Chemotherapy Overview

Dr. Rathnakar U.P.
Departments of Pharmacology Kasturba Medical College, Mangalore www.scribd.com July 2011

Antimicrobial Drugs: General Considear tions
‡ Greatest contribution of the 20th century to therapeutics ‡ They are one of the few curative drugs. ‡ Developing countries-infective diseases predominate. ‡ As a class, they are one of the most frequently Used as well as ‡ Misused drugs.

Antimicrobial Drugs:
Scientific Basis of Antimicrobial Chemotherapy

‡ Germ theory of disease -Louis Pasteur and Robert Koch-linked specific microorganisms to specific diseases ‡ Modern chemotherapy based on this idea

Antimicrobial Drugs: Definitions
‡ Chemotherapy‡ Treatment of systemic infections with specific drugs that selectively suppress the infecting microorganism without significantly affecting the host. [Includes treatment of malignacy with drugs] ‡ Antibiotics² ‡ Substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms ‡ Chemotherapeutic agent ‡ [initially] restricted to synthetic compound. ‡ Antimicrobial agent (AMA) ² ‡ Synthetic as well as naturally obtained drugs that attenuate micro organisms.

Antimicrobial Drugs: Classification
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Organism -Bacteria, Fungus, Virus, Parasites Chem.structure -Sulfonamides, Quinolones etc. Spectrum -narrow[eg.Penicillin] and broad[eg.TC] Bacteriostatic[TC] or cidal[Penicillins]SourceFungi[Penicilin], Bacteria[Polymyxin- B], Actinomycetes[ Chloramphenicol] ‡ Mechanism of action

Mechanism of action

Mechanism of action-Biochemical Targets

Class I -reactions result in the synthesis of the precursor molecules necessary for Class II- reactions, which result in the synthesis of the constituent molecules; Class III -assembled into macromolecules by class III reactions.

Mechanism of action-Biochemical Targets

Class I reactions are not promising targets -bacterial and human cells use similar mechanisms (TCA cycle) to obtain energy from glucose. Second, even if glucose oxidation was blocked, many other compounds (amino acids, lactate, etc.) could be utilised by bacteria as an alternative energy source. Class II- reactions, which result in the synthesis of the constituent moleculesFolate synthesis Class III -are better targets - some pathways exist in parasitic but not in human cells Peptidiglycan, protein, Nucleic acid synthesis[eg.DNA gyrase, polymerase, direct action on DNA,

Mechanism of actionFormed structures as Targets ‡ Cellmembrane-Polymyxin B ‡ Microtubules and/or microfilamentsAlbendazole ‡ Food vacuoles ²Chloroquine ‡ Muscle fibres-Piperazine

Use of AMAs Problems
1. Toxicity- Local, Systemic 2. Hypersensitivity reactions 3. Drug resistance 4. Superinfection 5. Nutritional deficiencies 6. Masking of infection 1. Toxicity‡ Local‡ At the site-pain ‡ Systemic‡ organ damage NephrotoxicAminoglycosides Bone marrowChloramphenicol

Use of AMAs Problems
2. Hypersensitivity reactions All AMAs can Eg. Penicillins 3. Drug resistance
Unresponsiveness of microorganisms to AMAs [=Tolerance] NaturalNo targets for AMAs Eg. G-ve or AFB for penicillins Acquired: sensitive resistant Eg-Staph., Myco Clinical problem

Use of AMAs Problems-Drug resistance
2. Drug resistanceHow? [Mechanism of development of
resistance]

Drug resistanceMutation

1. Mutation 2. Gene transfer

Spontaneous genetic change leading to resistance [Not induced by AMAs-random events] Selective preservation [under dosing] of resistance organisms in a colony over a period of time

Use of AMAs Problems-Drug resistance
Transfer of resistance VerticalMutants Daughter cells Horizontal Acquire genetic material from donor cells 1. Conjugation 2. Transduction 3. Transformation
Conjugation Transfer of genetic material by direct contact Transduction Genetic material carried by bacteriophages Transformation Resistant material released into the surounding media by a bacteria is incorporated by a sensitive bacteria

Mechanism of resistance
‡ Reduced entry of antibiotic into pathogen ‡ Enhanced export of antibiotic by efflux pumps ‡ Eenzymes that destroy the antibiotic ‡ Alteration of target proteins ‡ Development of alternative pathways to those inhibited by the antibiotic ‡ Alteration of microbial proteins that transform prodrugs to the effective moieties

Mechanism of resistance
Reduced entry of antibiotic into pathogen ‡ Enhanced export of antibiotic by efflux pumps ‡ Over express efflux pumps Eg. Chloroquine and PF

Alteration of porin channels or transporter proteins Eg.-G-ve bacteria and AG Trypanosoma brucei and melarsoprol

Mechanism of resistance
‡ Eenzymes that destroy the antibiotic ‡ Alteration of target proteins[Drug tolerant] Drug binding proteins are altered Eg; Pneumococci and penicillins. Trimethoprim and reduced DHF affinity

Eg.: ‡ Aminoglycosidemodifying enzyme-AGs ‡ lactamases- Beta lactams

Mechanism of resistance
‡ Development of alternative pathways to those inhibited by the antibiotic ‡ Incorporation of the drug

Sulfonamide resistant bacteria switch over to utilizing preformed folic acid in place of synthesizing it from PABA taken up from the medium.

Organism not only becomes resistant to an antimicrobial agent but subsequently starts requiring it for growth

Cross resistance
‡ Acquisition of resistance to one AMA, conferring resistance to another AMA, ‡ To which the organism has not been exposed, is calle ‡ Common among chemicaly related drugs ‡ Eg-resistance to one tetracycline means insensitivity to all others. ‡ Unrelated-TC and Chloramphenicol ‡ Two way-Erythromycin & Clindamycin ‡ One way-Neomycin & Streptomycin NO

Drug resistance -prevention
1. No ²indiscriminate [Eg.For viral] 2. No-inadequate [Dose & duration] 3. No-unduly prolonged use Minimizes the selection pressure and resistant strains will get less chance to preferentially propagate. 4. For acute localized infections -shorter courses of AMAs
5. Rapidly acting and narrow spectrum) AMAs whenever possible; 6. Broad-spectrum drugs -used only when a specific one cannot be determined 7. Combination of AMAs whenever prolonged therapy is undertaken, e.g. tuberculosis, SABE. 8. Infections by organisms notorious for developing resistance,e .g. Staph.a ureus, E . coli, M . tuberculosis, Proteus, etc. must be treated intensively.

Problems- use of AMAs1. Toxicity- Local, Systemic 2. Hypersensitivity reactions 3. Drug resistance 4. Superinfection 5. Nutritional defeciencies 6. Masking of infection Superinfection [Supra] ‡ New infection as a result of antimicrobial therapv. ‡ Normal flora Bacteriocins &  Competitively inhibit ‡ Antibiotics [TC] destroy flora Superinfection [eg.Candida]

Problems-use of AMAs Superinfection
‡ Sites Oropharynx, GIT, respiratory and genitourinary,occasionally skin. OrganismsCandida, staphyllococci, Cl.deficile, Proteus, Pseudomonas Prevention Use narrow-spectrum AMA Do not use AMAs to treat trivial, self limiting, or untreatable (viral) infections. Do not un-necessarily prolong antimicrobial therapy

Conditions predisposing to superinfections

‡

‡ ‡

‡

Use of AMAs Problems
1. 2. 3. 4. Toxicity- Local, Systemic Hypersensitivity reactions Drug resistance Superinfection

Masking of infection
‡ A short course of an AMA may be sufficient to treat one infection but only briefly suppress [MASK] another one contacted concurrently. ‡ Syphilis & gonorrheaPenicillin ‡ Tuberculosis & respiratory infection-Streptomycin

Nutritional deficiencies
‡ B complex and vit K synthesized by intestinal flora ‡ Prolonged use of AMAs ² alter flora ‡ Result in vitamin deficiencies.

Antimicrobial therapy-Disease progression

To prevent infection [Chemo Prophyla xis]

To treat very early [Avoid universal prophy]

Cost of waiting too high [Neutrop enia, malaria]

Mono Or combinat ion

AIDS, Transplants [infection controlled, pathology remains]

Frequency of dosing-Factors

‡ Concentration dependent killing ‡ Time dependent killing ‡ Post antibiotic affect[PAE]

Frequency of dosing-Factors
Concentration dependent killing
[Aminoglycosides, fluoroquinolones, and carbapenems] Increase in the rate of bacterial killing as the concentration of antibiotic increases from 4- to 64-fold the MIC of the drug Can be given once-a-day bolus infusion achieves high peak levels, favoring rapid killing of the infecting pathogen.

Frequency of dosing-Factors
Time dependent killing
[Beta-lactams, glycopeptides, macrolides, clindamycin, and linezolid] Increasing the concentration of antibiotic to higher multiples of the MIC does not significantly increase the rate of kill. Penicillins and cephalosporins, dosing schedules that ensure blood levels greater than the MIC 60 to 70 percent of the time have been demonstrated to be clinically effective.

Frequency of dosing-Factors
Post antibiotic effect[PAE]
‡ Persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC. ‡ To measure the PAE of an antibiotic, a test culture is first incubated in antibiotic-containing medium and then transferred to antibiotic-free medium. ‡ The PAE is defined as the length of time it takes (after the transfer) for the culture to achieve logphase growth. ‡ Antimicrobial drugs exhibiting a long PAE (several hours) often require only one dose per day. ‡ Eg.Aminoglycosides and fluoroquinolones, exhibit a long PAE, particularly against gram-negative bacteria.

Chemoprophylaxis
Prophylaxis ²
‡ Treating patients who are not yet infected or have not yet developed disease.

The goal ²
‡ Prevent infection or to prevent development of a potentially dangerous disease in those who already have evidence of infection.

Ideally‡ A single, effective, nontoxic drug is successful in preventing infection by a specific microorganism or eradicating an early infection.

Principle ² ‡
Prophylaxis is targeted therapy-eg.streptococci and Rh.fever

Prophylaxis to prevent colonization
‡ Infection by any or all microorganisms present in the environment of a patient often fails

Chemoprophylaxis Indications
‡ Against specific organisms ‡ Immunosuppressed patients such as those with AIDS ‡ On anti-rejection medications ‡ Prevent wound infections after various surgical procedures ‡ Infective endocarditis ²prophylaxis

Chemoprophylaxis Against specific organisms
‡ Rheumatic :[A Streptococci] Long acting penicillin G ‡ Tuberculosis: [Children, HIV positive] Isoniazid/or Rifampicin ‡ HIV infection:[Health care workers exposed to blood by needle stick injury/new born of HIV +ve mothers]: zidovudine +lamivudine + indinavir. ‡ Meningococcal meningitis:[especially in contacts] Rifampin/ sulfadiazine/ ceftriaxone

Chemoprophylaxis Infective endocarditis
‡ Prosthetic heart valve ‡ Previous infective endocarditis ‡ Congenital heart disease ‡ Single dose of oral amoxicillin 30 minutes to 1 hour before the procedure or ‡ i.v ampicillin or ceftriaxone in those unable to take oral medication.
Undergoing procedures like dental extraction, endoscopies, tonsillectomy etc.

Prophylaxis of surgical site infection[SSI]
‡ Lasted 2 hours or more. ‡ Prosthesis is inserted into the bone or soft tissue. ‡ In diabetics, corticosteroid recipients and other immunocompromised subjects, infants, elderly, malnourished ‡ Extensive tissue handling/use of electrocautery ‡ Extensive, prolonged ,combined use of AMAs after practicallv all surgeries- NOT RECOMMENDED

Prophylaxis of surgical site infection[SSI] AMAs ‡ ‡ ‡ ‡ ‡ Peak is when clot is forming Present during procedure Oral-1 h before i.v-Just before anesthesia AMAs-ref. text book

Choice of AMAs
Patient
1. Age 2. Kidney/liver function 3. Presence of pus, foreign body, necrotic material, clot, vegetation in heart[SBE] 4. Drug allergy 5. Immune status 6. Pregnancy 7. Genetic

1. 2. 3. 4.

Organism Prophylactic Preemptive Empirical Definitive

1. 2. 3. 4. 5. 6.

Drug Spectrum Cidal or static Toxicity PK profile Route Cost

‡ ‡ ‡

‡ ‡

Therapy with Combined Antimicrobial Agents Effect of combination Bacteria are incubated in broth with serial dilutions of antibiotics, Synergism of the antibiotics: Inhibition of growth by the drug combination at concentrations less than or equal to 25% of the MIC of each drug acting alone. Additive: If 25%-50% of the inhibitory concentration of each drug is required to produced inhibition, suggesting that the two drugs are working independently of each other.

‡ Antagonistic

.

‡ If more than 50% of the MIC of each drug is necessary to produce an inhibitory effect, the drugs are said to be

Therapy with Combined Antimicrobial Agents
Static VS Cidal

‡ Bacteriostatic (Tetracyclines, erythromycin,) + Bactericidal drugs (b-lactam antibiotics, aminoglycosides)«..ANTAGONISTIC

‡ Bactericidal+ Bactericidal------Additive or synergistic

COMBINATIONS OF ANTIMICROBIAL AGENTS

-Indications

Use of antibiotics in combination may be justified 1. Empirical therapy of an infection 2. Polymicrobial infections; 3. To enhance antimicrobial activity for a specific infection (i.e., for synergy); 4. To prevent emergence of resistance.

COMBINATIONS OF ANTIMICROBIAL AGENTS

-Indications

1. Empirical therapy
‡ Common reason for using a combination of antibiotics. ‡ Eg.community-acquired pneumonia, a macrolide for Mycoplasma+ cefuroxime for pneumococci and G-ve ‡ Prolonged administration of multiple antibiotics should be avoided ‡ Expensive, ‡ Antibiotic resistance against multiple agents, ‡ Additional adverse effects.

COMBINATIONS OF ANTIMICROBIAL AGENTS

-Indications

2. Polymicrobial infections [broaden spectrum]
‡ Intra-abdominal, hepatic, and brain abscesses, and some genital tract infections may - typically mixed aerobic-anaerobic infections. ‡ Mixed infections may be caused by two or more different microorganisms -different in antibiotic sensitivity ‡ No single agent can provide the required coverage.

COMBINATIONS OF ANTIMICROBIAL AGENTS

-Indications

3. For synergistic action i. Penicillin+Streptomycin in, enterococcal or viridans SBE, pseudomonas infections ii. Sulfonamide+ trimethoprimSequential blockade iii Flucytosine + amphotericin B Cryptococcus neoformans

COMBINATIONS OF ANTIMICROBIAL AGENTS

-Indications

4. To prevent emergence of resistance
‡ Valid primarily for chronic infections-needing prolonged therapy; has ‡ Tuberculosis, ‡ Leprosy and now ‡ H. pylori, ‡ HIV. ‡ Not useful-acute and short-lived infections. ‡ Except-rifampin given with ciprofloxacin prevents Staph.a ureus resistance to the latter.

COMBINATIONS OF ANTIMICROBIAL AGENTS

Disadvantages

‡ Risk of increased toxicity, ‡ Selection of multiple-drug resistant microorganisms, ‡ Eradication of normal host flora superinfection, ‡ Increased cost.

Misuse of AMAs
‡ Treatment of nonresponsive infections-Viral ‡ Therapy of fever of unknown origin-25% infections-maskingtb ‡ Dosing errorsexcessive or low ‡ Pus, FB, Necrotic tissue ‡ Lack of bacteriological info

Failure: AMA
‡ Wrong selection of drug, dose, route or duration ‡ Begun too late. ‡ Abscessees, foreign bodies ‡ Control of diabetes ‡ Immune status : leukaemias, neutropenia ‡ Infecting organism present behind barriers, such as vegetation on heart valves, blood brain-barrier. ‡ Trying to treat untreatable (viral) infections or other causes of fever (malignancy, collagen diseases).

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