30S)
3. MSLK (50S)
4. Linezolid (both)


What is the spectrum of aminoglycosides?
What are they often used in combination with?
Are they bacteriostatic or bactericidal?

They are mainline drugs for G-.
They are given with penicillin or cephalosporin (never vanco) for eterococcal endocarditis
They are bactericidal


What is the structure of aminoglycosides?
Why does this restrict how they must be administered?

They have 3 or 4 amino sugars.
One of them lacks an oxygen in the ring (cyclohexitol).
The amino groups off the sugar rings will be charged at neutral pH and have poor membrane penetration so they cannot be taken orally


What is the mechanism of action of aminoglycosides?
(bacteriostatic and bactericidal effects)

They inhibit protein synthesis by blocking initiation and elongation--> static

They also cause mRNA misreading- the acceptor site on the 30S subunit binds and activates tRNA leading to proteins with AA substitutions that incorporate into the membrame causing leakage and cell lysis -->cidal


How do aminoglycosides gain access to the ribosome structures to kill bacteria?

How does this affect what bacteria are naturally resistant to aminoglycosides?

1. Diffuse through G- porins
2. Actively pumped over cell membrane (dependent on O2, neutral/high pH, normal osmolarity)

Aminoglycosides thus are not good at treating:
1. anaerobes
2. bacteria in low pH (UTI)


What are the mechanisms of resistance to aminoglycosides?

1. altered ribosomal subunit by adding carbohydrate groups
2. Transferase enzymes (phospho, acetyl, adenyl) rendering the drug unable to bind the ribosome


How is resistance to b-lactams different in mechanism from resistance to aminoglycosides?

b-lactams are inactivated by the b-lactamases

Aminoglycosides are not hydrolyzed, they are just blocked from binding the ribosome


What is the pharmokinetics of aminoglycosides?
1. absorption
2. distribution
3. elimination

1. polar so not absorbed well from GI.
2. limited to extracellular fluids and poor CSF and eye distribution. Over concentrate in the ear and renal cortex
3. glom filtration


What are the adverse effects of aminoglycosides?

How are these effects reduced?

1. ototoxic and nephrotoxic
2. neuromuscular blockade
3. damage to optic nerve

Aminoglycosides have a post-antibiotic effect so they are given one or two times a day and bacteria continue to be killed after the removal of the drug


What are the four aminoglycosides we are responsible for?

1. streptomycin
2. gentamicin and tobramycin
3. Amikacin
4. Neomycin


What specifically would streptomycin be used to treat?

1. Drug resistant TB
2. combined w/ b-lactam for enterococcus endocarditis

(minor for tularemia and plague)


What are gentamicin and tobramycin used to treat?

Gram neg bacteria specifically:
Pseudomonas aeruginosa


What is the benefit of using Amikacin?

it is resistant to a lot of the inactivation transferase enzymes so it works on drug resistant strains


What is neomycin used for ?

prepare the bowel for surgery


What is the spectrum of tetracycline?
Are they bacteriostatic or bactericidal?

They are broad spectrum for many G+ and G- and are bacteriostatic


What is the mechanism of action for tetracycline?

It binds to the 30S subunit of bacteria inhibiting tRNA from getting to the acceptor site inhibiting initiation and elongation


How has resistance to tetracycline developed?

To gain access to the 30S subunit tetracycline must enter G- porins.
Resistant strains still allow the drug to enter, but they have developed efflux pumps to get the drug back out (the pump is induced by tetracycline)


How do tetracycline, doxycycline and minocycline differ in their hydrophobicity?
Which are long lasting and which are short acting?

The hydrophobicity depends on substitutions of 5. 6 and 7 on the rings.

Tetracycline is short-acting and 40% absorbed
Doxy and minocycline are long-lasting and >90% absorbed)


Which tetracycline drug has the longest half life? How is it eliminated?

Doxycycline has the longest half life and is hepatically excreted


How is tetracycline excreted?

Tetra= renally
Doxy= hepatically
Mino= mainly hepatic, a little renal


What kind of tetracycline drug would you use for a patient that has kidney failure?

doxy because its excreted mainly hepatically


What two drugs are poorly absorbed in the presence of cations (milk, antacids, etc)

Tetracyclines and Fluroquinolones


What are the adverse effects of using tetracycline?

1. broad spectrum = superinfection
2. Binds to Caphosphate in teeth.bones causing discoloration if taken during 1st or 2nd dentation
3. hepatotoxic especially in pregnancy
4. photooxidize in UV so avoid bright sunlight


When would superinfection be likely when using tetracycline?
What would be a sign that superinfection was occuring?

If the patient had been taking it for over 2 weeks
C dificile overgrowth would cause diarrhea


What is tetracycline the drug of first choice for?
What else is it used to treat?

Rickettsia infections like RMSF

It is also used to treat:
2. mycoplasma and chlamydia
3. gonorrhea and syphilis in pen allergic


What are the major macrolides?
Which are 14-membered and which are 15?

14 = erythromycin and clarithromycin
15= azithromycin


What is the spectrum for macrolides? Are they bacteriostatic or bactericidal?

They work on G+ and are static.
They sub for b-lactams in allergic patients


What is the mechanism of action for macrolides?

They bind to the 23S RNA in the 50S subunit inhibiting peptidyl transferase (which adds AA to a peptide chain)


Which macrolide is acid labile?
How is it given orally?

erythromycin but it can be given orally with enteric coated prep


What is unusual about the distribution of azithromycin?

It binds avidly to tissue as is released over weeks (5 day z-pack)


How are macrolides eliminated?

Hepatically through the bile


What are the adverse effects of macrolides?

They can cause epigastic distress, hepatotoxicity, drug-drug interactions


What specific bacteria are macrolides used against?
What is it the drug of first choice for?

Listeria in patients allergic to B-lactams
chlamydia & mycoplasma
Drug of first choice for Legionella


What differentiates clarithromycin from the other macrolides?

1. better bioavailability
2. M. Avium


What is clindamycin active against?

G+ infections but especially:
1. anaerobes
2. B. fragilis, C. perfringens


What is the mechanism of action of clindamycin?

It binds 50S ribosomal subunit and is antagonized by the macrolides (erythro, clarithromycin and azithromycin)


What is the mechanism of action of quinupristin and dalforpristin?

they binds 50S and cause release of incomplete chains of peptide.
When used together = bactericidal


What is the adverse reaction of quinupristin-dalforpristin?

It inhibits p450 so there are drug interactions esp. with cyclosporine


What is quinupristion-dalfopristin used to treat?

2. VRE (faecalis is resistant)


What is the mechanism of action of Linezolid?
What are the adverse reactions?

It binds 23S RNA subunit of the 50S ribosomal subunit (30S and 50S) and prevents initiation and binding of tRNA

It is a mild MAOI so avoid aged cheese and wine


What is linezolid used to treat?

multidrug resistant G+
VRE, MRSA, pneumonias, skin infections


What is Daptomycin used to treat?
When can it not be used?


It can't be used in pulmonary infections because it can't bind surfactant


What is the mechanism of action of Daptomycin?

binds phosphatidyl glycerol in bacterial membranes and depolarizes


What is metronidazole used to treat?

1. anaerobic- b. fragilis, C. dificil, C. perfringens
2. protozoa- T vaginalis, G lamblia, E. histolytica


What is drug has a similar mechanism of action to metronizadole?

nitrofurantoin because they both get into cells, are reduced and cause toxic intermediates to destroy the cell


What is bacitracin used to treat?

Topical for G+ and G- infections like eczema/ulcers
Orally for C. dificile in GI


What is the mechanism of dapsone? What does it treat?
What drug is it used in combo with?

It treats leprosy and acts like sulfonamide (blocks purine, pyrimidine synthesis)
It is used with Rifampin