Synthetic antibacterial agents

SULFONAMIDES TRIMETHOPRIM QUINOLONES NITROFURANS METRONIDAZOLE

CHEMISTRY

SULFONAMIDES

Sulfonamides (sulfanilamide)

are

derivatives

of

para-aminobenzenesulfonamide

Most are relatively insoluble in water, but their sodium salts are readily soluble. The minimal structural prerequisites for antibacterial action are embodied in sulfanilamide itself. The sulfur must be linked directly to the benzene ring. The para- NH2 group (the N of which is designated N4) can be replaced only by moieties that can be converted in vivo to a free amino group. Substitutions in the amide NH2 group (N1) have variable effects on antibacterial activity of the molecule, but substitution of heterocyclic aromatic nuclei at N1 yields highly potent compounds.

Effects on Microbes Usefulness of sulfonamides has diminished due to the emergences of resistant strains. These drugs are bacteriostatic, and host defenses are essential for eradication of the infection. MECHANISM OF ACTION Sulfonamides competitively inhibit dihydropteroate synthase Sensitive microorganisms must synthesize their own folic acid, while bacteria that can use preformed folate are not affected. Mammalian cells require preformed folic acid and are not affected by sulfonamides.

dihydropteroate synthase

Susceptible bacteria require extracellular PABA in order to form dihydrofolic acid, an essential step in the production of purines and the synthesis of nucleic acids. Sulfonamides are structural analogs of PABA that competitively inhibit dihydropteroate synthase. Drugs inhibit growth by reversibly blocking folic acid synthesis.

SYNERGISTS OF SULFONAMIDES Trimethoprim exerts a synergistic effect with sulfonamides. It potently and selectively inhibits microbial dihydrofolate reductase, the enzyme that reduces dihydrofolate to tetrahydrofolatethe form required for one-carbon transfer reactions.

Susceptible bacteria require extracellular PABA in order to form dihydrofolic acid, an essential step in the production of purines and the synthesis of nucleic acids. Sulfonamides are structural analogs of PABA that competitively inhibit dihydropteroate synthase. Drugs inhibit growth by reversibly blocking folic acid synthesis.

ACQUIRED BACTERIAL RESISTANCE TO SULFONAMIDES Resistance to sulfonamide results from altered constitution of the bacterial cell that causes (1)A lower affinity for sulfonamides by dihydropteroate synthase, (2)decreased bacterial permeability or active efflux of the drug, (3)an alternative metabolic pathway for synthesis of an essential metabolite, or (4)an increased production of an essential metabolite or drug antagonist.

Classification

Class Rapidly absorbed and excreted

Sulfonamide Sulfisoxazole Sulfamethoxazole Sulfadiazine

Serum t1/2 hrs 5-6 11 10

Poorly absorbed- active Sulfasalazine in bowel lumen Topically used Long-acting Sulfacetamide Silver sulfadiazine Sulfadoxine 100-230

Pharmacokinetics
Oral administration, absorbed well, Distributed widely to tissues and body fluids, including CNS and cerebrospinal fluid, placenta, and fetus; 20-90% protein binding rate; Acetylated or glucuronidated in the liver, Sulfonamides and inactive metabolites are excreted into the urine, they are more soluble at alkaline than at acid pH. In renal failure patient, drug dose must be reduced.

Clinical uses of Sulfonamides

a. Sulfamethoxazole + Trimethoprim (Trimethoprim0 a. Treatment of urinary tract infections b. Respiratory tract infections, sinusitis, bronchitis, pneumonia, otitis media, and dysentery, b. Sulfadiazine (SD) +Trimethoprim First-line therapy for treatment of acute toxoplasmosis 3. Sulfadoxine+Trimethoprim Used as a second-line agent in treatment for malaria. 4. Sulfasalazine ulcerative colitis, enteritis, and other inflammatory bowel disease. 5. Silver sulfadiazine For prevention of infection of burn wounds 5. Sodium sulfacetamide (SA-Na) Bacterial conjunctivitis, as adjunctive therapy for tarchoma

Adverse effects of Sulfonamides

1. Allergenic reactions All sulfonamides and their derivatives, including carbonic anhydrase inhibitors, thiazides, furosemide, bumetanide, torsemide, diazoxide, and the sulfonylurea hypoglycemic agents are cross- allergnic. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea. Stevens-Johnson syndrome, is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. 2. Urinary tract disturbances Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hemturia, or even obstruction. SD & Sulfamethoxazole, when in large doses, fluid intake is poor, can cause crystalluria. Sodium bicarbonate to alkalinize the urine, adequate fluids,

3.

Hematopoietic disturbances Hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, or leukemoid reactions. Provoke hemolytic reactions in patients whose red cells are deficient in glucose-6-phosphate dehydrogenase.

Trimethoprim
It Inhibits bacterial dihydrofolic acid reductase about 50000 times more efficiently than the same enzyme of mammalian cells. Pyrimethamine, inhibits the activity of dihydrofolic acid reductase of protozoa more than that of mammalian cells. Dihydrofolic acid reductases convert dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA.

Sulfonamides & Trimethoprim

They produces sequential blocking in this metabolic sequence, resulting in marked enhancement of the activity of both drugs. The combination often is bactericidal, compared to the bacteriostatic activity of a sulfonamide alone.
Resistance to trimethoprim Reduced cell permeability Overproduction of dihydrofolate reductase, Production of an altered reductase with reduced drug binding By mutation, plasmid-encoded,

Pharmacokinetics of Trimethoprim
Given orally, absorbed well distributed widely in body fluids and tissues, including cerebrospinal fluid, 65-70% protein-bound, 50-60% Trimethoprim excreted in the urine within 24 hours. Trimethoprim concentrates in prostatic fluid and in vaginal fluid, it has more effects than many other drugs. Trimethoprim Sulfamethoxazole=1 5, they have similar half-life

Clinical uses of Trimethoprim

Oral Trimethoprim alone in acute urinary tract infections Oral Trimethoprim+Sulfamethoxazole a. P carinii pneumonia, shigellosis, systemic salmonella infections caused by ampicillin- or chloramphenicol-resistant bacteria, b. Complicated urinary tract infections, prostatitis, some nontuberculous mycobacterial infections c. Many respiratory tract pathogens IV Trimethoprim+Sulfamethoxazole a. The agent of choice for moderately severe to severe pneumocystis pneumonia, such as in AIDS patients b. Used for G- bacterial sepsis, including that caused by some multiple-drugresistant species such as enterobacter and serratia, shigellosis, typhoid fever, or urinary tract infection.

Oral Pyrimethamine + Sulfonamide a. Leishmaniasis b. Toxoplasmosis c. Falciparum malaria

Adverse effects of Trimethoprim a. Hematologic toxicity Megaloblastic anemia, leukopenia, and granulocytopenia b. Nausea and vomiting, drug fever, vasculitis, renal damage, and CNS disturbances

Chemistry of Quinolones
They are synthetic fluorinated analogs of nalidixic acid.

Classification of Quinolones
1. First-generation of quinolones Nalidixic acid, oxolinc acid, cinoxacin, Useful only for treatment of lower urinary tract infections. 2. Second-generation of quinolones Pipemidic acid, its activity against Gram negative bacilli is more powerful. The resistance to these drugs is less. 3. Third-generation of quinolones Fluoroquinolones,
they were originally developed because of their excellent activity against Gram negative aerobic bacteria; they had limited activity against G+ organisms.

Chemistry of Quinolones

Classification of Quinolones
4. The newer fluoroquinolones Moxifloxacin and trovafloxacin, they have enhanced G+ activity, also have good activity against anaerobic bacteria, which other fluoroquinolones lack.

Antimicrobial effects of Quinolones

a. Broad spectrum a. First-generation, G- aerobic bacteria; b. Second-generation, more activity against G- aerobic bacteria; c. Third-generation, fluoroquinolones, possess excellent G negative activity & moderate to good activity against G+ bacteria, anaerobes,

Fluoroquinolones also are active against agents of atypical pneumonia, such as mycoplasmas and chlamydiae, and intracellular pathogens, e.g. legionella species and some mycobacteria, including Mycobacterium tuberculosis and M avium complex. b. Bactericidal Ciprofloxacin is the most active agent against G- bacteria, particularly Pseudomonas aeruginosa. Levofloxacin has superior activity against G+ organisms, including Streptococcus pneumoniae. Clinafloxacin has the best activity of them against G+ cocci.

Mechanism of action

They block bacterial DNA synthesis by inhibiting bacterial topoisomerase (DNA gyrase) and topoisomerase . Inhibiton of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibiton of topoisomerase probably interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division. The gyrase is composed of two A subunits and two B subunits. The A subunits can cut one of double strands of the DNA to permit passage of the other segment of DNA through the break and negative supercoil is formed; the break is then resealed. This is an ATP-dependent reaction. The energy is provided by B units. Quinolones is an inhibitor of A subunits. Therefore, the action of gyrase is inhibited and DNA replication or transcription is blocked as result of the death of bacteria. Novobiocin is an inhibitor of the B subunit of DNA gyrase and is active mainly
+

Resistance to Quinolones
Due to a. mutations in the quinolone binding region of the target enzyme b. A change in the permeability of the organism DNA gyrase is the primary target in E coli, with single-step mutants exhibiting amino acid substitution in the A subunit of gyrase. Topoisomerase is a secondary target in E coli that is altered in mutants expressing higher levels of resistance. In staphylococci and streptococci, the situation is reversed, topoisomerase is the primary target, and gyrase is the secondary target. Resistance to one fluoroquinolone, particularly if of high level, generally confers cross-resistance to all other members of this class.

Pharmacokinetics of Quinolones

Clinical uses of Quinolones

1. Nalidixic acid is only second-line drug treating urinary infection with gram-negative bacilli (Bacillus coli, Bacillus proteus , etc). 2. Pipemidic acid not only is used treating infection of urinary tract but also treating intestinal and biliary tract infection with sensitive bacteria. 3. Fluoroquinolones are extensively used treating general infection. a. urinary tract infections, even when caused by multifrug-resistant bacteria, b. Intestinal and biliary tract infections c. Soft tissue infections d. Bone, joint and in intra-abdominal e. Respiratory tract infections

Clinical uses of Quinolones

Ciprofloxacin and ofloxacin are effective for gonococcal infection, including disseminated disease. They are occasionally used for treatment of tuberculosis and atypical mycobacterial infections. They are suitable for eradication of meningococci from carriers. Ofloxacin is effective for chlamydial urethritis or cervicitis. Ciprofloxacin is a second-line agent for legionellosis. Levofloxacin, sparfloxacin are used for treatment of upper and lower respiratory tract infections.

Adverse effects of Quinolones

a. b. c. d. e. The most common effects are nausea, vomiting, and diarrhea. Headache, dizziness, insomnia, skin rash, occasionally. Liver toxicity is rarely for trovafloxacin. Photosensitivity occurs with lomefloxacin and pefloxacin. Fluoroquinolones may damage growing cartilage and cause an arthropathy. They are not used in patients under 18 years of age. The arthropathy is reversible. Since fluoroquinolones are excreted in breast milk, they are contraindicated for nursing mothers, also for gravida.

Antiseptic agents for UTI

1. 2. Nitrofurantoin Furazolidone It is not absorbed from GI tract after oral administration, used to treat GI tract infections. Antibiotic activity and adverses are same as nitrofurantoin.

Nitrofurans
It is bacteriostatic and bactericidal for many G+ and G- bacteria. Resistance emerges slowly, there is no cross-resistance between nitrofurantoin and other antimicrobial agents. The mechanism of action is not clearly defined.

Nitrofurantoin
Activity of nitrofurantoin is greatly enhanced at pH 5.5 or below. It is well absorbed after ingestion. It is excreted into the urine by both glomerular filtration and tubular secretion. It is used to treat urinary tract infection. Nitrofurantoin antagonizes the action of nalidixic acid. Anorexia, nausea, and vomiting are the principal side effects. Neuropathies and hemolytic anemia occur in glucose-6-phosphate dehydrogenase dificiency. Rashes, pulmonary infiltration and other hypersensitivity reactions may occur.

Metronidazole

Metronidazole
It is a nitroimidazole antiprotozoal and antibacterial drug. Activity against anaerobes, including bacteroides and clostridium species. Well absorbed after oral administration, widely distributed in tissues, also be given by iv, or by rectal suppository.

Metronidazole
It penetrates well into the crerbrospinal fluid, reaching levels similar to those in serum. It is metabolized in the liver and may accumulate in hepatic failure. It is used to treat anaerobic or mixed intra-abdominal infections, vaginitis (trichomonas, bacterial vaginosis), antibiotic-associated enterocolitis, and brain abscess.

Metronidazole
The mechanism of action The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity.

Metrnidazole
Adverse effects include nausea, diarrhea, stomatitis, and peripheral neuropathy with prolonged use. It has a disulfiram-like effect, and patients should be instructed to avoid alcohol.