M3 SYNTHETIC ANTIBACTERIAL AGENTS

Nalidixic Acid (NegGram)

treatment for urinary tract infections caused by G(-)

glucuronide and 7 carboxylic acid

Inactive metabolite of nalidixic acid

7-hydroxy metabolite

Active metabolite of nalidixic acid

Quinolones

series of synthetic antibacterial agents patterned after nalidixic acid

Quinolones (Norfloxacin, Ciprofloxacin, Lomefloxacin)
Cinnolines (Cinoxacin)
Naphthyridines (Nalidixic Acid, Enoxacin)

Isosteric heterocyclic groupings in this class include

Naphthyridines

Quinolones

Cinnolines

Quinolones

confined to the treatment of urinary tract infections.

vertigo, anxiety confusion

Quinolones: Adverse Effects incidence of CNS effects

gamma-aminobutyric acid receptors (GABA)

Quinolones attributed to antagonism of ______

nausea, vomiting, diarrhea

Quinolones: Adverse Effects Gastrointestinal

Achilles Tendon Rupture

Tendinopathy AKA

Involved in binding to DNA Gyrase

Pos 2, 3, 4:

+ substituent – reduces activity

Pos 2:

Alkyl groups – essential for activity

Pos 1

Aryl groups

optimal potency with 2,4 difluorophenyl

Pos 5, 6, 7, 8:

position may be substituted with good effects

Pos 6 (Fluorine)

enhances antibacterial activity (inc cell penetration, DNA gyrase affinity)

Pos 7

+ piperazinyl and 3-aminopyrrolidinyl – enhances activity against P. aeruginosa

3-carboxylic acid group

Nalidixic Acid, Oxolinic Acid, Cinoxacin

FIRST gen fluoroquinolones

have moderate gram negative activity and minimal systemic distribution

FIRST gen fluoroquinolones list

Oxolinic acid
Nalidixic acid (NegGram, Wintomylon)
Cinoxacin (Cinobac)

Second gen fluoroquinolones

have expanded gram negative activity and atypical pathogen coverage, but limited gram-positive activity

Second gen fluoroquinolones list CLASS 1

Lomefloxacin (Maxaquin)
Enoxacin (Penetrex)
Norfloxacin (Noroxin)

Second gen fluoroquinolones list CLASS 2

Class II

Ofloxacin (Floxin, Floxin IV)

Ciprofloxacin (Cipro, Cipro IV)

THIRD gen fluoroquinolones

retain expanded gram-negative and atypical intracellular activity but have improved gram positive coverage

THIRD gen fluoroquinolones list

Levofloxacin (Levaquin)

Sparfloxacin (Zagam)*

Moxifloxacin (Avelox)

FOURTH gen fluoroquinolones

improve gram-positive coverage, maintain gram-negative coverage, and gain anaerobic coverage

FOURTH gen fluoroquinolones list

Gemifloxacin (Factive)
Gatifloxacin (Tequin)
Moxifloxacin (Avelox,Vigamox)
Clinafloxacin
Trovafloxacin (Trovan) (withdrawn)
Sitafloxacin

Cinoxacin

close congener (isostere) of oxolinic acid (no longer marketed in the United States) and has antibacterial properties similar to those of nalidixic and oxolinic acids

Norfloxacin

broad-spectrum activity against G(-) and G(+) aerobic bacteria

15%

Norfloxacin is ____ protein bound and is metabolized in the liver

800-mg

Norfloxacin single oral dose approved for treatment of uncomplicated gonorrhea

400-mg

Enoxacin dose for uncomplicated gonococcal urethritis and effective in chancroid

98%

Enoxacin Oral bioavailability approaches _______

CYP450

Enoxacin mediated liver metabolism.

70-80%

Ciprofloxacin Oral bioavailability approaches

• provide the best

distribution of the currently

marketed quinolones

• higher potency against most

G(-), including P. aeruginosa,

than other quinolones

Ciprofloxacin

First line treatment of bacterial gastroenteritis by G(-) bacilli

Ceftriaxone

Ciprofloxacin + ________ for disseminated gonorrhea

Doxycycline

Ciprofloxacin + ________ for gonococcal urethritis eradication

Ciprofloxacin

For post-exposure Inhalational anthrax

Ticarcillin sodium

Mezlocillin sodium

Aminophylline

Ciprofloxacin not be mixed with solutions of _____

Ofloxacin

• resembles ciprofloxacin in its antibacterial spectrum

and potency.

• widely distributed into most body fluids and tissues,

and with higher concentrations achieved in CSF

95-100%

Ofloxacin Oral bioavailability approaches _____

Ofloxacin

For treatment of chronic bronchitis and pneumonia by G(-) bacilli, pelvic inflammatory disease, gonococci and chlamydia

3S(–) isomer

3R(+) isomer: Levofloxacin

Lomefloxacin

Only quinolone for which once-daily oral dosing suffices. Highest incidence of photosensitivity.

95-98%

Lomefloxacin Oral bioavailability approaches

acute bacterial exacerbations of chronic bronchitis

Lomefloxacin Primary indications:

Sparfloxacin

Exhibits higher potency against gram positive bacteria, especially staphylococci and streptococci. More active against gram negative; chlamydia and anaerobe Bacteroides fragilis, permits once-a-day dosing for most indications.

Nitrofurans

first nitroheterocyclic compounds to be introduced into chemotherapy

5-position

Nitrofurans anti-microbial activity is present only when the nitro group is in the_____.

Nitrofurazone (Furacin)

Topical treatment of burns, especially when bacterial resistance to other agents may be a concern. Bactericidal against most bacteria commonly causing surface infections: S. aureus, Streptococcus spp., E. coli

Furazolidone

bactericidal activity against intestinal pathogens, active against the protozoan Giardia lamblia.

Nitrofurantoin

Treatment of UTI by E. coli, enterococci, S. aureus, Klebsiella, Enterobacter, and Proteus spp.

Methenamine (Urothropin, Uritone)

Activity of hexamethylenetetramine depends on the liberation of formaldehyde. Internal urinary antiseptic as treatment for chronic urinary tract infections.

Methenamine Mandelate (Mandelamine)

Very soluble in water and has the advantage of providing

its own acidity. Carry out a preliminary acidification of the urine for 24

36 hours before administration

Methenamine Hippurate

Readily absorbed after oral administration and is concentrated in the urinary bladder, where it exerts its antibacterial activity. Its activity is increased in acid urine.

Phenazopyridine Hydrochloride (Pyridium)

active in vitro against Staphylococci, Streptococci, Gonococci, and E. coli, it has no useful antibacterial activity in the urine.

Isoniazid

Isonicotinic acid hydrazide, isonicotinyl hydrazide, or INH. Inhibit the synthesis of mycolic acids high–molecular-weight, branched β-hydroxy fatty acids. mycobacterial catalase–peroxidase enzyme complex is required for the bioactivation of isoniazid

Ethionamide (Trecator SC)

Weak bacteriostatic activity in vitro but, because of its lipid solubility, is effective in vivo secondary drug treatment for tuberculosis for INH resistant forms

Pyrazinamide

First-line status in short-term tuberculosis treatment regimens because of its tuberculocidal activity and comparatively low short-term toxicity.

pyrazinoic acid

Bioactivation of pyrazinamide to ______ by an amidase present in mycobacteria

Ethambutol (Myambutol)

Active only against dividing mycobacteria rapidly absorbed after oral administration, and peak serum levels occur in about 2 hours. Bacteriostatic drug, interfering with the biosynthesis of arabinogalactan in the cell wall, halting multiplying bacilli

Aminosalicylic Acid

This agent was once quite popular, until significant resistance to the drug developed. It interferes with the incorporation of p aminobenzoic acid into folic acid

Clofazamine (Lamprene)

Exerts a slow bactericidal effect on M. leprae. Unknown mechanisms of antibacterial and anti inflammatory. But known to bind to nucleic acids and concentrate in reticuloendothelial tissue. It can also act as an electron acceptor and may interfere with electron transport processes

Rifamycins

group of chemically related antibiotics obtained from Streptomyces mediterranei

Rifampin (rifampicin, Rifadin, Rimactane)

Most active agent in clinical use for the treatment of tuberculosis. Only in combination with other antiTB due to rapid development of resistance

Rifabutin

prophylaxis of disseminated Mycobacterium Avium Complex in AIDS patients very lipophilic compound with a high affinity for tissues

Cycloserine (Seromycin)

from the fermentation beer of three different Streptomyces species

S. orchidaceus

S. garyphalus

S. lavendulus

Cycloserine (Seromycin) species.

Capreomycin

Isolated from Streptomyces capreolus, tuberculostatic drug inhibit protein synthesis by binding to the 70S ribosomal unit. Toxic effects: damage to cranial nerve and renal system.

Fritz Mietzsch and Joseph Klarer

Synthesized azo dyes with sulfonamides as potential antimicrobial agents

Gerard Domagk

Evaluated Mietzsch-Klarer dyes Prontosil

Sulfonamides

Are infrequently used as single agents. Drugs of choice for infections such as PCP, toxoplasmosis, nocardiosis, and other bacterial infections, they have been largely replaced by the fixed drug combination TMP–SMX

Sulfisoxazole

Sulfamethoxazole

Sulfadiazine

Sulfadoxin

Oral Absorbable Agents

Sulfasalazine (Salicylazosulfapyridine)

Oral Non-Absorbable Agents

Sodium Sulfacetamide

Mafenide Acetate

Topical Agents

Dapsone

used in the treatment of both lepromatous and tuberculoid types of leprosy often in combination with Clofazimine and Rifampin

+ Pyrimethamine for Malaria

+ Trimethoprim for PCP

Choice for dermatitis hepetiformis

Metronidazole (Flagyl, Protostat, Metro IV)

Tx of amebic dysentery, giardiasis, trichomoniasis active against all facultative anaerobe/ obligate aerobes, gram (+) bacilli, and cocci First line for C. difficile colitis infections

Diloxanide

Hydrolysis of the amide is required for the amebicidal effect. Furoate salt used in the treatment of asymptomatic carriers of E. histolytica

Iodoquinol (Yodoxin, Diodoquin, Dioquinol)

for acute and chronic intestinal amebiasis but is not effective in extraintestinal disease

Emetine

direct amebicidal action on various forms of E. histolytica protoplasmic poisons that inhibit protein synthesis in protozoal and mammalian cells by preventing protein elongation

Pentamidine Isethionate (NebuPent, Pentam 300)

Slow IV infusion or deep IM injection treatment of P. carinii pneumonia. Aerosol for prophylaxis against PCP in patients with HIV, with history of PCP, or low peripheral CD4 lymphocytes

Atovaquone (Mepron)

Antimetabolite for ubiquinone 6 interferes with the function of electron transport enzymes alternative to (TMP-SMX) for the treatment and prophylaxis of PCP

Eflornithine

treatment of meningoencephalitic stage of West African sleeping sickness, caused by Trypanosoma brucei gambiense Myelosuppresive drug causing anemia, leukopenia, thrombocytopenia

Nifurtimox (Lampit)

only agent clinically active against acute and chronic T. cruzi infections

Benznidazole (Radanil, Rochagan)

employed for the tx of Chagas disease A/E: peripheral neuropathy and bone marrow suppression

Melarsoprol (Mel B, Arsobal)

Treatment for later stages of African trypanosomiasis advantage of excellent penetration into the CNS and, therefore, is effective against meningoencephalitic.

Sodium Stibogluconate (Pentostam)

drug of choice for all forms of Leishmaniases. antileishmanial action of sodium stibogluconate requires its reduction to the trivalent form, which is believed to inhibit phosphofructokinase in the parasite

Suramin Sodium

high-molecular weight bisurea derivative containing six sulfonic acid groups as their sodium salts. effective in the tx and prophylaxis of Trypanosomiasis

Piperazine

Treatment of pinworm and roundworm infestations

Enterobius vermicularis

pinworm sn

Ascaris lumbricoides

roundworm

Piperazine

blocks the response of the ascaris muscle to acetylcholine, causing flaccid paralysis in the worm, which is dislodged from the intestinal wall and expelled in the feces.

Diethylcarbamazepine

For filariasis onchocerciasis, loiasis, ascariasis