Al al-Bayt University



PART 6: CHEMOTHERAPEUTIC DRUGS

Anti-infectives: Are drugs designed to act on foreign organisms that have invaded and infected the human host with selective toxicity, which means that they affect biological systems or structures found in the invading organisms but not in the host.

• Anti-infectives include antibiotics, antivirals, antifungals, antiprotozoals,anthelmintic agents and antineoplastics drugs used for treating diseases caused by abnormal cells such as cancers.

I. Antibiotics

Microbial infection:

Microorganisms are everywhere in both the external environment and many parts of the internal environment of our bodies. They can be harmful to humans or they can be beneficial under normal circumstances but become harmful when conditions are altered in some way. Every major class of microbes contains organisms that can infect humans. This includes bacteria, viruses, fungi, and protozoan. The focus of this chapter is common bacterial infections.

Bacteria classified according to:

➢ Their shape, this property is called their morphology (figure below).

➢ The basis of their response to the gram stains procedure.

✓ Gram-positive organisms:

• Stain purple with gram staining

• Have very thick wall.

• Have outer capsule.

✓ Gram-negative organisms:

• Stain red.

• Have a cell wall structure that is more complex, with a smaller outer capsule and peptidoglycan layer and two cell membranes: an outer and an inner membrane.

Gram-negative bacterial infections are more difficult to treat, because the drug molecules have a harder time penetrating the more complex cell walls of gram-negative organisms.

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Signs and symptoms of infection:

Fever, chills, sweats, redness, pain and swelling, fatigue, weight loss, increased white blood cell WBC count, and the formation of pus. Not all patients exhibit signs of the infection.

To help the body and its normal host defenses combat an infection, antibiotic therapy is often required. Antibiotics are most effective when their actions are combined with functioning bodily defense mechanisms. Often patients will become colonized with bacteria. Colonization does not require antibiotic treatment.

Antibiotic: having or pertaining to the ability to destroy or interfere with the development of a living organism. The term is used most commonly to refer to antibacterial drugs.

Sites of origin:

← Community-associated infections

➢ An infection that is acquired by a person who has not been hospitalized or had a medical procedure within the past year

← Healthcare-associated infections

➢ The infection that a patient acquires during the course of receiving treatment for another condition in a health care facility.

➢ Contracted in a hospital or institutional setting.

➢ Were not present or incubating in the patient on admission to the facility.

➢ More difficult to treat because causative microorganisms are often drug resistant and the most virulent.

➢ Methicillin resistance staphylococcus aureus MRSA most common

➢ Often they are acquired from various devices, such as mechanical ventilators, intravenous infusion lines, catheters, and dialysis equipment.

Areas of the hospital where the risk for acquiring a hospital-associated infection is particularly high are the critical care, dialysis, oncology, transplant, and burn units. This is because the host defenses of the patients in these areas are typically compromised, which makes them more vulnerable to infection.

The most common mode of transmitting hospital-associated infections is by direct contact. The most important thing health care professionals can do to prevent the spread of these potentially deadly infections is to wash their hands.

Healthcare-Associated Infections: Prevention

• Hand washing

• Disinfectant: Kills organisms. Used only on nonliving objects

• Antiseptic: Generally only inhibits the growth of microorganisms but does not necessarily kill them. Applied exclusively to living tissue

Pharmacology overview:

Antibiotics have three general uses:

← Empiric therapy: treatment of an infection before specific culture information has been reported or obtained

← Definitive therapy: antibiotic therapy tailored to treat organism identified with cultures

← Prophylactic therapy: treatment with antibiotics to prevent an infection, as in intraabdominal surgery or after trauma

Host factors in choosing antibiotics:

• Age of the patient.

• Lactation and/ or pregnancy.

• A drug history.

• Kidney and liver functions.

• Genetic characteristics (G6PD deficiency)

• Host defenses.

• Site of infection.

Chemotherapeutic spectra:

A. Narrow-spectrum antibiotics

Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a narrow spectrum.

B. Extended-spectrum antibiotics

Extended spectrum is the term applied to antibiotics that are modified to be effective against gram-positive organisms and also against a significant number of gram-negative bacteria.

C. Broad-spectrum antibiotics

Drugs such as tetracycline, fluoroquinolones and carbapenems affect a wide variety of microbial species and are referred to as broad-spectrum antibiotics. Administration of broadspectrum antibiotics can drastically alter the nature of the normal bacterial flora and precipitate a superinfection due to organisms such as Clostridium difficile, the growth of which is normally kept in check by the presence of other colonizing microorganisms.

Super infection can occur when antibiotics reduce or completely eliminate the normal bacterial flora. When normal flora is killed by antibiotics, other bacteria or fungi are permitted to take over and cause infection. Example:

Antibiotic associated colitis (psudomembranous colitis).Development of vaginal yeast infection.

Antibiotics:

Antibiotics classified based on chemical structure or mechanism of action.

Based on chemical structure can be classified into (1)penicillins, (2)cephalosporins, (3)quinolones, (4)sulfonamides, (5)aminoglycosides, (6)tetracyclines, (7)macrolides.

The four most common mechanism of action:

1- Interference with a bacterial cell wall synthesis.

2- Interference with a bacterial protein synthesis.

3- Interference with replication of DNA and RNA.

4- Antimetabolite action that disrupts critical metabolic reactions inside the bacterial cell.

Also can be classified into:

← Bactericidal: kill bacteria

← Bacteriostatic: inhibit growth of susceptible bacteria, rather than killing them immediately; will eventually lead to bacterial death

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A. Cell wall synthesis inhibitors:

Some antimicrobial drugs selectively interfere with synthesis of the bacterial cell wall—a structure that mammalian cells do not possess. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms. They have little or no effect on bacteria that are not growing and dividing. The most important members of this group of drugs are the β-lactam antibiotics (named after the β-lactam ring that is essential to their activity), vancomycin, and daptomycin.

##Beta-Lactam antibiotics:

The beta-lactam antibiotics are very commonly used drugs, so named because of the beta-lactam ring that is part of their chemical structure. This broad group of drugs includes four major subclasses: penicillins, cephalosporins, carbapenems, and monobactams. They share a common structure and mechanism of action. They inhibit the synthesis of the bacterial peptidoglycan cell wall.

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1- Penicillins:

The penicillins are among the most widely effective and the least toxic drugs known, but increased resistance has limited their use.

Mechanism of action: Cell wall synthesis inhibitors.

The penicillins interfere with the last step of bacterial cell wall synthesis (cross-linkage), resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. These drugs are bactericidal and work in a time-dependent fashion.

Antibacterial spectrum:

1- Natural penicillins

← penicillin G, penicillin V

← They are obtained from fermentations of the fungus Penicillium chrysogenum.

← Penicillin G (benzyl-penicillin) is the cornerstone of therapy for infections caused by a number of grampositive and gram-negative cocci, gram-positive bacilli, and spirochetes

← Penicillin V has a similar spectrum to that of penicillin G.

← Penicillin V is more acid stable than penicillin G and is often employed orally in the treatment of infections.

← Penicillins are susceptible to inactivation by β-lactamases (penicillinases) that are produced by the resistant bacteria.

← Depot forms: Procaine penicillin G and benzathine penicillin G are administered IM and serve as depot forms. They are slowly absorbed into the circulation and persist at low levels over a long time period.

E INHIBITOR + ANTIBIOTIC

2- Penicillinase-resistant drugs (antistaphylococcal penicillins)

← cloxacillin, dicloxacillin, Flucloxacillin, oxacillin, and methicillin (no longer used due to its toxicity).

← The penicillinase-resistant penicillins have minimal to no activity against gram-negative infections.

← Cloxacillin is available in oral or injectable form.

← Flucloxacillin is available in oral form.

← The penecillinase-resistant penicillins are able to resist breakdown by the penicillin-destroying enzyme (penicillinase) commonly produced by bacteria such as staphylococci. For this reason they may also be referred to as antistaphylococcal penicillins there are, however certain strains of staphylococci, specifically S.aureus, that are resistant to these drugs. Such bacteria therefore require alternative antibiotic regimens.

3- Extended-spectrum penicillins:

← Aminopenicillins: amoxicillin, ampicillin.

← They have an antibacterial spectrum similar to that of penicillin G but are more effective against gram negative bacilli.

← Resistance to these antibiotics is now a major clinical problem.

← Formulation with a β-lactamase inhibitor, protects amoxicillin or ampicillin from enzymatic hydrolysis and extends their antimicrobial spectra.

4- Antipseudomonal penicillins):

← piperacillin, ticarcillin, carbenicillin

← They are called antipseudomonal penicillins because of their activity against Pseudomonas aeruginosa

← These agents are available in parenteral formulations only.

← They are effective against many gram-negative bacilli

← They are reserved for serious infections.

Beta-lactemase inhibitors:

Three of beta-lactemase inhibitors are clavulanic acid (clavulanate), tazobactam, and sulbactam. These drugs bind with the beta-lactemase enzyme itself to prevent the enzyme from breaking down the penicillin molecule, although they are not always effective. The following are examples of currently available combinations of penicillin and beta-lactemase inhibitors:

• Ampicillin/ Sulbactam.

• Amoxicillin/ Clavulanic acid.

• Ticarcillin/ Clavulanic acid.

• Piperacillin/ tazobactam.

Pharmacokinetics

Absorption:

← Most of the penicillins are incompletely absorbed after oral administration, and they reach the intestine in sufficient amounts to affect the composition of the intestinal flora.

← Food decreases the absorption of all the penicillinase-resistant penicillins and ampicillin because the drugs are destroyed by stomach acid. Therefore, they should be taken on an empty stomach.

← Amoxicillin does not affected by food.

Distribution:

← The β-lactam antibiotics distribute well throughout the body.

← All the penicillins cross the placental barrier, but none have been shown to have teratogenic effects (category B in pregnancy).

← However, penetration into bone or cerebrospinal fluid (CSF) is insufficient for therapy unless these sites are inflamed.

Metabolism:

← Host metabolism of the β-lactam antibiotics is usually insignificant.

Excretion:

← Patients with impaired renal function must have dosage regimens adjusted.

Adverse effects:

Hypersensitivity: Approximately 5% percent of patients have some kind of reaction, ranging from rashes to angioedema (marked swelling of the lips, tongue, and periorbital area) and anaphylaxis.

Common adverse effects such as nausea, vomiting and diarrhea: Diarrhea is a common problem that is caused by a disruption of the normal balance of intestinal microorganisms.

Nursing implications: Provide the following patient teaching:

← Take oral doses with water (not juices) as acidic fluids may nullify drug’s antibacterial action

← Try to drink a lot of fluids and to maintain nutrition (very important) even though nausea, vomiting, and diarrhea may occur.

← Report difficulty breathing, severe headache, severe diarrhea, dizziness, weakness, mouth sores, and vaginal itching or sores to a health care provider.

2- Cephalosporins:

The cephalosporins are β-lactam antibiotics that are closely related both structurally and functionally to the penicillins. Most cephalosporins are produced semisynthetically.Cephalosporins have the same mode of action as penicillins, and they are affected by the same resistance mechanisms. However, they tend to be more resistant than the penicillins to certain β-lactamases.

The safety profiles, contraindications, and pregnancy ratings of the cephalosporins are very similar to those of the penicillins. The most commonly reported adverse effects are mild diarrhea, abdominal cramps, rash, and purities. Because cephalosporins are chemically very similar to penicillins, a person who has had an allergic reaction to penicillin may also have an allergic reaction to a cephalosporin, this is referred to as cross-sensitivity (1%-4%). However, only those patients who have had a serious anaphylactic reaction to penicillin should definitely not be given cephalosporins.

Antibacterial spectrum

Cephalosporins have been classified as first, second, third, fourth, and advanced generation, based largely on their bacterial susceptibility patterns and resistance to β-lactamases.

First-genration cephalosporins:

First-generation cephalosporins are usually active against gram-positive bacteria and have limited activity against gram-negative bacteria. They are available in both parenteral and oral forms. Currently available first-generation caphalosporins include cefadroxil, cafazolin, and cephalexin.

← Used for surgical prophylaxis, and for susceptible staphylococcal infections

➢ Cefazolin: IV or IM

➢ Cephalexin, Cefadroxil: PO.

Second-generation cephalosporins:

The second-generation cephalosporins display greater activity against gram-negative organisms,

Whereas activity against gram-positive organisms is weaker

← Cafaclor (given orally, associated with serum sickness).

← cefoxitin (Mefoxin): IV and IM

➢ Also kills gram negative anaerobic bacteria.

← cefuroxime

➢ Cefuroxime sodium given parentral, cefuroxime axetil given orally.

➢ Surgical prophylaxis

➢ Does not kill anaerobes

Third-generation cephalosporins:

← Most potent group against gram-negative bacteria and less active against gram-positive bacteria.

← Can penetrate blood brain barrier, can be used to treat CNS infections.

← Examples: Cefotaxime, Cefpodoxime, Cefdinir, and ceftriaxone (Rocephin)

← Cefotaxime, and ceftriaxone: given as IV and IM injection, long half-life, once-a-day dosing

← Cefdinir and cefpodoxime: given in oral form, twice daily dose.

← Ceftriaxone is excreted through the bile into the feces and, therefore, is frequently employed in patients with renal insufficiency.

Fourth-generation cephalosporins

← Cefepime.

← Given in parenteral form

← Broader spectrum of antibacterial activity than third generation, especially against gram-positive bacteria

← Uncomplicated and complicated UTI

Advanced generation:

← Ceftaroline is a broadspectrum, advanced-generation cephalosporin that is administered IV as a prodrug, ceftaroline fosamil.

3- Carbapenems:

The carbapenems are a relatively new class of broad-spectrum antibiotics effective against gram-positive and gram-negative bacteria. Because of this, they are often reserved for complicated body cavity and connective tissue infections in acutely ill hospitalized patients.

One hazard of carbapenem use is drug-induced seizure activity, which occurs in a relatively small percentage of patients (associated with imipenem than other carbapenems). There is a small risk of cross allergy in patients with penicillin allergies.

Currently available carbapenems include:

- Imipenem/cilastatin.

- Meropenem.

Imipenem/cilastatin:

Imipenem is a semisynthetic carbapenem antibiotic, and cilastatin, an inhibitor of an enzyme that breaks down imipenem in kidney into toxic metabolite, Compounding the imipenem with cilastatin protects the parent drug and, thus, prevents the formation of the toxic metabolite.

Meropenem is the second drug in the carbapenem class of antibiotics. It appears to be somewhat less active against gram-positive organisms than imipenem/cilastatin. Imipenem/cilastatin and meropenem are administered IV

4- Monobactams:

← aztreonam (Azactam)

← Has antimicrobial activity directed primarily against gram-negative pathogens. It lacks activity against gram positive organisms and anaerobes.Primarily active against aerobic gram-negative bacteria.

← Administered IV or IM.

← Can accumulate in renal failure patients.

← Used for moderately severe systemic infections and UTIs.

← It’s believed to have less allergic cross-sensitivity with other beta-lactams.

##Vancomycin:

← Natural, bactericidal antibiotic. Destroying bacteria by binding to the bacteria cell wall. Is the Treatment of choice for MRSA and other gram-positive infections

➢ Oral vancomycin is poorly absorbed from the GIT, so it’s used for local effects on the surface of the GIT to treat pseudomembrenous colitis. IV administration is indicated for systemic infections. It is should be used with caution in those with preexisting renal dysfunction or hearing loss, as well as in elderly patients and neonates. Excreted by kidney. Half-life 6-10 hours. Dose is adjusted based on renal function and serum trough levels

← Unique adverse effects:

➢ Infusion related reactions due to histamine release: Fever, chills, phlebitis Flushing/itching of head, neck, face, upper trunk (red man syndrome). Antihistamine may be ordered to reduce these effects. And has a dose-related ototoxicity and nephrotoxicity.

← This drug should be infused over 60-90 minutes. Rapid infusions may cause hypotension. Monitor IV site closely. And should ensure adequate hydration (2 L fluids/24 hr) if not contraindicated to prevent nephrotoxicity.

B. Protein synthesis inhibitors:

1- Macrolides:

• Erythromycin.

• Azithromycin (Zlithromax)

• Clarithromycin)

Mechanism of action:

← Prevent protein synthesis within bacterial cells and considered bacteriostatic but in high enough concentrations, may also be bactericidal.

Antibacterial spectrum

1. Erythromycin: This drug is effective against many of the same organisms as penicillin G. Therefore, it may be used in patients with penicillin allergy.

2. Clarithromycin: Clarithromycin has activity similar to erythromycin, but it is also effective against Haemophilus influenzae. Its activity against intracellular pathogens, such as Chlamydia, Legionella, Moraxella, Ureaplasma species and Helicobacter pylori, is higher than that of erythromycin.

3. Azithromycin: Although less active against streptococci and staphylococci than erythromycin, azithromycin is far more active against respiratory infections due to H. influenzae and Moraxella catarrhalis. Azithromycin is the preferred therapy for urethritis caused by Chlamydia trachomatis. Mycobacterium avium is preferentially treated with a macrolide-containing regimen, including clarithromycin or azithromycin.

Adverse effects:

o GI effects ( Nausea, vomiting, and diarrhea) Jaundice, and ototoxicity. primarily with erythromycin

o Newer drugs, azithromycin and clarithromycin: fewer GI adverse effects, longer duration of action, better efficacy, better tissue penetration

Pharmacokinetics:

← Administration: Clarithromycin, and azithromycin, are stable in stomach acid and are readily absorbed. Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin. Erythromycin and azithromycin are available in IV formulations.

← They are distributed well in all tissues except CSF.

← Azithromycin has the longest half-life so it can be given once daily.

← Erythromycin and azithromycin are primarily concentrated and excreted in the bile as active drug. In contrast, clarithromycin and its metabolites are eliminated by the kidney as well as the liver. The dosage of this drug should be adjusted in patients with renal impairment

← Interference with the metabolism of drugs, such as theophylline, statins, and numerous antiepileptics, has been reported for clarithromycin.

Nursing implications:

← These drugs are highly protein-bound and will cause severe interactions with other protein-bound drugs

← The absorption of oral erythromycin is enhanced when taken on an empty stomach, but because of the high incidence of GI upset, many drugs are taken after a meal or snack

← An interaction with digoxin can occur, can lead to higher concentration of digoxin in serum.

2- Tetracyclines:

• Doxycycline.

• Tetracycline.

Antibacterial spectrum:

The tetracyclines are bacteriostatic antibiotics effective against a wide variety of organisms, including gram-positive and gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species. They are commonly used in the treatment of acne and Chlamydia infections (doxycycline).

Pharmacokinetics:

← Tetracyclines are adequately absorbed after oral ingestion. Administration with dairy products or other substances that contain calcium, magnesium and aluminum antacids or iron supplements decreases absorption, particularly for tetracycline, due to the formation of nonabsorbable chelates. Doxycycline is available as oral and intravenous (IV) preparations.

← In renally compromised patients, doxycycline is preferred, as it is primarily eliminated via the bile into the feces.

Adverse effects:

← Gastric discomfort.

← Strong affinity for calcium

o Discoloration of permanent teeth and tooth enamel in fetuses and children, or nursing infants if taken by the mother

o May retard fetal skeletal development if taken during pregnancy.

← Alteration in intestinal flora may result in superinfection (overgrowth of nonsusceptible organisms such as Candida), Diarrhea, and Pseudomembranous colitis.

Contraindication: Should not be used in children under age 8 or in pregnant/lactating women because tooth discoloration will occur if the drug binds to the calcium in the teeth

Nursing implications:

← Avoid milk products, iron preparations, antacids, and other dairy products because of the chelation and drug-binding that occurs

← Take all medications with 6 to 8 ounces of fluid, preferably water

← Because of photosensitivity, avoid sunlight and tanning beds

3- Aminoglycosides:

← Amikacin. Gentamicin.

← Neomycin. Streptomycin.

← Tobramycin.

The three aminoglycosides most commonly used for the treatment of systemic infections are:

• Amikacin, Gentamicin and tobramycin.

Antibacterial spectrum:

The aminoglycosides are effective for the majority of aerobic gram negative bacilli, including those that may be multidrug resistant, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp. Additionally, aminoglycosides are often combined with a β-lactam antibiotic to employ a synergistic effect, particularly in the treatment of Enterococcus faecalis and Enterococcus faecium infective endocarditis.

Pharmacokinetics:

Due to their structure all aminoglycosides (except neomycin) must be given parenterally to achieve adequate serum levels.

Neomycin is not given parenterally due to severe nephrotoxicity. It is administered topically for skin infections or orally for bowel preparation prior to colorectal surgery.

More than 90% of the parenteral aminoglycosides are excreted unchanged in the urine.Accumulation occurs in patients with renal dysfunction, and dose adjustments are required.

Adverse effects:

← Nephrotoxicity (renal damage)

← Ototoxicity (auditory impairment and vestibular impairment [eighth cranial nerve])

← Neuromascular paralysis.

← Skin rash is common with topical neomycin.

Contraindications:

← Known drug allergy.

← The pregnancy categories of these drugs range from C to D.

← Should be avoided in lactating women.

← Should be used with caution in premature, full-term neonates and pediatrics.

Interactions:

← The risk for nephrotoxicity can be increased with concurrent use of other nephrotoxic drugs such as vancomycin, cyclosporine, and amphotericin B. Concurrent use with loop diuretics increases the risk for ototoxicity. Aminoglycosides can potentiate warfarin toxicity.

Serum levels of these drugs are routinely monitored in patient’s blood samples. Dosages are then adjusted to maintain known optimal levels that maximize drug efficacy and minimize the risk for toxicity. This process is known as therapeutic drug monitoring.

Aminoglycoside therapy is commonly monitored in this way due to the nephrotoxicity and ototoxicity associated with these drugs. Most commonly, dosing is adjusted to the patient’s level of renal function, based on estimates of creatinine clearance calculated from serum creatinine values.

Aminoglycosides work primarily through concentration-dependent killing. For this reason, although these drugs were originally given in three daily intravenous doses, the current predominant practice is once-daily aminoglycoside dosing.

Benefits of once daily dosing:

← Provide a sufficient plasma drug concentration for bacterial kill, along with equal or lower risk for toxicity compared with multiple daily dosing regimens.

← Reduces the nursing care time required.

← Trough (lowest) levels are routinely measured to ensure adequate renal clearance of the drug and avoid toxicity. The trough levels above 2mcg/ml are associated with greater risk of ototoxicity and nephrotoxicity.

Nursing implication:

← Monitor peak and trough blood levels of these drugs to prevent nephrotoxicity and ototoxicity

← Symptoms of ototoxicity include dizziness, tinnitus, and hearing loss

← Symptoms of nephrotoxicity include urinary casts, proteinuria, and increased BUN and serum creatinine levels

4- Chloramphenicol.

• Because of its toxicity, its use is restricted to life-threatening infections for which no alternatives exist. Can be given orally or I.V. now used topically.

• Eliminated by liver metabolism.

• Is very effective in typhoid fevers.

• Can lead to anemia.

• In newborn infants, chloramphenicol is less rapidly broken down so that accumulation may occur, producing the so-called ‘grey baby syndrome’ with circulatory collapse and shock.

5- Clindamycin:

Clindamycin is a semisynthetic antibiotic. It can be either bactericidal or bacteriostatic, depending on the concentration of the drug at the site of infection and on the infecting bacteria. It inhibits protein synthesis in bacteria. It is indicated for the treatment of chronic bone infections, genitourinary tract infections, intraabdominal infections, anaerobic pneumonia, septicemia caused and serious skin and soft tissue infections caused by susceptible bacteria.

Clindamycin is contraindicated in infants younger than 1 month of age. Gastrointestinal tract adverse effects are the most common and include nausea, vomiting, abdominal pain, and diarrhea. Pseudomembrenous colitis is often associated with antibiotic therapy, especially clindamycin therapy. It is available in oral, injectable, and topical forms. Lincomycin is antibiotic related to clindamycin

6- Linezolid:

Is a synthetic oxazolidinone, used to treat vancomycin-resistant Enterococcus faecium (VREF, VRE). It is available in oral and injectable forms. The most commonly reported adverse effects are headache, nausea, diarrhea, and vomiting. May cause serotonin syndrome if taken with SSRIs, and tyramine-containing foods

C. Antimetabolite (folic acid antagonists)

Enzymes requiring folate-derived cofactors are essential for the synthesis of purines and pyrimidines (precursors of RNA and DNA) and other compounds necessary for cellular growth and replication. Therefore, in the absence of folate, cells cannot grow or divide. To synthesize the critical folate derivative, tetrahydrofolic acid, humans must first obtain preformed folate in the form of folic acid from the diet. In contrast, many bacteria are impermeable to folic acid and other folates and, therefore, must rely on their ability to synthesize folate.

The sulfonamides (sulfa drugs) are a family of antibiotics that inhibit synthesis of folate. A second type of folate antagonist—trimethoprim—prevents microorganisms from converting dihydrofolic acid to tetrahydrofolic acid, with minimal effect on the ability of human cells to make this conversion. Thus, both sulfonamides and trimethoprim interfere with the ability of an infecting bacterium to perform DNA synthesis. Combining the sulfonamide sulfamethoxazole with trimethoprim (the generic name for the combination is

cotrimoxazole) provides a synergistic combination.

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1- Sulfonamides:

• There are many compounds in the sulfonamide family, only sulfamethoxazole combined with trimethoprim, known as co-trimexazole and often abbreviated as SMX-TMP is used commonly in clinical practice.

• Silver sulfadiazine used topically.

• Sulfasalazine, another sulfonamide, is not used as antibiotic and used to treat ulcerative colitis.

• In addition, sulfadiazine in combination with the dihydrofolate reductase inhibitor pyrimethamine is the preferred treatment for toxoplasmosis.

• Sulfadoxine in combination with pyrimethamine is used as an antimalarial drug.

Indications: Treatment of UTIs caused by susceptible strains and treatment of upper respiratory tract.

Adverse effects: Sulfa allergy, crystalurea, and hemolytic anemia is encountered in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Granulocytopenia and thrombocytopenia can also occur.

Kernicterus: This disorder may occur in newborns, because sulfa drugs displace bilirubin from binding sites on serum albumin. The bilirubin is then free to pass into the CNS, because the blood–brain barrier is not fully developed.

Contraindications:

• Cases of known drug allergy to sulfonamides. Chemically related drugs such as the sulfonylureas, thiazide and loop diuretics, and carbonic anhydrase inhibitors are generally considered relatively safe in patients who has sulfonamide allergy. However, the cyclooxygenase-2 inhibitor celecoxib should not be used.

• Contraindicated in pregnant women at term and in infants younger than 2 months of age.

Ineractions:

Sulfonamides may potentiate the hypoglycemic effects of sulfonylureas in diabetes treatment, the toxic effect of phenytoin, and the anticoagulant effect of warfarin.

Nursing implications:

• Administer oral drug on an empty stomach 1 hour before or 2 hours after meals with a full glass of water to promote adequate absorption of the drug.

• Discontinue immediately if hypersensitivity reactions occur to prevent potentially fatal reactions.Monitor CBC and urinalysis test results before and periodically during therapy to check for adverse effects.

• Provide the following patient teaching:

• Avoid driving or operating dangerous machinery because dizziness, lethargy, and ataxia may occur.

• Try to drink a lot of fluids and maintain nutrition (very important), even though nausea, vomiting, and diarrhea may occur.

• Report difficulty in breathing, rash, ringing in the ears, fever, sore throat, or blood in the urine.

D. Inhibit DNA replication

1- Fluroquinolones:

Antimicrobial spectrum

Fluoroquinolones are bactericidal. In general, fluoroquinolones are effective against gram-negative organisms, atypical organisms (Legionellaceae, Chlamydiaceae), gram-positive organisms (streptococci), and some mycobacteria (Mycobacterium tuberculosis)

Levofloxacin and moxifloxacin are sometimes referred to as “respiratory fluoroquinolones,” because they have excellent activity against S. pneumoniae, which is a common cause of community-acquired pneumonia (CAP). Moxifloxacin also has activity against many anaerobes.

Fluoroquinolones may be classified into “generations” based on their antimicrobial targets.

• First generation: Nalidixic acid (nonfluorinated quinolone with a narrow spectrum of susceptible organisms).

• Second generation: Ciprofloxacin, Norfloxacin, and Ofloxacin (active against aerobic gram-negative and atypical bacteria).

• Third generation: Levofloxacin (increased activity against gram-positive bacteria).

• Fourth generation: Moxifloxacin (against anaerobic and gram-positive organisms).

Mechanism of action:

Quinolone antibiotics destroy bacteria by altering their DNA. They accomplish this by interfering with the bacterial enzymes DNA gyrase and topoisomerase IV. Quinolones do not seem to affect the corresponding mammalian enzymes and therefore do not inhibit the production of human DNA. These drugs kill susceptible strains of mostly gram-negative and some gram-positive organisms.

Indications:

They are suitable for treating complicated urinary tract infections; treat respiratory, skin, gstrointestinal, bone, and joint infections, and sexually transmitted diseases.

Adverse effects:

• In general, these agents are well tolerated.The most common adverse effects of fluoroquinolones are nausea, vomiting, and diarrhea. Headache and dizziness or lightheadedness may occur. Thus, patients with central nervous system (CNS) disorders, such as epilepsy, should be treated cautiously with these drugs.

• Fluoroquinolones can cause phototoxicity, and patients taking these agents should be advised to use sunscreen and avoid excess exposure to sunlight. If phototoxicity occurs, discontinuation of the drug is advisable.

• Articular cartilage erosion (arthropathy) has been observed in immature animals exposed to fluoroquinolones.

• Therefore, these agents should be avoided in pregnancy and lactation and in children under 18 years of age.

• An increased risk of tendinitis or tendon rupture may also occur with systemic fluoroquinolone use.

Interactions: Absorption of ciprofloxacin affected by antacids and milk.

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2- Metronidazole (flagyl):

➢ Used for anaerobic organisms

➢ It works by inerfering with microbial DNA synthesis.

➢ Intraabdominal and gynecologic infections and used for treatment of Protozoal infections

➢ It is available in both oral and injectable forms.

➢ It is classified as a pregnancy category B drug, although it is not recommended for use during the first trimester of pregnancy.

E. Urinary tract antiseptic:

Nitrofurantoin:

➢ Primarily used for UTIs, damage bacterial DNA.

➢ Use carefully if renal function is impaired because the drug concentrates in the urine

➢ May cause rare fatal hepatotoxicity, hemolytic anemia can occur in G6PD deficiency patients.

➢ Usually well-tolerated if patient is kept well-hydrated

➢ The drug is available for oral use only.

Nursing implications for antibiotics:

← Before beginning therapy, assess drug allergies; hepatic, renal, and cardiac function; and other lab studies. Be sure to obtain thorough patient health history, including immune status. Assess for conditions that may be contraindications to antibiotic use or that may indicate cautious use and assess for potential drug interactions

← It is ESSENTIAL to obtain cultures from appropriate sites BEFORE beginning antibiotic therapy

← Instruct patients to take antibiotics exactly as prescribed and for the length of time prescribed; they should not stop taking the medication early when they feel better

← Assess for signs and symptoms of superinfection: fever, perineal itching, cough, lethargy, or any unusual discharge

← For safety reasons, check the name of the medication carefully because there are many drugs that sound alike or have similar spellings

← Each class of antibiotics has specific adverse effects and drug interactions that must be carefully assessed and monitored

← Monitor for therapeutic effects and for adverse reactions

II. Antitubercular drugs:

Tuberculosis:

Tuberculosis TB is the medical diagnosis of any infectious disease caused by a bacterial species known as mycobacterium. TB is most commonly characterized by granulomas in the lungs. These are nodular accumulations of inflammatory cells (e.g., macrophages, lymphocytes) that are delimited (“walled off” with clear boundaries) and have a center that has a cheesy or caseated consistency.

Tuberculosis (TB) caused by Mycobacterium tuberculosis abbreviated MTB are far more common. MTB is an aerobic bacillus. This bacterium’s need for highly oxygenated body sites explains why Mycobacterium infections most commonly affect the lungs. However, other common sites of infection are the growing ends of bones and the brain. Less common sites of infection include the kidney, liver, and genitourinary tract, as well as virtually every other tissue and organ in the body.

These tubercle bacilli (a common synonym for MTB) are conveyed in droplets expelled by infected people or animals during coughing or sneezing and then inhaled by the new host. After these infectious droplets are inhaled, the infection spreads to the susceptible organ sites by means of the blood and lymphatic system. MTB is a very slow-growing organism, which makes it more difficult to treat than most other bacterial infections.

Many of the antibiotics used to treat TB work by inhibiting growth rather than by directly killing the organism. The reason is that microorganisms that grow more slowly are more difficult to kill because their cells are not as metabolically active as those of the faster-growing organisms. Most bactericidal drugs work by disrupting critical cellular processes in the organisms are those with faster (not slower) metabolic activity.

Pharmacology overview:

Antitubercular Drugs:

TB treatment generally includes four first-line drug. Second-line drugs are typically less effective, more toxic, and less extensively studied. They are used for patients who cannot tolerate the first-line drugs or who are infected with resistant TB.

First-line drugs

• isoniazid (INH)*

• ethambutol

• pyrazinamide (PZA)

• rifapentine

• rifabutin

• rifampin

*Primary drug used

← Second-line drugs (reserved for more complicated cases, such as those resistant to primary drugs)

• capreomycin

• amikacin

• cycloserine

• levofloxacin

• ethionamide

• ofloxacin

• kanamycin

• para-aminosalicyclic acid (PAS)

← M. tuberculosis is slow growing and requires treatment for months to years. Latent TB can be treated for 9 months with isoniazid (INH) monotherapy or with 12 once-weekly doses of INH (900 mg) and rifapentine (900 mg). In contrast, active TB disease must be treated with several drugs. Treatment for drug-susceptible TB lasts for at least 6 months, while treatment of multidrug-resistant TB (MDR-TB) typically lasts for about 2 years.

The antimycobacterial activity, efficacy, and potential adverse and toxic effects of the various drugs determine the class to which they belong. Isoniazid is a primary antituberculur drug and is most widely used. It can be administered either as the sole drug in the prophylaxis of TB or in combination with other antituberculur drugs in the treatment of TB. An important consideration during drug selection is the relative likelihood of drug-resistant organisms and drug toxicity. Following are other key elements that are important in the planning and implementation of effective therapy:

• Drug-susceptibility tests should be performed on the first mycobacterium species that is isolated from a patient specimen (to prevent the development of MDR-TB). Even before the results of susceptibility tests are known, begin a regimen with multiple antitubercular drugs (to reduce chances of development of resistance)

• Adjust drug regimen once the results of susceptibility testing are known

• Monitor patient compliance closely during therapy

• Problems with successful therapy occur because of patient nonadherence to drug therapy and the increased incidence of drug-resistant organisms

The major effects of drug therapy include reduction of cough and, therefore, reduction of the infectiousness of the patent. This normally occurs within 2 weeks of the initiation of drug therapy, assuming that the patient’s TB strain is drug sensitive.

Antitubercular therapy:

← Effectiveness depends upon:

➢ Type of infection. Adequate dosing. Sufficient duration of treatment. Adherence to drug regimen and selection of an effective drug combination

1- Isoniazide INH: Drug of choice for TB. Resistant strains of Mycobacterium emerging

← Isoniazid is readily absorbed after oral administration. Absorption is impaired if isoniazid is taken with food, particularly high-fat meals. The drug diffuses into all body fluids, cells, and caseous material (necrotic tissue resembling cheese that is produced in tuberculous lesions). Drug concentrations in the cerebrospinal fluid (CSF) are similar to those in the serum. Isoniazid metabolized in liver to inactive products. Excretion is through glomerular filtration and secretion, predominantly as metabolites. Isoniazide contraindicated with liver disease

← Adverse effects: Peripheral neuropathy appears to be due to a relative pyridoxine deficiency. This can be avoided by supplementation of 25 to 50 mg per day of pyridoxine (vitamin B6)., hepatotoxicity, Central nervous system (CNS) adverse effects can occur, including convulsions in patients prone to seizures. Hypersensitivity reactions with isoniazid include rashes and fever.

2-Rifamycins: rifampin, rifabutin, and rifapentine

Rifampin: Rifampin has broader antimicrobial activity than isoniazid and can be used as part of treatment for several different bacterial infections. Because resistant strains rapidly emerge during monotherapy, it is never given as a single agent in the treatment of active tuberculosis.

Pharmacokinetics: Absorption is adequate after oral administration. Distribution of rifampin occurs to all body fluids and organs. Concentrations attained in the CSF are variable, often 10% to 20% of blood concentrations. The drug is taken up by the liver and undergoes enterohepatic recycling.

Rifampin undergoes autoinduction, leading to a shortened elimination half-life over the first 1 to 2 weeks of dosing. Elimination of rifampin and its metabolites is primarily through the bile and into the feces; a small percentage is cleared in the urine.Urine, feces, and other secretions have an orange-red color, so patients should be forewarned. Tears may even stain soft contact lenses orange-red.

Adverse effects: Rifampin is generally well tolerated. The most common adverse reactions include nausea, vomiting, and rash. Hepatitis and death due to liver failure are rare. There is a modest increase in the incidence of hepatic dysfunction when rifampin is coadministered with isoniazid. When rifampin is dosed intermittently, especially with doses of 1.2 g or greater, a flu-like syndrome can occur, with fever, chills, and myalgia, sometimes extending to acute renal failure, hemolytic anemia, and shock.

3-Pyrazinamide

Pyrazinamide is a synthetic, orally effective short course agent used in combination with isoniazid, rifampin, and ethambutol. The precise mechanism of action is unclear. The drug distributes throughout the body, penetrating the CSF. Pyrazinamide may contribute to liver toxicity. Uric acid retention is common but rarely precipitates a gouty attack. Most of the clinical benefit from pyrazinamide occurs early in treatment. Therefore, this drug is usually discontinued after 2 months of a 6-month regimen.

4- Ethambutol

Ethambutol bacteriostatic and specific for mycobacteria. Inhibit synthesis of the mycobacterial cell wall. Ethambutol is well distributed throughout the body. Penetration into the CNS is minimal. Both the parent drug and metabolites are primarily excreted in the urine. The most important adverse effect is optic neuritis, which results in diminished visual acuity and loss of ability to discriminate between red and green. The risk of optic neuritis increases with higher doses and in patients with renal impairment. Visual acuity and color discrimination should be tested prior to initiating therapy and periodically thereafter.

Nursing implications:

← Obtain a thorough medical history and assessment

← Perform liver function studies in patients who are to receive isoniazid or rifampin

(especially in elderly patients or those who use alcohol daily)

← Assess for contraindications to the various drugs, conditions for cautious use, and potential drug interactions

Patient education is critical

← Therapy may last for up to 24 months

← Take medications exactly as ordered, at the same time every day

← Emphasize the importance of strict adherence to regimen for improvement of condition or cure

← Remind patients that they are contagious during the initial period of their illness—instruct in proper hygiene and prevention of the spread of infected droplets

← Teach patients to take care of themselves, including adequate nutrition and rest

← Patients should not consume alcohol while on these medications or take other medications, including over-the-counter medications, unless they check with their physician

← Rifampin causes oral contraceptives to become ineffective; another form of birth control will be needed

← Patients who are taking rifampin should be told that their urine, stool, saliva, sputum, sweat, or tears may become reddish orange; even contact lenses may be stained

← Pyridoxine may be needed to combat neurologic adverse effects associated with INH therapy

← Oral preparations may be given with meals to reduce GI upset, even though recommendations are to take them 1 hour before or 2 hours after meals

Monitor for adverse effects

← Instruct patients on the adverse effects that should be reported to the physician immediately

← These include fatigue, nausea, vomiting, numbness and tingling of the extremities, fever, loss of appetite, depression, jaundice

Monitor for therapeutic effects

← Decrease in symptoms of TB, such as cough and fever

← Lab studies (culture and sensitivity tests) and CXR should confirm clinical findings

← Watch for lack of clinical response to therapy, indicating possible drug resistance

III. Antifungal Drugs:

Fungal infections:

Fungi are a very large and diverse group of microorganisms. Some fungi are part of the normal flora of the skin, mouth, intestines, and vagina.

Fungi differ from bacteria in that the fungus has a rigid cell wall that is made up of chitin and various polysaccharides and a cell membrane that contains ergosterol. The composition of the protective layers of the fungal cell makes the organism resistant to antibiotics. Conversely, because of their cellular makeup, bacteria are resistant to antifungal drugs.

The infection caused by a fungus is called a mycosis. A variety of fungi can cause clinically significant infections or mycoses. These are called pathologic fungi, and the infections they cause range in severity from mild infections with annoying symptoms to systemic mycoses that can become life threatening. These infections are acquired by various routes: the fungi can be ingested orally; they can grow on or in the skin, hair, or nails; and, if the fungal spores are airborne, they can be inhaled.

Fungal integumentary infections known as dermatomycoses.

The most severe systemic infections are generally affect people whose host immune defenses are compromised.

In addition, the use of antibiotic therapy, antineoplastics, or immunosuppressants (corticosteroids) may result in colonization of Candida albicans, followed by development of a systemic infection. When the infection affects the mouth is called thrush or oral candidiasis. Oral candidiasis common in newborn infants and immunocompromised patients. Vaginal candidiasis, commonly called a “Yeast infection”, often affects pregnant women, women with diabetes mellitus, women taking oral contraceptives and antibiotics.

Antifungal drugs:

← Drugs used to treat infections caused by fungi

➢ Systemic

➢ Topical

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1- Systemic antifungals:

The drugs used to treat fungal infections are called antifungal drugs. Systemic mycotic infections and some dermatomycoses are treated with oral or parenteral drugs. There are few such drugs because the fungi that cause these infections have proved to be very difficult to kill.

• Polyenes: Amphotericin B.

• Azoles: fluconazole, ketoconazole, itraconazole.

• Griseofulvin.

• Flucytosine.

• Caspofungin.

a. Amphotericin B:

In spite of its toxic potential, amphotericin B remains the drug of choice for the treatment of several life-threatening mycoses.

Mechanism of action:

The polyenes act by binding to sterols in the cell membranes of fungi. The main sterol in fungal membranes is ergosterol. Human cell membranes have cholesterol instead of ergosterol. Once the drug molecule binds to the ergosterol, a channel forms in the fungal cell membrane that allows potassium and magnesium ions to leak out of the fungal cell. This loss of ions causes fungal cellular metabolism to be altered, which leads to death of the cell.

Indications:

Amphotericin B is effective against a wide range of fungi. It is sometimes given with flucytosine for treatment of candida and cryptococcal infections because of the synergy of the two drugs.

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Pharmacokinetics:

Amphotericin B is administered by slow, intravenous (IV) infusion. Amphotericin B is extensively bound to plasma proteins and is distributed throughout the body. Inflammation favors penetration into various body fluids, but little of the drug is found in the CSF, vitreous humor, or amniotic fluid. However, amphotericin B does cross the placenta.

Adverse effects:

➢ General adverse effects: have included reactions during infusions. These have included fevers, chills, and rigors in 50% of patients during intravenous administration. The intensity of these acute, infusion-related side effects usually decreased over time, and have been lessened by pretreatment with corticosteroids, nonsteroidal anti-inflammatory drugs, antihistamines, and meperidine.

➢ Renal side effects.

➢ Gastrointestinal side effects.

➢ Hypotension associated with hypokalemia.

b. Flucytosine (5-flurocytosine)

Mechanism of action:

• Taken up by fungal cells and interferes with DNA synthesis

• Result: fungal cell death

• Older drug; newer drugs are more commonly used

• Can be used as combination with amphotericin B for synergestic effect.

c. Griseofulvin:

Mechanism of action:

o It enters the fungal cell through an energy-dependent transport system and inhibits cell division.

o Disrupts cell division

o Result: inhibited fungal mitosis (reproduction)

o Older drug; newer drugs are more commonly used

← Is administered orally in the treatment of various fungal infections.

← Griseofulvin induces hepatic cytochrome P450 activity

d. Azoles:

Mechanism of action:

They are most effective in combating rapidly growing fungi and work by inhibiting fungal cell cytochrome P-450 enzymes. These enzymes are needed to produce ergosterol. When the production of ergosterol is inhibited, this lead to a leaky cell membrane that allows needed electrolytes to escape. The fungal cells die because they cannot carry on cellular metabolism.

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1- Fluconazole can pass into Cerebrospinal fluid CSF and inhibit the growth of cryptococcal fungi. This makes it effective in the treatment of cryptooccal meningitis and active against oropharyngeal and vaginal candida infections. It is available in both oral and injectable forms. Nausea, vomiting, and rashes are a problem.

2- Itraconazole is capable of only poor CSF penetration but can be widely distributed throughout other areas of the body. Is with a broad antifungal spectrum and used orally and locally. Is extensively metabolized by the liver. Adverse effects: Nausea, vomiting, rash, edema, and headache.

3- Ketoconazole was the first orally active azole available for the treatment of systemic mycoses. It is given orally and topically. The most common side effects are jaundice, nausea, drowsiness and rarely adrenal suppression.

e. Terbinafine:

← Terbinafine inhibits fungal squalene epoxidase, thereby decreasing the synthesis of ergosterol.

Terbinafine is used in a systemic oral form (available in tablet form) for treatment of onchomycoses-fungal infections of the fingernails or toenails..

Topical forms of terbinafine are also used for various skin infections. It is available in a topical cream, gel, and spray for treating dermatologic infections.

Contraindications

← Liver failure

← Renal failure

← Drug allergy

Interactions

← Many antifungal drugs are metabolized by the cytochrome P-450 enzyme system

← Co-administration of two drugs that are metabolized by this system may result in competition for these enzymes, and thus higher levels of one of the drugs

2- Topical antifungal drugs:

Fungi that cause these mycoses are called dermatophytes. These diseases include a variety of tinea infections, which are often referred to as ringworm, although the causal organism is a fungus, not a worm.

These mycoses include tinea infections such as athlete’s foot (tinea pedis), jock itch (tinea cruris), and yeast infections of the mouth and vagina often caused by Candida. Because the antifungal drugs reserved for use as topical agents are often too toxic for systemic administration, care is necessary when using them near open or draining wounds that might permit systemic absorption.

Candida infections are most commonly caused by candida abicans, a yeastlike opportunistic fungus present in the normal flora of the mouth, vagina, and intestinal tract. Because these infections favor warm, moist areas of the skin and mucous membranes, they most commonly occur orally, vaginally, and cutaneously in sites such as beneath the breasts and in diapered areas. They may also cause nail infections.

Many of the fungi that cause topical infections are very difficult to eradicate. The organisms are very slow growing, and antifungal therapy may be prolonged from several weeks to 1 year. Systemically administered antifungal drugs are sometimes used to treat skin conditions as well. The most commonly reported adverse effects of topical antifungals are local irritation, pruritis, and scaling.

← Clotrimazole.

➢ Vaginal suppository or cream for yeast infections

➢ Other forms like cream used for other fungal infections

← Miconazole.

➢ Topical cream

➢ Vaginal suppository or cream

← Nystatin:

➢ As oral drops, but is poorly absorbed orally, it is used topically to treat oral candidiasis.

➢ Binds to the wall of the fungus, disrupting its integrity.

➢ Used topically to treat vaginal candida (v.Supp) and topically as skin cream.

← Ciclopirox:

← Used as shampoo, gel, or spray.

Nursing implications:

← Before beginning therapy, assess for hypersensitivity, possible contraindications, and conditions that require cautious use

← Obtain baseline VS, CBC, liver and renal function studies, and ECG

← Assess for other medications used (prescribed and over-the-counter) so as to avoid drug interactions

← Follow manufacturer’s directions carefully for reconstitution and administration

← Monitor vital signs of patients receiving IV infusions every 15 to 30 minutes

← During IV infusions, monitor I&O to identify adverse effects

← amphotericin B

← To reduce the severity of the infusion-related reactions, pretreatment with an antipyretic (acetaminophen), antihistamines, antiemetics, and corticosteroids may be given

← Use IV infusion pumps and the most distal veins possible

← Some oral forms should be given with meals to decrease GI upset; others require an empty stomach—be sure to check

← Monitor for therapeutic effects

IV. Antiprotozoal drugs.

Because they are unicellular eukaryotes, the protozoal cells have metabolic processes closer to those of the human host than to prokaryotic bacterial pathogens. Therefore, protozoal diseases are less easily treated than bacterial infections, and many of the antiprotozoal drugs cause serious toxic effects in the host, particularly on cells showing high metabolic activity. Most antiprotozoal agents have not proven to be safe for pregnant patients.

Parasitic protozoa: live in or on humans

• Malaria

• Amebiasis

• Giardiasis

• Leishmaniasis.

• Toxoplasmosis.

Chemotherapy for malaria:

• Malaria is an acute infectious disease caused by four different Plasmodium species that are P.vivax, P.flaciparum, P.malariae, P.ovale. The P.flaciparum and p.vivax are the most common. Cause: the bite of an infected adult female anopheles mosquito

• Can also be transmitted by infected individuals via blood transfusion, congenitally, or from infected needles by drug abusers

• Diagnosis must be confirmed with laboratory testing and the susceptibility of infecting parasites are determined by geographic location

Malaria Parasite (Plasmodium):

Two interdependent life cycles

➢ Sexual cycle: occurs in the mosquito

➢ Asexual cycle: occurs in the human

o Knowledge of the life cycles is essential in understanding antimalarial drug treatment

o Drugs are effective only during the asexual cycle

Asexual cycle: two phases. Erythrocytes = RBCs

➢ Exoerythrocytic phase: Occurs “outside” the erythrocyte, also known as the tissue phase

➢ Erythrocytic phase: Occurs “inside” the erythrocyte, also known as the blood phase

Malaria signs and symptoms are often described in terms of the classic malaria paroxysm. A paroxysm is a sudden recurrence or intensification of symptoms. Symptoms include chills and rigors, followed by fevers of up to 40 C and diaphoresis, frequently leading to extreme fatigue and prolonged sleep. This syndrome often repeats itself periodically in 48-72-hour cycles. Other common symptoms include headache, nausea, and joint pain.

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Antimalarial Drugs:

Antimalarial drugs are usually given in combination form to attack the Plasmodium at various stages of its life cycle. Using this approach, it is possible to prevent the acute malarial reaction in individuals who have been infected by the parasite. Quinine (generic) was the first drug found to be effective in the treatment of malaria; it is no longer available.

Antimalarials used today include:

➢ Chloroquine

➢ Hydroxychloroquine.

➢ Mefloquine.

➢ Primaquine.

➢ Pyrimethamine.

o Erythrocytic phase drugs: chloroquine, hydroxychloroquine, mefloquine, pyrimethamine

o Primaquine: Only exoerythrocytic drug

A. Primaquine

Primaquine, is an oral antimalarial drug that eradicates exoerythrocytic (tissue) forms of Plasmodia. [Note: Primaquine is the only agent that prevents relapses of the P. vivax and P. ovale malarias, which may remain in the liver in the exoerythrocytic form after the erythrocytic form of the disease is eliminated.]

The sexual (gametocytic) forms of all four plasmodia are destroyed in the plasma or are prevented from maturing later in the mosquito, thereby interrupting transmission of the disease. [Note: Primaquine is not effective against the erythrocytic stage of malaria and, therefore, is used in conjunction with agents to treat the erythrocytic form (for example, chloroquine and mefloquine).]

B. Chloroquine

Chloroquine is a synthetic 4-aminoquinoline that has been the mainstay of antimalarial therapy, and it is the drug of choice in the treatment of erythrocytic P. falciparum malaria, except in resistant strains. Chloroquine is less effective against P. vivax malaria. It is highly specific for the asexual form of plasmodia. Chloroquine is used in the prophylaxis of malaria for travel to areas with known chloroquine-sensitive malaria. [Note: Hydroxychloroquine is an alternative to chloroquine for the prophylaxis and treatment of chloroquine-sensitive malaria.] It is also effective in the treatment of extraintestinal

amebiasis.

C. Atovaquone–proguanil

The combination of atovaquone–proguanil is effective for chloroquine-resistant strains of P. falciparum, and it is used in the prevention and treatment of malaria. Atovaquone

inhibits mitochondrial processes such as electron transport, as well as ATP and pyrimidine biosynthesis. Cycloguanil, the active metabolite of proguanil, inhibits plasmodial dihydrofolate reductase, thereby preventing DNA synthesis.

The combination should be taken with food or milk to enhance absorption. Common adverse effects include nausea, vomiting, abdominal pain, headache, diarrhea, anorexia, and dizziness.

D. Mefloquine

Mefloquine is an effective single agent for prophylaxis and treatment of infections caused by multidrug-resistant forms of P. falciparum. Its exact mechanism of action remains undetermined.

Because of the potential for neuropsychiatric reactions, mefloquine is usually reserved for treatment of malaria when other agents cannot be used. ECG abnormalities and cardiac arrest are possible if mefloquine is taken concurrently with quinine or quinidine.

E. Pyrimethamine

Pyrimethamine inhibits plasmodial dihydrofolate reductase required for the synthesis of tetrahydrofolate (a cofactor needed for synthesis of nucleic acids). It acts as a blood schizonticide and a strong sporonticide when the mosquito ingests it with the blood of the human host. Pyrimethamine is not used alone for P. falciparum; it is available as a fixed-dose combination with sulfadoxine. Resistance to this combination has developed, so it is usually administered with other agents, such as artemisinin derivatives.

Sulfonamides, tetracyclines, clindamycin Used in combination with antimalarials to increase protozoacidal effects

Drug effects: Kill parasitic organisms

← Hydroxychloroquine also has antiinflammatory effects and used for rheumatoid arthritis and systemic lupus erythematosus

Other protozoal infections:

• Amebiasis

• Giardiasis

• Toxoplasmosis

• Leshmaniasis.

1- Amebiasis:

Amebiasis (also called amebic dysentery) is an infection of the intestinal tract caused by Entamoeba histolytica. The disease can be acute or chronic, with varying degrees of illness, from no symptoms to mild diarrhea to fulminating dysentery. The diagnosis is established by isolating E. histolytica from feces.

Therapeutic agents for amebiasis are classified as luminal, systemic, or mixed amebicides according to the site of action.

A. Mixed amebicides

1. Metronidazole:

Metronidazole is the mixed amebicide of choice for treating amebic infections. [Note: Metronidazole is also used in the treatment of infections caused by Giardia lamblia, Trichomonas vaginalis,

anaerobic cocci, and anaerobic gram-negative bacilli and is the drug of choice for the treatment of pseudomembranous colitis caused by the anaerobic, gram-positive bacillus Clostridium difficile.]

Mechanism of action: Disruption of DNA synthesis as well as nucleic acid synthesis

Pharmacokinetics:

Metronidazole is completely and rapidly absorbed after oral administration. [Note: For the treatment of

amebiasis, it is usually administered with a luminal amebicide, such as iodoquinol or paromomycin. This combination provides cure rates of greater than 90%.] Therapeutic levels can be found in vaginal and seminal fluids, saliva, breast milk, and cerebrospinal fluid (CSF). Metabolism of the drug occurs in liver. The drug accumulates in patients with severe hepatic disease. The parent drug and its metabolites are excreted in the urine.

Adverse effects: The most common adverse effects are nausea, vomiting, epigastric distress, and abdominal cramps. An unpleasant, metallic taste is commonly experienced.

2. Tinidazole: Tinidazole is similar to metronidazole in spectrum of activity, absorption, adverse effects, and drug interactions. It is used for treatment of amebiasis, amebic liver abscess, giardiasis, and trichomoniasis.

← Metronidazole:

• In mild symptoms oral metronidazole  500 to 750 mg tid in adults (12 to 17 mg/kg tid in children) for 7 to 10 days is recommended.

• Severe intestinal and extraintestinal amebiasis 750 mg tid in adults (12 to 17 mg/kg tid in children) for 7 to 10 days is used.

← Tinidazole:

• In mild symptoms tinidazole 2 g po once/day in adults for 3 days can be used.

• Severe intestinal and extraintestinal amebiasis,  tinidazole  2 g po once/day in adults for 5 days can be used.

B. Luminal amebicides

After treatment of invasive intestinal or extraintestinal amebic disease is complete, a luminal agent, such as iodoquinol, diloxanide furoate, or paromomycin, should be administered for treatment of the asymptomatic colonization state.

C. Systemic amebicides

These drugs are useful for treating liver abscesses and intestinal wall infections caused by amebas.

Chloroquine and Dehydroemetine:

2- GIARDIASIS

Giardia lamblia has two life cycle stages: the binucleate trophozoite with four flagella and the drug-resistant, four-nucleate cyst. Ingestion, usually from contaminated drinking water, leads to infection. The trophozoites exist in the small intestine and divide by binary fission. Occasionally, cysts are formed that pass out in stools. Although some infections are asymptomatic, severe diarrhea can occur, which can be very serious in immunocompromised patients. The treatment of choice metronidazole one alternative is tinidazole.

Metronidazole: 250 mg po tid in adults (5 mg/kg po tid in children) for 5 to 7 days can be used.

Tinidazole: 2 g once in adults is as effective as and less toxic than metronidazole.

3- Leishmaniasis:

There are three types of leishmaniasis: cutaneous, mucocutaneous, and visceral. [Note: In the visceral type (liver and spleen), the parasite is in the bloodstream and can cause very serious problems.] Leishmaniasis is transmitted from animals to humans (and between humans) by the bite of infected sandflies. The diagnosis is established by demonstrating the parasite in biopsy material and skin lesions. For visceral leishmaniasis, parenteral treatments may include amphotericin B and pentavalent antimonials, such as sodium stibogluconate. Miltefosine is an orally active agent for visceral leishmaniasis.

Sodium stibogluconate

The exact mechanism of action has not been determined. Because it is not absorbed after oral administration, sodium stibogluconate must be administered parenterally.Metabolism is minimal, and the drug is excreted in urine. Adverse effects include injection site pain, pancreatitis, elevated liver enzymes, arthralgias, myalgias, gastrointestinal upset, and cardiac arrhythmias. Renal and hepatic function should be monitored periodically.

4- Toxoplasmosis:

One of the most common infections in humans is caused by the protozoan T. gondii, which is transmitted to humans when they consume raw or inadequately cooked infected meat. An infected pregnant woman can transmit the organism to her fetus. Cats are the only animals that shed oocysts, which can infect other animals as well as humans.

The treatment of choice for this condition is a combination of sulfadiazine and pyrimethamine. Leucovorin is commonly administered to protect against folate deficiency.

Pyrimethamine with clindamycin, or the combination of trimethoprim and sulfamethoxazole, are alternative treatments.

V. Anthelmintic Drugs:

• Drugs used to treat parasitic worm infections: helminthic infections

• Unlike protozoa, helminths are large and have complex cellular structures

• Drug treatment is very specific to the organism.

• It is VERY IMPORTANT to identify the causative worm this is done by finding the parasite ova or larvae in feces, urine, blood, sputum, or tissue

Worms:

← Cestodes (tapeworms)

← Nematodes (roundworms)

← Trematodes (flukes)

← Platyhelminthes (flatworms)

Disease we will discuss here:

• Pinworms.

• Tapeworms.

• Ascariasis.

a- Pin worms:

← They live in gut and females migrate to anus where they lay eggs and provoke itching.

← Due to itching hands becoming contaminated with eggs which then transferred to food.

← Cleanliness is important in treatment.

← Whole family of an infected patient must be examined to infestation and may need to eradicate worms from whole family.

Treatment:

← Mebendazole:

• Given as a single dose 100mg and repeated after 2 weeks.

• Shouldn’t be given to children under 2 years.

• Side effects rarely occur like nausea and diarrhea.

← Albendazole: As a single dose 400mg and repeated after 2 weeks.

← Mebendazole (Vermox)

o Inhibits uptake of glucose and other nutrients, leading to autolysis and death of the parasitic worm

b- Tape worms:

Treatment: Praziquantel give as single dose.

← praziquantel (Biltricide)

➢ Paralyzes worms’ musculature and immobilizes their suckers this causes worms to dislodge from mesenteric veins to the liver; then killed by host tissue reactions

c- Ascariasis:

Treatment is achieved by:

✓ Mebendazole 100mg bid for 3 days.

✓ Albendazole 400mg once as a single dose.

[pic]

Adverse effects:

← Vary with each drug.

← Common adverse effects

➢ Nausea

➢ Vomiting

➢ Diarrhea

➢ Dizziness

➢ Headache

← Effects with use of mebendazole: Possible myelosuppression

Nursing implications:

← Before beginning therapy, perform a thorough health history and medication history, and assess for allergies

← Be sure to collect specimens before beginning drug therapy

← Check baseline vital signs

← Check for conditions that may contraindicate use, and for potential drug interactions

← Some drugs may cause the urine to have an asparagus-like odor, or cause an unusual skin odor or a metallic taste; be sure to warn the patient ahead of time

← Administer all drugs as ordered and for the prescribed length of time

← Most drugs should be taken with food to reduce GI upset

← Antimalarial Drugs:

← When used for prophylaxis, these drugs should be started 1 to 2 weeks before potential exposure to malaria, and for 4 weeks after leaving the area. Medications are taken weekly, with 8 ounces of water

← Instruct patient to notify physician immediately if ringing in the ears, hearing decrease, visual difficulties, nausea, vomiting, profuse diarrhea, or abdominal pain occurs

← Alert patient to the possible recurrence of the symptoms of malaria so that he or she will know to seek immediate treatment

VI. Antiviral drugs:

Viruses cause a variety of conditions, ranging from warts, to the common cold and “flu,” to diseases such as chickenpox and measles. A single virus particle is composed of a piece of DNA or RNA inside a protein coat. To carry on any metabolic processes, including replication, a virus must enter a cell. Once a virus has fused with a cell wall and injected its DNA or RNA into the host cell, that cell is altered—that is, it is “programmed” to control the metabolic processes that the virus needs to survive. The virus, including the protein coat, replicates in the host cell. When the host cell can no longer carry out its own metabolic functions because of the viral invader, the host cell dies and releases the new viruses into the body to invade other cells.

Therapy for viral diseases is further complicated by the fact that the clinical symptoms appear late in the course of the disease, at a time when most of the virus particles have replicated. At this stage of viral infection, administration of drugs that block viral replication has limited effectiveness. However, some antiviral agents are useful as prophylactic agents. The few virus groups that respond to available antiviral drugs are discussed in this chapter. To assist in the review of these drugs, they are grouped according to the type of infection they target.

1- AGENTS FOR INFLUENZA A AND RESPIRATORY VIRUSES

Influenza A and other respiratory viruses, including influenza B and respiratory syncytial virus (RSV), invade the respiratory tract and cause the signs and symptoms of respiratory “flu.” Vaccines have been developed to stimulate immunity against influenza A and RSV. Preventing the viral infection is the best option, but if patients do develop a viral infection, some drug therapies are available.

Agents for Influenza A and respiratory viruses include:

• Amantadine.

• Oseltamivir (Tamiflu).

• Ribavirin (Virazole).

• Nimantadine.

• Zanamivir (Relenza)

2- AGENTS FOR HERPES AND CYTOMEGALOVIRUS

Herpes viruses account for a broad range of conditions, including cold sores, encephalitis, shingles, and genital infections. Cytomegalovirus (CMV), although slightly different from the herpes virus, can affect the eye, respiratory tract, and liver and reacts to many of the same drugs.

Antiviral drugs used to combat these infections include:

• Aacyclovir (Zovirax)

• Cidofovir.

• Famciclovir (Famvir).

• Foscarnet (Foscavir),

• Ganciclovir (Cytovene).

• Valacyclovir (Valtrex).

• Valganciclovir (Valcyte).

3- TREATMENT OF HEPATIC VIRAL INFECTIONS

The hepatitis viruses thus far identified (A, B, C, D, and E) each have a pathogenesis specifically involving replication in and destruction of hepatocytes. Of this group, hepatitis B (a DNA virus) and hepatitis C (an RNA virus) are the most common causes of chronic hepatitis, cirrhosis, and

hepatocellular carcinoma and are the only hepatic viral infections for which therapy is currently available. [Note: Hepatitis A is a commonly encountered infection caused by oral ingestion of the virus, but it is not a chronic disease.]

Chronic hepatitis B may be treated with peginterferon-α-2a, which is injected subcutaneously once weekly. [Note: Interferon-α-2b injected intramuscularly or subcutaneously three times weekly is also useful in the treatment of hepatitis B, but peginterferon-α-2a has similar or slightly better efficacy with improved tolerability.]

Oral therapy for chronic hepatitis B includes:

• Lamivudine.

• Adefovir.

• Entecavir.

• Tenofovir.

• Telbivudine.

The preferred treatment for chronic hepatitis C is the combination of peginterferon-α-2a or peginterferon-α-2b plus ribavirin, which is more effective than the combination of standard interferons and ribavirin. For genotype 1 chronic hepatitis C virus (HCV), an NS3/4A protease inhibitor (such as boceprevir or telaprevir) should be added to pegylated interferon and ribavirin.

Drugs:

1- Acyclovir

Acyclovir is the prototypic antiherpetic therapeutic agent. Herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), and some Epstein-Barr virus–mediated infections are sensitive to acyclovir. It is the treatment of choice in HSV encephalitis. The most common use of acyclovir is in therapy for genital herpes infections. It is also given prophylactically to seropositive patients before bone marrow transplant and post–heart transplant to protect such individuals from herpetic infections.

Pharmacokinetics: Acyclovir is administered by intravenous(IV), oral, or topical routes. [Note: The efficacy of topical applications is questionable.] The drug distributes well throughout the body, including the cerebrospinal fluid (CSF). Acyclovir is partially metabolized to an inactive product. Excretion into the urine occurs both by glomerular filtration and tubular secretion. Acyclovir accumulates in patients with renal failure.

Adverse effects: Side effects of acyclovir treatment depend on the route of administration. For example, local irritation may occur from topical application; headache, diarrhea, nausea, and vomiting may result after oral administration. Transient renal dysfunction may occur at high doses or in a dehydrated patient receiving the drug intravenously.

2- Ganciclovir

Ganciclovir is an analog of acyclovir that has greater activity against CMV. It is used for the treatment of CMV retinitis in immunocompromised patients and for CMV prophylaxis in transplant patients.

3- Interferons

Interferons are a family of naturally occurring, inducible glycoproteins that interfere with the ability of viruses to infect cells. The interferons are synthesized by recombinant DNA technology. At least three types of interferons exist—α, β, and γ.

Pharmacokinetics: Interferon is not active orally, but it may be administered intralesionally, subcutaneously, or intravenously. Cellular uptake and metabolism by the liver and kidney account for the disappearance of interferon from the plasma. Negligible renal elimination occurs.

Adverse effects: Adverse effects include flu-like symptoms, such as fever, chills, myalgias, arthralgias, and GI disturbances. Fatigueand mental depression are common. These symptoms subside with continued administration.

The principal dose-limiting toxicities are bone marrow suppression, severe fatigue and weight loss, neurotoxicity characterized by somnolence and behavioral disturbances, autoimmune disorders such as thyroiditis and, rarely, cardiovascular problems such as heart failure.

[pic]

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Systemic antifungals:

• Amphotericin B.

• Caspofungin.

• Flucytosine.

• Griseofulvin.

• Terbinafine.

• Azoles:

➢ Fluconazole.

➢ Itraconazole.

➢ Ketoconazole.

Topical antifungals:

• Azoles:

➢ Clotrimazole.

➢ Itraconazole.

➢ Ketoconazole.

➢ Miconazole.

• Ciclopirox.

• Nystatin.

• Terbinafine.

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