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UTHCSA-Infectious Disease Module-Pharmacology


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What are bacteriostatic drugs and give some examples.
Bacteriostatic drugs inhibit the multiplication of bacteria so that the immune system can do the rest.

Examples: the macrolides and clindamycin.
What are bactericidal drugs and provide some examples.
Bactericidal drugs kill bacteria.

Examples: Beta-lactams, fluoroquinolones, aminoglycosides.
Explain time-dependent killing.
Depends on maintaining a plasma drug concentration (Cp) above the minimal inhibitory concentration (MIC). Does not enhance killing.

Examples: Beta-lactams and vancomycin
Explain concentration-dependent killing.
The rate and efficiency of killing increases as the Cp rises.

Examples: FQ's and aminoglycosides.
Resistance: Which bugs do what?
G+: change in binding sie of drug (MRSA, VRE, PCN-strep)

G-: pumps the drug out and has beta-lactamases. **(S. aureus also has B-lactamase activity).
How does penicillin work?
Transpeptidation and formation of the G+ cell wall is performed by penicilin binding proteins (PBP's). Penicillin resembles the normal D-Ala-D-ala substrate of PBP and covalently binds PBP inactivating it. Therefore, the bug cannot make a cell wall and dies by osmotic burst.
What are some of the ways bacteria evade penicillin treatment?
The most common cause of resistance is the production of B-lactamases by G- bacteria and S. aureus.

MRSA, Pen R-strepneumo and VRE produce a PBP that does not interact with penicillin. These are encoded by a plasmid or gene casset.

G- bacteria pump penicillin out.
What is the distribution of the penicillin family?
CSF- if inflammed (meningitis)
What is the primary route of elimination for penicillin?
Renal. Have to titrate in renal disease (to prevent seizures). Probenecid inhibits renal tubular secretion of pen and increases the t1/2.
What causes pen hypersensitivity and what percent of patients are truly allergic?
Penicillin hypersensitivity is caused by a major determinant of penicillin metabolism, penicilloic acid and protein. This is recognized as foreign by the immune system. Worst case scenario---> SYSTEMIC ANAPHYLAXIS!!! Roughly 1.0% of patients.
Penicillin G
Always i.v.
DOC for Beta-hemolytic strep, susceptible pneumococcus, meningococcal meningitis.

Effective for syphilis and gonorrhea.
Penicillin V
p.o. version of penicillin (low F). Often replaced by amoxicillin in cases of strep throat.
procaine penicillin G (generic) and benzathine penicillin G (Bicillin)

Prophylactic Tx for group A strep in military.

Tx for syphillis.
What are the penicillinase-resistant penicillins and what are they used for?
oxacillin (iv), nafcillin (iv), cloxacillin (p.o.), dicloxacillin (p.o.).

DOC's for non-MRSA S. aureus soft tissue infections.

*Always superior to vancomycin*
How do you treat MRSA soft tissue infections?
Inpatient: i.v. vancomycin

Outpatient: clindamycin, TMP/SMX or doxycycline.
What are the beta-lactamase inhibitors and provide some penicillin/Beta-lactamase inhibitor combinations commonly used.
clavulanate, sulbactam and tazobactam. Help stabilize lactamase-sensitive penicillins.

Common combos:

ampicillin-sulbactam, amoxicillin-clavulanate, ticarcillin-clavulanate, piperacillin-tazobactam
What are the aminopenicillins?
Extended spectrum penicillins. Sinilar to Pen G, but with more G- coverage (E.coli & H. flu).

They are:

amoxicillin & ampicillin
-not effected by food

*DOC for otitis media.*

Also used for strep pneumo
i.v. Ampicillin/Sulbactam

*DOC for Listeria and Enterococcus*

*If enterococcus is resistant to ampicillin, use vancomycin. *
What are the antipseudomonal penicillins?
Ticarcillin & Piperacillin (i.v.)

Designed specifically to kill Pseudomonas aeruginosa (that nasty bug that likes burns and cystic fibrosis).

Often found in the following pairings:

ticarcillin/clavulanate (ticar-clav)

piperacillin/tazobactam (pip-tazo)

*DOC: ICU Pseudomonas*

*Always combine with an aminoglycoside (gentamicin) for life-threatening infections*
Name the carbapenems.
imipenem/*cilastatin (i.v.)

*Cilastin prevents the breakdown of imipenem. " The kill is lastin with cilastin."
What are the carbapenems used for?
These are the drugs of last resort for patients that have not responded to pip-tazo or cefepime. Used for polymicrobial life-threatening infections from trauma or a nosocomial setting. DOC-whopping Enterobacter and Citrobacter.

*not to be used in febrile neutropenic patients. Stick with pip-tazo. *
Monobactam (i.v.)

Used for the patient with a massive G- infection and who is allergic to Pen.
Name the cephalosporins by generation
1st Generation-
cefazolin, cephalexin

2nd- cefoxitin, cefotetan

3rd- cefotaxime, ceftriaxone, ceftazidime, cefdinir

What is the mechanism of action for the cephalosporins?
Same as Pen, but generally more resistant to Beta-lactamases.
What are the bugs that cephalosporins are useless against?
Enterococcus, Listeria, Pen-resistant pneumococcus, MRSA
What is the trend with the four generations of cephalosporins?
1st- G+ and PEcK (Proteus, E.coli & Klebsiella)
2nd- G+, some G- and anaerobes (cefoxitin, cefotetan)
3rd- More G- at expense of less G+
4th- Moderate G+ and excellent G- (like adding gen 1 & gen 3)
What are the 1st-generation cephalosporins used for?
cefazolin (i.v.)-DOC for surgical prophylaxis. Also used for Tx of soft-tissue infections.

cephalexin (p.o.)- safe to use in pregnant women.
What are the 2nd-generation cephalosporins used for?
cefoxitin & cefotetan- DOC's for abdominal Sx-prophylaxis.

Good anaerobic coverage.

Can be used to treat pelvic-inflammatory disease (PID)
What are the 3rd-generation cephalosporins used for?
cefotaxime (i.v.) (t1/2= 1 hr) & ceftriaxone (i.v.) (t1/2= 8h)- strep pneumo & Neisseria meningitis, severe otitis media, inpatient community acquired pneumonia (CAP). **Remember, outpatient CAP-clarithromycin

cefotaxime- community acquired meningitis.

ceftriaxone- Tx for gonorrhea (large i.m. dose)

ceftazidime (i.v.) for P. aeruginosa *use with gentamycin*

cefdinir (p.o.) for otitis media after two failures of amoxicillin Tx.
What are the 4th-generation cephalosporins used for?
cefepime (i.v.)-

ICU, especially for neutropenic patients. Inpatient strep pneumo. Mixed or unknown infection that must be stopped!

Good P. aeruginosa activity.
Which of the cephalosporins have good CNS penetration and can be used for the Tx of meningitis?
ceftazidime (3), ceftriaxone (3), cefotaxime (3), cefepime (4).
How does vancomycin work?
Vancomycin binds to the to D-ala-D-ala peptides of the bacterial cell wall preventing elongation of the peptidoglycan chain. No cell wall= no bug.
What is vancomycin used for?
G+, no G-

DOC for MRSA!!!

Can use for ampicillin-resistant enterococci, but up to 50% are resistant to vanc.

Pen-R strep neumo meningitis (ceftriaxone + vanc)

Febrile neutropenia along with pip-tazo for G- coverage.

**Only p.o. use: C. difficile that is unresponsive to metronidazole.
What are some of the side effects of vancomycin use?
Ototoxicity-at high dose

Renal toxicity- vastly overstated.

Red man syndrome: not an allergy!! Infuse vanc after pretreatment with diphenhydramine.
How do the tetracyclines work?
They bind to the 30S subunit of the bacterial ribosome and block tRNA access at the A site. BACTERIOSTATIC!!!

They are:

doxycycline & minocycline
What are the tetracyclines used for?
Available both p.o. and i.v.
Oral F= 100%

DOC for rickettsial infections (good intracellular activity)

Lyme disease

Community acquired pneumonia (CAP)(see pg 79 for bugs).

95% of MRSA strains (remember outpatient MRSA).

Chlamydia and Mycoplasma pneumoniae.

Acne: minocycline
What are some of the side effects of the tetracyclines?
GI disturbances, photosensitivity, superinfections with C. difficile of C. albicans.

Do not use tetracyclines in kids b/c it discolors new teeth.
What is the mechanism of resistance to the tetracyclines?
Either prevention of tetracycline binding to A-site or drug efflux.
What are the macrolides and how do they work?
erythromycin (i.v.-OUCH, p.o.), clarithromycin (p.o.) and azithromycin (i.v. & p.o.).

-Bind to 50S subunit of bacterial ribosome at the peptidytransferase site and prevents peptide chain elongation. No protein= no bug!

What is the mechanism of resistance to the macrolides?
Prevent drug from binding site on 50S and drug efflux.
What are the therapeutic uses of the macrolides?
Clarithromycin (p.o.)- DOC for outpatient CAP due to it's great intracellular and good extracellular activity.


Good for intracellular pathogens: Mycobacterium avium, Chlamydia and Mycoplasma.

Not good for soft tissue infections due to staph.

Erythromycin for topical acne Tx.

**Never for otitis media in kids!**
What are the side effects of the macrolides?
GI upset.

Erythromycin represses CYP450 so watch out for an increase in other drugs!!
What is the mechanism of action for clindamycin?
i.v. & p.o.


Binds the 50S and inhibits peptide chain elongation.
What is clindamycin used for?
skin and soft tissue infections caused by staph and BHS.

Can be used for outpatient Tx of MRSA cellulitis.

Anaerobes from aspiration pneumonia.

Alternative G+ coverage for sulfonamide, Pen allergy

Not in CSF. Good F and intracellular concentrations.
What are the SE's of clindamycin?
Rash, diarrhea and really bad diarrhea C. deficile.
What are the fluoroquinolones and what is the mechanism of action?
i.v.=p.o. F

metal supplements chelate drugs. Decrease F.

ciprofloxacin, gemifloxacin, levofloxacin and moxifloxacin.

Inhibit bacterial topoisomerases II and IV--stops DNA replication BACTERIOCIDAL!!
What are the uses of the FQ's?
Levo & moxi- inpatient CAP (macrolides for outpatient CAP)

Outpatient Tx of complicated UTI (levo, cipro).

Tx for Salmonella

MDR S. pneumoniae (not cipro)

Never use on someone coming from nursing home (resistant P. aeruginosa, endemic).

What are some of the SE's of the FQ's?
Tendon rupture, photosensitivity, Q-T prolongation.
What are the aminoglycosides and what is the mechanism of action?
streptomycin, neomycin, gentamycin, tobramycin, amikacin

Binds 30S and blocks peptide synthesis + membrane damage BACTERIOCIDAL!!!
What is the dosing of the aminoglycosides?
**Almost always used in combination.
G+ low (ie: low dose AG + vanc)
G- high (ie: high dose AG + pip/tazo)

AG's are concentration-dependent killers.
What are the aminoglycosides used for?
Good G- cover

Almost always used with a cell-wall synthesis inhibitor (pen, vanc) or anti-pseudomonal for synergy.
What are the SE's of the aminoglycosides?
SE's are concentration and time dependent.


Ototoxicity-irreversible (vestibular damage, ataxia).

Neuromuscular blockade.

MONITOR Cp's!!!!!!!!!!!!
What is the mechanism of action of linezolid and what is it's coverage?
Binds to 23S and inhibits 70S ribosome translation. BACTERIOSTATIC

Excellent G+ including MRSA, VRE and Pen-resistant pneumo.

Complete F by iv. or p.o.
What is linezolid used for?
MDSA, VRE, Pen-R pneumo and complicated soft tissue nasties.

Patients on i.v. vanc in hospital can be sent home with p.o. linezolid.
What are the side-effects of linezolid?
Reversible bone marrow depression.

Serotonin syndrome with those using SSRI's.

$$$$$$ $70/day.
What is the MOA and coverage of quinupristin/dalfopristin?
Q binds 50S and D enhances this interaction.

Great G+ MRSA, VRE, Pen-R pneumo. Prolonged post-antibiotic effect.
When is Q/D used?
Critically ill patients

In most cases, go with linezolid due to p.o. availability and better enterococcus coverage.
How does
trimethoprim/sulfamethoxazole (trim-sulfa) work and what does it cover?
p.o. Great F

Sulfa- prevents the conversion of PABA to dihydrofolate (DHF). The next step, the conversion of DHF to tetrahydrofolate (THF) is blocked by Trim. Both work together to decrease available purines for DNA synthesis. A RIP-ROARING GOOD TIME!!


Broad spectrum AB.
What is Trim-Sulfa used for?
Uncomplicated UTI

DOC--Pneumocystis jiroveci (carinii at times)in HIV/AIDS.

Inpatient soft tissue MRSA.

DOC for Nocardia

ICU: carbapenem-resistant Stenotrophomonas.
What are some SE's for Trim-Sulfa?
rash, Stevens-Johnson syndrome (skin falls off).


Blood dyscracias.
What is the MOA for nitrofurantoin and what does it cover?
P.O. Good F

Bacterial cell reduces it into a reactive intermediate that damages DNA. BACTERIOSTATIC at low and BACTERIOCIDAL at high doses.

Great for many G+ and G- that cause UTI's due to high urine concentrations.
What is nitrofurantoin used for?

Safe for pregnant women as well as amoxacillin and cephalexin (1st gen ceph).

*Does not work on pyelonephritis or prostatitis. *
SE's of nitrofurantoin?
with prolonged use--hepatitis, neuropathies and pulmonary fibrosis.
How does amphotericin B work?
binds to ergosterol in the fungal cell membrane to cause pores.

Extremely broad antifungal. The gold-standard drug.
What are the SE's of amphotericin B?
"shake & bake" via IL-1, IL-6 and TNF.

What is nystatin used for?
MOA is the same as amphotericin B. Topical Candida.

Oral thrush-swish in mouth.
How do the "azoles" work?
They inhibit the enzyme CYP450 lanosterol 14-demethylase, which inhibits ergosterol synthesis for the fungal membrane. Also screws up the electron transport chain.

What is fluconazole used for?
Great F

Candida albicans
What is itraconazole use for?

i.v. is new.
What are miconazole and clotrimazole used for?
Topical antifungal. MOA same as other azoles.

miconazole: bleeding in warfarin-treated patients.
What is voriconazole used for?
DOC for systemic Aspergillus.

Fluconazole-resistant Candida.

i.v.=p.o.= F of 96%
What is the MOA of the echinocandins?

Inhibits the synthesis of 1,3-B-D-glucan a key component of the Asperillus and Candida cell wall.

Will most likely replace amphotericin B.
What is capsofungin used for?
Salvage therapy for amphotericin B-resistant Aspergillus.

Cidal for fluconazole-resistant Candida.

Well tolerated and excellent pharmacokinetics.

How does flucytosine work?
Flucytosine is converted to 5-fluorouracil, which inhibits thymide synthase and DNA synthesis.

P.O. with rapid absorption, even into CSF.

Can cause bone-marrow suppression.
What is flucytosine used for?
Synergistic with azoles and amphotericin B.
How does metronidazole work?
Anaerobic bacteria convert metronidazole into a nitro radical that attacks DNA. Aerobic organisms cannot do this.

Good p.o. F
What is metronidazole used for?
Pseudomembrane colitis-C. difficle

Bacteroides fragillis

Trichomonas- oral and topical.


(kills both luminal and systemic infection)
What are the side-effects of metronidazole?
increased bleeding with warfarin

disulfiram-like reaction with ethanol (massive hangover)

Avoid during first trimester.

dizziness, dysgeusia
What are the antimalarial drugs?
chloroquine, primaquine, mefloquine and atovaquone-proguanil
What does chloroquine do?
p.o. 1x per week.

Prevents heme-polymerization in parasite. Free heme oxidizes the parasitic cell membrane.

Kills the erythrocyte stage.

Use with primaquine 1-2 hit for cure.

Prophylaxis for travel to chloroquine sensitive areas.

Mefloquine works the same way.
What does primaquine do?
p.o. qd

Kills liver form of parasite.


Use with chloroquine 1-2 hit.

**Causes hemolytic anemia in background of G6PD deficiency**

Avoid in pregnant women.
p.o. 1x per week


Cures multidrug resistent P. falciparum at the expense of n/v/d, ataxia, hallucinations.
Atovaquone- destroys mitochondrial membrane difference

Proguanil- helps atovaquone.

Used as prophylaxis for travel to chloroquine resistant areas.
What are the antihelminth drugs?
mebendazole, albendazole, pyrantel-pamoate, piperazine, ivermectin, prizaquantel
How does albendazole and mebendazole work and what are they use for?
Inhibits microtubules required for helminth glucose transport. No energy, cannot move and is pooped out.

Mebendazole- pinworm, hookworm.

Albendazole (general DOC for mixed roundworm infections,low F)- pinworm, roundworm, hookworm, tapeworm-pork (DOC)

SE's abdominal pain, liver (AST, ALT), reversible alopecia
How does pyrantel-pamoate work and what is it used for?
Nicotinic agonist paralyzes helminth..poop out.

roundworm, hookworm
How does piperazine work and what is it used for?
A GABA agonist at NMJ. Flaccid paralysis of helminth..pooped out.

What is the MOA of ivermectin and what is it used for?
Releases GABA and caused chloride conductance. Flaccid paralysis in helminths, insects and ectoparasites... poop out.

DOC for threadworm (immunocompromised, abdominal pain, weight loss, pulm edema)

A single dose given 2x year kills the filarial infection (onchocerciasis) that cause river blindness.

A single dose prevents worms & arthropods in livestock for 1 month.
What is the MOA of prizaquantel and what is it used for?
Opens Ca2+ channels to cause muscular tetany in worm..poop out.

DOC for Schistosomiasis (from the snail not endemic to US) dermatitis, anemia, fever, fatigue, diarrhea.
What are the drugs used to treat ectoparasites (lice & scabies)?
permethrin & ivermectin

permethrin- DOC for head-lice (1% cream) and scabies (5%).

ivermectin-not approved by FDA. Tx of scabies in immunocompromised and for permethrin-resistance.
p.o., topical

-accumulates in skin, nails and fat cells

MOA-prevents ergosterol synthesis by inhibiting squalene epoxidase, squalene kills fungal cells.

Pregnancy category B-animal studies show no evidence of toxicity to fetus.

DOC-fungal infection of the nails (onychomycosis)

Prolonged use hurts the liver.

-accumulates in keratin cells.

-inhibits fungal mitosis by binding to microtubules.

DOC-tinea capitis (ringworm)


Athletes foot.
What drug prevents the uncoating of influenza virus and is used as prophylaxis?

Inhibits the viral M2 ion channel, which is responsible for viral uncoating.

**High degree of resistance in H3/N2 flu. ***

Better in elderly and patients with renal disease due to few SE's.
What drug prevents the release/budding of influenza from cells and is used to decrease duration of flu symptoms?

inhibits neuramidase (NA)-mediated viral release.
What drugs are used to treat HSV and HSV?
Viral DNA polymerase inhibitors.

acyclovir (p.o., i.v., Top)- Tx for HSV and VZV.

valacyclovir (p.o.)- DOC for HSV (recurrent herpes, fever blisters) and VZV (shingles). Higher Cp than acyclovir. Converted to acyclovir.

famciclovir (p.o.)- converted to pencyclovir.

SE's- diarrhea and headache.

pencyclovir- topical

foscarnet (i.v.)- inorganic pyrophosphate that directly inhibits HSV pol.
How do you treat HSV keratitis?
trifluradine- topical for herpetic keratitis of eye.
What drugs treat CMV retinitis?
ganciclovir (p.o., i.v., ocular implant)

valganciclovir (p.o.)- DOC

Both inhibit viral DNA pol.

foscarnet (i.v.)- inorganic pyrophosphate that directly inhibits CMV pol.
-used to treat HSV/VZV refractory to acyclovir and ganciclovir/cidofovir-resistant CMV.

fomivirsen (intravitreal injection)- antisense nucleotide that binds and inhibits the translation of CMV transcripts.
What are the NRTI's that are used for the Tx of HIV and what is their MOA?
tenofovir (resistant HIV)

-phosphorylated in the cell and converted to "false nucleotides." Inhibit HIV RT.
What are the NNRTI's that are used for the Tx of HIV and what is the MOA?

-do not require phosphorylation by cell. Bind to different site than NRTI's.

Resistant to one, resistant to all.
What are some protease inhibitors that are used for the Tx of HIV?

ritonavir (pharmacokinetic enhancer)- represses the CYP450 isoform that metabolizes saquinavir. Increases the Cp of saquinavir.
What is a HIV fusion inhibitor that is used to Tx resistant HIV?
enfuvirtide (s.c.) a synthetic peptide which blocks the fusion of HIV with CD4+ cells.
How do you treat active TB?
Rifampin, Isoniazid, Pyrazinamide, Ethambutol

-prevents mycolic acid synthesis.

Baceriostatic for latent TB. Bacteriocidal for dividing TB.

Used with R, P and E for active TB.

Used alone if + PPD and clear X-ray.

SE's- slow acetylators. Hepatotoxicity (not bad enough to stop Tx). Neurotoxicity- INH looks like B6. Give B6.

No alcohol!!! Be careful over 35 y.o.
Rifampin & Rifabutin
-inhibits bacterial RNA pol.

used in combo with I, P and E for active TB.

Rifabutin does not induce P450 as much as rifampin. Can be used in HIV so HAART drugs are not cleared as quickly.

Used in place of prophylactic INH if over 35 y.o.

SE's- urine/skin turn orange.

Cat C pregnant.

-kills semi-dormant intracellular bacilli in macrophages.

Used with R, I and E
inhhibits arabinoglycan synthesis-a component of cell wall.

Used with R, I and P

**ocular damage**-get vision exam before, during and after.
aminoglycoside-inhibits protein synthesis.

i.m. or i.v. to Tx TB meningitis or disseminated (miliary) infection.

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