Bacteriostatic

Arrests growth and replication of pathogen

--> Patients immune system must finish the job

Kills pathogens

1. Alter uptake of drug by changing the lipopolysaccharide coat
2. Alter transport system so drug is removed from cell      
3. Increase metabolism through a pathway that bypasses effect of drug.                                                            

• B-lactams
• Polypeptides

• Aminoglycosides
• Chloramphenicol
• Clindamycin
• Macrolides
• Ketolide
• Streptogramin
• Oxazolidanone
• Tetracyclines

• Sulfonamides
• Trimethoprim

• Quinolones
• Urinary tract antiseptics

• Final step in synthesis of bacterial cell wall is a cross linking of adjacent peptidoglycan strands (traspeptidation)
• Penicillins and cephalosporins compete for the enzymes that catalyze transpeptidation and cross-linking
• Result is bacteria with structurally weatkend cell walls and death

- All contain a Beta lactam ring

• Penicillins
• Cephalosporins
• Carbapenems
• Monobactams (Aztreonam)

-Beta lactam ring is responsible for their antimicrobial action

-Some bacteria have beta-lactamase which opens the ring and inactivates the drug

- Most common mode of resistance is plasmid transfer of the genetic code for b-lactamase

-Specific b-lactamases: Penicillinase, Cephalosporinase

-B-lactamase inhibitors can be given concurrently

• Clavulanic acid
• Sulbactam
• **Tazobactam

-Chemically modify drug structure so that lactam ring is reistant to lactmases.

• Made by mold
• Include: Penicillin G, Penicillin V, Benzathin pen G
• Narrow spectrum - effective aganist one class of pathogen
• Pencillinase sensitive

Drugs:

-Methicillin

-Cloxacillin

-Dicloxacillin

-Nafcillin

-Oxacillin

Narrow Spectrum (Gr. +)

Synthesized to be penicillinase resistant

• Drugs

-Amoxicillin

-Ampicillin

• Broad spectrum (also some gram neg. activity)
• Penicillinase sensitive

Drugs:

- Azlocillin

-Carbenicillin

- Mezlocillin

-Piperacillin

-Ticarcillin

Active against pseudomonas

Relatively ineffective against gr. + organisms

• Generally, oral absorption of penicillins are poor (some exceptions)
• Most can only cross the blood brain barrier if it is inflammed (use in meningitis)
• Excreted by active tubular excretion which can be blocked by concurrent administration of probenecid (prolongs action)

Penicillins: Adverse Reactions

Hypersensitivity rxns:

-immediate, accelerated, late

Immediate rxns:

-Occurs within 20 mins after parenteral admin.

-Symptoms: pruritis, paresthesia, wwheezing, choking, fever, edema, urticaria

Can result in hypotension, shock, death

Mediated by IgE

 Accelerated rxns:

-Appears 1-72 hours after drug admin.

-Consists mainly of urticaria (Hives)

Late rxn:

-More common with semisynthetics

-Appears 72 hours to several wks after drug admin

-Mainly skin rashes

Serious skin rxns

Multiforme erythrema

Stevens Johnson Syndrome

TEN

Cephalosporins: 1st generation

Drugs:

-Cefazolin

-Cephalexin

Narrow specturm (similar to broad spectrum penicillins)

Sensitive to B-lactamases

Drugs:

- Cefaclor

-Cefamandole

-Cefoxitin

Increased activity toward gr. neg. organisms

Increased stability

Drugs:

-Cefotaxime

-Ceftazidime

-Ceftriaxone

Broader spectrum than previous generations

More resistant to B-lactamases

Drugs:

-Cefepime

-Cefpirome

Gr.+ and Gr.neg activity

-Effective against pseudomonas aeruginosa

-Also gr.neg organisms with multiple drug resistance patterns

• 3rd and some second generation drugs penetrate CNS (treat meningitis)
• 3rd gen. agents used in the trtmnt and prophylaxis of infections in hospitalized pts
• 4th gen. drugs targeted at organisms with multiple-drug resistance
• Some cross-allergy with penicillins
• Can interfere with Vit.K (increased bleeding)
• Disulfiram-like rxn:

-Block alcohol oxidation

-Acetaldehyde accumulates

Drugs:

-Imipenem

-Ertapenem

-Meropenem

All admin. IV

Imipenem is hydrolyzed by renal dipeptidase in the kidney to a toxic metabolite (and has no antimicrobial activity)

-Cilastatin inhibits dipeptidase so must be admin. w/ imipenem

Meropenem is stable to dipeptidase- does not require coadm. of cilastatin

• Aztreonam is only agent available
• Narrow spectrum: Aerobic gr.neg bacteria including pseudomonas,  Ineffective against gr.+ bacteria
• Highly resistant to B-lactamases

Vancomycin and Teicoplanin

- inhibit cell wall synthesis by preventing polymerization of the linear peptidoglycans

-Only effective aganist gr.+ organisms

-Poorly absorbed orally

-Dose related ototoxicity (tinnitus, high tone deafness, hearing loss)

-Red man syndrome 

Bacitracin

-Mixture of polypeptides that inhibit cell wall synthesis: Binds to lipid carrier that transports cell wall precursors

-Used topically due to serious nephrotoxicity

Fosfomysin

-Inhibits one of the first steps in the synthesis of peptidoglycan (enolpyruval transferase)

-Used for trtment of UTIs

Daptomycin

-Binds to membrane of bacteria and causes depolarization

-Loss of membrane potential results in death

• Require binding to intracellular protein (ribosomal subunit) so must enter the cell
• Major route of resistance is blockade of drug from entering the cell

GAS TNK

Gentamicin

Tobramycin

Amikacin

Kanamycin

Neomycin

Netilmicin

Streptomysin

Broad spectrum antimicrobials but anerobic bacteria are generally resistant

-Drug enters bacteria through oxygen dependent transport system

- Anerobes do not oxygen dependent metabolism

Poorly absorbed from GI tract

Most must be administrated parenterally

Highly polar, relatively insoluble in fat

Do not readily penetrate into cells

-Usually require a transport mechanism or coadm. of penicillins: Penicillins create cell wall abnormalities that allow aminoglycosides to penetrate the cell

Narrow margin of safety

Ototoxicity

-Cochlear (auditory):

Symptoms:tinnitus, deafness, high frequency hearing loss

Due to selective destruction of outer hair cells in organ of Corti

-Vestibular (vertigo)

Nephrotoxicity

-Due to rapid uptake of drug by proximal tubular cells and subsequent death

-Acute nephrotoxicity is reversible

Neurotoxicity

-Due to blockade of presyn. release of acetylcholine at neuromuscular junction (some post-syn. blockade can also occur)

-Symptoms: weakness and respiratory depression

• Tetracycline
• Chlortetracycline
• Demeclocycline
• Minocycline
• Oxytetracycline

• Accumulate in cytoplasm by an energy dependent transport system which is not present in mammalian cells ( so accumulates in bacterial cells)
• Resistance occurs when bacteria mutate to prevent entry of the drug into the cell.
• Food impairs absorption:

 -form insoluble chelates with Ca, Mg, and other metals

-Avoid antacids

-Does not occur with doxycycline and minocycline

• Deposited in teeth and bones (not recommended for kids and pregnancy)
• Caues Photosensitivity

• Broad spectrum (gr.+ and neg organisms, anerobes)
• Rickettsial diseases(Rocky Mtn spotted fever)
• Chlamydial diseases
• Cholera
• Lyme disease (spirochetes)
• Mycoplasma pneumonia

Erythromycin

Azithromycin

Clarithromycin

Dirithromycin

Troleandomycin

Useful in the treatment of:

• Mycoplasma infections
• Pneumonia
• Legionnaires' disease
• Chlamydial infections
• Diptheria
• Pertussis

GI upset is most common side effect (Motilin agonist)

- Ketolides were derived from macrolides

-Telithromycin is useful for macrolide resistance organisms

• Activity against intracellular respiratory pathogens

-Protein synthesis inhibitors

-Combo. drug:

• Dalfopristin + quinupristin
• Act synergistically to inhibit ribosome fxn

-Linezolid (an oxazolidinone)

• Inhibit protein synthesis by interfering with translation
• Effective against anaerobic gr.+ organisms
• Approved for vancomycin-resistant infections
• Also MAOI activity

Chloramphenicol

• Broad spectrum antibiotic effective against most anerobic and aerobic organisms except Pseudomonas aeruginsa
• Reserved for life threatening infections due to serious adverse effects
• Orally absorbed
• Penetrates CSF
• Dose related bone marrow depression
• Dose related reversible anemia
• idiosyncratic aplastic anemia (usually fatal)
• Grey baby syndrome:

-Infants have a decreased ability to conjugate chloramphenicol

-High levels of drug accumulate in blood

Symptoms: abdominal distention, vomiting, cyanosis, hypothermia, decreased respiration, vasomotor collapse

Lincosamides

• Clindamycin and lincomycin
• Lincomycin is rarely used
• Activity similar to erythromycin
• Penetrates most tissues including bone
• Effective against anerobes
• Pseudomembranous colitis can occur because Clostridium difficile is resistant to clindamycin

Folate Antagonists: Drugs

• Sulfamethoxazole
• Trimethoprim
• Cotrimoxazole
• Sulfacetamide
• Sulfadiazine
• Sulfapyridine
• Sulfasalazine
• Sulfisoxazole

-Bacteria cannot absorb folic acid

• Synthesize it from PABA (parabenzoic acid), pteridine, and glutamate

-Humans cannot make folic acid -->must take in through diet (vitamin)

Above difference provides a selective drug target

-Sulfonamides are structurally similar to PABA

• Block the incorporation of PABA into dihyropteroic acid

-Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate (inhibits dihydrofolate reductase)

• Enzyme is present in humans but drug has lower affinity for human enzyme

-Sulfonamides and trimethoprim act synergistically

• rarely used alone
• Sulfamethoxazole is most commonly combined with trimethoprim due to matching half lives

-Broad spectrum

-Used for UTIs, Pneumocystis carinii pneumonitis

• Ciprofloxacin
• Enoxacin
• Levofloxacin
• Norfloxacin
• Ofloxacin
• Sparfloxacin
• Trovafloxacin
• Gatifloxacin
• Gemifloxacin
• Lomefloxacin
• Moxifloxacin

• Primarily used to treat UTIs
• Inhibit NA synthesis by inhibiting DNA gyrase which is the bacterial enzyme responsible for unwinding and supercoiling DNA
• Only class of antimicrobials that inhibits DNA replication
• Broad spectrum
• Newer agents effective for UTIs, lower respiratory tract infections, bone and joint infections, prostatitis
• Some effective against Pseudomonas aeruginosa
• Some orally active

• Prodrug
• In acidic pH, hydrolyzed to ammonia and formaldehyde
• Formaldehyde is bactericidal

• Mycobacteria responsible for both tuberculosis and leprosy is slow growing: requires long term therapy
• Combination therapy (4-5 drugs) is often needed to prevent emergence of resistant strains

• Isoniazid
• Pyrazinamide
• Rifampin
• Ethambutol
• Streptomycin

• Aminosalicyclic acid
• Capreomycin
• Cycloserine
• Ethionamide
• Kanamycin
• Quinolones
• Rifabutin
• Viomycin
• Rifapentine

Isonazid

-Inhibits the synthesis of mycolic acids which are constituents of the mycobacterial cell envelope - unique in mycobacteria

-Polymorphism for isoniazid: fast and slow acetylators

- Hepatic Dysfxn:

• Elevated hepatic enzymes (10-20% of pts)
• Incidence increases with age
• Reversible in most pts.
• Hepatitis is most severe side effect

- Peripheral neuropathy due to pyridoxine deficiency

• Isoniazid combines with pyridoxine
• Can be overcome by coadmin. of pyridoxine

Isonazid

-Patient has a neg. TB test in the past but the test is positive 1 yr. later; pt. is referred to as a recent convertor

-Recommendation that person should be placed on isoniazid for 6-12 months as long as there is no evidence of clinical disease (i.e. pos. Chest Xray)

-Inhibits RNA synthesis

• Binds to the Beta subunit of DNA-dependent RNA polymerase forming an inactive complex

-Resistance occurs due to single step mutation that alters the beta subunit

-Effective against TB and some Gr.+ and neg. pathogens

-Deacetylated to an active metabolite

- Induces cytochrome P450 enzymes

• Increased metabolism of other drugs

-Can cause a drug induced hepatitis

Can color secretions (urine, saliva, feces, sweat, tears) red-orange

•  can result in discoloration of contact lenses

-Rifabutin- analog of rifampin that is active against some strains of resistant mycobacterium tuberculosis

• MOA is unknown
• Only effective against Mycobacterium tuberculosis - particularly effective against intracellular organisms
• Hyperuricemia occurs in all pts. but clinical gout is rare
• Hepatotoxicity

Ethambutol

-MOA unknown

-Least potent of 1st line drugs

-Can cause optic neuritis

• Loss of central vision
• Impaired red-green discrimination

-Hyperuricemia that can result in Gout

Dapsone

• Mainly used in the trtment of leprosy
• Durg resistance becoming a major problem requiring combination therapy
• Structural analog of PABA
• Competitive inhibitor of folic acid synthesis

-Fungal Infections:

• Many occur in poorly vascularized or avascular tissues (nails, hair, superficial layer of skin)
• Fungi are slow growing and more difficult to kill
• Many are opportunistic and host factors play an impt. role in overall prgonosis

- Drugs are usually poorly soluble resulting in difficulty in gaining access to site of action

-Can be classified by activity

• Systemic (disseminated balstomycosis, coccidiodomycosis)
• Superficial (dermatophytes of skin, hair and nails

- Also classified by MOA

• Azoles
• Polyenes

-Drugs:

• Amphotericin B
• Nystatin

- MOA: Binds ergosterol (prinicipal fungal membrane sterol) which disrupts membrane and results in los of electrolytes from cell

-Commonly used to treat disseminated yeast and fungal infections in immunosuppressed patients

-Nystatin used for topical trtment of Candida albicans (too toxic for systemic use)

-Amphotericin B is NOT orally absorbed - must be given IV or topically

-Nephrotoxicity:

• Most common and serious toxicity
• Related to dose and duration
• Need to keep pt. well hydrated to reduce nephrotoxicity

- With initial dose, fever, chills and tachypnea often occur

Imidazoles

-Topical:

• Butoconazole
• Clotrimazole
• Econazole
• Oxiconazole
• Sulconazole

-Topical and systemic:

• Ketoconazole
• Miconazole

Triazoles

-Systemic:

• Fluconazole
• Itraconazole
• Voriconazole
• Terconazole

- Broad spectrum fungistatic

- Inhibit syn. of ergosterol by inhibiting 14-alpha demethylase

- Advantages of triazoles vs. imidazoles

• fewer side effects
• better drug distribution
• fewer drug interactions

• IV antifungal agent
• Indicated for trtment of invasive aspergillosis and candidiasis
• Noncomp. inhibits the syn. of Beta(1,3)D-glucan, a major component of fungal cell walls

• Administered orally for trtment of superficial fungal infections
• Terbinafine and tolnaftate inhibit squalene epoxidase -- squalene accumulates inside the funal cell
• Terbinafine is effective against nail and hair fungi

• Binds to keratin in keratin precursor cells which then become reistant to fungal infections
• Dermatophyte infection can only be cured when infected cells are replaced by keratin containing griseofulvin
• Necessitates long term trtment

• Metronidazole
• Dehydroemetine
• Eflornithine
• Emetine
• Iodoquinol
• Melarsoprol
• Nifurtimox
• Pentamidine
• Quinacrine
• Sodium stibogluconate
• Suramin
• Atovaquone
• Meglumine antimonate
• Benznidazole
• Nitrazoxamide

-One of the MOST effective drugs against anaerobic bacteria and protozoans

-Penetrates protozoal and bacterial cell walls - cannot enter mammalian cells!

-Must be activated in the cell:

• Nitroreductase activates the drug
• Reduced metronidazole inhibits DNA replication by causing breaks and inhibiting repair

-Effective in the trtment of

• Vaginal trichomoniasis
• Giardiasis
• Amebiasis

-Side Effects:

• N/V/D
• Turns urine dark or red-brown
• Metallic taste
• Disulfiram-like rxn when taken with alcohol: abdominal cramping, vomiting, flushing, HA

• Chloroquine
• Primaquine
• Quinine
• Doxycycline
• Hydroxychloroquine
• Mefloquine
• Pyrimethamine

-Maleria caused by protozoan (plasmodium)

• Some strains for plasmodia can persist in liver resulting in relapse

-Symptoms are believed to be due to erythrocytic form of parasite

-DOC = Chloroquine

• Effective against liver forms - often used for prophylaxis or prevention of relapse
• Can cause hemolytic anemia in glucose-6-dehydrogenase deficient pts

- Used for prophylaxis for travelers entering areas where chloroquine sensitive maleria is present

- Can be toxic at high doses or long durations of therapy

• Can become concentrated in melanin containing structures leading to corneal deposits and blindness

Cinchonism can occur

• Sweating, tinnitis, impaired hearing, blurred vision, N/V/D

-Types of worms:

• Cestodes (flatworms, tapeworms)
• Trematodes (flukes)
• Nematodes (whip, pin, hook)

-Cestodes remain in intestine- trtment confined to intestine

-Trematodes move through blood and tissues- trtment must be systemic

• Praziquantel is DOC
• MOA: alteration of the membrane fxn of the worm to increase permeability
• Praziquantel is absorbed orally and therefore can have a systemic effect

-Drugs:

• Albendazole
• Mebendazole
• Pyrantel

-Albendazole and mebendazole inhibit tubule polymerization in worms- disrupts motility and replication

• Given orally with little systemic absorption

-Pyrantel paralyzes the worms!

-Mechanisms of controlling viral diseases

• Vaccination
• Chemo
• Stimulation of host defense mechanism

-Difficult to separate virus from host cell

-Most of drugs available block specific viral proteins involved in the synthesis of viral components in the host cell

• Abacavir
• Didanosine
• Lamvudine
• Stavudine
• Zalcitabine
• Zidovudine
• Amprenavir
• Delavirdine
• Efavirenz
• Nevirapine
• Emtricitabine
• Adefovir
• Tenofovir

• Inhibit formation of viral DNA from RNA by reverse transcriptase
• Nucleoside analogs related to thymidine and adenosine -get incorporated into viral DNA and terminate DNA elongation
• Nucleotide analogs work similarly but do not require as much phosphorylation
• Nonnucleoside inhibitors do not mimic natural nucleosides
• Reverse transcriptase enzyme mutates rapidly: use of 2 or more reverse transcriptase inhibitors delays emergence of resistance

- Interferes with processing of viral protein and prevents formation of new viral products

- Number of side effects

• Metabolic abnormalities
• Changes in fat deposition

Anti-HIV drugs: Protease inhibitors

( -NAVIR)

• Ampenavir
• Indinavir
• Nelfinavir
• Ritonavir
• Saquinavir
• Atasanavir
• Lopinavir
• Fosamprenavir

• Enfivirtide
• Analog of HIV protein that mediates fusion with cell membrane
• Traps virus in a conformational state that prevents fusion with cell
• Given IV

• Most are neuraminidase inhibitors which block release of virus from infected cells
• If used w/i 48 hrs of onset of illness, duration of illness is shortened by 1/2
• Rapid resistance occurs
• Amantadine
• Rimantadine
• Oseltamivir
• Zanamivir