Chemotherapy: It is the treatment of systemic infection or malignancy with the drugs which are having selective toxicity for the infecting organisms/malignant cells with no or minimal effect on the host cells.
- Chemotherapeutic agents: These are the substances, which kills or inhibits the invading microorganisms (malignant cells) with no or minimal pharmacodynamic effect in the recipient cells.
- Pasteur was the first to identify that microorganisms could destroy other microorganisms. Paul Ehrlich ‘The father of Modern Chemotherapy’ coined the term ‘Chemotherapy’.
- Chemotherapeutic substance should be maximum parasitotropic and minimum organotropic effects.
Antibiotics: They are produced by microorganisms such as fungi, bacteria and actinomycetes. They suppress the growth of other microorganisms and may eventually destroy them and are needed in very small amount. Although antibiotics are mainly produced by microorganisms, many are now obtained semi synthetically and some, for example chloramphenicol, can be completely synthesized. So it will be more appropriate to use the term antimicrobial agents (AMAs) for both synthetic as well as naturally obtained drugs that attenuate microorganisms.
- Domagk in 1936 demonstrated that prontosil, a sulfonamide dye is effective in some infections.
- The production of penicillin (A. Fleming) for clinical use in 1941 marked the beginning of the ‘golden era’ of antibiotics.
- In the last 65 years, several powerful antibiotics and their semi synthetic derivatives have been produced.
Bactericidal agents
- These antimicrobials irreversibly damage and kill the susceptible microorganisms. They act best against multiplying organisms.
- Examples are penicillin, amino glycosides, cephalosporins, isoniazid, etc. Fungicidal is the term used for killing fungus agents.
Bacteriostatic agents
- These antibiotics/antimicrobials do not kill the organisms. They reversibly inhibit the growth and multiplication of susceptible microorganisms, e.g. sulphonamides, tetracyclines, etc.
Classification of Antimicrobial Agents (AMAs) (Fig. 12.1.1)
- Narrow spectrum drugs
- Active against gram positive cocci and bacilli:
- Penicillin G
- Penicillinase resistance penicillin
- Macrolids
- Vancomycin and Lincomycin.
- Bacitracin
- Active against gram negative bacilli:
- Aminoglycosides
- Polymyxins
- Broad spectrum drugs
- Chloramphenicol
- Tetracyclines
- Broad Spectrum Penicillins: Ampicillines and Carbenicillines
- Cephalosporines
- Trimethoprime and Cotrimoxazole
Classification according to sources of antibiotics:
Classification according to mechanism of action (Fig. 12.1.2)
Based on their mechanism of action, antimicrobials are classified as drugs that:
- Damage cell membrane: Causing leakage of cell membrane: Polymyxins, Amphotericin B, Nystatin.
- Inhibit cell wall synthesis: Penicillins, Cephalosporins, Vancomycins, Bacitracin, Cycloserine.
- Inhibit protein synthesis: Aminoglycosides, Clindamycin.
- Bind to ribosomes: Chloramphenicol, Tetracyclines, Erythromycin
- Inhibit DNA gyrase: Fluroquinolones like Cipro;floxacin, Norfloxacin
- Inhibit DNA functions (DNA dependant RNA polymerase)—Rifampicin
- Inhibit DNA synthesis: Acyclovir, Zidovudine
- Interfere with metabolic steps: Sulfonamides, Sulfones, Trimethoprim, Pyrimethamine (antimetabolite action).
Factors that influence the successful chemotherapy of an infection are:
- Site: The drug should reach the site of infection.
- Concentration: It should attain adequate concentration at the site.
- Host defence: Active host defences reduce the antibiotic requirement.
- Sensitivity: The microorganism should be sensitive to the antimicrobial agent.
Bacterial sensitivity testings
1. KTB: Kirbey-Bauer Technique
- – Drug impregnated disc were used.
- – Clear zone of inhibition is producedResults – (a) Sensitive, (b) Intermediate sensitive and (c) Resistant
2. MIC: Minimum Inhibitory Concentration
It is the lowest concentration of an antibiotic which prevent visible growth of the bacteria, determined in microwell culture plates using serial dilutions of the antibiotics.
3. MBC: Minimum Bactericidal Concentration.
The MBC of the antibiotics is determined by sub-culturing from tubes with no visible growth.
- Antibiotic levels in tissue fluid (plasma) is very important
Resistance to Antimicrobial Agents
A state of unresponsiveness or insensitivity or decrease in sensitivity of microorganisms to drug (antimicrobial agent) is called bacterial resistance. It may occur in originally sensitive microorganisms which undergo a genetic change
- The resistance may bea. Natural or b. Acquired
Natural resistance
In natural resistance the organisms have never responded to the anti-microbial agent: may be due to the absence of the particular enzyme or target site affected by the drug, e.g. gram-negative bacilli are not sensitive to Penicillin G. As alternate drugs are available, this type of resistance is clinically not a problem.
Acquired resistance
Here, the microbes which were previously sensitive to the anti-microbial agents become resistant to AMA later on. Clinically this causes a problem.
- Bacteria acquire resistance by a change in their DNA. Such DNA changes may occur by: (i) Mutation or(ii) ® ¬ Transfer of genes.
- Mutation
- Mutation is the common cause of resistance to antimicrobial agents. It is a stable and heritable genetic change. It occurs spontaneously and randomly among microorganisms.
- In any population of bacteria, a few resistant mutants may be present. When the sensitive organisms are destroyed by the antibiotic, the resistant mutants freely multiply.
- It (mutation) may be a single step mutation resulting in high degree of resistance as seen in case of streptomycin, and rifampicin. In other cases, it may be a multiple step mutation in which resistant mutants may emerge by a slow stepwise process, e.g. in case of penicillin.
- Transfer of genetic material
- Many bacteria contain extra chromosomal genetic material called plasmids in the cytoplasm. These carry genes coding for resistance (called R-factors).
- These R-factors are transferred to other bacteria and spread resistance: This may take place by:
- Conjugation: It is the important mode of spread of resistance. The R-factor (extra chromosomal genetic material), is transferred from one bacterium to another by direct contact through a sex pilus or bridge (connecting tube) and the process is known as conjugation.
- Transduction: Plasmid DNA is transferred through bacteriophage, i.e. viruses which infect bacteria.
- Transformation: In this case, a resistant bacterium may release the resistance carrying DNA into the medium which may be imbibed by another sensitive organism (bacteria). Due to this, the recipient bacteria becomes unresponsive to drug.
Mechanism of Resistance to Antimicrobial Drugs
- Changing membrane permeability (Biochemical Mechanisms): Both Gram (+ ve) and Gram (− ve) bacteria may develop resistance to tetracycline, amino glycosides, beta-lactamase, chloramphenicol and polymyxins due to biochemical alteration of their envelope. Due to this, accumulation of drug or intracellular drug level in the bacteria is decreased.
- Increase distruction (degradation) of the drug: The antibiotics can be inactivated by enzymes synthesized by a large number of organisms. Classical examples are:
- Beta-lactum antibiotics are inactivated by beta-lactamases which are produced by staphylococci and enteric Gram (−ve) rods.
- Amino glycosides are inactivated by several enzymes which are produced by both Gram (+ve) and Gram (−ve) organisms.
- Chloramphenicol is inactivated by chloramphenicol acetyltransferase, produced by resistant strains of Gram (+ve) and Gram (−ve) organisms (See Fig. 12.1.1).
- Altered structural target for the drug: The binding site may be altered, e.g. binding sites for Aminoglycosides, on the ribosome's may be altered due to mutation.
- Altered metabolic pathway: Staphylococci and many other bacteria may show resistance to sulphonamides and trimethoprim by developing alternative metabolic pathways.
- Efflux pump: Some gram (−ve) bacteria can develop an enzyme, which can pump out terramycin from their body, so that the antibiotic can not be concentrated in these bacterial bodies.
Cross resistance
- It is the resistance seen among chemically related antimicrobial agents.
- When a microorganism develops resistance to one drug (AMA), it is also resistant to other drugs (AMA) of the same group having the same mechanism of action, even 360when not exposed to it, e.g. resistance to one tetracycline means resistance to all other tetracyclines. Other examples includes sulphonamides, beta-lactam antibiotics, amino glycosides, etc.
Multiple antibiotic resistance
Sometime a particular strain of bacteria may be resistant to many antibiotics. Such bacterial strains are called “multi-drug resistant” strains.
Test for resistance
Three methods are described for testing the specimen for resistance
- Disk diffusion (Kirby-Bauer technique).
- MIC
- Well method.
Prevention of resistance to antimicrobials
Drug resistance can be avoided to some extent by taking following measures:
- Antibiotics should be used only after confirmed diagnosis and when necessary.
- Prefer narrow spectrum antibiotics as compared to broad spectrum as far as possible.
- Selection of the appropriate antibiotic is absolutely important.
- Never treat the patient half heartedly; correct dose and duration of treatment should be followed.
- Combination of drugs should be used as in tuberculosis to delay the development of resistance.
COMBINATION OF ANTIMICROBIALS
The simultaneous use of two or more antimicrobial agents is some times justified. Combinations should be judiciously chosen keeping in mind their effect on the microorganisms as well as the host. The combination serves one of the following purposes.
- In the treatment of mixed infections
- Genitourinary infections, Intra-abdominal infections, brain abscesses are often mixed infections. Aerobic and anaerobic organisms may be involved.
- Combination of two or more anti-microbial can be used depending on the culture and sensitivity report.
- To obtain synergismCombination of antibiotics to attain synergism is recommended in:
- Amoxicillin and clavulanic acid to enhance antibacterial spectrum
- Bacterial endocarditis: Penicilln + streptomycin/gentamicin is synergistic.
- Pseudomonas infections: Carbenicillin + gentamicin
- Pneumocystic carini pneumonia: Trimethoprim + sulfamethoxazole
- Amoxicillin + clavulinic acid—b-lactamase producing organisms like H. influenzae.
- Tuberculosis: INH + rifampicin.
- Amphotericin B and rifampin in antifungal infection
- In treatment of severe infectionsSevere infections of unknown etiology as in septic shock with urinary tract infection, combination can be used:
- Drugs covering both gram-positive and gram-negative pathogens may be used initially till the culture report is available, e.g. penicillin + aminoglycoside; cephalosporin + aminoglycoside.
- If anaerobes are likely to be present, metronidazole may be added. Samples for culture should however be taken before starting the antibiotics.
- To reduce the adverse effects
- The doses needed may be lower when a combination is used.
- This may reduce the incidence and severity of adverse effects, e.g. Amphotericin B + flucytosine in cryptococcal meningitis.
- To prevent emergence of resistance
- In the treatment of tuberculosis and leprosy, combinations of drugs are used to prevent development of resistance.
Disadvantages of antimicrobial combination
- Increased cost of therapy.
- Toxicity: In each agent—especially if toxicity is overlapping—may get added up. Toxicity of one drug may be enhanced by another, e.g. many antitubercular drugs are hepatotoxic.
- Vancomycin + aminoglycoside → more severe renal toxicity
- Selection of resistant strains: the few resistant mutants that remain may multiply unchecked.
- Emergence of organisms resistant to multiple drugs.
SUPERINFECTIONS (OPPORTUNISTIC INFECTION)
Definition: Superinfection/supra-infection is the appearance of a infection resulting from the use of antimicrobials. Antimicrobial therapy, especially with broad/extended spectrum antibiotics, may lead to superinfection (over growth) with Proteus, resistant staphylococci, Pseudomonas, clostridium difficile or candida due to the removal of 361natural antibiosis of nonpathogenic organisms against pathogenic ones in the intestinal, respiratory and genitourinary tracts
- Antibacterial alter the normal microbial flora of the intestinal, respiratory and genitourinary tracts.
- The normal flora contributes to host defense mechanisms as follows—they inhibit colonization of pathogenic organisms by producing antibacterial substances called bacteriocins and by competing for nutrients.
- When the normal flora is destroyed by antibacterial, agents, there can be dangerous infections due to various organisms especially the normal commences.
- Opportunistic infections are more common when the patient's immune systems are compromized by diseases or drugs, e.g. during cancer chemotherapy and prolonged use of corticosteroids and patients of AIDS or even diabetes.
- The broader the antibacterial spectrum of a drug, the more is the chances of super-infection, as the alteration of the normal flora is greater. Common microorganisms causing super infections are given in the box below.
Misuse of antibiotics
- Antibiotics are most overused or misused drugs.
- Faulty practices of antibiotics like the use of antibacterial agents in viral infections which are self-limiting, using too low doses or unnecessary prolonged treatment, using antibiotics in all fever cases: are all irrational and can do more harm than any benefit.
SELECTION OF AN ANTIBACTERIAL AGENT
An ideal chemotherapeutic agent should be selectively toxic to the organism without producing any harmful effects to the host. So the physician should select a proper antimicrobial agent based on various factors like:
- The patient factors,
- The microbe factors,
- The properties of the drug and
- The clinical assessment.
- – Age of the patient, host defense status, renal and hepatic functions should be considered.
- – Whenever possible, bacteriological culture should guide the drug selection Narrow spectrum antibiotics are always better than broad spectrum antibiotics, except certain conditions.
- – When bacteriological examination is not possible, empirical therapy (broad spectrum antibiotics) should be started to cover all the likely organisms.
- – Drug toxicity and cost should be borne in mind. With proper clinical judgment considering the above factors, most infections can be successfully treated.
Antibiotics are used in two ways:
- Empirical therapyThe antibiotic must cover all the likely pathogens. A combination of drugs or a broad spectrum agent may be used. This therapy should be employed only in some specific situations like mixed infections.
- Definitive therapyWhen the organism is identified, specific antibacterial agents should be given.
Chemoprophylaxis
Chemoprophylaxis is the use of antimicrobial agents to prevent infection. This is recommended in the following situations:
- To protect healthy persons
- Penicillin G is given for prevention of gonorrhea or syphilis in patients after contact with infected personnel.
- For preventing meningococcal infection in all healthy children during an epidemic: rifampicin or sulfonamides may be used.
- To prevent infection in high risk patients
- In neutropenic patients—penicillin or fluoroquinolones or cotrimoxazole may reduce the incidence of bacterial infection.MicroorganismsManifestationsTreatmentCandida albicansOral thrush, diarrhea, vaginitisClotrimazoleStaphylococci Clostridium difficileEnteritis Pseudomembranous Entero-colitisCloxacillin Metronidazole, VancomycinE. coli PseudomonasUTINorfloxacin Carbenicillin
- In patients with valvular heart diseases even minor procedure like dental extraction, tonsillectomy or endoscopies may result in bacterial endocarditis (damage to mucosa results in bacteraemia). Penicillin is used for prophylaxis.
- Surgical prophylaxis: Certain guidelines are to be followed:
- Adequate antibacterial activity should be present during surgery. Hence the drug should be started before surgery.
- The drug should not be continued beyond 24 hours (risk of resistance).
- The drug should be effective against all organisms that are likely to contaminate the wound.