Antimicrobial Drug Classes:

Inhibitors of cell wall synthesis

Beta lactams

polypeptides

aminoglycosides

chloramphenicol

clindamycin

macrolides

ketolide

streptogrammin

oxazolidanone

tetracyclines

Sulfonamides

Trimethoprim

• penicillins and cephalosporins compete for the enzymes that catalyze transpeptidation and cross-linking (structures of the drugs are similar to the terminal portion of the peptidoglycan strands)
• result is bacteria with structurally weakened cell walls and death

• all contain a beta lactam ring: penicillins, cephalosporins, carbapenams, monobactams
• Beta lactam ring is responsible for their antimicrobial action
• some bacteria have beta lactamase which opens the ring and inactivates the drug
• beta lactamases: Penicillinase and Cephalosporinase

• Beta lactamase inhibitors can be given concurrently: Clavulanic acid, Tazobactam, and Sulbactam
• they chemically modify drug structure so that lactam ring is resistant to lactamases

• made by mold
• include: Penicillin G/V, Benzathin pen G
• narrow spectrum
• Penicillinase sensitive

• Drugs: Azlocillin, Carbenicillin Mezlocillin, Piperacillin, Ticarcillin
• narrow spectrum (gram positive)
• Synthesized to be penicillinase sensitive

• Drugs: Amoxicillin and Ampicillin
• broad spectrum (also some gram neg. activity)
• Penicillinase sensitive

• Drugs: Azlocillin, Carbenicillin, Mezlocillin, Piperacillin, Ticarcillin
• Active against pseudomonas
• relatively ineffective against gram + organisms

• oral absorption is poor
• most only cross BBB id it is inflamed
• excreted by active tubular excretion which can be blocked by concurrent admin. of probencid

• occurs iwthin 20 min after parenteral admin.
• symptoms: purititis, paresthesia, wheezing, choking, fever, edema, urticaria
• can result in hypotension, shock, death
• mediated by IgE

• Accelerated: appears 1-72 hrs after drug admin.
• consists mainly of urticaria
• Late: more common with semisynthetics
• appears 72 hrs to several wks after drug admin.
• mainly skin rashes

• Muliforme erythrema
• Stevens Johnson Syndrome
• TEN

• Drugs: Cefazolin and Cephalexin
• narrow spectrum (similar to broad spectrum penicillins)
• sensitive to beta lactamases

• Drugs: Cefaclor, Cefamandole, Cefoxitin
• increased activity toward gram negative organisms
• increased stability

• Drugs: Cefotaxime, Ceftazidime, Ceftriaxone
• broader spectrum than previous generations
• more R to beta lactamases

• Drugs: Cefepime and Cefpirome
• gram + and gram - activity
• effective against pseudomonas aeruginosa
• also gram - org with multiple drug R patterns

Cephalosporins

• 3rd and some 2nd generation drugs penetrate CNS--> treat meningitis
• 3rd generation is used in tx. and prophylaxis of infections in hospitalized pts
• 4th generation drugs targeted at organisms w/ multi-drug resistance

• some create cross-allergy w/ penicillins
• can interfere w/ Vit K --> increased bleeding
• Disulfiram-like rxn: block alcohol oxidation and acetylaldehyde accumulates

• Drugs: Imipenam, Ertapenam, Meropenam
• all admin. via I.V.
• Imipenam: hydrolyzed by renal dipeptidase in the kidney to a toxic metabolite (no antimicrobial activity)
• Cilistatin: inhibts dipeptidase-have to admin. w/ imipenam
• Meropenam: stable to dipeptidase-does NOT require co-admin of Cilistatin

• Aztreonam
• Narrow spectrum--> aerobic gram neg bacteria (includes pseudomonas)
• ineffective against gram + bacteria
• highly R to Beta lactamases

Vancomycin and Teicoplanin

• inhibit cell wall syn by preventing polymerization of the linear peptidoglycans
• only effect. against gram +
• poorly absorbed orally
• dose related Ototoxicity (tinnitus, high tone deafness, hearing loss)
• Red Man syndrome

• mixture of polypeptides that inhibit cell wall synthesis--> bind to lipid carrier that transports cell wall precursors
• used topically due to serious nephrotoxicity

• inhibits one of the 1st steps of synthesis of peptidoglycan
• used for tx of UTIs

• binds to membrane of bacteria and causes depolarization
• loss of membrane potential results in death

Protein Synthesis Inhibitors

• require binding to intracellular protein (ribosomal subunit) so must enter the cell
• major route of R is blockade of drug from entering the cell

Aminoglycosides

(GASTNNK)

Gentamycin

Amikacin

Steptomycin

Tobramycin

Neomycin

Netilmicin

Kanamycin

• Broad spectrum-not good for anaerobic bact.
• Drug enters bacteria via O2 dep. transport
• poorly absorbed from GI tract
• most must be given parenterally
• highly polar, insoluable in fat
• do not readily penetrate cells (require a transport system or coadmin. with penicillins

• narrow margin of safety
• Otoxicity-> cochlear (auditory) and vestibular (vertigo)
• Nephrotoxicity->due to rapid uptake by prox. tubular cells (acute is reversible)
• Neurotoxicity-> due to presyn. release of Ach at NMJ

Tetracyclines

(DOC TM)

• Demeclocycline
• Oxytetracycline
• Chlortetracycline
• Tetracycline
• Minocycline
• these drugs may decrease in efficacy

• accum. in cytoplasm by energy dep. transport
• R occurs when bacteria mutate to prevent entry of drug into cell
• Indications: broad spectrum (grm +/-, anaerobes), Rickettsial diseases, chlamydia, cholera, lyme disease, mycoplasm pneumo

• food impairs absorption-> forms insoluable chelates w/ Ca, Mg, and other metals; avoid antacids
• Deposits in teeth and bones (NOT good for pregos)
• photosensitivity

Macrolides

(ED CAT)

• Erythromycin
• Dirithromycin
• Clarithromycin
• Azithromycin
• Troleandomycin

• mycoplasma infections
• pneumonia
• Legionnaire's Disease
• Chlamydia
• Diptheria
• Pertussis
• GI upset is the most common side effect

• Ketolides are derived from these

• Telithromycin is useful for macrolide R to organsims (activity against intracellular resp. pathogens)

• Protein syn inhibitors
• Combo drug: Dalfopristin + quinupristin
• act synergistically to inhibit ribosome fxn
• Linezolid:inhibits protein syn via translation; effective against anaer. gm +; approved for vancomycin R infections; has MAOI activity (concern b/c of its drug/food interactions)

• broad spectrum (not effective against pseud)
• reserved for life threatneing infections (serious adv effects)
• orally absorbed
• penetrates CSF
• Dose related BM suppresion and dose related rever. anemia
• Grey Baby Syndrome

• Drugs: Lincosamide, Lincomycin (rarely used)
• activity similar to erythromycin
• penetrates most tissues including bone
• effective against anaerobes
• Pseudomembranous colitis-clostridium difficile is R to clindamycin

• Sulfamethoxazole
• Trimethoprim
• Cotrimoxazole
• Sulfacetamide
• Sulfa: -diazine -pyridine -salazine
• Sulfisoxazole

• bacteria cant absorb folic acid->syn it from PABA
• Humans cant syn folic acid either (diet)
• Sulfonamides: similar to PABA-block incorp of PABA ino dihydropteroic acid
• Trimethoprim: prevents reduction of dihydrofolate to tetrahydrofolate

• Sulfonamides and Trimethoprim act synergistically (rarely used alone)
• Sulfamethoxazole + trimethoprim (same 1/2 lives)
• broad spectrum
• used for UTIs, Pneumocystitis carini, pneumonitis

Quinolones

(prefix+ floxacin)

• Cipro+                   Gemi+
• Enoxacin                 Lome+
• Levo+                     Moxi+
• O+
• Nor+
• Spar+
• Trova+
• Gati+

• treats UTIs
• inhibit DNA syn. by inhibiting DNA gyrase (bacterial enzyme that unwinds and supercoils DNA)
• only class that inhibits DNA replication
• broad spectrum-sometimes effect. against P. aerugina
• some orally active

• a prodrug
• in acidic pH, hydrolyzed to ammonia and formaldehyde (bactericidal)

Antituberculosis/Antileprosy drugs

• Mycobacteria repsonsible for both TB and leprosy is slow growing
• requires long term therapy
• Combo therpay: 4-5 drugs is often needed to prevent remergence of R strains

Anti-TB and Antileprosy drugs:

First line

(RIPES)

• Rifampin
• Isonizid
• Pyrazinamide
• Ethambutol
• Streptomycin

Ant-TB and Antileprosy drugs:

2nd Line agents

1. Aminosalicyclic acid    7. Rifabutin
2. Capreomycin              8. Viomycin
3. Cycloserine                9. Rifapentine
4. Ehtionamide
5. Kanamycin
6. Quinolones

• inhibits syn of mycolic acids
• polymorphism->fast and slow acetylators
• heptic fxn: elevated enzymes (increases w/ age), revers. in most, hepatitis is a severe side effect
• peripheral neuropathy: due to pyridoxine deficiency

• chemoprophylaxis in recent converters
• -> pt has a neg TBtest in the past but tests + 1 yr later is a recent converter
• -> reccommendation that person should placed on this drug for 6-12 mon (as long as they have no evidence of disease)

• inhibits RNA syn (binds to beta subunit of DNA-dep RNA polymerase)
• R occurs due to sinlge step mutation that laters beta subunit
• effective against TB and some Gm +/- pathogens

• deacetylated to an active metabolite
• induces CYT P450 enzymes
• can cause a drug-induced hepatitis
• can color secretions a red-orange color
• Rifabutin: analog that is active against some strains of myco TB

• uknown MOA-only effective against Mycob. TB
• hyperuricemia occurs in all pts, but clinical gout is rare
• hepatoxicity

• unknown MOA
• least potent of 1st line drugs
• can cause optic neuritis: loss of central vision and impaired red-green discrimination
• Hyperuricemia that can result in gout

• used to Tx leprosy
• drug R is becoming a major porblem w/ combo therapy
• structural analog of PABA
• competitive inhibitor of folic acid syn

Antifungal Drugs

• fungal infections: -mainly occurs in poorly vascularized tissues, are slow growing and more difficult to kill, and most are opportunistics and host factors play an important role in overall prognosis

• drugs are usually poorly soluable
• can be classfied by activity: systemic or superficial
• also classified by MOA: Azoles, Polyenes, etc.

• Drugs: Amphotercin B and Nystatin
• MOA: binds ergosterol which disrupts membrane and results in loss of electrolytes from cell
• tx dissem. yeast/fungal infections in IMS pts
• Nystatin: treats candida albicans infect.
• Amphotercin B: not absorbed orally-give IV or topical

• Nephrotoxicity: related to dose and duration (keep pt well hydrated to avoid this)
• with inital dose, fever, chills, and tachypnea may occur

Azole antifungals: Imidazoles

Butoconazole, Clotrimazole, Econazole, Oxiconazole, Sulconazole (topical)

Ketoconazole and Micoazole (topical and systemic)

• broad spectrum fungistatic
• inhibit syn of ergosterol by inhibiting 14-alpha demethylase
• adv of traizoles vs. imidiazoles: fewer side effects, better drug distribution, fewer drug interactions

• Fluconazole
• Itraconazole
• Voriconazole
• Terconazole

• Caspofungin
• Flucytosine
• Griseofulvin
• Terbinafine
• Tolnaftate

• IV anitfungal agent
• indicated for tx of invasive apergillosis and candidiasis
• noncompetitively inhibts syn of beta (1,3)-D-glucan (major part of cell wall)

• admin orally for tx of superficial fungal infections
• terbinafine and tolnaftate inhibit squalene epoxidase (accum inside fungal cell)
• terbinafine is effective against hair and nail fungi

• binds to keratin in keratin precursor cells which then become R to fungal infections
• Dermatophyte infections are only cured when infected cells are replaced bu keratin w/ this drug
• requires long term treatment

Metronidazole

(Antiprotozoal Drug)

• the most effect. drug against aner. bacteria/protozoans
• penetrates protozoal and bacterial cell walls
• must be activated inside cell: Mitroreductase activates the drug, reduced metronidazole inhibits DNA replic. by causing breaks and inhibiting repair

• tx for Vaginal trichomoniasis, Giardiasis, Amebiasis
• Side effects: N/V/D, turns urine dark or red-brown, metallic taste
• Pt will get a Disulfiram-like rxn if they consume alcohol->abd cramping, vomiting, flushing, HA

• Chloroquine
• Primaquine
• quinine
• Doxycycline
• Hydroxychloroquinine
• Mefloquine
• Pyrimethamine

Antimalarial Drugs: Chloroquinine

• Maleria is caused by protozoan (plasmodium)
• symptoms are due to erythrocytic form of parasite
• Chloroquinine: DOC (but there are some R organisms to this drug); used for prophylaixs for travelers; can be toxic at high doses-can get concentrated in melanin leading to corneal deposits and blindness

• Primiquine: effective against liver forms-often used as prophylaxis to prevent relapse
• can cause hemolytic anemia in G6P def. pts 
• Quinine: can cause Cinchonsim: sweating, tinnitis, imparied hearing, blurred vision, N/V/D

• Types fo worms: cestodes, trematodes, nematodes
• Cestodes-stay in intestines
• trematodes-move thru blood and tissues; tx must be systemic

• Praziquintel: DOC for most infections
• MOA: due to alteration of the membrane fxn of the worm to increase permeability
• absorbed orally (has systemic effect)

• Drugs: Albendazole, Mebendazole, Pyrantel
• Albendazole and mebenazole: inhibit tubule polymeriazation in works-disrupts motility and replication-given orally with little systemic absorption
• Pyrantel: paralyzes the worm

• Mechanisms of controlling viral diseases: vaccination, chemotherapy, stim. of host defence mechansim
• difficult to sep. virus from host cell
• most drugs block specific viral proteins involved in the syn of viral components in the host cell

1. Abacavir          8. Delavirdine
2. Didanosine      9. Efavirenze
3. Lamivudine     10. Nevirapine
4. Stavudine       11. Emtrictabine
5. Zalcitabine     12. Adefovir
6. Zidovudine     13. Tenofovir
7. Ampreavir

• inhibit formation of viral DNA from RNA
• nucleoside analogs related to thymidine and adenosine: get incorp. into viral DNA and terminate DNA elongation
• nucleoside analogs work similarly but do not require as much phosphorylate
• Nonnucleoside inhibitors do not mimic natural nucleosides

• interfere w/ processing of viral protein and prevents formation of new viral products
• Many side effects: matbolic abnormalities and chgs. in fat deposition
• Drugs: Ampenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Atsanavir, Lopinavir, Fosaprenavir

Enfivirtide

• analog of HIV protein the mediates fusion w/ cell membrane
• traps virus in a conformational state that prevents fusion w/ cell
• has to be given I.V.

• Drugs: Amantadine, Rimantadine, Oseltamivir, Zanamivir
• most are neuraminidase inhibitors-block relase of virus from infected cells
• if used w/ in 48 hrs of onset, can shorten duration of illness by 1/2
• rapid R can occur

1. cycloserine
2. vancomycin
3. bacitracin
4. fosfomycin
5. penicillins
6. cephalosporins
7. monobactams and carbapenams

1. nafidixic acid
2. quinolones

1. rifampin

1. erthrymycin
2. chloramphenecol
3. clindamycin

1. trimethoprim
2. sulfonamides

1. polymyxins

Summary: Protein Synthesis (30S inhibitors)

Drugs

1. tetracycline
2. spectinomycin
3. streptomycin
4. gentamycin, tobramycin
5. amikacin