Pharmacology: Block 3: Anti-Infective agents

- HIV
- Immunocompromised
- Pre-op
- Endocarditis (recently not recommended)

You can test for CMV DNA. The patient will have DNA in the serum even before they are symptomatic. Then you can treat with Gancyclovir only to those that really need it.

To give to livestock so that they grow bigger!

Blocks the use of PABA in tetrahydrofolate synthesis

Alexander Fleming in 1928

Minimum toxic concentration / Minimum effective concentration

Penicillin

Because of nephrotoxicity

Giving vanco too fast causes release of histamine. Not a true allergic reaction.

gram +

Distribution to most areas = good.

Distribution to eye, brain, CSF, prostatic fluid = not good

That the antibiotic was isolated from the Streptomyces bacteria.

Because it was not isolated from Streptomyces. It was isolated from Micromonospora purpureae.

Mimial Inhibitory Concentration. The least amount of ABX that can kill bacteria.

Penicillin + Gentamicin

Excellent

Adequate with high doses

Not good. Sometimes have to give aminoglycosides intrathecally.

Ceftriaxone

Daptomycin - it's inactivated by surfactant.

Quinolones, macrolides, beta-lactams

MIC = Minimal Inhibitory Concentration

MBC = Minimal Bacteriocidal Concentration

TMP/SULFA

(Note that another drug for listeria is ampicillin)

Usually cidal.

Enterococcal endocarditis.

Enterococci are tolerant to penicillins and resistant to gentamicin. But together they are effective. This is because the penicillin punches holes in the membrane, allowing gentamicin to get into the bacteria.

Tetracycline and penicillin. Tetracycline blocks protein synthesis, blocking the cell growth that penicillin needs to cause lysis. The result is a bacteriostatic effect.

A study done in 1951 showed a sharp rise in meningitis with administration of tetracycline + penicillin. (But small sample size)

1. Penicillin + gentamicin

2. Trimethoprim + sulfamethoxazole

3. Clavulanate (inhibitor of β-lactamase) + amoxicillin

Penicillins are usually cidal, but they are static with enterococci.

Most recommend ampicillin (with or without an aminoglycoside) as the first choice.

When a disease is associated with the release of a toxin (Staph or E. coli)

Cidal

The higher the concentration, the greater the activity - aminoglycosides, quinolones.

The extent of killing depends on the time of exposure - β-lactams, vancomycin.

Based on the "time above MIC"

Need frequent dosing.

Based on the area under the curve.

1. Endocarditis: 28-42 days
2. Osteomyelitis: 42 days
3. Prostatitis: ?

Penicillin: 4x day for 10 days, but no GAS is resistant.

Amoxicillin: Don't have to take as often

If penicillin resistant, take erythromycin or other macrolide (azithromycin)

Cephalosporins (even though GAS is sensitive) ??

GI distress

Secreted inside the bacterial cell wall, thus it can be overcome with increased doses of ABX

1. Gram + cocci
2. GAS
3. GBS
4. Spirochetes
5. S. pneumo (now some resistant)

They bind and inactivate the Penicillin Binding Proteins (PBP) that catalyze the joining of peptides in the cell wall.

The β-lactam "mimics the peptide bond"

1. Clavulanic acid + amoxicillin = Augmentin (PO)

2. Sulbactam + Ampicillin = Unasyn (IV)

3. Tazobactam + Piperacillin = Zosyn

Into the periplasm

Amoxicillin and ampicillin have extended spectrum and are effective against gram negatives like: H. flu, E. coli, Proteus mirabilis.

With β-lactamase inhibitor gives activity to Staph and other gram negatives.

Animal bites
Interabdominal wounds

Bacterioides fragilis.

By altering the penicillin binding proteins from PBP2 to PBP2a (which has a low affinity for β-lactams).

Also by altering the fem genes.

1. Methicillin
2. Nafcillin
3. Oxacillin

All are resistant to S. aureus β-lactamase, but NOT gram negative β-lactamases!

Also note that these are not effective against MRSA!

Pump the drug out. Also seen with pseudomonas resistant to piperacillin.

Piperacillin

- Has activity against Pseudomonas and other gram negatives.

- When paired with tazobactam (Pip/Tazo or Zosyn), is effective against Pseudomonas and anaerobes

Ampicillin has activity against some gram negatives, but only piperacillin has activity against pseudomonas.

HUGE

Penicillins = 5 membered ring
Cephalosporins = 6 membered ring

Bind to PBP to prevent cross-linking, preventing formation of peptidoglycan.

Cephalosporins are more resistant to β-lactamases than penicillins

They do not penetrate into the CNS

The broadness of the spectrum

Cefazolin

Enterococcus
Listeria
Pseudomonas

That they cover everything that penicillins do plus...

Cefazolin: GAS, non-fragilis anaerobes, S. aureus, E. coli.

Cellulitis

Cefazolin: GAS, non-fragilis anaerobes, S. aureus, E. coli

H. flu and extended gram - spectrum

B. fragilis and Serratia

They induce chromosomal β-lactamases.

Thus never use a 2nd gen ceph with a β-lactam ABX

Greatly expanded gram - spectrum (including citrobacter, serratia marcescens)

Also longer half-lives

Cross the BBB well

2nd or 3rd gen ceph
Extended spectrum penicillin

Listeria (need to add ampicillin to the regimen)

3rd gen ceph

1. Ceftriaxone
2. Cefotaxime

30 minutes.

Imipenem
Ertapenem

Very broad spectrum. Effective against gram +, enterococci, and resistant gram - species.

Highly resistant to β-lactamases

Aztreonam - only has gram - activity

Because they inhibit the growth of the cell wall

Aztreonam. Broad gram - activity. Often given with vancomycin because of absence of gram + activity.

Cilastatin, because imipenem can be hydrolyzed by dehydropeptidase in the mammilian kidney.

Cilastatin is a dehydropeptidase inhibitor.

In the family enterobacteriaceae

Cefotaxime
Ceftriaxone
Ceftazidime
Aztreonam ???

10%

0.01%

about 0.5%.

Thus 2nd/3rd gen cephs are unlikely to cause a reaction in those with penicillin allergies.

Are not immunologically mediated.

Amoxicillin. Patients with EBV mono that are treated with amoxicillin will develop a maculo-papular rash.

This does NOT mean that the patient is allergic to amoxicillin. The patient can be treated again in the future.

about 50%

A 1st generation ceph like Cefazolin.

Steven-Johnson syndrome
Toxic Epidermal Necrolysis

Seen mainly with sulfa drugs

(both basically skin sloughing)

Vancomycin

Gram +, particularly MRSA

penicillin is faster-acting that vancomycin

Binding to the D-Ala-D-Ala terminus of nascent peptidoglycan assembly

Red man syndrome due to histamine release.

For enterococci like E. faecium and E. faecalis.

Also the drug of choice for treatment of enterococcal endocarditis in a patient with penicillin allergies.

Vancomycin Insensitive Staph Aureus.

Vancomycin

If arthritis, will be painful to move joint.

Examples:
Erythromycin, azithromycin, clarithromycin

M of A:
Inhibit protein synthesis (50S), bacteriostatic

M of E:
Bile and minially in urine

Targets:
Gram +, but not MRSA
Some gram -
Atypicals
Some anaerobes

Examples:
GNATS: Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin

M of A:
Inhibit protein synthesis (30S), bactericidal

M of E:
Excreted unchanged in urine

Targets:
Staph (combine with β-lactams)
Gram -

Examples:
Tetracycline, doxycycline

M of A:
Inhibit protein synthesis (30S)

M of E:
Excreted mostly in the urine

Targets:
Some gram +
Some gram -
Atypicals

S. aureus
S. pyogenes
Anaerobes above the diaphragm

Attractive for gram + infections in patients with penicillin allergies.

Active against penicillin-resistant S. pneumoniae.

C. difficile.

No - this is a static drug, don't want to use.

Static

Acne.

Both get into secretions well, but tetra goes into the urine, while doxy does not.

Doxycycline

Tetracyclines

Tetracyclines

Tetracyclines

Tetracyclines

Plauge
Pelvic inflammatory Disease

Doxycycline has anti-malarial effects.

Nalidixic acid (NegGam, Wintomylon)

Active against gram - only, rapid resistance is a problem

Ciprofloxacin (Ciprobay, Cipro, Ciproxin)

Covers a broader spectrum of gram negatives, including Pseudomonas.

Often used for traveller's diarrhea. Not good against gram + or S. pneumo (thus not acceptable drug for community acquired pneumonia)

Levofloxacin (Cravit, Levaquin)

Activity against gram +, once a day dosing. Also activity against gram - aerobes.

Broad spectrum against gram + and gram - aerobes.

Affects S. pneumoniae and H. influenzae, thus can be used to treat community aquired pneumonia.

Stains developing teeth
Incorporates into bones

Metal or milk

Against "atypical organisms" like Rickettsiae, Mycoplasma, Chlamydia.

A gylcylcycline

Very broad spectrum with activity against vanc resistant streph and staph. Broad aerobic and anaerobic spectrum.

Eliminated in the biliary system (no need to adjust for renal failure)

Main uses are for MRSA and cellulitis

Most common: vomiting and nausea.

Tetra binds Ca and incorporates into bone and teeth.

Photophobia, sensitivity to light

Prolonged use can cause yeast infections due to broad spectrum actions against anaerobes.

Dose carefully in patients with hepatic failure.

Tetracycline (and not doxycyline)

Clarithromycin

Erythromycin can cause severe GI distress ("Erythromycin belly"), while Clarithromycin is fairly well tolerated.

Macrolides. Thus they have activity against Legionella, Mycoplasma.

Azithromycin

Gram + cocci, B. pertussis, Legionella, Mycoplasma.

Macrolides (azithromycin)

Macrolides (azithromycin)

Lyme disease, Chlamydia infection.

Has almost no serum level, but has a high tissue level.

Has a half-life of 2-4 days

A single dose of azith is equal to a 7 day course of doxy

A 5 day course.

Often prescribed for bone and joint infections.

Active against Staph, Strep, anaerobes (including B. fragilis)

Binds to the 50S subunit

Can be given IV or PO

Can cause C. diff enterocolitis

Binds to the 50S subunit

Broad spectrum:
static for gram -
cidal for S. pneumo, H. flu

Second-line for Rickettsial

Has bone marrow suppressive effect.

AE: in 1/20-40,000 cases can cause aplastic anemia - permanent bone marrow damage.

PABA, para-aminobenzoic acid

While mammals must take up folate from the environment, bacteria must synthesize it from PABA.

Sulfonamide competes with PABA.

Inhibits dihydrofolate reductase

para-aminobenzoic acid ---------dihydropteroate synthase --------> Dihydrofolic acid --------- dihydrofolate reductase --------> Tetrahydrofolic acid --------> Purines -------> DNA

TMP or Sulfa are static
TMP/Sulfa is cidal

S. pneumo

Respiratory infections

UTIs (esp E. coli), and some bacterial diarrheas.

No longer used for otitis media

TMP/SULFA

Broad spectrum with activity against gram + and gram - aerobes.

No activity against anaerobes!
No activity against pseudomonas!

Variable activity against S. aureus.

TMP/SULFA

cidal

Inhibits the 30S ribosomal subunit.

Predominantly gram - aerobes

No anaerobic spectrum!

Genatmicin

Used as 2nd line for TB, but is ototoxic

Aminoglycoside, used for non-TB mycobacteria (M. fortuitum)

Dosed daily because they are concentration-dependent drugs.

Nephrotoxicity, ototoxicity, vestibular toxicity.

Incidence can be reduced by avoiding high sustained (trough) levels of the drug.

Vanc + gentimicin

Prodrug - requires activation of active nitro group.

Only ANAEROBIC bugs can activate metronidazole!

Thus activity is limited to anaerobes and protozoans

Especially useful for B. fragilis and C. difficile

Adverse "antabuse" reaction to alcohol

Used to treat giardia and amebiasis.

"Antabuse" reaction to alcohol - flushing, dizziness.

Metallic taste

Metronidazole.

Good for resistant gram + strains like VRE.

Dalfopristin
Quinupristin

Cidal

Concentration

DNA gyrase inhibitors

Levofloxacin

3rd generation quinolone. Activity against gram + and gram - aerobes.

No anaerobic activity!

Because it destroys likely culprits aerobic gram - and gram + organisms, but does not disrupt normal colonic flora (mostly anaerobes)

Renally. So has good urine penetration.

2nd generation quinolone.

Broad spectrum

Works by inhibiting DNA polymerase

Causes orange urine and can cause liver disease.

Induces P450 enzymes, increasing the elimination of warfarin, protease inhibitors.

Infrequent dosing can lead to flu-like symptoms upon withdrawl and rarely acute tubular necrosis.

Use limited by rapid development of resistance

Major drug for TB

Penetrates tissues - used to eliminate carrier state.

Polyenes
Azoles
Pyrimidines

Broad spectrum
Activity against Candida, Aspergillus, Mucor, Cryptococcus

IV only

Administration leads to fever, chills, rigors

Amphotericin B is effective against Mucor, azoles and echinocandins are not.

Well absorbed
Well distributed in tissues
Not toxic
Available PO and IV
Long t1/2

Active against:
Most Candida (but not C. krusei or C. glabrata)
Coccidioides immitus
Cyptococcus

Not active against Aspergillus

Main problem: drug/drug interactions

Drug/drug interactions due to inhibition of P450 enzymes.

Fluconazole increases plasma concentrations of cyclosporin, tacrolimus, phenytoin, and sulfonylureas.

Histoplasmosis, Blastomycosis, Sporotrichosis

Can cause hepatotoxicity

Poorly absorbed orally

Inibits P450 enzymes and affects the metabolism of drugs like warfarin, statins, oral contraceptives.

Itraconazole levels are also reduced by many drugs like rifampin, INH, PPIs, H2-receptor blockers.

Posaconazole.

Voriconazole

Voriconazole

Posaconazole has better activity against Mucor

Variconazole

Rifampin

Liver function abnormalities, prolonged QT interval.

Transient visual disturbances with IV administration.

Caspofungin

Micafungin/Anidulafungin do not have P450 interactions

IV only

Block β-(1,3)-glucan synthesis

No activity against Cryptococci, Fusarium, Zygomycetes

Caspofungin
Anidulafungin
Micafungin

Broad spectrum, including azole resistant species.

Fungistatic for Aspergillus

Amphotericin and the Azoles are not effective because P. jiroveci lacks ergosterol.

TMP/SULFA

Because the mutation rate is so high.

Inhibits the synthesis of mycolic acid

Inhibits mycobacterial arabinosyl transferases, blocking cell wall formation.

Penetrates cell wall, M of A not well defined.

Heptatoxic

INH = Injures Neurons and Hepatocytes

Some combo of Dapsone + Rifampin + Clofazimine for 6-12 months.

HSV-1, HSV-2, VZV

In vitro activity against: CMV, EBV, HHV-6

Acyclovir is a nucleoside analogue that is phosphorylated by viral thymidine kinase. It then inhibits viral DNA polymerase and causes chain termination.

More extended spectrum than acyclovir. Used for CMV treatment and prophylaxis. IV and retinal implant.

Valganciclovir is the PO form.

Ganciclovir is much more toxic. Bone marrow suppression and neutropenia

Used for resistant CMV and other Herpes viruses.

IV only - weekly dose

Nephrotoxic

Interferon alpha

It enhances the serum half life

Fever, myalgias, chills

Also neurologic and auto-immune issues.

Many contraindications, especially hepatic issues, auto-immune, arrhythmias, psychosis, etc.

Toxicities and that it is administered IM

IFN-α, some reverse transcriptase inhibitors and DNA polymerase inhibitors also being used.

PEG modified IFN + PO ribavirin

A guanosine analog

Lassa fever

IV form: 10 - 20% of patients have hemolytic anemia.

PO toxicities not as well defined.

Inhibits HBV DNA polymerase.

Development of resistance

HBV

HBV

AROZ:

Amantadine
Rimantadine
Oseltamivir
Zanamivir

Oseltamivir
Zanamivir

Bind to the M2 protein and inhibit uncoating.

Both only effective against influenza A.

When given for prophylaxis.

GI (nausea, vomiting), CNS (nervousness, difficulty concentrating, insomnia, light-headedness) are common side effects.

Rimantadine

Renal failure.

Oseltamivir and Zanamivir

Neuraminidase inhibitors/Sialic acid analogs

Chloroquinone and mefloquine

Primaquine

From wormwood.

Artemisinin combination treatment (ACT)

G6PD deficiency

Chloroquine
Malarone
Mefloquine
Doxycycline
Primaquine

Metronidazole, single 2 gram dose

Variesm but Metronidazole works.

Metronidazole, single 2 gram dose

Artemethers

Benzimidazoles

Thought to inhibit worm microtubule synthesis

Ascaris, Trichuris, Cutaneous and Visceral larva migrans, Echinococcus.

PO

Usually none. Prolonged use can cause pancytopenia.

Ascaris, Trichuriasis, hookworm, pinworm

Unusual

Liver cirrhosis.

Steven-Johnson Syndrome

Lots, but usually transient

Thought to increase membrane permeability fo Trematodes and Cestodes to calcium

Schistosomiasis, Taenia, Diphyllobothriasis, Clonorchiasis, Opisthorchiasis, Paragonimiasis

Schistosomiasis

Praziquantel

Carbapenems (Imipenem, Ertapenem)

1. Aminoglycosides
2. Vancomycin
3. Beta-lactams
- except nafcillin, oxacillin
- except ceftriaxone, cefoperazone
- especially imipenem
4. Sulfa-containing agents
5. Fluoroquinolones
6. NOT minocycline, doxycyline (both cleared by the liver)

a) Penicillins - Nafcillin, Oxacillin and Piperacillin - half-life increased by about 25-50%increase dosing interval by 50%.
b) Clindamycin - t1/2 increased by 100%; double dosing interval.
c) Doxycycline, Minocycline - avoid in liver failure

Aminoglycosides, vancomycin

Group A Streptococcus necrotizing fascitis - requires non-cell wall active agent (Clindamycin) because of high density of organisms, in non-dividing state.