1. THERAPEUTIC USES OF ANTIBIOTICS Dr. S. A. ZIAI Associate Professor Department of Pharmacology Shahid Beheshti University of Medical Sciences

2. Natural Penicillins Pneumococcal Infections Pneumococcal Pneumonia Pneumococcal Meningitis

3. Natural Penicillins

5. Pneumococcal Infections: –Penicillin G is choice for infections caused by sensitive strains of S. pneumoniae, but resistance is an increasing problem. pneumococcal pneumonia –a third-generation cephalosporin or high-dose penicillin G (i.e., 20–24 million units daily by continuous intravenous infusion) – Therapy should be continued for 7-10 days, including 3-5 days after the patient's temperature has returned to normal.

6. Natural Penicillins Pneumococcal Meningitis Until it is established that the infecting pneumococcus is sensitive to penicillin, pneumococcal meningitis should be treated with a combination of vancomycin and a third- generation cephalosporin Dexamethasone given at the same time as antibiotics was associated with an improved outcome The recommended therapy is 20-24 million units of penicillin G daily by constant intravenous infusion or divided into boluses given every 2-3 hours. The usual duration of therapy is 14 days.

7. Natural Penicillins Streptococcal Pharyngitis (Including Scarlet Fever) Streptococcal Toxic Shock and Necrotizing Fascitis Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis Infections Caused by Other Streptococci

8. Natural Penicillins Streptococcal Infections: Pharyngitis is the most common disease produced by S. pyogenes (group A β-hemolytic streptococcus). –The preferred oral therapy is with penicillin V, 500 mg every 6 hours for 10 days. –Penicillin therapy reduces the risk of subsequent acute rheumatic fever (not glomerulonephritis).

9. Natural Penicillins Streptococcal Toxic Shock : –These life-threatening infections are best treated with penicillin plus clindamycin (to decrease toxin synthesis). Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis: –penicillin G; daily doses of 12–20 million units are administered intravenously for 2–4 weeks (4 weeks for endocarditis).

10. Natural Penicillins Infections Caused by Other Streptococci The viridans group of streptococci are the most common cause of infectious endocarditis. These are nongroupable α-hemolytic microorganisms that are increasingly resistant to penicillin G (minimum inhibitory concentration [MIC] >0.1 µg/mL).

11. Natural Penicillins Because enterococci also may be α-hemolytic, and certain other α-hemolytic strains may be relatively resistant to penicillin, it is important to determine quantitative microbial sensitivities to penicillin G in patients with endocarditis. Patients with penicillin-sensitive VIRIDANS group streptococcal endocarditis can be treated successfully with daily doses of 12-20 million units of intravenous penicillin G for 2 weeks in combination with gentamicin 1 mg/kg every 8 hours. Some physicians prefer a 4-week course of treatment with penicillin G alone.

12. Natural Penicillins Enterococcal endocarditis is one of the few diseases treated optimally with two antibiotics. The recommended therapy for penicillin- and aminoglycoside-sensitive enterococcal endocarditis is 20 million units of penicillin G or 12 g ampicillin daily administered intravenously in combination with a low dose of gentamicin. Therapy usually should be continued for 6 weeks, but selected patients with a short duration of illness (<3 months) have been treated successfully in 4 weeks

13. Natural Penicillins Infections with Anaerobes: Many anaerobic infections are polymicrobial, and most of the organisms are sensitive to penicillin G. B. fragilis group, 75% of which may be resistant. Brain abscesses contain several species of anaerobes, and most experts use high doses of penicillin G (20 million units per day) plus metronidazole Or Chloramphenicol.

14. Natural Penicillins Pulmonary and periodontal infections (with the exception of β-lactamase-producing Prevotella melaninogenica) usually respond well to penicillin G, although a multicenter study indicated that clindamycin is more effective than penicillin for therapy of lung abscess Mild-to-moderate infections at these sites may be treated with oral medication (either penicillin G or penicillin V 400,000 units [250 mg] four times daily) More severe infections should be treated with 12–20 million units of penicillin G intravenously.

15. Natural Penicillins Staphylococcal Infections: –Patients with staphylococcal infection should receive penicillinase-resistant penicillins (e.g., nafcillin or oxacillin). –HA-MRSA: –HA-MRSA: Vancomycin, linezolid, quinupristin-dalfopristin, and daptomycin – –CA-MRSA: trimethoprim-sulfamethoxazole, doxycycline, and clindamycin

16. Natural Penicillins Meningococcal Infections: Penicillin G is the drug of choice for meningococcal disease. Patients should be treated with high doses of penicillin given intravenously. Penicillin G does not eliminate the meningococcal carrier state and is ineffective for prophylaxis.

17. Natural Penicillins Gonococcal Infections Uncomplicated gonococcal urethritis is the most common infection, and a single intramuscular injection of 250 mg ceftriaxone is the recommended treatment. Arthritis, disseminated gonococcal infections with skin lesions, and gonococcemia should be treated with ceftriaxone 1 g daily given either intramuscularly or intravenously for 7-10 days. Ophthalmia neonatorum also should be treated with ceftriaxone for 7-10 days (25-50 mg/kg per day intramuscularly or intravenously). Ophthalmia neonatorum also should be treated with ceftriaxone for 7-10 days (25-50 mg/kg per day intramuscularly or intravenously).

18. Natural Penicillins Syphilis Primary, secondary, and latent syphilis of <1-year duration may be treated with penicillin G procaine (2.4 million units per day intramuscularly) plus probenecid (1.0 g/day orally) for 10 days or with 1-3 weekly intramuscular doses of 2.4 million units of penicillin G benzathine (three doses in patients with HIV infection). Because neurosyphilis, & cardiovascular syphilis are potentially lethal and their progression can be halted (but not reversed), intensive therapy with 20 million units of penicillin G daily for 10 days is recommended.

19. Natural Penicillins There are no proven alternatives for treating syphilis in pregnant women, so penicillin-allergic individuals must be acutely desensitized to prevent anaphylaxis

20. Natural Penicillins Infants with congenital syphilis discovered at birth or during the postnatal period should be treated for at least 10 days with 50,000 units/kg daily of aqueous penicillin G in two divided doses or 50,000 units/kg of procaine penicillin G in a single daily dose

21. Natural Penicillins Most patients (70-90%) with secondary syphilis develop the Jarisch-Herxheimer reaction. Several hours after the first injection of penicillin, chills, fever, headache, myalgias, and arthralgias may develop. Manifestations usually persist for a few hours, and the rash begins to fade within 48 hours. Aspirin gives symptomatic relief, and therapy with penicillin should not be discontinued.

22. Natural Penicillins Actinomycosis Penicillin G is the agent of choice for the treatment of all forms of actinomycosis. The dose should be 10-20 million units of penicillin G intravenously per day for 6 weeks. Some physicians continue therapy for 2-3 months with oral penicillin V (500 mg four times daily). Surgical drainage or excision of the lesion may be necessary before cure is accomplished. Surgical drainage or excision of the lesion may be necessary before cure is accomplished.

23. Natural Penicillins Diphtheria There is no evidence that penicillin or any other antibiotic alters the incidence of complications or the outcome of diphtheria; specific antitoxin is the only effective treatment. However, penicillin G eliminates the carrier state. The parenteral administration of 2-3 million units per day in divided doses for 10-12 days eliminates the diphtheria bacilli from the pharynx and other sites in practically 100% of patients. A single daily injection of penicillin G procaine for the same period produces comparable results. A single daily injection of penicillin G procaine for the same period produces comparable results.

24. Natural Penicillins Anthrax Strains of Bacillus anthracis resistant to penicillin have been recovered from human infections. When penicillin G is used, the dose should be 12-20 million units per day.

25. Natural Penicillins Clostridial Infections Penicillin G is the agent of choice for gas gangrene; the dose is in the range of 12-20 million units per day given parenterally as an adjunct to the antitoxin. Adequate debridement of the infected areas is essential. Adequate debridement of the infected areas is essential.

26. Natural Penicillins Antimicrobial drugs probably have no effect on the ultimate outcome of tetanus. Debridement and administration of human tetanus immune globulin may be indicated. Penicillin is administered, however, to eradicate the vegetative forms of the bacteria that may persist. Metronidazole is preferred

27. Natural Penicillins Fusospirochetal Infections Gingivostomatitis, produced by the synergistic action of Leptotrichia buccalis and spirochetes that are present in the mouth, is readily treatable with penicillin. For simple "trench mouth," 500 mg penicillin V given every 6 hours for several days is usually sufficient to clear the disease.

28. Natural Penicillins Rat-Bite Fever The two microorganisms responsible for this infection, Spirillum minor in the Far East and Streptobacillus moniliformis in America and Europe, are sensitive to penicillin G, the therapeutic agent of choice. Because most cases due to Streptobacillus are complicated by bacteremia and, in many instances, by metastatic infections, especially of the synovia and endocardium, the dose should be large; a daily dose of 12-15 million units given parenterally for 3-4 weeks has been recommended.

29. Natural Penicillins Listeria Infections Ampicillin (with gentamicin for immunosuppressed patients with meningitis) and penicillin G are the drugs of choice in the management of infections owing to L. monocytogenes. The recommended dose of ampicillin is 1-2 g intravenously every 4 hours. The recommended dose of penicillin G is 15-20 million units parenterally per day for at least 2 weeks. When endocarditis is the problem, the dose is the same, but the duration of treatment should be no less than 4 weeks. When endocarditis is the problem, the dose is the same, but the duration of treatment should be no less than 4 weeks.

30. Natural Penicillins Lyme Disease Although a tetracycline is the usual drug of choice for early disease, amoxicillin is effective; the dose is 500 mg three times daily for 21 days. Severe disease is treated with a third- generation cephalosporin or up to 20 million units of intravenous penicillin G daily for 10-14 days.

31. Natural Penicillins Erysipeloid The causative agent of this disease, Erysipelothrix rhusiopathiae, is sensitive to penicillin. The uncomplicated infection responds well to a single injection of 1.2 million units of penicillin G benzathine. When endocarditis is present, penicillin G, 12-20 million units per day, has been found to be effective; therapy should be continued for 4-6 weeks. When endocarditis is present, penicillin G, 12-20 million units per day, has been found to be effective; therapy should be continued for 4-6 weeks.

32. Natural Penicillins Pasteurella Multocida Pasteurella multocida is the cause of wound infections after a cat or dog bite. It is uniformly susceptible to penicillin G and ampicillin and resistant to penicillinase-resistant penicillins and first-generation cephalosporins. When the infection causes meningitis, a third- generation cephalosporin is preferred because the MICs are slightly lower than for penicillin.

33. PROPHYLACTIC USES OF THE PENICILLINS Streptococcal Infections: –The administration of penicillin to individuals exposed to S. pyogenes protects against infection. –The oral ingestion of 200,000 units of penicillin G or penicillin V twice a day or a single injection of 1.2 million units of penicillin G benzathine is effective. –Indications for this type of prophylaxis include outbreaks of streptococcal disease in closed populations, such as boarding schools or military bases. Patients with extensive deep burns are at high risk of severe wound infections with S. pyogenes; "low- dose" prophylaxis for several days appears to be effective

34. PROPHYLACTIC USES OF THE PENICILLINS Syphilis : – –Prophylaxis for a contact with syphilis consists of a course of therapy as described for primary syphilis.

35. PROPHYLACTIC USES OF THE PENICILLINS Recurrences of Rheumatic Fever – –The intramuscular injection of 1.2 million units of penicillin G benzathine once a month yields excellent results. – –In cases of hypersensitivity to penicillin, sulfisoxazole or sulfadiazine, 1 g twice a day for adults, also is effective; for children weighing <27 kg, the dose is halved. Surgical Procedures in Patients with Valvular Heart Disease – –About 25% of cases of subacute bacterial endocarditis follow dental extractions.

36. Penicillinase-Resistant Penicillins ISOXAZOLYLOXACILLINCLOXACILLINDICLOXACILLIN semisynthetic penicillins are similar structurally and pharmacologically. All are relatively stable in an acid medium and are absorbed adequately after oral administration. All are relatively stable in an acid medium and are absorbed adequately after oral administration. All are markedly resistant to cleavage by penicillinase

37. Penicillinase-Resistant Penicillins

39. AMINOPENICILLINS Enterococci are about twice as sensitive to ampicillin as they are to penicillin G. From 30-50% of E. coli, a significant number of P. mirabilis, and practically all species of Enterobacter presently are insensitive. These antibiotics are less active against B. fragilis than penicillin G

40. AMINOPENICILLINS

41. AMINOPENICILLINS

42. AMINOPENICILLINS Upper Respiratory Infections – –Active against S. pyogenes and many strains of S. pneumoniae and H. influenza – –Sinusitis, otitis media, acute exacerbations of chronic bronchitis, and epiglottitis

43. AMINOPENICILLINS –20-30% of strains of S. pneumoniae now may be resistant to ampicillin – –Amoxicillin is the most active of all the oral β- lactam antibiotics against both penicillin-sensitive and penicillin-resistant S. pneumoniae. – –Based on the increasing prevalence of pneumococcal resistance to penicillin, an increase in dose of oral amoxicillin (from 40-45 up to 80-90 mg/kg per day) for empirical treatment of acute otitis media in children is recommended

44. AMINOPENICILLINS Urinary Tract Infections –Most uncomplicated urinary tract infections are caused by Enterobacteriaceae, and E. coli is the most common species; ampicillin often is an effective agent. –Enterococcal urinary tract infections are treated effectively with ampicillin alone.

45. AMINOPENICILLINS Meningitis –Ampicillin has excellent activity against L. monocytogenes, which causes meningitis in immunocompromised persons. –combination of ampicillin and vancomycin plus a third-generation cephalosporin is a rational regimen for empirical treatment of suspected bacterial meningitis.

46. AMINOPENICILLINS Salmonella Infections – fluoroquinoloneceftriaxone trimethoprim-sulfamethoxazole ampicillin –A fluoroquinolone or ceftriaxone is considered by some to be the drug of choice, but the administration of trimethoprim-sulfamethoxazole or high doses of ampicillin (12 g/day for adults) also is effective. – –In some geographic areas, resistance to ampicillin is common. – ampicillin, trimethoprim-sulfamethoxazole, or ciprofloxacin –The typhoid carrier state has been eliminated successfully in patients without gallbladder disease with ampicillin, trimethoprim-sulfamethoxazole, or ciprofloxacin.

47. CARBOXYPENICILLINS Carbenicillin and ticarcillin are active against some isolates of P. aeruginosa and certain indole-positive Proteus spp. They are ineffective against most strains of S. aureus, Enterococcus faecalis, Klebsiella, and L. monocytogenes. B. fragilis is susceptible to high concentrations of these drugs, but penicillin G is actually more active.

48. UREIDOPENICILLINS Mezlocillin and piperacillin, have superior activity against P. aeruginosa compared with carbenicillin and ticarcillin. Mezlocillin and piperacillin are useful for treatment of infections with Klebsiella. Piperacillin and related agents are important agents for the treatment of patients with serious infections caused by gram-negative bacteria.

49. UREIDOPENICILLINS Nosocomial infections in immune- compromised patients. These penicillins find their greatest use in treating bacteremias, pneumonias, infections following burns, and urinary tract infections owing to microorganisms resistant to penicillin G and ampicillin The bacteria especially responsible include P. aeruginosa, indole-positive strains of Proteus, and Enterobacter spp.

50. UREIDOPENICILLINS

51. Cephalosporins

53. First-generation Are excellent agents for skin and soft tissue infections owing to S. aureus and S. pyogenes. A single dose of cefazolin just before surgery is the preferred prophylaxis for procedures in which skin flora are the likely pathogens. Gram- positive bacteria Streptococcus pyogenes, Some virdans streptococci, Some Staphylococcus aureus, Some Streptococcus pneumoniae Gram- negative bacteria Some Eschericia coli, Some Klebsiella pneumoniae, Some Proteus mirabilis

54. Gram-positive bacteriaTrue cephalosporins have activity equivalent to first-generation agents. Cefoxitin and cefotetan have little activity Gram-negative bacteriaEscherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Neisseria spp. Anaerobic bacteriaCefoxitin and cefotetan have moderate anaerobic activity. Second-generation

55. Cefoxitin: special role is for treatment of certain anaerobic and mixed aerobic-anaerobic infections, such as pelvic inflammatory disease and lung abscess. Cefaclor is more active against H. influenzae and Moraxella catarrhalis than cephalexine. Second-generation

56. Cefuroxime: Against some Citrobacter and Enterobacter spp. Concentrations in CSF are ~10% of those in plasma; the drug is effective for treatment of meningitis owing to H. influenzae (including strains resistant to ampicillin), N. meningitidis, and S. pneumoniae. Second-generation

57. Cefotetan: Hypoprothrombinemia and inhibition of vitamin K activation with bleeding have occurred in malnourished. For colorectal surgery, where prophylaxis for intestinal anaerobes is desired, the second- generation agents, cefoxitin or cefotetan, are preferred. Second-generation

58. Third-generation cephalosporins are the drugs of choice for serious infections caused by Klebsiella, Enterobacter, Proteus, Providencia, and Haemophilus spp. They are the drugs of choice for meningitis caused by H. influenzae, sensitive S. pneumoniae, N. meningitidis, and gram-negative enteric bacteria. Third-generation

59. Cefotaxime is highly resistant to many β- lactamases and has good activity against many bacteria. Cefotaxime has been used effectively for meningitis caused by H. influenzae, penicillin- sensitive S. pneumoniae, and N. meningitides.

60. Ceftriaxone is the drug of choice for all forms of gonorrhea and for severe forms of Lyme disease. A single dose of ceftriaxone (125–250 mg) is effective in the treatment of urethral, cervical, rectal, or pharyngeal gonorrhea, including penicillinase- producing microorganisms. Third-generation

61. Gram-positive bacteriaStreptococcus pyogenes, Viridans streptococci, Many Streptocossus pneumoniae. Modest activity against Staphylococcus aureus Gram-negative bacteriaEscherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Many other Enterobacteriaceae, Pseudomonas aeruginosa. Fourth-generation

62. The fourth-generation cephalosporins are indicated for the empirical treatment of nosocomial infections. For example, cefepime is superior to ceftazidime and piperacillin for nosocomial isolates of Enterobacter, Citrobacter, and Serratia spp. Fourth-generation

63. Sulfonamides

64. Antibacterial spectrum  Resistance to sulfonamides is increasingly a problem.  Microorganisms that may be susceptible in vitro to sulfonamides include Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus ducreyi, Nocardia, Actinomyces, Calymmatobacterium granulomatis, and Chlamydia trachomatis.  Minimal inhibitory concentrations (MICs) range from 0.1 µg/mL for C. trachomatis to 4-64 µg/mL for Escherichia coli.  Peak plasma drug concentrations achievable in vivo are ~100-200 µg/mL.

65. Sulfonamide Therapy  Urinary Tract Infections  Nocardiosis  Toxoplasmosis

66.  URINARY TRACT INFECTIONS :  No longer a therapy of first choice : because sulfonamide-resistant  Trimethoprim–sulfamethoxazole  Patients with acute pyelonephritis with high fever are at risk of bacteremia and shock : Sulfonamide is contraindicated Sulfonamide Therapy

67.  Nocardiosis :  Sulfisoxazole or sulfadiazine  6-8 g daily several months after all manifestations have been controlled  Therapy in advanced cases: Sulfonamide +ampicillin/ erythromycin / streptomycin  Trimethoprim– sulfamethoxazole( choice ) Sulfonamide Therapy

68.  TOXOPLASMOSIS :  Treatment of choice: Pyrimethamine + sulfadiazine + folinic acid + 2 L of fluid intake daily to prevent crystalluria Sulfonamide Therapy

69. Use of Sulfonamides for Prophylaxis  Preventing streptococcal infections and recurrence of rheumatic fevers  Untoward responses usually occur during the first 8 weeks of therapy.  White blood cell counts should be carried out once weekly during the first 8 weeks.

70. TRIMETHOPRIM  The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole, although trimethoprim is 20- 100 times more potent.  Most gram-negative and gram-positive microorganisms are sensitive to trimethoprim, but resistance can develop when the drug is used alone.  Pseudomonas aeruginosa, Bacteroides fragilis, and enterococci usually are resistant.  There is significant variation in the susceptibility of Enterobacteriaceae to trimethoprim in different geographic locations because of the spread of resistance mediated by plasmids and transposons

71. Efficacy of Trimethoprim- Sulfamethoxazole in Combination  Chlamydia trachomatis and N. meningitidis are susceptible.  Although most S. pneumoniae are susceptible, there has been a disturbing increase in resistance.  From 50-95% of strains of Staphylococcus aureus, Staphylococcus epidermidis, S. pyogenes, the viridans group of streptococci, E. coli, Proteus mirabilis, Proteus morganii, Proteus rettgeri, Enterobacter spp., Salmonella, Shigella, Pseudomonas pseudomallei, Serratia, and Alcaligenes spp. are inhibited.  Also sensitive are Klebsiella spp., Brucella abortus, Pasteurella haemolytica, Yersinia pseudotuberculosis, Yersinia enterocolitica, and Nocardia asteroides.

72. BACTRIM THERAPEUTIC USES  Urinary Tract Infections (UTI) & bacterial prostatitis  Bacterial Respiratory Tract Infections  Acute otitis media in children  GI Infections : shigellosis /Acute diarrhea  Infection by Pneumocystis jiroveci in patients with AIDS.  Prophylaxis in Neutropenic Patients  Nocardia infections

73. Urinary Tract Infections  Uncomplicated lower urinary tract infection (UTI)  Single-dose therapy (320 mg trimethoprim plus 1600 mg sulfamethoxazole in adults)  A minimum of 3 days of therapy is more likely to be effective  In chronic and recurrent infections of the urinary tract  Small doses : reduce the number of recurrent urinary tract infections in women  presence of therapeutic concentrations of trimethoprim in vaginal secretions  Bacterial prostatitis

74. Bacterial Respiratory Tract Infections  Acute exacerbations of chronic bronchitis  Should not be used to treat streptococcal pharyngitis because it does not eradicate the microorganism  Acute otitis media in children & acute maxillary sinusitis in adults caused by susceptible strains of H. influenzae and S. pneumoniae

75. GI Infections  Shigellosis: Alternative to a fluoroquinolone  Typhoid fever: A second-line drug (ceftriaxone or a fluoroquinolone is the preferred treatment)  Travelers' diarrhea: for 5 days  Effective in the management of carriers of sensitive strains of Salmonella typhi and other Salmonella spp., however, failures have occurred.  Acute diarrhea owing to sensitive strains of enteropathogenic E. coli  However, antibiotic treatment of diarrheal illness owing to enterohemorrhagic E. coli O157:H7 may increase the risk of hemolytic-uremic syndrome, perhaps by increasing the release of Shiga toxin by the bacteria.

76. Infection by Pneumocystis jiroveci  High-dose therapy: effective for this severe infection in patients with AIDS  Adjunctive corticosteroids should be given at the onset of anti-Pneumocystis therapy  Adverse reactions are less frequent with the lower prophylactic doses  The most common problems are rash, fever, leukopenia, and hepatitis.sm in patients with AIDS

77. Prophylaxis in Neutropenic Patients  low-dose prophylaxis of infection by P. jiroveci  Significant protection against sepsis caused by g - in severely neutropenic patients

78. Miscellaneous Infections  Nocardia infections: treated successfully  Brucellosis  treatment of choice: doxycycline +streptomycin or gentamicin  trimethoprim-sulfamethoxazole may be an effective substitute for the doxycycline combination  Whipple's disease  Infection by Stenotrophomonas maltophilia  Intestinal parasites Cyclospora and Isospora  Wegener's granulomatosis  depending on the stage of the disease

79. FLUOROQUINOLONES

80. ANTIBACTERIAL SPECTRUM The fluoroquinolones are potent bactericidal agents against E. coli and various species of Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria (MIC90 usually are <0.2 μg/mL). Fluoroquinolones also have good activity against staphylococci, but not against methicillin-resistant strains (MIC90 = 0.1-2 μg/mL). Activity against streptococci is limited to a subset of the quinolones, including levofloxacin (LEVAQUIN), and moxifloxacin (AVELOX).

81. ANTIBACTERIAL SPECTRUM Several intracellular bacteria are inhibited by fluoroquinolones at concentrations that can be achieved in plasma; these include species of Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium (including Mycobacterium tuberculosis ). Several fluoroquinolones, including gemifloxacin, have activity against anaerobic bacteria

82. URINARY TRACT INFECTIONS  The fluoroquinolones are more efficacious than trimethoprim– sulfamethoxazole  Norfloxacin and ciprofloxacin XR are approved for use in the U.S. only for UTIs.

83. PROSTATITIS  Norfloxacin, ciprofloxacin, and ofloxacin are effective for the treatment of prostatitis caused by sensitive bacteria  Fluoroquinolones administered for 4– 6 weeks appear to be effective in patients not responding to trimethoprim–sulfamethoxazole.

84. SEXUALLY TRANSMITTED DISEASES  The quinolones are contraindicated in pregnancy.  Fluoroquinolones lack activity for Treponema pallidum  Fluoroquinolones have activity in vitro against N.gonorrhoeae, Chlamydia trachomatis, and Haemophilus ducreyi  For chlamydial urethritis/cervicitis, a 7-day course of ofloxacin is an alternative to a 7-day course with doxycycline or a single dose of azithromycin.  Chancroid (infection by H. ducreyi ) can be treated with 3 days of ciprofloxacin.

85. SEXUALLY TRANSMITTED DISEASES  A single oral dose of a fluoroquinolone is effective treatment for sensitive strains of N. gonorrhoeae  Increasing resistance to fluoroquinolones has made ceftriaxone the first-line agent  Pelvic inflammatory disease has been treated effectively with a 14-day course of ofloxacin combined with an antibiotic with activity against anaerobes ( clindamycin or metronidazole ).

86. GASTROINTESTINAL AND ABDOMINAL INFECTIONS  For traveler’s diarrhea,the quinolones are equal to trimethoprim–sulfamethoxazole in effectiveness, reducing the duration of loose stools by 1-3 days.  Norfloxacin, ciprofloxacin, and ofloxacin given for 5 days all are effective in the treatment of shigellosis  Shigellosis is treated effectively with either ciprofloxacin or azithromycin  Norfloxacin is superior to tetracyclines in decreasing the duration of diarrhea in cholera.

87. GASTROINTESTINAL AND ABDOMINAL INFECTIONS  Ciprofloxacin and ofloxacin treatment cures most patients with enteric fever caused by S. typhi, as well as bacteremic nontyphoidal infections in AIDS patients, and clears chronic fecal carriage.  The in vitro ability of the quinolones to induce the Shiga toxin (the cause of the hemolytic-uremic syndrome ) in E. coli suggests that the quinolones should not be used for Shiga toxin–producing E. coli

88. RESPIRATORY TRACT INFECTIONS  The major limitation to the use of quinolones for the treatment of community-acquired pneumonia and bronchitis was the poor activity against S. pneumoniae and anaerobic bacteria  Newer fluoroquinolones, including gemifloxacin, levofloxacin and moxifloxacin, have excellent activity against S. pneumonia.

89. RESPIRATORY TRACT INFECTIONS  The fluoroquinolones have activity against H.influenzae, Moraxella catarrhalis, S. aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila.  Either a fluoroquinolone ( ciprofloxacin or levofloxacin ) or azithromycin is the antibiotic of choice for L. pneumophila.  Fluoroquinolones can effectively eradicate both H. influenzae and M. catarrhalis from sputum.  Mild-to-moderate respiratory exacerbations owing to P. aeruginosa in patients with cystic fibrosis have responded to oral fluoroquinolones

90. BONE, JOINT, AND SOFT TISSUE INFECTIONS  The treatment of chronic osteomyelitis requires prolonged antimicrobial therapy with agents active against S. aureus and gram- negative rods  Clinical cures have been as high as 75% in chronic osteomyelitis in which gram-negative rods predominated

91. BONE, JOINT, AND SOFT TISSUE INFECTIONS  Failures have been associated with the development of resistance in S. aureus, P. aeruginosa, and Serratia marcescens  Diabetic foot infections : the fluoroquinolone s in combination with an agent with antianaerobic activity

92. OTHER INFECTIONS  Levofloxacin is approved to treat and prevent anthrax as well as plague due to Yersinia pestis  Treatment of tularemia  As part of treatment of multidrug-resistant tuberculosis and atypical mycobacterial infections as well as Mycobacterium avium complex infections in AIDS  Quinolones, when used as prophylaxis in neutropenic patients, have decreased the incidence of gram-negative rod bacteremias.

93. Macrolides

94. Respiratory Tract Infections  Azithromycin and clarithromycin are suitable choices for treatment of mild to moderate CAP among ambulatory patients.  In hospitalized patients, a macrolide is commonly added to a cephalosporin for coverage of atypical respiratory pathogens.  Azithromycin (or a fluoroquinolone) has supplanted erythromycin as the first-line agent for treatment of legionellosis.  The recommended dose is 500 mg daily, intravenously or orally, for a total of 10-14 days.  Macrolides are also appropriate alternative agents for the treatment of acute exacerbations of chronic bronchitis, acute otitis media, acute streptococcal pharyngitis, and acute bacterial sinusitis.

95. Skin and Soft-Tissue Infections  Macrolides are alternatives for treatment of erysipelas and cellulitis among patients who have a serious allergy to penicillin.

96. Chlamydial Infections  A single 1-g dose of azithromycin is recommended for patients with uncomplicated urethral, endocervical, rectal, or epididymal infections  During pregnancy, erythromycin base, 500 mg 4 times daily for 7 days, (or Azithromycin, 1 g orally as a single dose ) is recommended as first-line therapy for chlamydial urogenital infections.  Erythromycin base is preferred for chlamydial pneumonia of infancy and ophthalmia neonatorum (50 mg/kg/day in 4 divided doses for 10-14 days).  Azithromycin, 1 g/week for 3 weeks, may be effective for lymphogranuloma venereum.

97. THERAPEUTIC USES:  Diphtheria  Erythromycin 250 mg four times daily for 7 days is very effective for acute infections  Other macrolides likely are also effective but are not FDA-approved forthis indication  Antibiotics do not alter the course of an acute infection with diphtheria or decrease the risk of complications.  Pertussis  Erythromycin is the drug of choice for treating persons with B. pertussis disease  Clarithromycin and azithromycin also are effective

98. THERAPEUTIC USES:  Campylobacter Infections  Fluroquinolones largely have replaced erythromycin for this disease in adults.  Erythromycin remains useful for treatment of Campylobacter gastroenteritis in children.

99. THERAPEUTIC USES:  Helicobacter pylori Infection  Clarithromycin 500 mg, in combination with omeprazole, 20 mg, and amoxicillin, 1 g, each administered twice daily for 10–14 days, is effective for treatment of peptic ulcer disease caused by H. pylori.  Prophylactic Uses  Clarithromycin or azithromycin (or clindamycin) are recommended alternatives for the prevention of bacterial endocarditis in patients undergoing dental procedures.  Erythromycin is an effective alternative for the prophylaxis of recurrences of rheumatic fever in individuals who are allergic to penicillin.

100. Clindamycin Therapeutic uses  Clindamycin is the drug of choice for treatment of lung abscess and anaerobic lung and pleural space infections.  Clindamycin is not predictably useful for the treatment of bacterial brain abscesses; metronidazole, in combination with penicillin or a third- generation cephalosporin, is preferred.  Clindamycin is an alternative agent for the treatment of skin and soft-tissue infections, especially in patients with β-lactam allergies.  Clindamycin also is available as a topical solution, gel, or lotion and as a vaginal cream. It is effective topically (or orally) for acne vulgaris and bacterial vaginosis.  Clindamycin in combination with pyrimethamine and leucovorin (folinic acid, 10 mg/day) is effective for acute treatment of encephalitis caused by T. gondii in patients with AIDS.

101. TETRACYCLINES AND GLYCYLCYCLINES

102. Therapeutic Uses and Dosage The tetracyclines have been used extensively to treat infectious diseases such as rickettsiae, mycoplasmas, and chlamydiae and as an additive to animal feeds to facilitate growth The total daily dose of intravenous tetracycline for most acute infections is 1 g (or 2 g for severe infection), administered at 6- or 12-hour intervals Children >8 years : 25-50 mg/kg daily in four divided doses. Tetracycline The oral or intravenous dose for adults is 100 mg every 12 hours on the first day and then 50 mg every 12 hours, 100 mg once a day, or 100 mg twice daily when severe infection is present for children >8 years of age, the dose is 4-5 mg/kg per day in two divided doses the first day, then 2- 2.5 mg/kg given once or twice daily Doxycycline

103. … The dose for adults: 200 mg orally or intravenously initially, followed by 100 mg every 12 hours for children: 4 mg/kg initially followed by 2 mg/kg every 12 hours Minocycline Is administered intravenously to adults as a 100-mg loading dose, followed by 50 mg every 12 hours For children: wasn’t determined Tigecycline

104. Some notes The low pH of tetracycline invariably causes phlebitis if infused into a peripheral vein Demeclocycline is used rarely as an antimicrobial agent : higher risks of photosensitivity reactions and nephrogenic diabetes insipidus Tetracyclines should not be administered intramuscularly because of local irritation and poor absorption. GI distress, nausea, and vomiting can be minimized by administration of tetracyclines with food

105. ANTIMICROBIAL ACTIVITY Tetracyclines are bacteriostatic antibiotics with activity against a wide range of aerobic and anaerobic gram-positive and gram-negative bacteria. Glycylcyclines have activity against bacteria that resistant to the first- and second-generation tetracyclines.

106. Therapeutic Uses Respiratory Tract Infections Doxycycline: good activity against S. pneumoniae and H. influenzae and excellent activity against atypical pathogens such as Mycoplasma and Chlamydophilia pneumoniae Tigecycline : as a single agent for adults hospitalized with community-acquired bacterial pneumonia Skin and Soft- Tissue Infections Tetracycline, doxycycline, or minocycline: methicillin-resistant S. aureus often; complicated skin and soft-tissue infections Tigecycline : complicated skin and soft-tissue infections Tetracyclines: used for acne by inhibiting propionibacteria (250 mg bid) Intra-Abdominal Infections Tigecycline: excellent activity against these pathogens as well as Enterococcus Tetracyclines: has limited utility (resistance among enterobacteriaceae and gram negative anaerobes)

107. … GI Infections Tetracyclines: ineffective in infections caused by Shigella, Salmonella, or other Enterobacteriaceae. Doxycycline : 300 mg as a single dose is effective in reducing stool volume and eradicating Vibrio cholerae from the stool within 48 hours. Urinary Tract Infections Tetracyclines: isn't recommended because of resistant microorganism Tigecycline: little experience

108. … Sexually Transmitted Diseases Doxycycline: no longer is recommended for gonococcal infections Doxycycline:Chlamydia trachomatis often is a coexistent pathogen in acute pelvic inflammatory disease. 100 mg intravenously twice daily, is recommended for at least 48 hours followed by oral therapy at the same dosage to complete a 14-day course. Doxycycline : Acute epididymitis is caused by infection with C. trachomatis or Neisseria gonorrhoeae in men <35 years of age. Effective regimens include a single injection of ceftriaxone (250 mg) plus doxycycline, 100 mg orally twice daily for 10 days. Doxycycline: for nonspecific urethritis 100 mg every 12 hours for 7 days; however, azithromycin is usually preferred because it can be given as a single 1-g dose Doxycycline: for lymphogranuloma venereum,100 mg twice daily for 21 days Non-pregnant penicillin-allergic patients who have primary, secondary, or latent syphilis can be treated with a tetracycline regimen such as doxycycline, 100 mg orally twice daily for 2 weeks. Tetracyclines should not be used for treatment of neurosyphilis.

109. … Local Application Except for local use in the eye, topical use of the tetracyclines is not recommended. Minocycline sustained-release microspheres for subgingival administration are used in dentistry. Other Infections Brucella spp: Tetracyclines in combination with rifampin or streptomycin or doxycycline, 200 mg per day, plus rifampin, or the usual dose of doxycycline plus streptomycin 1 g daily, intramuscularly Tularemia, Actinomycosis, Yaws and relapsing fever, leptospirosis, Borrelia spp, atypical mycobacterial pathogens (M. marinum) : Tetracyclines Nocardiosis: Minocycline

110. Therapeutic Uses and Dosage of Chloramphenicol Typhoid Fever Third-generation cephalosporins and quinolones are drugs of choice for the treatment of typhoid fever because they are less toxic and because strains of Salmonella typhi often are resistant to chloramphenicol Bacterial Meningitis Chloramphenicol remains an alternative drug for the treatment of meningitis caused by H. influenzae, N. meningitidis, and S. pneumoniae in patients who have severe allergy to β-lactams and in developing countries

111. AMINOGLYCOSI DES

112. Therapeutic Uses AGs often are combined with a penicillin or cephalosporin for the therapy of serious gram neg. infections: P. aeruginosa, Enterobacter, Klebsiella, Serratia, and other species resistant to less toxic antibiotics, including: UTI, bacteremia, infected burns, osteomyelitis, pneumonia, peritonitis, and otitis

113. STREPTOMYCIN Less active against aerobic gram-negative rods PenicillinG + Streptomycin for treatment of streptococcal or enterococcal endocarditis Drug of choice for the treatment of tularemia Effective for all forms of plague Tuberculosis: Second line agent

114. GIN GENTAMICIN Enterococcal endocarditis: concomitant administration of penicillin and gentamicin for 4-6 weeks has been recommended because of an unacceptably high relapse rate with penicillin alone Gentamicin is generally preferred for its lesser toxicity; also, gentamicin should be used when the strain of enterococcus is resistant to streptomycin AGs should never be mixed in the same solution with penicillins because inactivated by penicillin

115. Pneumonia AGs never used as the sole agent to treat pneumonia acquired in the community or initial treatment for pneumonia acquired in the hospital

116. UTI AGs usually are not indicated for the treatment of uncomplicated UTI, although a single IM dose of gentamicin (5 mg/kg) can cure more than 90% of uncomplicated infections of the lower urinary tract

117. Meningitis Third-generation cephalosporins has reduced the need for AG in most cases, except for gram neg. resistant to β-lactams (Pseudomonas & Acinetobacter)

118. Endocarditis Penicillin and gentamicin in combination are effective as a short-course (i.e., 2-week) regimen for uncomplicated native-valve streptococcal endocarditis

119. TOBRAMYCIN  Antimicrobial activity, PK properties, and toxicity profile are very similar to gentamicin  Preferred AG for treatment of serious infections caused by P. aeruginosa

120. AMIKACIN  Broadest spectrum of antimicrobial activity  Resistant to many AG-inactivating enzymes  In hospitals where gentamicin-and tobramycin-resistant organisms are prevalent  Less active than gentamicin against enterococci  Not active against the majority of g+ anaerobics  For M.tuberculosis, including streptomycin- resistant and atypical strains

121. NEOMYCIN  Broad-spectrum antibiotic  Gram-negative species that are highly sensitive are E.coli, Enterobacter aerogenes, Klebsiella pneumoniae, and Proteus vulgaris  Gram-positive that are inhibited include S. aureus and E. faecalis  M.tuberculosis also is sensitive  Strains of P. aeruginosa are resistant  Irrigation of the bladder  Neomycin has been used topically in a variety of infections of the skin and mucous membranes

122. VANCOMYCIN A complex tricyclic glycopeptide It acts by inhibiting cell wall synthesis

123.  Gram-positive bacteria:  S.aureus and S.epidermidis, also strains resistant to methicillin  S.pyogenes, S.pneumoniae, and viridans streptococci  B.anthracis is highly sensitive  Essentially all species of gram-negative bacilli and mycobacteria are resistant Is the result of alteration of the D-Ala-D-Ala target to D- Ala-D-lactate or D-Ala-D-Ser, which bind vancomycin poorly

124. THERAPEUTIC USES  Vanco-resistant enterococci  Major nosocomial pathogens in the U.S  Enterococcal resistance  Pseudomembranous colitis  Vancomycin can be administered orally, although metronidazole is preferred

125. THERAPEUTIC USES  Should be used only to treat serious infections  like methicillin-resistant staphylococci and severe staphylococcal infections in patients allergic to penicillins and cephalosporins  Vancomycin is less rapidly bactericidal than the antistaphylococcal β -lactams (e.g., nafcillin or cefazolin) and may be less efficacious

127. IMIPENEM Disrupts bacterial cell wall synthesis Very resistant to hydrolysis by most β- lactamases

128. Excellent activity for aerobes and anaerobes  Streptococci  including penicillin-resistant S. pneumoniae  Enterococci  excluding E. faecium and non-β-lactamase-producing penicillin-resistant strains  Staphylococci  including penicillinase-producing  Not methicillin-resistant staphylococci  Listeria  Enterobacteriaceae  including organisms that are cephalosporin-resistant by virtue of expression of extended spectrum β-lactamases  Pseudomonas and Acinetobacter  most strains are inhibited  Anaerobes  including B. fragilis

129. Therapeutic Uses Wide variety of infections including:  urinary tract  lower respiratory  intra-abdominal and gynecological  skin and soft tissue  bone and joint  Imipenem should not be used as monotherapy for infections with P. aeruginosa because of the risk of developing resistance during therapy

130. MEROPENEM  Not sensitive to renal dipeptidase  Toxicity and clinical efficacy are similar to imipenem except that it may be less likely to cause seizures  Clinical experience with meropenem demonstrates therapeutic equivalence with imipenem

131. ERTAPENEM  Differs from imipenem and meropenem by having a longer serum t 1/2  Once-daily dosing  Inferior activity against P. aeruginosa and Acinetobacter spp.  Activity against gram-positive, Enterobacteriaceae, and anaerobes makes it attractive for use in intra- abdominal and pelvic infections

132. AZTREONAM Monocyclic β-lactam Resistant to β-lactamases elaborated by most gram-negative bacteria

133. Antimicrobialactivity Antimicrobial activity  differs from other β-lactams and resembles that of Aminoglycosides  Activity only against gram-negative bacteria  No activity against gram-positive bacteria and anaerobes  Activity against Enterobacteriaceae is excellent, as is that against P. aeruginosa  Highly active against H. influenzae and gonococci  Administered IM or IV

134. POLYMYXIN B & COLISTIN  Polymixins are group antibiotics elaborated by various strains of Bacillus polymyxa  Colistin is produced by Bacillus colistinus  Cationic detergents  Colistin (polymyxin E) is available as colistin sulfate for oral use and as colistimethate sodium for parenteral administration

135. Antimicrobial activities  Polymyxin B and colistin are restricted to gram-negative bacteria  Are not absorbed orally and poorly absorbed from mucous membranes and burn surfaces  They are cleared renally  Polymyxin B sulfate is available for ophthalmic, otic, and topical use  Colistin may be useful as a salvage regimen for infections caused by multiple-drug-resistant organisms