List of eight important antibacterial drugs:- 1. Sulfonamides 2. Trimethoprim 3. Co-Trimoxazole 4. Nitrofurantoin 5. Methenamine 6. Metronidazole 7. Quinolones 8. Fluoroquinolones.
Antibacterial Drug # 1. Sulfonamides:
Sulfonamides are rarely used, because of increasing bacterial resistance. They have been replaced by antibiotics, which are generally more potent and less toxic.
Mechanism of action:
Sulfonamides are bacteriostatic. They, being structural analogues of para-amino benzoic acid (PABA), are taken up by bacteria instead of PABA (competitive inhibition) and prevent bacterial folic acid synthesis, which is necessary for their multiplication. Susceptible bacteria are those, which need PABA, because they are incapable of using folic acid directly. Human cells use exogenous folic acid and thus, a lack of PABA does not affect them.
Sulfonamides, with exceptions, are readily absorbed following oral administration. They are widely distributed into body fluids and cross blood brain barrier to enter cerebrospinal fluid. They are metabolized by acetylation in the liver, which negates the antibacterial activity, but not the adverse effects. The acetylated fraction is very poorly soluble and tends to precipitate in the urine, unless an adequate flow in maintained.
Sulfonamides are effective against a fairly wide range of bacteria, which includes gram-positive bacteria and some gram-negative bacteria such as E. coli (the organism responsible for acute urinary tract infection), Haemophilus influenza and Shigella. Other susceptible organisms include B. anthrax, Nocardia, Toxoplasma.
Sulfonamides are rarely used in urinary tract infections and chronic bronchitis, provided the causative organisms are susceptible and for the prophylaxis of rheumatic fever. Sulfadimidine (1 g every 6 hours) or long acting sulfametopyrazine (2 g once weekly) are the preferred sulfonamides. Silver sulfadiazine is applied locally as a cream to prevent infections in burns. Sulfasalazine is used for ulcerative colitis, Crohn’s disease and rheumatoid arthritis.
Severe side effects of sulfonamides are rashes, Stevens-Johnson syndrome, renal failure, bone marrow depression and agranulocytosis. Sulfonamides are contraindicated in hepatic or renal failure and in porphyria.
Antibacterial Drug # 2. Trimethoprim:
Trimethoprim is chemically related to the antimalarial drug pyrimethamine. It is bacteriostatic in action and acts by interfering with folic acid metabolism at the phase when folic acid is converted to folinic acid to build up the cell nucleus. Trimethoprim selectively inhibits the enzyme dihydrofolate reductase which converts the folic acid to folinic acid resulting in the death of the bacterial cell. The pharmacological aspects of trimethoprim are very similar to sulfonamides. Trimethoprim can be used alone for urinary and respiratory infections, prostatitis, shigellosis and invasive salmonella infection.
Antibacterial Drug # 3. Co-Trimoxazole:
It is a combination of a sulfonamide (sulfamethoxazole) and trimethoprim in the proportion of 5 parts to 1 part and is bactericidal because of their synergistic activity. It has excellent tissue penetration, including bone, prostate and brain. Co-trimoxazole is the drug of choice in Pneumocystis crainii and Nocardia infection. It can also be used in acute exacerbation of chronic bronchitis, urinary tract infections and acute otitis media in children, provided the causative organism is susceptible. It is given in doses of500 mg twice daily. Side effects are essentially that of sulfonamides.
Antibacterial Drug # 4. Nitrofurantoin:
Nitrofurantoin has a fairly wide antibacterial spectrum against gram-negative bacteria responsible for urinary tract infections. It is well absorbed and is considerably concentrated in the urine. It is bactericidal and is used in uncomplicated lower urinary tract infections (especially in vancomycin-resistant Enterococcus faeciumi) except those caused by Proteus and P. aeruginosa. Prolonged therapy with nitro-furantoin should be avoided, as it is associated with chronic pulmonary syndromes that can be fatal. Nausea is the most common adverse effect and others include rashes, fever and blood disorders. It should not be used in impaired renal function, as accumulation will occur.
Antibacterial Drug # 5. Methenamine:
Methenamine is a urine/bladder antiseptic that is converted to formaldehyde in the urine when the pH is less than 6.0. It is rarely used because of the large number of antibiotics that are available. However, it has a limited role in uncomplicated UTI caused by multiple drug-resistant bacteria or yeast. Side effects include bladder irritation, dysuria, and hematuria with prolonged use. It is contraindicated in glaucoma, renal insufficiency, and acidosis and should not be used concomitantly with sulfonamides.
Antibacterial Drug # 6. Metronidazole:
Metronidazole (500 mg orally or by IV infusion every 8 hours) is one of the most important antimicrobial drug and is extensively used in diverse clinical conditions. It kills anaerobic bacteria and some protozoa.
Metronidazole is well absorbed orally (bioavailability 90%) and is widely distributed in the body tissues, attaining therapeutic concentrations in vaginal secretions, semen, saliva, breast milk and CNS. It penetrates into bone and abscess cavities. More than 50% of the drug is metabolized in the liver.
Metronidazole is highly effective against anaerobic bacteria and protozoa. It has greater activity against gram-negative than gram- positive anaerobes but is active against Clostridium perfringens (causative organism for gas gangrene, colitis and food poisoning) and C. difficile (causes pseudomembranous colitis). Protozoa that respond to metronidazole include Giardia lamblia, Entamoeba histolytica, and Trichomonas vaginalis. It has no direct effect on helminth Dracunculus medinensis, but helps in the elimination of guineaworm.
Metronidazole is one of the most widely used drugs in diverse clinical disorders, which includes;
Acute invasive intestinal amoebic dysentery and extra-intestinal amoebiasis including amoebic liver and brain abscess (800 mg 6 hourly/ 5-10 days). Urogenital trichomoniasis (2 g as a single dose or 200 mg 8 hourly/ 7 days). Giardiasis (2 g daily/ 3 days).
Metronidazole is highly effective against anaerobic infections in:
a. Leg ulcers and pressure sores
b. Bacterial vaginosis
c. Acute ulcerative gingivitis
d. Acute dental infections
e. Antibiotic associated colitis (pseuomembranous colitis)
Intra-abdominal infections and brain abscess (usually in combination with a cephalosporin). Surgical and gynecological sepsis in which its activity against colonic anaerobes, especially B. fragilis is important. Intravenous (500 mg every 8 hours) metronidazole together with human tetanus immunoglobulin in established cases of tetanus.
H. pylori eradication along with omeprazole (proton pump inhibitor) and clarithromycin.Topical metronidazole gel 0.75% in the management of acne rosacea and for reduction of the odour produced by anaerobic bacteria in fungating tumours.
Metronidazole may cause GIT disturbances. Rarely, it may cause neurological and blood disorders and anaphylaxis. With alcohol, it produces disulfiram like reactions.
Antibacterial Drug # 7. Quinolones:
Nalidixic acid was the first quinolone to be introduced in 1960 for the treatment of GIT and urinary infections, but bacterial resistance and side effects limited its use. The development of fluorinated derivatives called fluoroquinolones resulted in antibacterial activity with extended spectrum, higher potency, better tissue penetration and lesser bacterial resistance.
Antibacterial Drug # 8. Fluoroquinolones:
Mechanism of action:
Fluoroquinolones are rapidly bactericidal. They interfere with an enzyme (DNA gyrase) which is necessary for the cell division (DNA replication) of bacteria.
Fluoroquinolones have a wide range of antibacterial activity. They are active against both gram- positive and gram-negative bacteria. They are particularly active against gram-negative bacteria, including Salmonella, Shigella, Campylobacter, Neisseria and Pseudomonas. They are moderately active against gram-positive bacteria such as Strep, pneumonia and Enterococcus fecalis, Chlamydia, Mycoplasma and some Mycobacteria. Most anaerobic organisms are not susceptible.
Fluoroquinolones are well absorbed orally. The maximum serum levels are similar irrespective of the route (oral or IV) of administration. They are widely-distributed throughout the body. Concentrations in lung, sputum, muscle, bone, prostate and phagocytes exceed that in plasma. They are excreted in urine. Antacids, sucralfate, bismuth, iron, calcium and zinc preparations markedly impair oral absorption.
Norfloxacin (400 mg 12 hourly) and lomefloxacin (400 mg daily) orally are useful in urinary tract infections caused by gram-negative organisms, but are not the fluoroquinolones of choice. They are not used for systemic infections. They should not be used in children and pregnancy, in cases of porphyria and renal impairment.
Ciprofloxacin (500 mg orally once a day or 200-400 mg IV 12 hourly) and ofloxacin (200-400 mg orally or IV 12 hourly) are active against gram-negative aerobes including many ampicillin beta-lactamase-producing organisms. These drugs are commonly used for anthrax, urinary tract infections, pyelonephritis, infectious diarrhea, typhoid fever, prostatitis, gonorrhea (single-dose therapy) and intra-abdominal infections (with metronidazole). They are the preferred drugs in adults as a prophylactic for close contact with meningococcal meningitis.
Ciprofloxacin is the most active quinolone against P. aeruginosa and is the quinolone of choice for serious infections with this organism. It has relatively poor activity against gram-positive cocci and anaerobes, and should not be used as empiric mono-therapy for community-acquired pneumonia, skin and soft-tissue infections or intra-abdominal infections.
Levofloxacin (250-750 mg), gatifloxcin (400 mg), sparfloxacin (200-400 mg) and moxifloxacin (400 mg) are newer fluoroquinolones with improved coverage of aerobic gram-positive organisms (streptococci, staphylococci) and atypical respiratory pathogens (Chlamydia pneumonia, Mycoplasma, Legionella) but have less gram-negative activity (especially against P. aeruginosa) than ciprofloxacin. They can be used orally or IV, given every 12 hourly. Moxifloxacin and gatifloxacin have reasonable anaerobic activity, making them useful in mixed aerobic/anaerobic infections.
The important therapeutic uses of newer fluoroquinolones are:
a. Sinusitis, bronchitis and community acquired pneumonia
b. Urinary tract infections (except moxifloxacin, since it is minimally excreted in the urine)
c. Soft-tissue infections as an alternative to β lactum antibiotics
d. Postoperative surgical, obstetrical/gynaecological infections
e. Multidrug resistant TB and atypical mycobacterial infections
The principal adverse reactions with fluoroquinolones are gastrointestinal upsets (nausea) and skin rashes. They should be avoided, if possible, in patients with epilepsy as they have the potential to cause seizures, and in children they may cause damage to developing weight-bearing joints. They can also cause pain and inflammation of tendons, especially in older people.
Fluoroquinolones should be discontinued if psychiatric, neurological or hypersensitivity symptoms occur. NSAIDs and theophylline increase the risk of convulsions and anticoagulant action of warfarin is enhanced, if used with fluoroquinolones.