SULFONAMIDES SULFONAMIDES Assoc. Prof. Iv. Lambev (itlambev@mail.bg)

G. Domagk (1895–1964),

bacteriologist and pathologist discovered the first sulfonamide in

1935. Nobel prize forPhysiology and Medicine

in 1939.

Mechanism of action•Unlike man, most bacteria cannot utilize external folic acid, a nutrient which is essential for growth, and they have to synthesize it from para-aminobenzoic acid (PABA). Sulfonamides are struc- turally similar to PABA and inhibit the enzyme dihydrofolate synthetase in the biosynthetic pathway for folic acid. •High concentrations of PABA antagonize the effectiveness of sulfonamides.

PABA Sulfanilamide

PABA

DHF synthetase

DHFA

DHF reductase

THFA Purines

DNA

Dietary folatein man

Sulfonamides

( )

Proteins

Trimethoprim

( )

Spectrum of activity

•Sulfonamides have a bacteriostatic action on a wide range of Gram-positive and Gram- negative microorganisms and also are active against toxoplasma, nocardia species, and chlamydia.

•Sulfonamides alone are usually reserved for the treatment of nocardiosis and toxоplasmosis.

•Resistance is common and due to the production of dihydrofolate synthetase with reduced affinity for binding of sulfonamides, and is transmitted in Gram-negative bacteria by plasmids.•Resistant strains of Staphylococcus aureus can synthesize more PABA than normal.

Pharmacokinetics•Most sulfonamides are well absorbed orally. They are widely distributed in the body and cross the BBB and placenta. •Sulfonamides are metabolized in the liver, initially by acetylation which shows genetic polymorphism. The acetylated product has no antimicrobial actions but retains toxic potential.

A large numberof parent drugs andN-acetyl metabolitesare excreted by thekidney.

Unwanted effects•Hypersensitivity reactions include rashes, vasculitis, Stevens-Johnson syndrome.•Haemolysis in patients with glucose-6- phoshate-dehydrogenase deficiency.•Crystalluria is a potential problem with overdose of these drugs or with acid urine.•Sulfonamides compete for bilirubin binding sites on albumin and can cause kernicterus in neonates.

Lyell syndromeafter oralintake ofCo-trimoxazole

Stevens–Johnsonsyndrome after oralintake of Co-trimoxazole(Color Atlas and Synopsisof Clinical Dermatology, 1999)

Clcr

t1/2 8–16 h: - sulfamethoxazolе - sulfametrolе

t1/2 > 16 h:- sulfadimethoxinе - sulfalen

DRUG PREPARATIONS

•collyrium 20% 10 ml

Sulfacetamidе

SulfadicramideFor local treatment

of bacterial conjunctivitis

Low GI abssorption (30%)

- Sulfaguanidinе in GI infections

Sulfasalazinе (Salazopyrin®)• colitis ulcerosa

•BiseptolBiseptol®® - tab. 480 mg - tab. 480 mg•TrimezolTrimezol® ® - tab. 480 mg- tab. 480 mg•960 mg/12 h 7–10 days960 mg/12 h 7–10 days

Co-trimoxazolе (Co-trimoxazolе (BANBAN))

Sulfamethoxazole/Trimethoprim:Sulfamethoxazole/Trimethoprim:

Co-trimoxazolе (Co-trimoxazolе (BANBAN))

PABA

DHF synthetase

DHFA

DHF reductase

THFA Purines

Sulfamethoxazole

()

Trimethoprim

()

Trimethoprim inhibits dihydrofolatereductase which converts dihydrofolateto tetrahydrofolate:

The bacterial enzyme is inhibited at 50 000times lower concentrations than themammalian equivalent. The combination of trimethoprim with thesulfonamide sulfamethoxazole (known asco-trimoxazole – BAN) acts synergisticallyto prevent folate synthesis by bacteria.However, resistance to the sulfamethoxazolecomponent, and the incidence of unwantedeffects limit the value of this combination.

Trimethoprim has a wide spectrum ofactivity against Gram-positive and Gram-negative bacteria. The combination withsulfamethoxazole is also effective againstProteus and Pneumocystis carinii (this is now its major indication).Trimethoprim and sufamethoxazole arewell absorbed from the gut. Their t1/2 isabout 11 h. Trimethoprim is excretedunchanged by the kidney. Co-trimoxazoleis availble for p.o. and i.v. use.

Adverse effects

•Nausea, vomiting, and diarrhoea, which are usually mild.•Skin rashes.•Folate deficiency leading to megaloblastic changes in the bone marrow is rare except in patients with depleted folate stores.•Marrow depression with agranulocytosis.

Sulfamethoxazole/Trimethoprim…

Basic antitubercular drugsBasic antitubercular drugs•Synthetic drugs (p.o.): Isoniazid, Synthetic drugs (p.o.): Isoniazid, Ethambutol, Pyrazinamide, EthionamideEthambutol, Pyrazinamide, Ethionamide

•Antibiotics: Rifampicin (p.o.), RifamycinAntibiotics: Rifampicin (p.o.), Rifamycin (i.v. infusion), Rifabutin; Streptomycin(i.v. infusion), Rifabutin; Streptomycin

Drugs for treatment of leprosyDrugs for treatment of leprosyp.o.: Rifampicin, Clofazimine, Dapsonep.o.: Rifampicin, Clofazimine, Dapsone

ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS

ANTITUBERCULAR DRUGSFirst line drugs:

IsoniazidRifampicin EthambutolPyrazinamideStreptomycinThese drugs are use routinely. They have high antitubercular efficacy,and low toxicity.

Second line drugs Antibiotics:

•Aminoglycosides: Kanamycin, Amikacin •Other rifamicins: Rifabutin, Pifapentine•Some macrolides: Azithromycin, Clarithromycin•Other antibiotics: Capreomycin, Cycloserine

Synthetic drugs:•Fluoroquinolones: Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxacin •Ethionamide, Para-aminosalicylic acid•Linezolid

These drugs are no more effective than the first-line agents. Their toxicities are often more serious. They are active against atypical strains of mycobacteria.

Isoniazid (5 mg/kg/24 h p.o. )inhibits production of long-chainmycolic acids which are unique to the cellwall of mycobacteria species. It is bacterio-cidal against dividing microorganisms. Resistance is due to random mutation. It can be troublesome in the developing countries.

Oral absorption of isoniazid is good, butreduced by food. It diffuses well into thebody tissues, including the CSF, and pene-trates into macrophages so that it is effe-ctive against intracellular tubercle bacilli. Isoniazid undergoes genetically controlledpolymorphic acetylation in the liver. A highpercentage of fast acetylators being foundin Japanese and Eskimo populations. In European populations 40–50% are rapid acetylators.

Unwanted effects of isoniazid

•Nausea and vomiting.•Peripheral neuropathyPeripheral neuropathy in highdoses. This can be preventedby prophylactic oral use of pyridoxine (vit. B6). High risk patients are with diabetes,alcoholism, chronic renal failure, malnutrition.•Hepatotoxicity.•Systemic lupus erythematosus-like syndrome.

(B6)

Ethambutol impairs synthesis of thecell wall of mycobacteria. It is primarily bacteriostatic. Its oral bioavailabilityis 77%. Only a small amount is metabo-lized and most is eliminated unchanged by the kidney. Unwanted effects:

•Headache, dizziness•Optic neuritis (dose-related,

but usually reversible).

Pyrazinamide has a bactericidal effect.

This semisynthetically modified antibiotic product of Streptomyces mediterranei has been an importantcomponent of the treatment of tuberculosis in humans.Rifampicin acts by inhibiting RNA polymerase, which catalyzes the transcription of DNA to RNA. Rifampicinis bactericidal and has a wide spectrum:● Brucella, Staphiloccocus spp.● Gram-positive and Gram-negative anaerobic bacteria areinhibited at low concentrations, including Bacteroides fragilis.● Chlamydia and Rickettsia are susceptible.● Mycobacterium tuberculosis.● Mycobacterium leprae.

Rifampicin (Rifampin – USAN)

Absorption from the gut is almost complete,but is delayed by food. Peak plasma levelsreach 3 h after a single oral dose of600 mg. The t1/2 is 3 h.About 8590% of the drug is protein bound in plasma but rifampicin penetrateswell into most tissues, cavities, and exuda-tes. It is metabolized by deacetylation andis excreted mainly in the bile. The drugand its metabolite undergo prolongedenterohepatic recirculation.

Rifampicin

Unwanted effects of rifampicin•Sometimes influenza-like symptoms, flushing, rashes.•Hepatotoxicity, usually only producing a transient rise of transaminases in plasma.•Induction of drug-metabolizing enzymes in the liver. Important interactions include those with oral contraceptives, phenytoin, warfarin, and sulphonylureas.•Urine and tears become pink/red which may be a useful guide to compliance.

Streptomycin is an aminoglycosideantibiotic. Its antibacterial activity is dueto its binding to the 30S subunit of thebacterial ribosome and inhibiting of proteinsynthesis. It has a wide spectrum of anti-bacterial activity but it is primarily used totreat mycobacterial infections (i.m.).•The main problems are eighth nerve toxi- city (vestibulotoxicity more than deaf- ness), nephrotoxicity, allergic reactions,resistance.

DRUG TREATMENT OF TUBERCULOSIS

•Mycobacterium tuberculosis readily deve- lops resistance to monotherapy. Three or four drugs are used for the first 2 months, and then the treatment is continued with 2 drugs for a further 4–7 months.

A standard regimen in the UK includesA standard regimen in the UK includesrifampicin and isoniazid for 6 monthsrifampicin and isoniazid for 6 months with ethambutol and pyrazinamide forwith ethambutol and pyrazinamide forthe first 2 months only.the first 2 months only.

PRINCIPLES OF RATIONAL PRINCIPLES OF RATIONAL ANTIBACTERIALANTIBACTERIALCHEMOTHERAPYCHEMOTHERAPY

(Adapted from Laurence et al., 1997 & others)(Adapted from Laurence et al., 1997 & others)

The following principles, many of whichapply to drug therapy in general, are a guide to good clinical practicewith antimicrobial agents.

(1) Make a diagnosis precisely:(1) Make a diagnosis precisely: – defining the site of action; – defining the microorganism(s) responsible and their sensitivity to drugs; – biological samples for laboratory must be taken before treatment is begun.

(2) (2) Aims of therapyAims of therapyThe goal of antibacterial therapy is to help the body eliminate infectious organisms without toxicity to the host. It is important to recognize that the natural defense mechanisms of a patient are of primary importance inpreventing and controlling infection. Examples of natural defenses against bacterial invasion arenatural defenses against bacterial invasion are:● the mucociliary escalator in the respiratory tract● the flushing effect of urination● the normal flora in the GIT.All such mechanisms can be affected by disease or therapeutic interventions.

Once microbial invasion occurs, various host responses serve to combat the invading organisms, including:● ● the inflammatory responsethe inflammatory response● ● cellular migration and phagocytosiscellular migration and phagocytosis● ● the complement systemthe complement system● ● antibody productionantibody production.The difficulty of controlling infections in immunocom-promised patients emphasizes that antibacterial therapy is most effective when it supplements endogenous defense mechanisms rather than when acting as the sole means of control.

(3) Consider factors affecting the success (3) Consider factors affecting the success of antibacterial therapyof antibacterial therapy•Bacterial susceptibility Various factors need to be considered in susceptibility testing. The minimum inhibitory concentration (MIC) is the concentration of drug that must be attained at the infection site to achieve inhibition of bacterial replication. In general, if bacteria are not susceptible to a drug in vitro they will be resistant in vivo.•Distribution to the site of infection To be effective, an antibacterial agent must be distributed to the site of infection and come into contact with the infecting organism in adequate concentrations of the active drug form.

Bacteria that locate intracellularly (Bartonella, Brucella, Chlamydoia, Mycobacterium, Rickettsia)will not be affected by antibacterial agents that remain in the extracellular space. Staphylococcus is facultatively Staphylococcus is facultatively intracellular and may sometimes resist treatmentintracellular and may sometimes resist treatmentbecause of intracellular survivalbecause of intracellular survival. . Drugs that accumulate in leukocytes and other cells include fluoroquinolones, lincosamides,sulfonaides and macrolides but aminoglycosides and β-lactams do not achieve effective intracellular concentrations.

An infectious/inflammatory process often adversely affects the distribution of a drug in vivo. An exception is inflammation of the meninges (meningitis), which reduces the normal barrier between blood and CSF,so that antibacterial agents that normally cannot crossthis barrier reach the CSF. This breakdown of barriers by inflammation does notoccur to an appreciable extent with the blood–prostatebarrier and blood–bronchus barrier.Effective antibacterial concentrations may not be achieved in poorly vascularized tissues, e.g. the extremities duringshock, sequestered bone fragments or heart valves.

(4) Remove barriers to cure) Remove barriers to cure (e.g. lack of freedrainage of abscesses, obstruction in the urinary or respiratory tracts).

(5) Decide whether therapy is necessary(5) Decide whether therapy is necessary..As a general rule, acute infections requirechemotherapy whilst chronic infectionsmay not. Chronic abscess or empyemarespond poorly. Even some acute infectionssuch as gastroenteritis are better managedsymptomatically than by antimicrobials.

(6(6) Choose the most suitable route of ) Choose the most suitable route of administration of antibacterial drug(s)administration of antibacterial drug(s)

Often there is a choice of routes of administration, although some drugs (such as aminoglycosides) must be given parenterally if systemic activity is desired. Other factors influencing route selection include the characteristics of the disease being treated, likelytreatment duration, the patient’s temperament and owner’s capability.

● Topical administration is valuable for disorders of eye and ear and some skin or gut infections. High drug concentration may be achieved locally in this way and some drugs too toxic for routine systemic administration (bacitracin, neomycin, polymyxins) can be useful topically.● Oral administration is adequate in most infections and is usually preferable for home treatment. Some owners find it easier to administer drugs orally with food but the potential ADRs of ingesta on systemicdrug availability should be considered.

If in doubt, administration on an empty stomach (no food for 1–2 h before and after dosing) is recommended, as the most common outcome of drug–ingesta interactions is impaired systemic drug availability.● Parenteral administration is not routinelyadvantageous but can be useful for fractious,unconscious or vomiting patients, or those withoral/pharyngeal/esophageal pain or dysfunction.

(7) Select the best drugs(7) Select the best drugs.. This involves consideration of: – specificity (the antimicrobial activity of a drug must cover the infecting organisms); – pharmacokinetic factors (the chosen drug must reach the site of infection (e.g. by crossing BBB); – the patients (who may previously had allergic reactions to antimicrobials or whose routes of drug elimination may be impaired, e.g. by renal disease).

In some infections the choice of antimicro-bials follows automatically from the clinic-cal diagnosis because the causative organ-nism is always the same, and is virtuallyalways sensitive to the same drug, e.g.segmental pneumonia in a young personwhich is almost always caused by S. pneu-monia (benzylpenicillin), some haemolyticstreptococcal infections, e.g. scarlet fever and erysipelas (benzylpenicillin), typhus (tetracycline), leprosy, lues.

In the other cases the infecting organism isidentified by the clinical diagnosis, but noassumption can be made as to its sensitivityto any one antimicrobial, e.g. tuberculosis.In the most cases the infecting organism is not identified by the clinical diagnosis, e.g.in urinary tract infections, meningitis, etc.In the last two categories the choice of antimicrobial drug may be guided by:

– knowledge of the likely pathogens– simple staining and sensitivity tests.

8. Compliance8. Compliance

•As with all drug therapy, antibacterials will not be effective unless administered correctly to the patient. •It is very important for the successful treatment to keep a compliance from patients.

(9)(9) Indications for combination therapyIndications for combination therapy::– to avoid the development of resistance in chronic infections (e.g. FIV, HIV, tuberculosis).– to broaden the antibacterial spectrum:

a) in a known mixed infection;b) unusual pathogens, including Mycobacterium,

Rhodococcus and fungi.c) if the microorganism cannot be predicted (septicemia complicating neutropenia);

– to obtain potentation (e.g. penicillin plus gentamicin for enterococcal endocarditis)

(10) Antimicrobial therapy and pregnancy(10) Antimicrobial therapy and pregnancy

PRC B have:•Azithromycine•Erythromycine•Penicillins•Most cephalosporines

or lactationor lactation

PRCsPRCs LRCsLRCs

A: controlled studies

show no risk (Vit. B9)

B: no evidence of risk in

humans (Penicillins)

C: risk cannot be ruled

out (Bisoprolol)

D: positive evidence of

risk (Diazepam)

X: contraindicated in

pregnancy (Estrogens)

L1: safest (Ibuprofen,

Paracetamol)

L2: safer (Cephalosporins,

Omeprazole)

L3: moderately safe

(Acarbose, Aspirin)

L4: possibly hazardous

(Diazepam, Lithium)

L5: contraindicated

(ACE inhibitors)

(11) Administer the drug in optimum dose(11) Administer the drug in optimum doseand frequencyand frequency

– Inadequate dose may encourage the development of microbial resistance.– Intermittent dosing is preffered to continual infusion.– Plasma concentration monitoring can be applied to optimize therapy with aminoglyco- sides, fluoroquinolones, cephalosporins, etc. in patients with kidney disease.

(12) Continue therapy (12) Continue therapy until apparentuntil apparentcure has been achieved.cure has been achieved. – Most acute infections are treated for 5 to 10 days. There are many exceptions to this, such as typhoid fever, tuberculo- sis, and infective endocarditis, in which relapse is possible long after apparent clinical cure and so the drugs are continued for a long time, determined by clinical experience.

(13) Test for cure(13) Test for cure.. In some infections, microbio- logical proof of cure is desirable because disappearance of symptoms and signs occurs before the microorganisms are eradicated, e.g. urinary tract infections (examinations must be done after withdrawal of chemotherapy).(14) Prophylactic chemotherapy(14) Prophylactic chemotherapy for surgicaland dental procedures should be of very limited duration. It should be started at the time of surgery to reduce the risk of producing resistant microorganisms.

(15) Remeber that the most important carriers (15) Remeber that the most important carriers of cross infections are your 10 fingers.of cross infections are your 10 fingers.