CHEMOTHERAPY

CHEMOTHERPY

INTRODUCTION

The term ’çhemotherapy’ broadly refers to the use of any chemical compound that selectively acts on microbes or cancer. Paul Ehrlich introduced the term chemotherapy in 1907 to describe his important early studies of Trypanosoma brucei. The search for anti infective/ chemotherapeutic agents began long time ago, however, agents used against microbes were found to be equally toxic to humans. The search for safe, effective chemotherapeutic drugs is hindered by the common evolutionary legacy humans share with all living organisms; success requires exploitation of metabolic or structural differences between normal human cells and disease-producing cells.

The more closely related the undesirable cells are to normal human cells, the more difficult the task of finding a magic bullet (i.e a drug that is selectively toxic to microbes). For example, it is easier to cure malaria than cancer because malaria parasite lacks basic features of human cells compared to cancerous cells which are altered human cells. The discovery of chemotherapeutic agents with selective toxicity as we have today can be traced to Alexander Fleming’s chance observation of the antibacterial effect of a substance secreted by Penicillium notatum moldin the 28 may year 1928, which led to the discovery of penicillins.

As noted above from the definition of chemotherapy, the range of pharmacological agents that will be studied under this topic include antimicrobials and cytotoxic drugs. The term ‘antibiotics’ from the onset generally refers to antimicrobials in entirety. However, in recent times, its usage has been limited to antibacterials only.

Antimicrobials to be studied include antibacterials, antifungals, antivirals, antihelminths, antiprotozoals. Others include agents used in specific disease conditions such as tuberculosis, leprosy, malaria and HIV infection.

GENERAL PRINCIPLES OF ANTIBIOTIC THERAPY

Chemotherapy of human disease is complex, as it depends on a complex patient–drug–pathogen interaction. This interaction has the following components:

-         Pharmacokinetics: What the patient does to the drug. To be clinically useful, a chemotherapeutic drug must have both selective toxicity against pathogens and favourable pharmacokinetics. The processes of absorption, distribution, metabolism, and elimination compose a drug’s pharmacokinetics. The concentration of the drug in a patient’s body as a function of time is determined by the dose administered and the drug’s pharmacokinetics in that patient. For example, a patient with renal failure will have diminished renal clearance of gentamicin. Also, absorption from the gastrointestinal tract can be affected by other drugs and by food. Aluminum, calcium, and magnesium ions in antacids or dairy products form insoluble chelates with all tetracyclines and inhibit their absorption. Food inhibits tetracycline absorption but enhances doxycycline absorption; food delays but does not diminish metronidazole absorption; fatty food enhances griseofulvin absorption.

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-         Pharmacodynamics: What the drug does to the patient. In the case of antibiotic chemotherapy, the ideal pharmacodynamic response is usually no pharmacodynamic response; the pharmacological target is not normal human cells but rather a parasite, a virus-infected human cell, or a cancerous cell. The less selective the chemotherapeutic drug, the greater the severity of adverse effects. Compared with other pharmacological agents, antibacterial chemotherapeutic drugs are remarkably safe. Toxicity is common mainly in patients who are given inappropriately high doses or who develop high drug levels because of decreased drug clearance. Most antibiotics are renally cleared, so renal failure is a common cause of diminished antibiotic drug clearance.

          The adverse reactions associated with the use of antibacterial chemotherapy  include allergic reactions, toxic reactions resulting from inappropriately high drug doses, interactions with other drugs, reactions related to alterations in normal body flora such as pseudomembranous colitis, and idiosyncratic reactions.

-          Immunity: What the patient does to the pathogen. In the absence of antibiotic therapy, many patients survive infection, even infection by highly virulent pathogens. The effectiveness of chemotherapy is enhanced by adequate immune function, although some antibiotics suppress immune function e.g sulphonamides and chloramphenicol. For example, a patient with AIDS who is exposed to tuberculosis may develop the disease in spite of receiving a course of postexposure prophylactic antituberculosis chemotherapy, which would be effective in a patient with an intact immune system.

-         Resistance: What the pathogen does to the drug. Some pathogens are naturally resistant to certain chemotherapeutic drugs. Resistance can occur through mutation, adaptation, or gene transfer. For example, once some drugs enter the cell, they may be enzymatically inactivated. Some bacteria possess pumps that remove drugs from the bacterial cytosol. The antibiotic also may be ineffective as a result of mutation of genes coding for the target site. Some organisms, such as Staphylococcus aureus, Neisseria gonorrhoeae, and Haemophilus influenzae, may produce β-lactamase and therefore be resistant to penicillin and its congeners ( other β- lactams)

-         Selective toxicity: What the drug does to the pathogen. As discussed above, an ideal antibiotic is that which is selectively toxic to microbes.

STATIC/CIDAL EFFECTS

Antibiotics also can be classified according to whether they are static (inhibitory) or cidal (lethal). The classification of drugs as either static or cidal is based on laboratory assessment of the interaction of pathogen and antibiotic drug.

Cidal effects can be a result of the disruption of the cell wall or membrane. Cell lysis may occur when water diffuses into the bacterial cytosol through the antibiotic-induced holes in the membrane, causing the bacteria to swell and burst. Cidal effects also can occur as a consequence of inhibition of bacterial DNA replication or transcription.

Static effects occur when the toxic effects of a chemotherapeutic drug are reversible. For example, inhibition of folate synthesis by sulfonamides interferes with methylation, an important biochemical synthetic process. Reversal of this static effect can occur when the antibiotic concentration falls or if a compensatory increase in the synthesis of the inhibited enzymes occurs.

The static versus cidal designation is however a false dichotomy, since there is a continuous spectrum of activity between the two categories. The place of a drug along this spectrum will depend on both the pharmacological properties of the drug and such clinical factors as immune system function, drug concentration in tissue, and duration of therapy. A cidal drug may prove to be merely static if an inappropriately low dose or short treatment course is prescribed. A static drug may be cidal if given in high doses for prolonged courses to exquisitely sensitive pathogens.

ANTIBACTERIALS

Bacteria are single cell organisms which are capable of causing disease to humans. There are various classifications of bacteria, however, the classifications based on metabolic pattern (aerobic and anaerobic) and gram staining ( gram positive and gram negative) are usually employed when discussing antimicrobials.

Primarily, antimicrobials are used against sensitive organisms – different bacteria have different degree of sensitivity to antimicrobials. Thus, the designation of antimicrobials to be used in certain conditions/ infections or body regions is based on the premise that certain forms of bacteria are known to usually cause infections in certain designated body parts/ regions. Below is a summary of different bacteria with the usual infections they cause in different body regions.

HEAD AND NECK

          Meningitis

Pneumococci, Meningococci, Hemophilus influenzae, Listeria

          Sinusitis

Pneumococci, H. influenzae, Moraxella

          Acute otitis media

Pneumococci, H. influenzae, Moraxella

          Pharyngitis

Group A streptococci

CHEST CAVITY

          Pneumonia

Pneumococcus, H. influenzae

          Pleural cavity

Pneumococcus, Staphylococcus

          Endocarditis

Streptococcus, Staphylococcus, Enterococci

ABDOMEN

Likely organisms in intraabdominal infections come from the GI tract. Therefore all enteric flora need to be considered. This may include

-         Aerobic (Enterobacteriaceae) and anaerobic (Bacteroides, Fusobacteria) gram negatives rods.

-         Aerobic (Enterococci and Streptococci) and anaerobic Gram positives cocci (Streptococci)

-         Anaerobic Gram positive rods (Clostridia)

SKIN

          Skin infections

-         Skin flora-Gram positive cocci

-         Staphylococcus aureus and Streptococcus pyogenes

Complex skin infections

-         Skin flora plus enteric flora.

URINARY TRACT

Because of proximity to GI tract, enteric flora are the prime suspects in most cases 

-         Aerobic Enteric Gram negative rods

-         Aerobic Gram positive cocci from the gut

-         Unusual to find Staphylococci, streptococci, or anaerobes.

Broad/Narrow spectrum antibiotics (antibacterials)

Broad spectrum antibiotics refers to an antibiotic that acts against a wide range of disease causing bacteria (usually gram +ve and gram – ve bacteria)and thus may be used to treat a wide variety of infectious diseases. This is in contrast to a narrow spectrum antibiotic which is effective against specific families of bacteria and thus, are used in specific infections where the causative organisms are known. Examples of narrow spectrum antibiotics include the macrolides, clindamycin and vancomycin.

CLASSIFICATION

The groups of antibacterials that are effective clinically include

a.      The beta (β)- lactams – This includes

-         Penicillins

-         Cephalosporins

-         Carbapenems

b.     Sulphonamides ( and trimethoprim)

c.      Quinolones

d.     Nitrofurans

e.      Aminoglycosides

f.       Tetracyclines

g.     Lincosamides

h.     Macrolides

i.       Chloramphenicol

j.        Metronidazole

k.     Glycopeptides (vancomycin)

PENICILLINS

The penicillins are a large group of bactericidal compounds. They can be subdivided and classified by their chemical structure and spectrum of activity. The structure common to all penicillins is a β - lactam ring. The antimicrobial activity of penicillin resides in the β-lactam ring. Splitting of the β - lactam ring by either acid hydrolysis or β – lactamases results in the formation of penicilloic acid, a product without antibiotic activity. Penicillins may be classified into four groups:

-         Natural penicillins G (parenteral) and V (oral)

-         Antistaphylococcal (penicillinase - resistant) penicillins e.g oxacillin, nafcillin, cloxacilin

-         Aminopenicillins e.g amoxicillin. Ampicillin

-         Antipseudomonal penicillins e.g carbenicillin, piperacillin, ticarcillin

MOA – Penicillins exert their antibacterial effect by inhibition of bacterial cell wall synthesis through their binding to specific penicillin-binding proteins (PBP) on the cell wall of bacteria. When β - lactam antibiotics inactivate PBPs, the consequence to the bacterium is a structurally weakened cell wall, aberrant morphological form, cell lysis and death.

SPECTRUM OF ACTIVITY: Generally, the penicillins are broad spectrum antibiotics having considerable effect on both gram positive and gram negative organisms. However, all the types of penicillins can be inactivated by β – lactamases( penicillinases) except the penicillinase-resistant penicillins. The antipseudomonal penicillins have an additional effect on gram negative organisms of which pseudomonas aeruginosa is an example. Methicillin-resistant Staphylococcus  aureus(MRSA) and methicillin- resistant Staphylococcus epidermidis (MRSE) are resistant in vitro to all β-lactam antibiotics.

ADVERSE EFFECTS

While being associated with a low percentage of adverse reactions, the β -lactams are the most frequent source of troublesome allergic reactions among the antibiotics. Symptoms may include urticaria, pruritus, bronchospasm, angioedema, laryngeal edema, and hypotension. Other adverse effects may include anaemia (haemolytic), interstitial nephritis, eosinophilia etc.

CEFALOSPORINS (formerly cephalosporins)

The cephalosporins are semisynthetic broad - spectrum antibiotics with a beta-lactam ring, which is the reason behind their antibacterial activity. They are similar to the penicillins and therefore share similar properties such as inactivation by β – lactamases (cephalosporinases) and occurrence of side effects such as allergy.

Classification – Cephalosporins can be classified into four different generations based on antibacterial spectrum and stability to β-lactamases.

1^st generation – cefazolin, cefadroxil, cefalexin.

2^nd generation -  cefaclor, cefuroxime, cefixime, cefotetan, cefmetazole.

3^rd generation – ceftriaxone, cefdinir, ceftazidime.

4^th generation – cefepime.

MOA – As for other β – lactams

SPECTRUM OF ACTIVITY – Cefalosporins are broad-spectrum antibiotics with variable activity against gram +ve and gram –ve organisms. Generally, the 1^st generation have the least while the 4^th generation have the highest level of antibacterial activity and stability to β-lactamases. 

ADVERSE EFFECTS: This may include hypersensitivity reactions ( some patients allergic to penicillins may be cross-sensitive to the cephalosporins), coagulation disorders (bleeding), overgrowth of bacteria (pseudomemebranous colitis) etc.

CARBAPENEMS

The first carbapenem, imipenem ( used with cilastatin) also has a β – lactam ring and therefore has similar mechanism of action compared to other β – lactams. The antibacterial spectrum of imipenem is among the broadest of all of the β - lactam antibiotics. Imipenem is active against most gram-positive, gram-negative, and anaerobic bacteria. Imipenem–cilastatin is only available for intramuscular or intravenous administration because oral bioavailability is poor.

An extremely unique feature of imipenem is that it is hydrolyzed by renal dipeptidase to a metabolite that is inactive against bacteria but is toxic to humans. Coadministration of cilastatin inhibits the renal dipeptidase, which both prevents the formation of the toxic metabolite and decreases imipenem clearance, prolonging the half-life of the drug. Cilastatin in itself lacks antibacterial property. 

The notable adverse effect of imipenem–cilastatin is seizures affecting 1% of patients.  Another example of this class of drugs is meropenem.

SULFONAMIDES (and trimethoprim)

Sulfonamides are synthetic antibacterials. They are a large group of compounds that are structural analogues of p-aminobenzoic acid (PABA). Trimethoprim (not a sulfonamide) is usually used synergistically with some sulfonamides. Examples of sulfonamide antibiotics include sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfathiazole.

MOA - Both sulfonamides and trimethoprim sequentially interfere with folic acid synthesis by bacteria. Sulfonamides, as structural analogues, competitively block PABA incorporation through inhibition of the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet; thus, the sulfonamides selectively inhibit microbial growth.

Trimethoprim acts at a second step in the folic acid synthetic pathway; that is, it competitively inhibits dihydrofolate reductase. This is the enzyme that catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid, the active form of folate.

Because trimethoprim and sulfamethoxazole have their effects at different points in the folic acid synthetic pathway, a synergistic effect results when the two are administered together. However, either of the two drugs can be used alone. The incidence of bacterial resistance to the combination is less than that observed when the drugs are used individually.

SPECTRUM OF ACTIVITY: Both sulfonamides and trimethoprim are broad spectrum antibiotics. Trimethoprim has little anaerobic activity.

ADVERSE EFFECTS: The sulfonamides do cause hypersensitivity reactions (e.g., rashes, eosinophilia, and drug fever) in a small number of patients.  Stevens-Johnson syndrome is also associated with sulfonamide use; it is characterized by fever, malaise, erythema multiforme, and ulceration of the mucous membranes of the mouth and genitalia.

Hemolytic anaemia may develop in persons with a genetic deficiency of red blood cell glucose-6-phosphate dehydrogenase (G6PD).

Sulfonamides compete for sites on plasma proteins that are responsible for the binding of bilirubin. As a result, less bilirubin is bound, and in the newborn, the unbound bilirubin can be deposited in the basal ganglia and subthalamic nuclei, causing kernicterus, a toxic encephalopathy. For this reason, sulfonamides should not be administered to newborns or to women during the last 2 months of pregnancy. Because both drugs may interfere with folic acid metabolism, their use during pregnancy is usually contraindicated by the potential for effects on the fetus, such as the development of neural tube defects associated with folate deficiency.

 QUINOLONES

The quinolones are a group of synthetic antibiotics. Like cefalosporins, they are classified into generations.Each generation (first through fourth) has spectrum specificity and unique pharmacological properties, although there is considerable overlap:

-         First :nalidixic acid and cinoxacin;

-         Second : norfloxacin, ciprofloxacin, ofloxacin, enoxacin, and lomefloxacin;

-         Third : levofloxacin, sparfloxacin, gatifloxacin;

-         Fourth : trovafloxacin and moxifloxacin.

MOA – Through the inhibition of DNA synthesis in bacteria

SPECTRUM OF ACTIVITY – Broad spectrum antibiotics with most anaerobes not being susceptible. Methicillin-resistant Staphylococcus aureus and Enterococcus faecium are resistant. The fourth-generation quinolones also possess activity against anaerobes.

ADVERSE EFFECTS

The most frequently reported side effects are associated with the GI tract - these

include nausea, vomiting, diarrhea, and abdominal pain. CNS effects such as drowsiness, weakness, headache, dizziness, and in severe cases, convulsions also occur. Allergic reactions (e.g., rashes, urticaria, and eosinophilia) have been observed.

The use of the quinolones in pregnant or breastfeeding women and children whose epiphysial plates have not closed is generally contraindicated.

URINARY ANTISEPTICS (Nitrofurans)

Urinary antiseptics are drugs that exert their antimicrobial effect in the urine and are devoid of virtually any significant systemic effect. Prolonged use for prophylaxis and/or suppression is common in recurrent or chronic UTIs where other antimicrobials can be used only for short durations because they do not sustain sterility. Nitrofurans (nitrofurantoin) are used in the treatment and/or prophylaxis of microbial infections, primarily in the urinary tract. Acidification of urine increases urinary antibacterial efficacy of the drug, therefore, acidifying agents, including cranberry juice, can be useful.

MOA: Dual - Through the inhibition of DNA synthesis and protein synthesis in bacteria.

SPECTRUM OF ACTIVITY: Nitrofurantoin is primarily active against gram-negative bacteria and some susceptible gram-positive organisms; It is a urinary specific broad-spectrum antibiotic. Nitrofurantoin however, lacks deep tissue penetration and therefore cannot be used in UTIs like pyelonephritis.

ADVERSE EFFECTS

Nausea and vomiting are the most commonly observed adverse effects. Pulmonary hypersensitivity reactions may also occur.

AMINOGLYCOSIDES

This class of antimicrobials are amine-containing carbohydrates. The major clinically important aminoglycosides are amikacin, gentamicin, kanamycin, netilmicin, neomycin, streptomycin, and tobramycin.

MOA - The antibacterial actions of the aminoglycosides involve two possibly synergistic effects. First, they bind to bacterial cell membrane thereby disrupting membrane integrity. Secondly, aminoglycosides bind to various sites on bacterial 30S ribosomal subunits, disrupting the initiation of protein synthesis. In addition, they have a postantibiotic effect; that is, they continue to suppress bacterial regrowth even after removal of the antibiotic from the bacterial microenvironment which possibly explains their effective once daily dosing regimen.

SPECTRUM OF ACTIVITY – They are bactericidal notably against gram –ve organisms, although some gram +ve organisms are susceptible. Infact, aminoglycosides are the drug of choice in serious gram –ve infections. Of particular importance is the use of neomycin in eradicating facultative gut flora in patients with fulminant hepatitis and hepatic encephalopathy; streptomycin for tuberculosis; and gentamicin for conjunctivitis.

ADVERSE EFFECTS

Notable side effects include nephrotoxicity and ototoxicity. Others include nausea, vomiting, colitis etc.

  

TETRACYCLINES

These are a group of ligands with a four-ringed structure synthesised naturally and semisynthetically. The tetracyclines affect both eukaryotic and prokaryotic cells but are selectively toxic for bacteria, because they readily penetrate microbial membranes. Examples include oxytetracycline, minocycline, doxycycline, tetracycline, chlortetracycline etc.

MOA: This is through the inhibition of protein synthesis mediated by binding of the drug to the 30S subunit of ribosomes in bacteria.

SPECTRUM OF ACTIVITY: The tetracyclines display broad-spectrum activity and are effective against both gram-positive and gram-negative bacteria. Minocycline is somewhat more active and oxytetracycline and tetracycline are somewhat less active than other members of this group. Doxycycline, with its longer half-life and lack of nephrotoxicity, is a popular choice for patients with preexisting renal dx or those who are at risk for developing renal insufficiency. It is the preferred parenteral tetracycline and has demonstrated antimalarial properties.

Food impairs absorption of all tetracyclines except doxycycline and minocycline.  Since the tetracyclines form insoluble chelates with calcium (such as are found in many antacids), magnesium, and other metal ions, their simultaneous administration with milk(calcium), magnesium hydroxide, aluminum hydroxide, or iron will interfere with absorption.

ADVERSE EFFECTS

Oral administration can cause nausea, vomiting, epigastric burning, stomatitis, and glossitis. Other side effects include hepatotoxicity, nephrotoxicity and photosensitivity (susceptibility to sunburns). Staining of both the deciduous and permanent teeth and retardation of bone growth can occur if tetracyclines are administered after the fourth month of gestation or if they are given to children less than 8 years of age.

MACROLIDES

Antibiotics in this group include erythromycin, clarithromycin, azithromycin oleandomycin and troleandomycin.

MOA : Macrolides bind to the 50S ribosomal subunit of bacteria thereby inhibiting translocation and peptide bond formation, steps in protein synthesis.

ANTIBACTERIAL SPECTRUM

This is similar to that of penicillins and a major indication for their use is in patients known to be hypersensitive to penicillins. The newer macrolides, clarithromycin and azithromycin have similar indications as erythromycin but with an extended spectrum of activity. Clarithromycin, for example is used as part of a triple regimen in eradicating helicobacter pylori (peptic ulcer) while azithromycin is extremely beneficial in the treatment of sexually transmitted infections.

ADVERSE EFFECTS

The incidence of side effects associated with erythromycin therapy is very low. Mild gastrointestinal upset with nausea, diarrhea, and abdominal pain ; Rashes (hypersensitivity reaction) with fever and eosinophilia. Thrombophlebitis may follow intravenous administration, as may transient impairmentof hearing. Ototoxicity is also common with long term use.

 LINCOSAMIDES

Lincosamides share a similar property with tetracyclines and macrolides in that they are all produces by the streptomyces spp. This may also be the reason for their identical mode of action. Examples include lincomycin and the semisynthetic clindamycin. Lincomycin however has a limited use because of toxic effects and may be limited severe life threatening infections. 

MOA - They bind to the 50S ribosomal subunit at a binding site close to the binding sites for chloramphenicol and erythromycin, where they inhibit protein synthesis.

ANTIBACTERIAL SPECTRUM

Clindamycin, like erythromycin, mostly has activities against gram +ve organisms. Organisms resistant to erythromycin are also resistant. However, a strong point of clindamycin is its wide anaerobic spectrum. There is almost no effect on aerobic gram   - ve organisms e.g E. Coli, Proteus mirabilis.

ADVERSE EFFECTS

The most notable side effect associated with clindamycin is antibiotic-associated diarrhoea and pseudomembranous colitis.

CHLORAMPHENICOL

Chloramphenicol (chloromycetin) is a broad spectrum antibiotic active against a wide range of gram +ve and gram –ve bacteria and most anaerobes. It acts through the inhibition of protein synthesis by binding to the 50S subunit of ribosomes.

The potentially fatal nature of chloramphenicol restricts its use to a few life-threatening infections in which the benefits outweigh the risks. There is no justification for its use in treating minor infections. Chloramphenicol is no longer recognized as the treatment of choice for any bacterial infection. In almost all instances, other effective antimicrobial agents are available.

The most publicized adverse effects are those involving the hematopoietic system; they are manifested by toxic bone marrow depression or idiosyncratic aplastic anaemia.

Newborn infants, especially those born prematurely, cannot adequately metabolise and excrete chloramphenicol and because of these, high levels of free chloramphenicol may accumulate and cause a potentially fatal toxic reaction, the gray baby syndrome. This syndrome is characterized by abdominal distension, vomiting, progressive cyanosis, irregular respiration, hypothermia, and vasomotor collapse.

VANCOMYCIN

Vancomycin is a narrow spectrum bactericidal glycopeptide produced by the soil microbe Streptomyces orientalis. Vancomycin is a drug of specific importance despite its toxicity- this is because it is considered the drug of choice for MRSA and MRSE. It is also active against clostridium difficile, the responsible organism in antibiotic associated colitis.

It primarily inhibits the growth of gram +ve bacteria through the inhibition of bacterial cell wall synthesis at a point distinct from that of penicillins and cephalosporins. However, because of the wide availability of equally effective and less toxic drugs, vancomycin is considered as a second-line drug in the treatment of most infections caused by susceptible organisms.

ADVERSE EFFECTS

The major adverse effect associated with vancomycin therapy is ototoxicity, which may result in tinnitus, hightone hearing loss, and deafness in extreme instances.

More commonly, the intravenous infusion of vancomycin can result in chills, fever, and a maculopapular skin rash often involving the head and upper thorax (red man / red neck syndrome). Vancomycin is rarely nephrotoxic when used alone.

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