Antimicrobial

Antimicrobials are the drugs that inhibit/kill the infecting organism and to have no/minimal effect on the recipient.

Antimicrobial are one of the most frequently used as well as misused drugs.

This type of therapy is generally called chemotherapy which has come to mean ‘treatment of systemic infections with specific drugs that selectively suppress the infecting microorganism without significantly affecting the host.’

Antibiotics

These are substances produced by microorganisms, which selectively suppress the growth or kill other microorganisms at very low concentrations.

This definition excludes other natural substances which also inhibit microorganisms but are produced by higher forms (e.g.antibodies) or even those produced by microbes but are needed in high concentrations (ethanol,lactic acid, H2O2).

Chemotherapeutic agent

chemotherapeutic agent’ was restricted to synthetic compounds, but now since many antibiotics and their analogues have been synthesized, this criterion has become irrelevant; both synthetic and microbiologically produced drugs need to be included together. It would be more meaningful to use the term

SULFONAMIDES

Sulfonamides were the first antimicrobial agents (AMAs) effective against pyogenic bacterial

infections. Sulfonamido-chrysoidine (Prontosil Red) was one of the dyes included by Domagk to treat experimental streptococcal infection in mice and found it to be highly effective.

Chemistry

All sulfonamides may be considered to be derivatives of sulfanilamide (p-aminobenzene sulfonamide). Individual members differ in the nature of N1(Sulfonamido N) substitution, which governs solubility, potency and pharmacokinetic property. A free amino group in the para position (N4) is required for antibacterial activity.

Classification

1. Short acting (4–8 hr): Sulfadiazine

2. Intermediate acting (8–12 hr): Sulfamethoxazole

3. Long acting (~7 days): Sulfadoxine, Sulfamethopyrazine

4. Special purpose sulfonamides: Sulfacetamide sod., Mafenide, Silver sulfadiazine,Sulfasalazine

ANTIBACTERIAL SPECTRUM

Sulfonamides are primarily bacteriostatic against many gram-positive and gram-negative bacteria. However, bactericidal concentrations may be attained in urine

Mechanism of action

1) inhibit bacterial folate synthase → FA is not formed and a number of essential metabolic reactions suffer.

2) Sulfonamides competitively inhibit the union of PABA with pteridine residue

3) Sulfonamides chemically similar to PABA, that may itself get incorporated to form an altered folate which is metabolically injurious

Resistance to sulfonamides

Most bacteria are capable of developing resistance to sulfonamides.

(a) Produce increased amounts of PABA

(b) Their folate synthase enzyme has low affinity for sulfonamides,

(c) Adopt an alternative pathway in folate metabolism

PHARMACOKINETICS

Absorption: - rapidly and completely absorbed from g.i.t.

Distribution: - widely distributed in the body—enter serous cavities, CSF, placenta.

Metabolism: - in liver by acetylation.

Excretion: - mainly by the kidney through glomerular filtration

ADVERSE EFFECTS

• Nausea, vomiting and epigastric pain.

• Crystalluria

• Hypersensitivity rashes, urticaria and drug fever. Photosensitization

Stevens-Johnson syndrome and exfoliative dermatitis

• Hepatitis

• Sulfonamides cause haemolysis in a dose dependent manner in individuals with G-6-PD deficiency.

Neutropenia and other blood dyscrasias are rare.

• Kernicterus may be precipitated in the newborn, especially premature, by displacement of bilirubin from plasma protein binding sites and more permeable blood-brain barrier

Interactions

Sulfonamides inhibit the metabolism of phenytoin, tolbutamide and warfarin enhance their action.

They displace methotrexate from binding and decrease its renal excretion—toxicity can occur.

Fixed dose combinations of sulfonamides with penicillin are banned in India.

USES

Systemic use of sulfonamides alone (not combined with trimethoprim or pyrimethamine) is rare now.

For suppressive therapy of chronic urinary tract infection, for streptococcal pharyngitis and gum infection

Combined with trimethoprim (as cotrimoxazole) sulfamethoxazole is used for many bacterial

infections, P. jiroveci and nocardiasis Along with pyrimethamine, certain sulfonamides are used for malaria and toxoplasmosis.

Ocular sulfacetamide sod. (10–30%) is a cheap alternative in trachoma/inclusion conjunctivitis,

Topical silver sulfadiazine or mafenide are used for preventing infection on burn Surfaces

COTRIMOXAZOLE

The fixed dose combination of trimethoprim and sulfamethoxazole is called cotrimoxazole

Trimethoprim is a diaminopyrimidine related to the antimalarial drug pyrimethamine which selectively inhibits bacterial dihydrofolate reductase (DHFRase).

COTRIMOXAZOLE

sulfonamide and trimethoprim are bacteriostatic, but the combination becomes cidal against many organisms. Maximum synergism is seen when the organism is sensitive to both the components, but even when it is moderately resistant to one component, the action of the other may be enhanced.

COTRIMOXAZOLE

Sulfamethoxazole was selected for combining with trimethoprim because both have nearly the same t½ (~ 10 hr). Optimal synergy in case of most organisms is exhibited at a concentration ratio of sulfamethoxazole 20 : trimethoprim 1, the MIC of each component may be reduced by 3–6 times.

Mechanism of action

Spectrum of action

Antibacterial spectra of trimethoprim and sulfonamides overlap considerably.

Additional organisms covered by the combination are—Salmonella typhi, Serratia, Klebsiella, Enterobacter, Yersinia enterocolitica, Pneumocystis jiroveci and many sulfonamideresistant strains of Staph. aureus, Strep. pyogenes, Shigella, enteropathogenic E. coli, H.influenzae, gonococci and meningococci.

Resistance

Mutational or plasmid mediated acquisition of a DHFRase having lower affinity for the inhibitor.

Adverse effectsAll adverse effects seen with sulfonamides can be produced by cotrimoxazole.

• Patients with renal disease may develop uremia. Dose should be reduced in moderately severe renal impairment.

• A high incidence (upto 50%) of fever, rash and bone marrow hypoplasia due to cotrimoxazole has been reported among AIDS patients with Pneumocystis jiroveci infection.

• The elderly are also at greater risk of bone marrow toxicity from cotrimoxazole.

• Diuretics given with cotrimoxazole have produced a higher incidence of thrombocytopenia

Uses

Urinary tract infections

Respiratory tract infections

Typhoid

Bacterial diarrhoeas and dysentery

Pneumocystis jiroveci

Chancroid

7. Cotrimoxazole is an effective alternative to penicillin for protecting agranulocytosis patients and treating respiratory and other infections in them.

Intensive parenteral cotrimoxazole therapy has been used successfully in septicaemias, but other drugs are more commonly employed now.

FLUOROQUINOLONES

These are quinolone antimicrobials having one or more fluorine substitutions. The ‘first generation’ fluoroquinolones (FQs) introduced in 1980s have one fluoro substitution. In the 1990s, compounds with additional fluoro and other substitutions have been developed—further extending antimicrobial activity to gram-positive cocci and anaerobes, and/or confering metabolic stability (longer t½). These are referred to as ‘second generation’ FQs.

Classification

First generation fluoroquinolones

Norfloxacin Ofloxacin Ciprofloxacin Pefloxacin

Second generation fluoroquinolones

Lomefloxacin Sparfloxacin Levofloxacin Gatifloxacin Moxifloxacin

Mechanism of action

FQs inhibit the enzyme bacterial DNA gyrase & topoisomeraseIV, which nicks double-stranded DNA, introduces negative supercoils and then reseals the nicked ends. This is necessary to prevent excessive positive supercoiling of the strands when they separate to permit replication or transcription.

The bactericidal action probably results from digestion of DNA by exonucleases whose production is signalled by the damaged DNA.

Higher potency against gram-positive bacteria

Greater affinity for topoisomerase IV

In gram-positive bacteria the major target of FQ action is a similar enzyme topoisomerase IV which nicks and separates daughter DNA strands after DNA replication.

Mechanism of resistance

Chromosomal mutation: - producing a DNA gyrase or topoisomerase IV with reduced affinity for FQs,

Due to reduced permeability/increased efflux of these drugs across bacterial membranes.

Absorption: - absorbed orally, but food delays absorption, and first pass metabolism occurs.

Distribution:-high tissue penetrability: concentration in lung, sputum, muscle, bone, prostate and phagocytes exceeds that in plasma,

Excretion: - in urine. (by glomerular filtration and tubular Secretion)

Pharmacokinetics

Adverse effects

Ciprofloxacin has good safety record: side effects occur in ~10% patients, but are generally mild; withdrawal is needed only in 1.5%.

Gastrointestinal

CNS

Skin/hypersensitivity

Tendonitis and tendon rupture

Interactions

• Inhibits the metabolism of theophylline, caffeine and warfarin

• NSAIDs may enhance the CNS toxicity of FQs; seizures are reported.

• Antacids, sucralfate and iron salts given concurrently reduce absorption of FQs.

Contraindication

Ciprofloxacin and other FQs are contraindicated during pregnancy

Uses

Ciprofloxacin is effective in a broad range of infections including some difficult to treat ones.

Because of wide-spectrum bactericidal activity, oral efficacy and good tolerability, it is being extensively employed for blind therapy of any infection, but should not be used for minor cases or where gram-positive organisms and/or anaerobes are primarily causative

1. Urinary tract infections:

2. Gonorrhoea:

3. Chancroid:

4. Bacterial gastroenteritis:

5. Typhoid:

6. Bone, soft tissue, gynaecological and wound infections:

7. Respiratory infections:

8. Tuberculosis

9. Gram-negative septicaemias:

10. Meningitis

11. Prophylaxis: of infections in neutropenic/ cancer and other susceptible patients.

12. Conjunctivitis: by gram-negative bacteria: topical therapy is effective