1. BACTERIA AND MYCOBACTERIA Infectious Diseases

2. Classification by Susceptible Organism A microbe is a unicellular or small multicellular organism. Microbes that are capable of producing disease are called pathogens. Types of microbes include: – Bacteria – Viruses – Protozoa – some Algae and Fungi – some Worms (Helminths)

3. Drugs to treat Infection Drugs used to treat infection can be classified according to the type of microbe they affect. The major classifications include: Antibacterial drugsAntiviral drugs Antiretroviral drugs Antifungal drugs Antiparasitic drugsAntiprotozoal drugs Anti-helminthic drugs

4. Classification by Mechanism of Action Antimicrobial drugs work in a variety of ways: – Inhibit organism’s cell wall synthesis – Disrupt organism’s cell wall permeability – Inhibit of protein synthesis of organism – Inhibit of nucleic acid synthesis of organism – Inhibit of metabolic pathways of organism (antimetabolites) – Inhibition of enzyme activity

5. Selective Toxicity Selective toxicity is the ability to suppress or kill an infecting microbe without injury to the host. Selective toxicity is achievable because the drug accumulates in a microbe at a higher level than in human cells. The drug has a specific action on cell structures or biochemical processes that are unique to the microbe. Understanding selective toxicity has made antimicrobial drugs safe and effective for managing infection in humans.

6. Challenge Question The most common location of drug resistant bacteria is A. Inner city apartments B. Homeless shelters C. Jails D. Hospitals

7. Challenge Question The most common location of drug resistant bacteria is A. Inner city apartments B. Homeless shelters C. Jails D. Hospitals D. Hospitals - Hospitals are more likely than any other location to harbor resistant bacteria!

8. Antibiotics Antibiotics generally refer to the classification of drugs used to combat bacteria In addition to being classified by their mechanisms of action, antibiotic drugs are further classified as: Bacteriostatic (slow growth of bacteria) Bacteriocidal (kill the bacteria)

9. Antimicrobial Resistance Antimicrobial resistance is a microbe’s resistance to a drug. Antimicrobial resistance is a major problem, especially in highly developed countries where antimicrobial agents are used daily.

10. Factors that Facilitate the Development of Drug Resistance Too low of an antibiotic dosage Too long of a time between doses Inadequate duration (days) of medication therapy Patients frequently stop taking antibiotics when they feel better. Preventative use of antibiotics or use for viruses. Presence of antibiotics in commercially prepared meats?

11. Pathophysiology: Methicillin-Resistant Staphylococcus Aureus (MRSA) The Staph pathogen is widely resistant to all of the penicillins, not just methicillin. Many strains of MRSA are also resistant to other antibiotics. Closely related to MRSA is methicillin-resistant Staphylococcus epidermidis (MRSE). MRSE frequently colonizes the nasal passages of health care workers, resulting in the spread of nosocomial infections. Vancomycin is the drug of choice to manage infections caused by MRSA and MRSE.

12. Pathophysiology: Penicillin-Resistant Streptococcus Pneumoniae In the past, penicillins have successfully treated pneumococcal infections. Because they are used so frequently, particularly in children and the elderly, strains of penicillin- resistant streptococci are emerging. To decrease penicillin resistance among Streptococcus pneumoniae, the CDC suggested that – Clinicians stop using drugs as prophylaxis for otitis media. – Patients at increased risk of infections should be immunized.

13. Pathophysiology: Vancomycin- Resistant Enterococcus (VRE) Enterococcus – a gastric infection - is generally treated with a combination of antibiotics: an aminoglycoside with a penicillin or an aminoglycoside with a cephalosporin. The penicillin or cephalosporin damages the bacterial cell wall and allows the aminoglycoside to penetrate the cell. Strains of Enterococcus have developed resistance to penicillin, gentamicin, and vancomycin.

14. Pathophysiology: Multiple Drug– Resistant Mycobacterium Tuberculosis (MDR-TB) Multiple drug–resistant TB is increasingly common. Although some of the bacilli are inherently resistant, others develop resistance over the long course of TB treatment, which can last as long as 2 years. The cause of MDR-TB is inadequate drug therapy. To decrease the incidence of MDR-TB, multiple drug therapy is implemented at the onset of treatment, followed by a decrease in the number of drugs.

15. Pathophysiology: Nosocomial Infections A nosocomial infection is an infection that occurs in a hospital or hospital-like setting. According to the WHO, an estimated 2 million patients annually in the US acquire a nosocomial infection. They occur because hospitals have: – A high prevalence of pathogens – A high prevalence of compromised hosts – An efficient mechanism of transmission from patient to patient.

16. Pathophysiology: Extended Spectrum Beta-lactamase Colonization Beta-lactamases are enzymes that provide resistance to β-lactam antibiotics such as penicillins and cephalexin by breaking the antibiotics' structure. Some people carry beta-lactamases in their bodies and are called “colonized”. There is evidence that the prevalence of Extended Spectrum Beta-lactamase (ESBL)producing bacteria have been gradually increasing in acute care hospitals leading to the spread of drug resistance.

17. General Considerations for Selecting Antimicrobial Therapy The most important factor in managing infections is to “match the drug with the bug.” Several factors must be considered when choosing the drug of choice or an alternative: -Identification of the pathogen-Drug susceptibility -Drug spectrum-Drug dose -Time to affect the pathogen-Site of infection -Patient assessment

18. Drug Susceptibility To choose the right drug for the infection, a drug susceptibility test is optimal. The site of infection is frequently a clue to the causative agent. Prescribing antibiotic treatment before the pathogen has been definitively identified is called empiric therapy. The most common test to identify drug susceptibility is called a culture and sensitivity.

19. Drug Susceptibility (cont.) Disk diffusion test: This is the most commonly performed test to determine drug susceptibility.

20. Drug Spectrum Choosing a drug with the narrowest possible spectrum is important. The range of microbes against which a drug is active is its spectrum. Narrow-spectrum drugs affect only a few microorganisms, whereas broad-spectrum drugs affect many microorganisms. Broad-spectrum antibiotics encourage drug resistance An alternative to the use of broad-spectrum antimicrobials is combination therapy.

21. Drug Spectrum (cont.) Combination therapy is used frequently for an initial severe infection in which the pathogen is unknown. Once the pathogen is known, the appropriate drug can be administered. Although combination therapy has many benefits, it also has many disadvantages compared with monotherapy. Drug Dose: Choosing the antimicrobial agent with the lowest effective dose is important. Pediatric doses are often calculated as mg/kg/day.

22. Duration Choosing the antimicrobial agent that takes the shortest time to affect the pathogen is equally important. The drug must remain at the site of infection at high drug concentrations for a long enough time. The duration of treatment depends on: – The type of pathogen – The site of infection – The presence or absence of host defenses. The duration of antimicrobial treatment is generally 7 to 10 days, but it may be extended to 30 days or more for some infections.

23. Site of Infection To be effective, a drug must be able to reach the site of infection at a high concentration. Poor vascularization = Poor drug concentrations Areas difficult to get antimicrobials into include: – Brain and meninges – Inner ear – Within a closed abscess – Around foreign objects, e.g. Pacemakers or Prosthetic joints

24. Patient Assessment Factors Health status: – Immune status and other diseases of the patient. Life span and gender: – Infants and the elderly are most vulnerable to drug toxicity. Culture and inherited traits: – Some genetic factors may influence antimicrobial therapy; e.g. CyP450 liver enzyme metabolism – Global health factors

25. Challenge Question ___________ is prescribing antibiotics before identification of the pathogen. A. Empiric therapy B. Standard of care C. Prophylactic therapy D. Inoculation therapy

26. Challenge Question Empiric therapy is prescribing antibiotics before identification of the pathogen.

27. Monitoring Antimicrobial Therapy Successful antimicrobial therapy eradicates the infection. Some antimicrobial agents have the ability to induce toxic adverse effects. Serum drug levels should be monitored for drugs that have a high potential for severe adverse effects. Serum peak (high) and trough (low) levels may be measured. The goal is to keep the serum drug level within the therapeutic margin.

28. Bacterial Cell Physiology Bacteria are surrounded by a rigid cell wall that is responsible for maintaining the integrity of the internal cellular environment. The interior of the cell has a high osmotic pressure. If the bacterial cell wall is not intact, the internal osmotic pressure draws fluid into the cell until it bursts. Even when the cell wall is breached by an antibiotic, bacterial death may not occur because of bacterial resistance.

29. Pathophysiology Bacteria may cause infections in any body organ, structure, or fluid. In addition to the original bacterial infection, the loss of certain “good” bacteria may result in a superinfection. Drugs that affect the bacterial cell wall must be able to penetrate the cell wall to bind to molecular targets on the cell.

30. Beta-lactamase Beta-lactamase drugs are enzymes that disrupt the beta-lactam ring of the cell wall.

31. Penicillins Penicillins were the first antibiotics. Identified in 1929 and developed by Alexander Fleming from Penicillium molds. Subsequent versions of penicillin have been developed to decrease the adverse effects of the drug and to modify its ability to act on resistant bacteria. Penicillins are also called beta-lactam antibiotics Penicillins are classified as narrow spectrum. Prototype drug: Penicillin (Amoxicillin)

32. Penicillin: Core Drug Knowledge Pharmacotherapeutics – Infections caused by susceptible gram-positive bacteria Pharmacodynamics – Inhibits the third and final stage of bacterial cell wall synthesis Side effects – GI upset Adverse effects – Rash, fever, wheezing, possibly allergy (anaphylaxis and death)

33. Cephalosporins The cephalosporins are similar to penicillins in structure and in activity Also considered beta-lactam antibiotics. 4 generations of cephalosporins have been introduced, each group with its own spectrum of activity. Prototype drug: cephalexin (Keflex)

34. Cefalexin: Core Drug Knowledge Pharmacotherapeutics – Treats many kinds of infections Pharmacodynamics – Disrupts bacterial cell wall synthesis Side effects – GI symptoms, headache, dizziness, lethargy Adverse effects – Rash, paresthesias (numbness & tingling), and nephrotoxicity

35. Vancomycin Vancomycin (Vancocin) is a complex and unusual antibiotic. It is the only drug in its class. The use of Vancomycin is limited by its toxicity. Vancomycin is usually used when other antibiotics fail to resolve an infection. It is able to eradicate most gram-positive pathogens.

36. Vancomycin: Core Drug Knowledge Pharmacotherapeutics – Treating bacterial septicemia, endocarditis, bone and joint infections Pharmacodynamics – Inhibits cell wall synthesis by altering the cell’s permeability Adverse effects – Ototoxicity and nephrotoxicity

37. Challenge Question The oral form of vancomycin is used to treat A. Gastric ulcers B. Prostatitis C. Rupture of diverticulum D. Clostridium difficile

38. Challenge Question The oral form of vancomycin is used to treat A. Gastric ulcers B. Prostatitis C. Rupture of diverticulum D. Clostridium difficile Oral administration is used in treating some GI infections, such as clostridium difficile (C. diff)

39. ANTIBIOTICS AFFECTING PROTEIN SYNTHESIS

40. Inhibition of Protein Synthesis Ribosomes from human cells and those from bacterial cells are structurally different. Some antibiotics bind with or interact with the bacterial ribosomes thus inhibiting the bacterial cell’s protein synthesis and causing cell death Examples: – Tetracyclines – Aminoglycoside antibiotics – Erythromycin and clindamycin – Chloramphenicol

41. Physiology The process of protein synthesis in cells is divided into two sections: transcription and translation. – Transcription occurs within the nucleus, producing messenger ribonucleic acid (mRNA). RNA combines with Amino Acids (taken in through diet) in the cytoplasm to create proteins.

42. Protein Synthesis

43. Antibiotics that Affect Protein Synthesis A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins in the cell. It usually refers to antibiotics that act at the ribosome level - either on the ribosome itself or on the translation factor. Trivia fact: Ricin, the chemical toxin derived from the Castor Oil Plant (Castor Beans) works in this manner. Ricin has been implicated in biological terrorism attacks.

44. Macrolide Antibiotics The macrolide antibiotics have been in use since 1952. They are characterized by molecules made up of large-ring lactones. Macrolides are bacteriostatic or bactericidal in susceptible bacteria. Prototype drugs: Erythromycin, Azithromycin (Zithromax)

45. Azithromycin: Core Drug Knowledge Pharmacotherapeutics Treat Legionnaire disease, Mycoplasma pneumoniae pneumonia, diphtheria, chlamydial infections, and chancroids (boils on the genitals) Pharmacodynamics Inhibiting RNA-dependent protein synthesis at the chain elongation step Side effects – GI symptoms Adverse effects – Urticaria (hives), Rash, Interstitial nephritis

46. Aminoglycosides Aminoglycosides have been in use since 1944. They are extremely effective antibiotics for treating severe infections. However, their use is limited because of the potential for serious adverse effects. Prototype drug: Gentamicin

47. Gentamicin: Core Drug Knowledge Pharmacotherapeutics – Serious infections Pharmacodynamics – Entering the bacterial cell and binding to the 30S ribosomal subunit Adverse effects – Neurotoxicity, nephrotoxicity, ototoxicity, and neuromuscular blockade

48. Oxazolidinones Oxazolidinones are the first new class of antibiotics developed specifically for treating methicillin-resistant Staphylococcus aureus (MRSA) infections. Prototype drug: linezolid (Zyvox)* *not on list MRSE Abscess

49. Inhibition of Nucleic Acid Synthesis Many bacteria use enzymes for replication that do not exist in human cells. Nucleic acid synthesis in cells is dependent on folic acid (folate): – Fluoroquinolones inhibit DNA-gyrase, an enzyme needed for bacterial DNA replication. Ciprofloxacin (Cipro), Levofloxacin (Levaquin) – Sulfonamides inhibit bacterial folate synthesis Sulfamethoxazole (Bactrim)

50. Quinolones/Fluoroquinolones Quinolones/Fluoroquinolones are effective for aerobic gram-negative and gram-positive infections. Like cephalosporins, quinolones are subdivided into 4 generations. Prototype drug: ciprofloxacin (Cipro)

51. Ciprofloxacin: Core Drug Knowledge Pharmacotherapeutics – Active against aerobic gram-negative organisms Pharmacokinetics – Administered: oral, parenteral, and topical. Metabolism: liver. Excreted: urine and feces. Pharmacodynamics – Inhibits deoxyribonucleic acid (DNA) gyrase, an enzyme needed for bacterial DNA replication

52. Ciprofloxacin: Core Drug Knowledge (cont.) Contraindications and precautions – Allergy, pregnancy, and lactation Side effects – GI upset, headache, and restlessness Adverse effects – Arthropathy: Inflammation of one or more joints

53. Challenge Question The most clinically important adverse reaction of ciprofloxacin (Cipro) is: – A. Photosensitivity – B. Arthropathy – C. Hepatotoxicity – D. Neurotoxicity

54. Challenge Question The most clinically important adverse reaction of ciprofloxacin (Cipro) is: B. Arthropathy The most clinically important adverse reaction is arthropathy (joint disease). This often irreversible adverse reaction can occur in children under 18 years of age.

55. Medications to Treat Urinary Tract Infections

56. Physiology Normally, several host defenses protect a person from UTI. – The urinary bladder is lined with a mucin layer that acts as a barrier against bacterial invasion. Elderly and postmenopausal women produce less mucin and therefore are at a higher risk for UTI. Another host defense is the washout phenomenon. – When you urinate, you “wash out” organisms Immune mechanisms provide another host defense.

57. Pathophysiology Urinary tract infections can be: – Complicated or uncomplicated, – Acute, recurrent, or chronic. Types Asymptomatic bacteriuria: no symptoms of UTI Cystitis: infection of the lower urinary tract Prostatitis: associated with urethritis or cystitis Acute pyelonephritis: infection of the kidneys and renal pelvis

58. Diagnosis of UTI Diagnosis of UTI is based on the patient’s symptoms and a positive urine dipstick test. A urinalysis (UA) is required for women who are pregnant or over the age of 55, men with urinary symptoms, and patients with recurrent symptoms. – A successful UA requires a midstream or clean- catch urine specimen. When obtaining urine for a UA from a catheterized patient, the urine should be withdrawn from the proximal port on the catheter tubing and not from the urine collection bag.

59. Sulfonamides Sulfonamides have been the mainstay of treatment for UTIs for many years. Unfortunately, the incidence of sulfonamide- resistant bacteria has steadily increased. Prototype drug: sulfamethoxazole/trimethoprim (SMZ-TMP) (Bactrim DS, Septra DS)

60. Sulfamethoxazole-Trimethoprim: Core Drug Knowledge Pharmacotherapeutics – Uncomplicated UTIs and systemic infections Pharmacokinetics – Administered: oral. Metabolism: liver. Peak: 4 hours. Pharmacodynamics – Interferes with the synthesis of folic acid (folate) in the offending organism.

61. Sulfamethoxazole-Trimethoprim: Core Drug Knowledge (cont.) Side effects – Nausea, vomiting, diarrhea Adverse effects – Hematologic effects (e.g., anemia) Maximizing therapeutic effects – Administer SMZ-TMP 1 hour before or 2 hours after a meal with a full glass of water to enhance the absorption of the drug. Minimizing adverse effects – Administer SMZ-TMP with a full glass of water. – Fluid intake should increase by 1.5 L/day.

62. Urinary Tract Antiseptics Urinary tract antiseptics are drugs that work by local action because high serum levels are not achievable. Prototype: Nitrofurantoin (Macrodantin, Macrobid) – Presumed to interfere with several bacterial enzyme systems – Although nitrofurantoin has a broad spectrum of activity, it is not an effective systemic drug because it is rapidly excreted by the kidneys. – Contraindicated in patients with renal impairment

63. Urinary Tract Analgesic Phenazopyridine (Pyridium) is used frequently for UTIs but does not have any antibacterial activity. The precise mechanism of action is not known. It is excreted in the urine, where it exerts a topical analgesic effect. – It is indicated for the symptomatic relief of pain, burning, frequency, and urgency. – It is important to teach the patient that his or her urine will appear orange or dark red. Side effects – Headache, rash, pruritus (itching), and GI disturbances.

64. Drugs Treating Mycobacterial Infections

65. Disruption of Cell Wall Permeability Drugs that disrupt the integrity of the bacterial cell wall cause the cell to leak components that are vital to its survival.

66. Challenge Question Mycobacteria are slow-growing microbes that require short treatment. A. True B. False B. False! Mycobacteria are slow-growing microbes that require prolonged treatment, generally with multiple medications. Many of the antimycobacterial drugs may be used for more than one type of infection.

67. Pathophysiology (Examples) Tuberculosis (TB) is a mycobacterial infection that is found most frequently in the lungs. – TB is an airborne disease spread by droplet nuclei. Symptoms of active TB include night sweats, cough, low-grade fever, fatigue, weight loss, and anorexia. Leprosy – Is a chronic infectious disease caused by M. leprae. The disease mainly affects the skin, the peripheral nerves, the mucosa of the upper respiratory tract, and the eyes.

68. Drugs for Treating Mycobacterium Tuberculosis Infection Anti-TB drugs are divided into first- and second- line drugs. First-line drugs are those that are effective for treatment and have manageable toxicities. Because TB can easily become drug resistant, combination therapy with three to four drugs is common. Prototype drug: isoniazid (INH)

69. Isoniazid: Core Drug Knowledge Pharmacotherapeutics – Used to treat or prevent TB Pharmacokinetics – Administered: oral or IM. Metabolism: liver. Excreted: urine and feces. Peak: 12 hours. Pharmacodynamics – Disrupts the synthesis of the bacterial cell wall of the tuberculosis bacterium.

70. Isoniazid: Core Drug Knowledge (cont.) Contraindications and precautions – Acute hepatic disease Adverse effects – Hepatotoxicity, peripheral neuropathy, and encephalopathy Drug interactions (lots!) – Antiseizure drugs, alcohol, aluminum-based antacids, benzodiazepines, disulfiram, enflurane, ketoconazole, meperidine, warfarin

71. Isoniazid: Planning and Interventions Maximizing therapeutic effects – Administer INH to the patient with an empty stomach 1 hour before or 2 hours after meals to increase absorption. Minimizing adverse effects – Advise patients to report any symptoms of hepatitis, including anorexia, malaise, fatigue, jaundice, or nausea.

72. Drugs for Treating Mycobacterium Leprae (Leprosy) Infection Multidrug therapy, the standard approach for other mycobacterial infections, is also recommended for treating leprosy. Rifampin is the drug of choice for both types of leprosy. Rifampin is also used in Tuberculosis treatment Prototype: Rifampin

73. Rifampin: Core Drug Knowledge Pharmacotherapeutics – Treating leprosy. – Used in TB Treatment as second line drug. Pharmacokinetics – Administered: parenterally or orally. Metabolism: liver. Excreted: feces. Pharmacodynamics – Blocks initiation of RNA transcription

74. Rifampin: Core Drug Knowledge (cont.) Contraindications and precautions – Hypersensitivity Side/Adverse effects – Discolor bodily fluids, GI disturbances, fever, chills, headache, and fatigue – Liver toxicity, renal toxicity

75. Rifampin: Teaching, Assessment, and Evaluations Patient and family education – Explain the potential effect of rifampin on the liver. – Advise patients with soft contact lenses to consult their ophthalmologist for an alternate form of contacts or glasses as it may discolor tears and stain the soft lenses. Ongoing assessment and evaluation – Periodic testing of hematopoietic, renal, and hepatic function should be arranged.

76. Homework: Case Study Assignment Review the Case Study: Strep Throat and answer the associated questions. Post in the ‘Assignments’ tab.