CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AGENTS

1. CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AGENTS

2. BASIC QUESTIONS Clinical pharmacology of main groups of antibiotics Problems of antibiotic resistance Clinical pharmacology of sulfonamides Clinical pharmacology of fluoroquinolones

3. Infectious diseases Due to constant changes in our lifestyles and environments, there are constantly new diseases that people are susceptible to, making protection from the threat of infectious disease urgent. Many new contagious diseases have been identified in the past 30 years, such as AIDS, Ebola, and hantavirus. Increased travel between continents makes the worldwide spread of disease a bigger concern than it once was. Additionally, many common infectious diseases have become resistant to known treatments.

4. ANTIBACTERIAL DRUGS. Mechanisms of Action 1. Inhibition of bacterial cell wall synthesis or activation of enzymes that disrupt bacterial cell walls (eg, penicillins, cephalosporins, vancomycin) 2. Inhibition of protein synthesis by bacteria or production of abnormal bacterial proteins (eg, aminoglycosides, clindamycin, erythromycin, tetracyclines). These drugs bind irreversibly to bacterial ribosomes, intracellular structures that synthesize proteins. When antimicrobial drugs are bound to the ribosomes, bacteria cannot synthesize the proteins necessary for cell walls and other structures. 3. Disruption of microbial cell membranes (eg, antifungals) 4. Inhibition of organism reproduction by interfering with nucleic acid synthesis (eg, fluoroquinolones, rifampin, anti–acquired immunodeficiency syndrome antivirals) 5. Inhibition of cell metabolism and growth (eg, sulfonamides, trimethoprim)

5. Actions of antibacterial drugs on bacterial cells •

6. Beta-Lactam Antibiotics PenicillinsThe penicillins are classified as BETA-lactam drugs because of their unique four-memberedlactam ring.They share features of chemistry, mechanism of action, pharmacologic and clinical effects, andimmunologic characteristics with cephalosporins, monobactams, carbapenems, and -lactamaseinhibitors, which also are -lactam compounds.

7. A penicillin culture

8. Clinical indications for use of penicillins include bacterial infections caused by susceptible microorganisms. As a class, penicillins usually are more effective in infections caused by gram-positive bacteria than those caused by gram-negative bacteria. However, their clinical uses vary significantly according to the subgroup or individual drug and microbial patterns of resistance. The drugs are often useful in skin/ soft tissue, respiratory, gastrointestinal, and genitourinary infections. However, the incidence of resistance among streptococci, staphylococci, and other microorganisms continues to grow. PENICILLINSIndications for Use

9. Aminopenicillins

10. Cephalosporins and cephamycins are similar to penicillins chemically, in mechanism of action, and in toxicity. Cephalosporins are more stable than penicillins to many bacterial β-lactamases and therefore usually have a broader spectrum of activity. Cephalosporins are not active against enterococci and Listeria monocytogenes. Cephalosporins & Cephamycins

11. CephalosporinsIndications for Use Clinical indications for the use of cephalosporins include surgical prophylaxis and treatment of infections of the respiratory tract, skin and soft tissues, bones and joints, urinary tract, brain and spinal cord, and bloodstream (septicemia). In most infections with streptococci and staphylococci, penicillins are more effective and less expensive. In infections caused by methicillin-resistant S. aureus, cephalosporins are not clinically effective even if in vitro testing indicates susceptibility. Infections caused by Neiserria gonorrhoeae, once susceptible to penicillin, are now preferentially treated with a third-generation cephalosporin such as ceftriaxone. Cefepime is indicated for use in severe infections of the lower respiratory and urinary tracts, skin and soft tissue, female reproductive tract, and infebrile neutropenic clients. It may be used as monotherapy for all infections caused by susceptible organisms except P. aeruginosa; a combination of drugs should be used for serious pseudomonal infections.

12. These are drugs with a monocyclic -lactam ring . They are relatively resistant to lactamases and active against gram-negative rods (including pseudomonas and serratia). They have no activity against gram-positive bacteria or anaerobes. Aztreonam is the only monobactam available in the USA. It resembles aminoglycosides in its spectrum of activity. Aztreonam is given intravenously every 8 hours in a dose of 1–2 g, providing peak serum levels of 100 g/mL. The half-life is 1–2 hours and is greatly prolonged in renal failure. Penicillin-allergic patients tolerate aztreonam without reaction. Occasional skin rashes and elevations of serum aminotransferases occur during administration of aztreonam, but major toxicity has not yet been reported. The clinical usefulness of aztreonam has not been fully defined. Monobactams

13. These substances resemble beta-lactam molecules but themselves have very weak antibacterial action. They are potent inhibitors of many but not all bacterial lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. Beta -Lactamase inhibitors are most active against Ambler class A lactamases (plasmid-encoded transposable element [TEM] - lactamases in particular) such as those produced by staphylococci, H influenzae, N gonorrhoeae, salmonella, shigella, E coli, and K pneumoniae. They are not good inhibitors of class C -lactamases, which typically are chromosomally encoded and inducible, produced by enterobacter, citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal lactamases of legionella, bacteroides, and branhamella. Beta-Lactamase Inhibitors (Clavulanic Acid, Sulbactam, & Tazobactam)

14. The indications for penicillin- β-lactamase inhibitor combinations are empirical therapy for infections caused by a wide range of potential pathogens in both immunocompromised and immunocompetent patients and treatment of mixed aerobic and anaerobic infections, such as intraabdominal infections. Doses are the same as those used for the single agents except that the recommended dosage of piperacillin in the piperacillin-tazobactam combination is 3 g every 6 hours. This is less than the recommended 3–4 g every 4–6 hours for piperacillin alone, raising concerns about the use of the combination for treatment of suspected pseudomonal infection. Adjustments for renal insufficiency are made based on the penicillin component. Beta-Lactamase Inhibitors (cont’d)

15. Augmentin contains amoxicillin and clavulanate. It is available in 250-, 500-, and 875-mg tablets, each of which contains 125 mg of clavulanate.

16. The carbapenems are structurally related to beta-lactam antibiotics. Ertapenem, imipenem, and meropenem are licensed for use in the USA. Imipenem has a wide spectrum with good activity against many gram-negative rods, including Pseudomonas aeruginosa, gram-positive organisms, and anaerobes. It is resistant to most lactamases but not metallo- lactamases. Enterococcus faecium, methicillin-resistant strains of staphylococci, Clostridium difficile, Burkholderia cepacia, and Stenotrophomonas maltophilia are resistant. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Consequently, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use.Meropenem is similar to imipenem but has slightly greater activity against gram-negative aerobes and slightly less activity against gram-positives. It is not significantly degraded by renal dehydropeptidase and does not require an inhibitor. Ertapenem is less active than meropenem or imipenem against Pseudomonas aeruginosa and acinetobacter species. It is not degraded by renal dehydropeptidase. carbapenems

17. The usual dose of imipenem is 0.25–0.5 g given intravenously every 6–8 hours (half-life 1 hour). The usual adult dose of meropenem is 1 g intravenously every 8 hours. Ertapenem has the longest half-life (4 hours) and is administered as a once-daily dose of 1 g intravenously or intramuscularly. Intramuscular ertapenem is irritating, and for that reason the drug is formulated with 1% lidocaine for administration by this route. A carbapenem is indicated for infections caused by susceptible organisms that are resistant to other available drugs and for treatment of mixed aerobic and anaerobic infections. Carbapenems are active against many highly penicillin-resistant strains of pneumococci. A carbapenem is the beta- lactam antibiotic of choice for treatment of enterobacter infections, since it is resistant to destruction by the lactamase produced by these organisms. Strains of Pseudomonas aeruginosa may rapidly develop resistance to imipenem or meropenem, so simultaneous use of an aminoglycoside is recommended for infections caused by those organisms. Ertapenem is insufficiently active against P aeruginosa and should not be used to treat infections caused by that organism. Imipenem or meropenem with or without an aminoglycoside may be effective treatment for febrile neutropenic patients. Carbapenems (cont’d)

18. Chloramphenicol is a potent inhibitor of microbial protein synthesis. It binds reversibly to the 50S subunit of the bacterial ribosome. Chloramphenicol

19. CHLORAMPHENICOL Because of potential toxicity, bacterial resistance, and the availability of other effective drugs (eg, cephalosporins), chloramphenicol is all but obsolete as a systemic drug. It may be considered for treatment of serious rickettsial infections, such as typhus or Rocky Mountain spotted fever, in children for whom tetracyclines are contraindicated, ie, those under 8 years of age. It is an alternative to a β-lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillinresistant strains of neumococci. The dosage is 50–100 mg/kg/d in four divided doses. Chloramphenicol is occasionally used topically in the treatment of eye infections because of its wide antibacterial spectrum and its penetration of ocular tissues and the aqueous humor. It is ineffective for chlamydial infections.

20. Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse. To avoid this toxic effect, chloramphenicol should be used with caution in infants and the dosage limited to 50 mg/kg/d or less (during the first week of life) in full-term infants and 25 mg/kg/d in remature infants. Chloramphenicol. Toxicity for Newborn Infants

21. Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. They are active against many gram-positive and gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and L forms; and against some protozoa, eg, amebas. The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may remain susceptible to doxycycline or minocycline, drugs that are less rapidly transported by the pump that is responsible for resistance Tetracyclines

22. A tetracycline is the drug of choice in infections with Mycoplasma pneumoniae, chlamydiae, rickettsiae, and some spirochetes. They are used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter pylori. In cholera, tetracyclines rapidly stop the shedding of vibrios, but tetracycline resistance has appeared during epidemics. Tetracyclines remain effective in most chlamydial infections, including sexually transmitted diseases. Tetracyclines are no longer recommended for treatment of gonococcal disease because of resistance. A tetracycline—usually in combination with an aminoglycoside—is indicated for plague, tularemia, and brucellosis. tetracyclines. Clinical Uses

23. TETRACYCLINES. CLINICAL USES (cont’d) Tetracyclines are sometimes employed in the treatment of protozoal infections, eg, those due to Entamoeba histolytica or Plasmodium falciparum. Other uses include treatment of acne, exacerbations of bronchitis, community-acquired pneumonia, Lyme disease, relapsing fever, leptospirosis, and some nontuberculous mycobacterial infections (eg, Mycobacterium marinum). Tetracyclines formerly were used for a variety of common infections, including bacterial gastroenteritis, pneumonia (other than mycoplasmal or chlamydial pneumonia), and urinary tract infections. However, many strains of bacteria causing these infections now are resistant, and other agents have largely supplanted Tetracyclines.

24. PRINCIPLES OF THERAPY WITH TETRACYCLINES 1. Culture and susceptibility studies are needed beforetetracycline therapy is started because many strains oforganisms are either resistant or vary greatly in drug susceptibility.Cross-sensitivity and cross-resistance arecommon among tetracyclines. 2. The oral route of administration is usually effective andpreferred. Intravenous (IV) therapy is used when oraladministration is contraindicated or for initial treatmentof severe infections. 3. Tetracyclines decompose with age, exposure to light,and extreme heat and humidity. Because the breakdownproducts may be toxic, it is important to storethese drugs correctly.

25. Erythromycin Clarithromycin (is derived from erythromycin) Azithromycin(differs from erythromycin and clarithromycin mainly in pharmacokinetic properties). The drug is slowly released from tissues (tissue half-life of 2–4 days) to produce an elimination half-life approaching 3 days.These unique properties permit once-daily dosing and shortening of the duration of treatment in many cases.For example, a single 1 g dose of azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis. Community-acquired pneumonia can be treated with azithromycin given as a 500 mg loading dose, followed by a 250 mg single daily dose for the next 4 days. Ketolides (Telithromycin) is approved for clinical use.Many macrolide-resistant strains are susceptible to ketolides Macrolides

26. Aminoglycosides Streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin The pharmacodynamic properties of aminoglycosides are: • Concentration-dependent killing • Significant post-antibiotic effect They are used most widely against gram-negative enteric bacteria, especially in bacteremia and sepsis, in combination with vancomycin or a penicillin for endocarditis, and for treatment of tuberculosis.The aminoglycosides also exhibit a significant post-antibiotic effect (PAE). PAE is the persistent suppression of bacterial growth following antibiotic exposure.

27. Aminoglycosides Contraindications to Use • Aminoglycosides are contraindicated in infections for which less toxic drugs are effective. The drugs are nephrotoxic and ototoxic and must be used very cautiously in the presence of renal impairment. Dosages are adjusted according to serum drug levels and creatinine clearance. The drugs must also be used cautiously in clients with myasthenia gravis and other neuromuscular disorders because muscle weakness may be increased.

28. Clindamycin is indicated for treatment of anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut; infections originating in the female genital tract, eg, septic abortion and pelvic abscesses; and aspiration pneumonia. Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures. Clindamycin plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain. Lincosamides

29. Oxazolidinones • Linezolid  is a member of the oxazolidinones, a new class of synthetic antimicrobials. It is active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such as corynebacteria and Listeria monocytogenes. • The recommended dosage for most indications is 600 mg twice daily, either orally or intravenously. Linezolid is approved for vancomycin-resistant E faecium infections; nosocomial pneumonia; community-acquired pneumonia; and skin infections, complicated or uncomplicated. It should be reserved for treatment of infections caused by multidrug-resistant gram-positive bacteria.

30. Oxazolidinones • The principal toxicity of linezolid is hematologic—reversible and generally mild. • Thrombocytopenia is the most common manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks. Anemia and neutropenia may also occur. • Cases of optic and peripheral neuropathy and lactic acidosis have been reported with prolonged courses of linezolid.

31. Empirical ‘blind’ therapy Most antibiotic prescribing, especially in the community, is empirical. Even in hospital practice, microbiological documentation of the nature of an infection and the susceptibility of the pathogen is generally not available for a day or two. Initial choice of therapy relies on a clinical diagnosis and, in turn, a presumptive microbiological diagnosis. Such ‘blind therapy’ is directed at the most likely pathogen(s) responsible for a particular syndrome such as meningitis, urinary tract infection or pneumonia. Examples of ‘blind therapy’ forthese three conditions are ceftriaxone, trimethoprim andamoxicillin + erythromycin, respectively. Initial therapyin the severely ill patient is often broad spectrum in orderto cover the range of possible pathogens but should betargeted once microbiological information becomesavailable.

32. Antibiotic Combination Therapy Antimicrobial drugs are often used in combination. Indications for combination therapy may include: • Infections caused by multiple microorganisms (eg, abdominal and pelvic infections) • Nosocomial infections, which may be caused by many different organisms • Serious infections in which a combination is synergistic (eg, an aminoglycoside and an antipseudomonal penicillin for pseudomonal infections) • Likely emergence of drug-resistant organisms if a single drug is used (eg, tuberculosis). Although drug combinations to prevent resistance are widely used, the only clearly effective use is for treatment of tuberculosis. • Fever or other signs of infection in clients whose immune systems are suppressed. Combinations of antibacterial plus antiviral and/or antifungal drugs may be needed

33. Problems of antibiotic resistance Because of the overuse of antibiotics, many bacteria have developed a resistance to common antibiotics. This means that newer antibiotics must continually be developed in order to treat an infection. However, further resistance seems to come about almost simultaneously. This indicates to many scientists that it might become more and more difficult to treat infectious diseases. The use of antibiotics outside of medicine also contributes to increased antibiotic resistance. One example of this is the use of antibiotics in animal husbandry. These negative trends can only be reversed by establishing a more rational use of antibiotics through treatment guidelines.

34. Factors that encourage the spread of resistance • Patient-related factors are major drivers of inappropriate antimicrobial use. For example, many patients believe that new and expensive medications are more efficacious than older agents. In addition to causing unnecessary health care expenditure, this perception encourages the selection of re­sistance to these newer agents as well as to older agents in their class. • Self-medication with antimicrobials is another major factor contributing to resistance. Self-medicated antimicrobials may be unnecessary, are often inadequately dosed, or may not contain adequate amounts of active drug, especially if they are counterfeit drugs. In many developing countries, antimi­crobials are purchased in single doses and taken only until the patient feels better, which may occur before the patho­gen has been eliminated. Inappropriate demand can also be stimulated by marketing practices. Direct-to-consumer advertising allows pharmaceu­tical manufacturers to market medicines directly to the public via television, radio, print media, and the Internet. In par­ticular, advertising on the Internet is gaining market pen­etration, yet it is difficult to control with legislation due to poor enforceability.

35. Factors that encourage the spread of resistance • Physicians can be pressured by patient expectations to prescribe antimicrobials even in the absence of appropriate indications. In some cultural settings, antimicrobials given by injection are considered more efficacious than oral formulations. Such perceptions tend to be associated with the over-prescribing of broad-spectrum injectable agents when a narrow-spectrum oral agent would be more appropriate. Prescribing “just to be on the safe side" increases when there is diagnostic uncertainty, lack of prescriber knowledge regarding optimal diagnostic approaches, lack of opportunity for patient follow-up, or fear of possible litigation. In many countries, antimicrobials can be easily obtained in pharmacies and markets without a prescription.

36. Factors that encourage the spread of resistance • Patient compliance with recommended treatment is another major problem. Patients forget to take medication, interrupt their treatment when they begin to feel better, or may be unable to afford a full course, thereby creating an ideal envi­ronment for microbes to adapt rather than be killed. In some countries, low quality antibiotics (poorly formulated or manufactured, counterfeited or expired) are still sold and used for self-medication or prophylaxis.

37. Factors that encourage the spread of resistance • Hospitals are a critical component of the antimicrobial resistance problem worldwide. The combination of highly susceptible patients, intensive and prolonged antimicrobial use, and cross-infection has resulted in nosocomial infections with highly resistant bacterial pathogens. Resistant hospital-acquired infections are expensive to control and extremely difficult to eradicate. Failure to implement simple infection control practices, such as handwashing and changing gloves before and after contact with patients, is a common cause of infection spread in hospitals throughout the world. Hospitals are also the eventual site of treatment for many patients with severe infections due to resistant pathogens acquired in the community. In the wake of the AIDS epidemic, the prevalence of such infections can be expected to increase.

38. Sulfonamides are infrequently used as single agents. Formerly drugs of choice for infections such as Pneumocystis jiroveci (formerly P carinii) pneumonia, toxoplasmosis, nocardiosis, and occasionally other bacterial infections, they have been largely supplanted by the fixed drug combination of trimethoprim-sulfamethoxazole. Many strains of formerly susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant. Sulfonamides

39. Sulfisoxazole and sulfamethoxazole are short- to medium-acting agents that are used almost exclusively to treat urinary tract infections. The usual adult dosage is 1 g of sulfisoxazole 4 times daily or 1 g of sulfamethoxazole 2 or 3 times daily. Sulfadiazine achieves therapeutic concentrations in cerebrospinal fluid and in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. Pyrimethamine, an antiprotozoal agent, is a potent inhibitor of dihydrofolate reductase. Sulfadoxine is available only as Fansidar, a combination formulation with pyrimethamine, which is used as a second-line agent in treatment for malaria Sulfonamides. Oral Absorbable Agents

40. Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease Topical Agents Sodium sulfacetamide ophthalmic solution or ointment is effective treatment for bacterial conjunctivitis and as adjunctive therapy for trachoma. Mafenide acetate is used topically to prevent bacterial colonization and infection of burn wounds. Sulfonamides. Oral Nonabsorbable Agents

41. Adverse Effects of Sulfonamides Adverse effects can result from oral and sometimes topical sulfonamides; effects include: Hypersensitivity reactions, such as rashes, Stevens-Johnson syndrome, vasculitis, serum sickness, drug fever, anaphylaxis, and angioedema Crystalluria, oliguria, and anuria Hematologic reactions, such as agranulocytosis, thrombocytopenia, and, in patients with G6PD deficiency, hemolytic anemia Kernicterus in neonates Photosensitivity Neurologic effects, such as insomnia, and headache Hypothyroidism, hepatitis, and activation of quiescent SLE may occur in patients taking sulfonamides. These drugs can exacerbate porphyrias.

42. Fluoroquinolones The important quinolones are synthetic fluorinated analogs of nalidixic acid. They are active against a variety of gram-positive and gram-negative bacteria. Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Earlier quinolones (nalidixic acid, oxolinic acid, cinoxacin) did not achieve systemic antibacterial levels. These agents were useful only for treatment of lower urinary tract infections. Fluorinated derivatives (ciprofloxacin, levofloxacin, and others) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues.

43. Norfloxacinis the least active of the fluoroquinolones against both gram-negative and gram-positive organisms Ciprofloxacin, enoxacin, lomefloxacin, evofloxacin, ofloxacin, and pefloxacincomprise a second group of similar agents possessing excellent gram-negative activity and moderate to good activity against grampositive bacteria. Gatifloxacin, moxifloxacin, sparfloxacin, and rovafloxacin comprise a third group of fluoroquinolones with improved activity against gram-positive organisms, particularly S.pneumoniae and to some extent staphylococci.

44. Conditions treated with Fluoroquinolones: indications and uses The serum elimination half-life of the fluoroquinolones range from 3 -20 hours, allowing for once or twice daily dosing.All of the fluoroquinolones are effective in treating urinary tract infections caused by susceptible organisms. They are the first-line treatment of acute uncomplicated cystitis in patients who cannot tolerate sulfonamides or TMP, who live in geographic areas with known resistance > 10% to 20% to TMP-SMX, or who have risk factors for such resistance.

45. Conditions treated with Fluoroquinolones: indications and uses Urinary tract infections (norfloxacin, lomefloxacin, enoxacin, ofloxacin, ciprofloxacin, levofloxacin, gatifloxacin, trovafloxacin) Lower respiratory tract infections (lomefloxacin, ofloxacin, ciprofloxacin, trovafloxacin) Skin and skin-structure infections (ofloxacin, ciprofloxacin, levofloxacin, trovafloxacin) Urethral and cervical gonococcal infections (norfloxacin, enoxacin, ofloxacin, ciprofloxacin, gatifloxacin, trovafloxacin) Prostatitis (norfloxacin, ofloxacin, trovafloxacin) Acute sinusitis (ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin (Avelox), trovafloxacin) Acute exacerbations of chronic bronchitis (levofloxacin, sparfloxacin (Zagam), gatifloxacin, moxifloxacin, trovafloxacin) Community-acquired pneumonia (levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, trovafloxacin)

46. Fluoroquinolones are approved for use only in people older than 18. They can affect the growth of bones, teeth, and cartilage in a child or fetus. • The FDA has assigned fluoroquinolones to pregnancy risk category C, indicating that these drugs have the potential to cause teratogenic or embryocidal effects. Giving fluoroquinolones during pregnancy is not recommended unless the benefits justify the potential risks to the fetus. • These agents are also excreted in breast milk and should be avoided during breast-feeding if at all possible. The fluoroquinolones side effects

47. Gastrointestinal effects. nausea, vomiting, diarrhea, constipation, and abdominal pain, which occur in 1 to 5% of patients. • CNS effects. Headache, dizziness, and drowsiness have been reported with all fluoroquinolones. Insomnia was reported in 3-7% of patients with ofloxacin. Severe CNS effects, including seizures, have been reported in patients receiving trovafloxacin. • Phototoxicity. Exposure to ultraviolet A rays from direct or indirect sunlight should be avoided during treatment and several days (5 days with sparfloxacin) after the use of the drug. The degree of phototoxic potential of fluoroquinolones is as follows: lomefloxacin > sparfloxacin > ciprofloxacin > norfloxacin = ofloxacin = levofloxacin = gatifloxacin = moxifloxacin. • Musculoskeletal effects. Concern about the development of musculoskeletal effects, evident in animal studies, has led to the contraindication of fluoroquinolones for routine use in children and in women who are pregnant or lactating. The fluoroquinolones side effects

48. Tendon damage (tendinitis and tendon rupture). Although fluoroquinolone-related tendinitis generally resolves within one week of discontinuation of therapy, spontaneous ruptures have been reported as long as nine months after cessation of fluoroquinolone use. Potential risk factors for tendinopathy include age >50 years, male gender, and concomitant use of corticosteroids. • Hepatoxicity. Trovafloxacin use has been associated with rare liver damage, which prompted the withdrawal of the oral preparations from the U.S. market. However, the IV preparation is still available for treatment of infections so serious that the benefits outweigh the risks. • Cardiovascular effects. The newer quinolones have been found to produce additional toxicities to the heart that were not found with the older compounds. Evidence suggests that sparfloxacin and grepafloxacin may have the most cardiotoxic potential. • Hypoglycemia/Hyperglycemia. • Hypersensitivity. The fluoroquinolones side effects

49. Antibiotics are among the safest of drugs, especially those used to treat community infections. They have had a major impact on the life-threatening infections and reduce the morbidity associated with surgery and many common infectious diseases. This in turn is, in part, responsible for the overprescribing of these agents which has led to concerns with regard to the increasing incidence of antibiotic resistance. CONCLUSION

50. Clinical pharmacology of tetracyclines • The fluoroquinolones side effects • Answer in the form of attached Microsoft Word file send to my e-mail: meretskyy@tdmu.edu.te.ua • Subject: Lecture “CLINICAL PHARMACOLOGY OF ANTIBACTERIALAGENTS”. Student (Your name and surname) QUESTION FOR HOME ASSIGNMENTS