Pharmacology-IV Student Book PDF Zagazig University

Pharmacology-IV Zagazig University Faculty of Pharmacy Dept. of Pharmacology & Toxicology STUDENT BOOK OF PHARMACOLOGY-IV Fourth Year Pharm D Students By Prof. Salah Gharieb Prof. Mo...

Pharmacology-IV Zagazig University Faculty of Pharmacy Dept. of Pharmacology & Toxicology STUDENT BOOK OF PHARMACOLOGY-IV Fourth Year Pharm D Students By Prof. Salah Gharieb Prof. Mona Fouad Ass. Prof. Islam Ahmed Elazizy 1 ‫‪Pharmacology-IV‬‬ ‫رسالة الكلية‬ ‫تهدف كلية الصيدلة جامعة الزقازيق إلى إمداد املجتمع املحلى واإلقليمي بصيادلة ذوي‬ ‫كفاءة عالية ومهارات مهنية متميزة وقيم أخالقية تسهم في تطوير الصناعات الدوائية‬ ‫وتوكيد جودة الدواء وتحسين الخدمات الصحية باملجتمع وذلك عن طريق تطوير‬ ‫وتحديث البرامج األكاديمية وطرق التعليم والتعلم ودعم األنشطة الطالبية املختلفة‬ ‫وتنمية قدرات أعضاء هيئة التدريس ومعاونيهم والجهاز اإلدارى واإلرتقاء باألبحاث‬ ‫العلمية والتطبيقية الهادفة ومواصلة التعليم الصيدلي املستمر‬ ‫‪2‬‬ Pharmacology-IV Course Contents Week Content Lecturer 1 Endocarditis Prof. Salah Ghareib 2 Surgical prophylaxis Prof. Salah Ghareib 3 Pneumonia Prof. Mona Fouad 4 Pneumonia Prof. Mona Fouad 5 Influenza; Sinusitis, RSV infection Prof. Mona Fouad 6 Urinary tract infections Prof. Mona Fouad 7 Midterm exam 8 Acute otitis media; Eye infection Prof. Mona Fouad 9 Skin and skin-structure infections Ass. Prof. Islam Ahmed 10 Osteomyelitis Ass. Prof. Islam Ahmed 11 Meningitis; Brain abscess Ass. Prof. Islam Ahmed 12 Peritonitis Ass. Prof. Islam Ahmed 13 Clostridium difficile infection Ass. Prof. Islam Ahmed 3 Pharmacology-IV Part I Prof. Salah Gharieb 4 Pharmacology-IV INFECTIOUS DISEASES I. INFECTIVE ENDOCARDITIS A. Introduction 1. Infection of the heart valves or other endocardial tissue 2. Platelet-fibrin complex becomes infected with microorganisms: Vegetation 5 Pharmacology-IV 3. Main risk factors include mitral valve prolapse, prosthetic valves and intravenous drug abuse. 4. Three or four cases per 100,000 people per year B. Presentation and Clinical Findings 1. Signs and symptoms a. Fever: Low grade and remittent b. Cutaneous manifestations (50% of patients): Petechiae (including conjunctival), Janeway lesions, splinter hemorrhage. c. Cardiac murmur (90% of patients) d. Arthralgias, myalgias, low back pain, arthritis e. Fatigue, anorexia, weight loss, night sweats 2. Laboratory findings a. Anemia: Normochromic, normocytic b. Leukocytosis c. Elevated erythrocyte sedimentation rate and C-reactive protein d. Positive blood culture in 78%–95% of patients 6 Pharmacology-IV 3. Complications a. Congestive heart failure: 38%–60% of patients b. Emboli: 22%–43% of patients c. Mycotic aneurysm: 5%–10% of patients C. Microbiology 1.Three to five blood cultures of at least 10 mL each should be obtained during the first 24–48 hours. 2. Empiric therapy should be initiated only in acutely ill patients. In these patients, three blood samples should be obtained during a 15- to 20-minute period before antibiotics are initiated Incidence of Microorganisms in Endocarditis 7 Pharmacology-IV D. Treatment (treatment Recommendation for Endocarditis) HACEK = Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella; MIC = minimum inhibitory concentration; PCN = penicillin 8 Pharmacology-IV Endocarditis Prophylaxis Recommended Prophylaxis for Dental or Respiratory Tract Procedures 9  Pharmacology-IV II. SURGICAL PROPHYLAXIS A. Introduction 1. Prophylaxis: Administering the putative agent before bacterial contamination occurs 2. Early therapy: Immediate or prompt institution of therapy as soon as the patient presents; usually, contamination or infection will have preceded the initiation of therapy (e.g., dirty wounds). B. Classification of Surgical Procedures 10 Pharmacology-IV C. Risk Factors for Postoperative Wound Infections 1. Bacterial contamination a. Exogenous sources: Flaw in aseptic technique b. Endogenous sources i. Most important except in clean procedures ii. Patient flora causes infection. 2. Host resistance a. Extremes of age b. Nutrition (i.e., malnourished patients) c. Obesity d. Diabetes mellitus (decreased wound healing and increased risk of infection) e. Immunocompromised f. Hypoxemia g. Remote infection h. Presence of foreign body (healthy person tolerates inoculum of 105, but in the presence of a foreign body, only 102 are needed) D. Indications for Surgical Prophylaxis 1. Common postoperative infection with low morbidity 2. Uncommon postoperative infection with significant morbidity and mortality 11 Pharmacology-IV E. Principles of Prophylaxis 1. Timing: Antibiotics must be present in the tissues at the time of bacterial contamination (incision) and throughout the operative period; on-call dosing is not acceptable. a. Administering antibiotics earlier than immediately preoperatively (within 60 minutes before incision or 60–120 minutes if using vancomycin or a fluoroquinolone) is unnecessary. b. Initiating antibiotics postoperatively is no more effective than administering no prophylaxis. c. Antibiotics should be redosed for extended surgical procedures. d. Redose if the surgery lasts longer than 4 hours (or more than 2 half-lives of the antibiotic) or involves considerable blood loss. Principles of prophylaxis. Source: Information from: Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med 1992;326:281-6 12 Pharmacology-IV 2. Dosage a. Adequate dosing is necessary to prevent postoperative skin infections. Obese patients have a higher incidence of postoperative infections. b. Appropriate dosing i. Cefazolin: 2 g (3 g for patients weighing 120 kg or more) ii. Ceftriaxone, cefotetan, cefoxitin: 2 g iii. Clindamycin: 900 mg iv. Vancomycin: 15 mg/kg 3. Duration a. Most procedures, including GI, orthopedic, and gynecologic procedures, warrant antibiotics only as long as the patient is in the operating room; administration beyond surgical closure is not necessary. b. Cardiac procedures may warrant 24 hours of antibiotics after surgery. 4. Spectrum a. Need only activity against skin flora unless the operation violates a hollow viscus mucosa b. GI, genitourinary, hepatobiliary, and some pulmonary operations warrant additional antibiotics. c. Colorectal surgery is one procedure in which broad-spectrum aerobic and anaerobic coverage is most effective. d. Try to avoid a drug that may be needed for therapy if infection occurs. 5. Adverse reactions and bacterial resistance a. Antibiotic prophylaxis should not cause greater morbidity than the infection it prevents. 13 Pharmacology-IV b. Overuse may lead to resistance, which could prevent further use of the antibiotic for surgical prophylaxis or other infections (duration of administration is an important factor). 6. Cost a. Prophylaxis can account for a substantial portion of the antibiotic budget. b. Must be weighed against the cost of treating one person with a postoperative infection F. Antibiotic Prophylaxis in Specific Surgical Procedures Note: For patients colonized with MRSA, a single preoperative dose of vancomycin can be added. 1. Gastrointestinal tract a. Gastric or duodenal i. Because of acidity, little normal flora ii. Rates of intragastric organisms and postoperative infections increase with increasing pH iii. Indicated for morbid obesity, esophageal obstruction, decreased gastric acidity, or decreased GI motility iv. Recommendation: Cefazolin 2 g before induction b. Biliary i. Biliary tract normally has no organisms. ii. Indicated for high-risk patients. (Often, intraoperative cholangiography reveals unexpected common duct stones, so some studies recommend using antibiotics in all biliary surgery. In addition, studies have shown an increase in infection rates without risk factors.) 14 Pharmacology-IV (a) Acute cholecystitis (b) Obstructive jaundice (c) Common duct stones (d) Age older than 70 years iii. Recommendation: Cefazolin, cefoxitin, cefotetan, or ceftriaxone 2 g or ampicillin/sulbactam 3 g before induction c. Appendectomy i. Acutely inflamed or normal appendix: Less than 10% risk ii. Evidence of perforation: More than 50% risk (treatment necessary) iii. If perforated appendix, treat for 3–7 days iv. Recommendation: Cefoxitin or cefotetan 2 g (or cefazolin plus metronidazole) before induction d. Colorectal i. A 30%–77% infection rate without antibiotics ii. One of the few surgical procedures in which coverage for aerobes and anaerobes has proved most effective iii. Preoperative antibiotics (a) Combined oral and parenteral regimens may be better than parenteral regimens alone. (b) Oral regimens are inexpensive; however, some data suggest they are less effective when used alone (without parenteral agents), have greater toxicity, and may increase the risk of C.difficile infections. e. Recommendation i. Cefazolin or ceftriaxone 2 g plus metronidazole 500 mg (or cefoxitin or cefotetan 2 g or ampicillin/sulbactam 3 g or ertapenem 1 g or 15 Pharmacology-IV gentamicin/tobramycin 5 mg/kg plus clindamycin 900 mg– metronidazole 500 mg) before induction ii. With or without neomycin 1 g orally and erythromycin 1 g orally at 19, 18, and 9 hours before surgery or neomycin 2 g orally and metronidazole 2 g orally at 13 and 9 hours before surgery iii. Mechanical bowel preparation is not recommended and may be harmful. 2. Obstetrics and gynecology a. Vaginal or abdominal hysterectomy i. Antibiotics are most effective in vaginal hysterectomies but generally are given for both procedures. ii. Recommendation: Cefazolin or cefoxitin or cefotetan 2 g (or ampicillin/sulbactam 3 g) before inductionb. Cesarean section. Recommendation: Cefazolin 2 g after the cord is clamped 3. Cardiothoracic a. Cardiac surgery i. Antibiotics decrease the risk of mediastinitis ii. Recommendation: Cefazolin or cefuroxime 2 g preinduction (plus intraoperative doses), if MRSA is probable or patient has been hospitalized, use vancomycinb. a. Pulmonary resection (i.e., lobectomy and pneumonectomy). Recommendation: Cefazolin 2 g before induction (or ampicillin/sulbactam 3 g or vancomycin 15 mg/kg) c. Vascular surgery i. High mortality with infected grafts 16 Pharmacology-IV ii. Recommendation: Cefazolin 2 g before induction and every 8 hours for three doses; if MRSA is probable, use vancomycin 4. Orthopedic a. Prophylaxis is indicated when surgery involves prosthetic materials (i.e., total hip or knee, nail, or plate). Recommendation: Cefazolin 2 g before induction (or vancomycin) 5. Head and neck a. Indicated for major surgical procedures when an incision is made through the oral or pharyngeal mucosa b. Recommendation: Cefazolin or cefuroxime 2 g plus metronidazole 500 mg or ampicillin/sulbactam 3 g or clindamycin 900 mg before induction 6. Urologic a. In general, not recommended b. Indicated if patient has a positive urine culture before surgery (should treat and then operate) c. If therapy is unsuccessful, cover for the infecting organism and operate 17 Pharmacology-IV Part II Prof. Mona Fouad 18  Pharmacology-IV III- RESPIRATORY TRACT INFECTIONS Pneumonia 1. Pneumonia is the most common cause of death attributable to infectious diseases (very high rates in older adults). 2. Hospital-acquired pneumonia (HAP) is the second most common nosocomial infection (0.6%–1.1% of all hospitalized patients). There is a higher incidence in patients in the intensive care unit recovering from thoracic or upper abdominal surgery and in older adults. 3. Mortality rates a. Community-acquired pneumonia (CAP) without hospitalization: Less than 1% b. CAP with hospitalization: About 14% c. Ventilator-associated pneumonia (VAP): About 20%–50% 19  Pharmacology-IV B. Community-Acquired Pneumonia 1. Definition: Acute infection of the pulmonary parenchyma, accompanied by an acute infiltrate consistent with pneumonia on chest radiograph or auscultatory findings, acquired in the community. Patients must not have been hospitalized recently, nor had regular exposure to the health care system. 20  Pharmacology-IV 2. Symptoms of CAP are listed below. Older adults often have fewer and less severe findings (mental status changes are common). a. Fever or hypothermia b. Rigors c. Sweats d. New cough with or without sputum (90%) e. Chest discomfort (50%) f. Onset of dyspnea (66%) g. Fatigue, myalgias, abdominal pain, anorexia, and headache 21  Pharmacology-IV 3. Hospitalization should be based on a clinical prediction rule for prognosis (e.g., Pneumonia Severity Index [PSI] – Table 1 and Table 2). 22 Pharmacology-IV 23 Pharmacology-IV 4. ICU or general medicine floor should be based on a clinical prediction rule for prognosis (e.g., 2007 Infectious Diseases Society of America/American Thoracic Society [IDSA/ATS] criteria for defining severe community- acquired pneumonia – Table 3). C. HAP and VAP 1. HAP: Pneumonia in a nonventilated patient that occurs 48 hours or more after admission and was not incubating at the time of admission 2. VAP: Pneumonia that arises more than 48 hours after endotracheal intubation 4. Risk factors for nosocomial pneumonia a. Intubation and mechanical ventilation b. Supine patient position c. Enteral feeding d. Oropharyngeal colonization e. Stress bleeding prophylaxis f. Blood transfusion g. Hyperglycemia h. Immunosuppression or corticosteroids i. Surgical procedures: thoracoabdominal, upper abdominal, thoracic 24 Pharmacology-IV j. Immobilization k. Nasogastric tubes l. Previous antibiotic therapy m. Admission to the intensive care unit n. Advanced age o. Underlying chronic lung disease. D. Microbiology (Table 3) Table 3. Incidence of Pneumonia by Organism COPD = chronic obstructive pulmonary disease; 25  Pharmacology-IV HIV = human immunodeficiency virus. E. Therapy of pneumonia 1. CAP a. Empiric treatment of nonhospitalized patients i. No comorbidities or risk factors for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa (a) Amoxicillin (dosing 1 g three times daily) (b) Doxycycline (c) Macrolide (clarithromycin or azithromycin) if local pneumococcal resistance to macrolides is less than 25%. ii. Comorbidities (chronic obstructive pulmonary disease [COPD], diabetes mellitus, alcoholism, chronic renal or liver failure, congestive heart failure, malignancy, asplenia, or immunosuppression) (a) Respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin dosing 750 mg once daily) (b) Macrolide or doxycycline with amoxicillin/clavulanate or cefpodoxime or cefuroxime b. Empiric treatment of hospitalized patients with non-severe pneumonia (may need to add other antibiotics if the patient has risk factors for Pseudomonas aeruginosa or MRSA) i. Respiratory fluoroquinolone (moxifloxacin or levofloxacin) ii. β-Lactam (ampicillin/sulbactam, ceftriaxone, or ceftaroline) plus a macrolide (or doxycycline) c. Empiric treatment of hospitalized patients with severe pneumonia necessitating intensive care unit treatment (may need to add other antibiotics if the patient has risk factors for P. aeruginosa or methicillin-resistant S. aureus [MRSA]) 26  Pharmacology-IV i. Ampicillin/sulbactam plus either a respiratory fluoroquinolone or a macrolide ii. Ceftriaxone plus either a respiratory fluoroquinolone or a macrolide iii. Ceftaroline plus either a respiratory fluoroquinolone or a macrolide d. Treatment duration: At least 5 days; duration should be guided by a validated measure of clinical stability (resolution of vital sign abnormalities, ability to eat, and normal mentation) 2. CAP and Risk Factors for MRSA or P. aeruginosa a. Treat with CAP guideline regimens. b. Additional antibiotics with MRSA activity i. Include if prior respiratory isolation of MRSA ii. Include if patient has severe pneumonia and locally validated risk factors for MRSA (especially hospitalization and parenteral antibiotics given in past 90 days) iii. Vancomycin or linezolid. c. Additional antibiotics with Pseudomonas activity i. Include if prior respiratory isolation of P. aeruginosa ii. Include if patient has severe pneumonia and locally validated risk factors for P. aeruginosa (especially hospitalization and parenteral antibiotics given in past 90 days). iii. Piperacillin/tazobactam, cefepime, ceftazidime, imipenem, meropenem, or aztreonam - Therapy with additional antibiotics should be de-escalated on the basis of culture results, nasal PCR for MRSA, and clinical improvement. 27  Pharmacology-IV 2. VAP a. Empiric regimen should include antibiotics with activity against S. aureus (MSSA), P. aeruginosa, and other gram-negative organisms. b. Options for single agents: Piperacillin/tazobactam, cefepime, levofloxacin, imipenem, or meropenem. c. Two antibiotics with activity against P. aeruginosa should be included if the patient has risk factors for MDR organisms (see below) or if P. aeruginosa resistance in the hospital unit to the antibiotic considered for monotherapy is greater than 10%. In addition, use two agents for patients with structural lung disease (bronchiectasis or cystic fibrosis). 28  Pharmacology-IV i. Options for first agent: Antipseudomonal β-lactam (ceftazidime, cefepime, imipenem, meropenem, piperacillin/tazobactam, or aztreonam). Ceftazidime and aztreonam only if an antibiotic with MRSA activity is also being used. ii. Options for second agent: Aminoglycoside, fluoroquinolone (ciprofloxacin, levofloxacin) or colistin (aztreonam may be used with another β-lactam if no other second option is available) d. Risk factors for MDR organisms i. Intravenous antibiotic therapy within the past 90 days ii. Hospitalization of 5 days or more (VAP only) iii. Septic shock at time of VAP (VAP only) iv. Acute respiratory distress syndrome preceding VAP (VAP only) v. Acute renal replacement therapy before VAP (VAP only) e. An antibiotic with activity against MRSA should be included if the patient has risk factors for MDR organisms (see below) or if MRSA incidence in the hospital unit is greater than 10%–20%. i. Options if MRSA activity necessary: Vancomycin or linezolid ii. If a MRSA agent is used, then ceftazidime and aztreonam are potential alternative choices for the antipseudomonal agent. f. Ideally, dose antibiotics based on pharmacokinetic/pharmacodynamic data, including antibiotic serum concentrations, extended infusions of β-lactams and weight-based dosing of aminoglycosides g. Antibiotics should be de-escalated on the basis of culture results. Antibiotic therapy for P. aeruginosa can be de-escalated to one active agent on the basis of culture and sensitivity results. 29  Pharmacology-IV Antibiotic therapy for MRSA can be de-escalated/discontinued on the basis of nasal PCR for MRSA results. h. Treatment duration: 7-day course is recommended for most infections. 3. HAP a. Empiric regimen should include antibiotics with activity against S. aureus (MSSA), P. aeruginosa, and other gram-negative organisms. b. Options for single agents: Piperacillin/tazobactam, cefepime, levofloxacin, imipenem, or meropenem. c. Two antibiotics with activity against P. aeruginosa should be included if the patient has received antibiotics in the past 90 days or has a high risk of mortality (indicated by the need for ventilator support or septic shock due to HAP). -In addition, use two agents for patients with structural lung disease (bronchiectasis or cystic fibrosis). i. Options for first agent: Antipseudomonal β-lactam (ceftazidime, cefepime, imipenem, meropenem, piperacillin/tazobactam, or aztreonam) ii. Options for second agent: Aminoglycoside, fluoroquinolone (ciprofloxacin, levofloxacin), or colistin (aztreonam may be used with another β-lactam if no other second option is available) iii. Aminoglycosides should not be used as monotherapy. d. An antibiotic with activity against MRSA should be included -if the patient has risk factors for MDR organisms, -if MRSA incidence in the hospital unit is greater than 10%–20%, or -if the patient is at a high mortality risk. i. Options if MRSA activity necessary: Vancomycin or linezolid ii. If a MRSA agent is used, then ceftazidime and aztreonam are potential alternative choices for the antipseudomonal agent. iii. Use oxacillin, nafcillin, or cefazolin for proven MSSA infections. e. Ideally, dose antibiotics according to pharmacokinetic/pharmacodynamic data, including antibiotic serum concentrations, extended infusions of β-lactams, and weight-based dosing of aminoglycosides. f. Antibiotics should be de-escalated according to culture results. 30  Pharmacology-IV Antibiotic therapy for P. aeruginosa can be de-escalated to one active agent on the basis of culture and sensitivity results. Antibiotic therapy for MRSA can be de-escalated/discontinued on the basis of nasal PCR for MRSA results. g. Treatment duration: A 7-day course is recommended for most infections. F. Antibiotic Resistance 1. Innate resistance – Based on characteristics of the microorganism (e.g., P. aeruginosa has innate resistance to vancomycin) 2. Acquired resistance a. Mutations – Chromosomal alterations passed to daughter cells only b. Horizontal gene transfer i. Plasmids – Extrachromosomal DNA that codes for resistance; mobile; can code for resistance to multiple antibiotics ii. Transposons – Resistance genes transferred within or between chromosomal DNA or plasmids iii. Integrons – DNA component that contains a site where a gene cassette that codes for resistance can be integrated into the bacterial DNA 3. Mechanisms of resistance a. Decreased uptake i. β Lactams ii. Fluoroquinolones iii. Aminoglycosides (especially Pseudomonas) b. Enzyme modification and degradation i. β Lactamases (see Table 4) ii. Aminoglycoside hydrolytic enzymes (e.g., acetyltransferase, phosphotransferase, adenyl transferase) – Enteric gram-negative bacteria c. Altered target site i. β Lactams (e.g., altered penicillin-binding proteins (PBPs), mecA) – Staphylococcus, Streptococcus, and Enterococcus ii. Glycopeptides (e.g., vanA and vanB) – Vancomycin resistance in Enterococcus iii. Fluoroquinolones (e.g., gyrA and parC mutations) 31  Pharmacology-IV iv. Ribosomal mutations (e.g., macrolides, tetracyclines) v. Sulfonamides (e.g., altered genes encoding dihydropteroate synthase) vi. Trimethoprim (e.g., altered genes encoding dihydrofolate reductase or overproduction of dihydrofolate reductase) d. Efflux pumps i. Macrolides (e.g., mef-encoded efflux in Streptococcus) ii. Fluoroquinolones iii. Tetracyclines Table 4. β-Lactamases CRE = carbapenem-resistant Enterobacteriaceae; ESBL = extended-spectrum β-lactamase; KPC = Klebsiella pneumoniae carbapenemase; NDM = New Delhi metallo-β-lactamase; OXA = oxacillinase; VIM = Verona integron-encoded metallo-β-lactamase. Influenza 1. Characteristics of influenza infection a. Epidemic with significant mortality b. Epidemics begin abruptly → peak in 2–3 weeks → resolve in 5–6 weeks. 32 Pharmacology-IV c. Occurs almost exclusively in the winter d. Average overall attack rates of 10%–20% e. Mortality greatest in those older than 65 years (especially with heart and lung disease): More than 80% of deaths caused by influenza are from this age group. 2. Is it influenza, COVID-19, or the common cold? 3. Pathophysiology a. Type A i. Influenza further grouped by variations in hemagglutinin and neuraminidase (e.g., H1N1, H3N2) ii. Changes through antigenic drift or shift (a) Drift: Annual, gradual change caused by mutations, substitutions, and deletions 33  Pharmacology-IV (b) Shift: Less common dramatic change leading to pandemics iii. Causes epidemics every 1–3 years b. Type B i. Type B influenza carries one form of hemagglutinin and one form of neuraminidase, both of which are less likely to mutate than the hemagglutinin and neuraminidase of type A influenza. ii. Changes through antigenic drift (minor mutations from year to year); when enough drifts occur, an epidemic is likely. iii. Causes epidemics every 5 years 4. Therapy a. Treatment with neuraminidase inhibitors indicated in patients with confirmed or suspected influenza and the following conditions: i. Hospitalized patients ii. Outpatients with severe or progressive illness iii. Outpatients at high risk of influenza complications (a) Patients younger than 2 years or 65 years and older (b) Patients with chronic disease states: Pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematologic (including sickle cell disease), metabolic disorders (including diabetes mellitus), or neurologic and neurodevelopment conditions (c) Immunosuppressed patients (d) Pregnant women and those within 2 weeks postpartum (e) Patients younger than 19 years who are receiving long-term aspirin therapy (f) American Indians and Alaska Natives (g) Patients who are morbidly obese (h) Residents of nursing homes and other long-term care facilities 34  Pharmacology-IV iv. Treatment may be considered for those without risk factors including: (a) Outpatients with illness onset less than 48 hours (b) Symptomatic outpatients who are household contacts of individuals at high risk of complications (c) Symptomatic health care providers who are caregivers for individuals at high risk of complications, including: (1) Outpatients with illness onset less than 48 hours (2) Symptomatic outpatients who are household contacts of individuals at high risk of complications (3) Symptomatic health care providers who are caregivers for individuals at high risk of complications b. Adamantanes i. Amantadine (Symmetrel), rimantadine (Flumadine) ii. Inhibit viral uncoating and release of viral nucleic acid by inhibiting M2 protein (a) Never effective against influenza B virus (b) Not recommended for treatment because of current universal resistance in influenza A c. Neuraminidase inhibitors i. Oseltamivir (Tamiflu), Zanamivir (Relenza), peramivir (Rapivab) ii. Inhibit neuraminidase; symptoms resolve 1–1.5 days sooner. iii. Adverse effects (a) Oseltamivir: Gastrointestinal (GI) (nausea and vomiting), central nervous system (CNS) (anxiety, headache, insomnia, etc.) (b) Zanamivir: Bronchospasm, cough (not recommended in patients with asthma or COPD) (c) Peramivir: Diarrhea; aspartate aminotransferase, alanine aminotransferase, creatinine phosphokinase, glucose elevation iv. Dosage 35  Pharmacology-IV (a) Oseltamivir: 75 mg orally twice daily for 5 days; decrease dosage to 30 mg twice daily orally in patients with a creatinine clearance (CrCl) of 31–60 mL/minute/1.73 m2 and 30 mg once daily orally in patients with CrCl 11–30 mL/minute/1.73m2. (b) Zanamivir: Two inhalations (5 mg/inhalation) twice daily for 5 days (c) Peramivir: 600 mg intravenously once; decrease dose to 200 and 100 mg in patients with a CrCl less than 50 and 30 mL/minute/1.73 m2, respectively (d) Initiate within 48 hours of symptom onset. d. Endonuclease inhibitors i. Baloxavir ii. Inhibits viral endonuclease which is vital for initiating viral transcription; symptoms resolve 1-1.5 days sooner. iii. Adverse effects: gastrointestinal, bronchitis, headache (all similar to placebo) iv. Dosage: 40 mg once (40-79 kg) or 80 mg once (greater than or equal to 80 kg) 5. Prevention a. Prophylaxis in the community i. Patients at very high risk of developing complications when influenza vaccination is contraindicated or for whom the vaccine is expected to have low effectiveness. Use for the duration of influenza activity. ii. Hematopoietic stem cell or lung transplant recipients. Use for the duration of influenza activity. iii. Patients at high risk of complications or people in close contact with these patients. Use short term and give vaccine. b. Prophylaxis for institutional outbreaks 36  Pharmacology-IV i. All exposed residents or patients in outbreak-affected units regardless of influenza vaccination history ii. Unvaccinated or recently vaccinated caregivers iii. Use prophylaxis for at least 14 days and continue for 7 days after the last identified case in the institution. c. Amantadine, rimantadine: Not recommended for prevention because of current universal resistance. d. Use neuraminidase inhibitors only: Oseltamivir 75 mg/day orally Coronavirus disease (COVID-19) 1. Characteristics of COVID-19 infection a. Caused by the SARS-CoV-2 virus b. Pandemic with significant mortality c. Occurs throughout the year d. Transmitted by exposure to respiratory fluids e. Incubation period of 3–6 days e. Mortality greatest in adults older than 65 years and in those with chronic conditions. 2. Therapy a. Symptomatic/not hospitalized/not receiving supplemental oxygen i. Ritonavir-boosted nirmatrelvir (Paxlovid) is preferred first-line therapy as of January 2023 (a) Dose: Nirmatrelvir 300 mg with ritonavir 100 mg orally twice daily for 5 days (b) Monitor patient closely for drug interactions ii. Remdesivir is preferred second-line therapy (see dose below) iii. Molnupiravir is an alternative therapy if preferred therapies are not available/appropriate 37  Pharmacology-IV b. Hospitalized/receiving supplemental oxygen i. Remdesivir (a) Dose: 200 mg once; then 100 mg daily for total of 5 days (b) Benefit greatest when given early in disease course (within 10 days of symptom onset) ii. Dexamethasone Dose: 6 mg orally or intravenously daily for 10 days; data also support doses of 20 mg daily for 5 days followed by 10 mg daily for 5 days and 12 mg daily for 10 days. -Do not continue after discharge unless patient is still receiving supplemental oxygen iii. In patients with rapidly increasing oxygen needs and systemic inflammation, -consider adding an immunomodulatory drug: baricitinib, tocilizumab, sarilumab 3. Prevention a. Vaccination i. Pfizer-BioNTech vaccine – mRNA vaccine (a) Approved for age 12 years or older; Emergency Use Authorization (EUA) is 6 months–11 years (b) Monovalent vaccine (1) Dose for age 12 years and older: 0.3 mL (30 mcg) intramuscularly for 2 doses, 3–8 weeks apart; first booster at 5 months or more after the second dose; second booster at 4 months or more after the first booster in adults age 50 years and older (2) Dose for age 5–11 years: 0.2 mL (10 mcg) intramuscularly for 2 doses 3–8 weeks apart; first booster at 5 months or more after second dose (3) Dose for age 6 months to up to 5 years: 0.2 mL (3 mcg) intramuscularly for 2 doses 3–8 weeks apart; first booster at 5 months or more after second dose (4) 38  Pharmacology-IV Adverse reactions: Injection site pain/swelling/redness, fatigue, headache, muscle pain, chills, joint pain, fever, nausea, malaise, lymphadenopathy, hypersensitivity reactions, myocarditis/pericarditis (c) Bivalent vaccine (1) 0.3 mL (30 mcg) intramuscularly for 1 dose (2) Give at least 2 months after last dose of primary series/booster ii. Moderna vaccine – mRNA vaccine (a) Approved for age 18 years and older; EUA is 6 months–17 years (b) Monovalent vaccine (1) Dose for age 12 years and older: 0.5 mL (100 mcg) intramuscularly for 2 doses 4–8 weeks apart; first booster (50 mcg) at 5 months or more after second dose; second booster (50 mcg) at 4 months or more after first booster in those age 50 years and older (2) Dose for age 6–11 years: 0.5 mL (50 mcg) intramuscularly for 2 doses 4–8 weeks apart (3) Dose for age 6 months up to 6 years: 0.25 mL (25 mcg) intramuscularly for 2 doses 4–8 weeks apart (4) Adverse reactions: Injection site pain/swelling/redness, headache, fatigue, myalgia, nausea, fever, hypersensitivity reactions, cerebral venous sinus thrombosis, thrombocytopenia (c) Bivalent vaccine (1) 0.5 mL (50 mcg) intramuscularly for 1 dose (2) Give at least 2 months after last dose of primary series/booster iii. Janssen/J&J vaccine – adenovirus vector vaccine (a) EUA is age 18 years and older 39  Pharmacology-IV (b) Dose: 0.5 mL (5 × 1010 virus particles) intramuscularly for 1 dose; first booster (0.5 mL) at 2 months or more after primary dose (c) Adverse reactions: Injection site pain/swelling/redness, fatigue, headache, muscle pain, chills, joint pain, fever, nausea, malaise, and lymphadenopathy; hypersensitivity reactions; Bell’s palsy; myocarditis/pericarditis iv. Novavax vaccine, adjuvanted – recombinant protein subunit (a) EUA is age 18 years and older (b) Dose: 0.5 mL (5 mcg + 50 mcg adjuvant) intramuscularly for 1 dose; first booster (0.5 mL) 3 weeks after primary dose (c) Adverse reactions: Injection site pain/tenderness/redness/swelling/pruritis, fatigue/malaise, muscle pain, headache, joint pain, nausea/vomiting, fever, chills, hypersensitivity reactions, lymphadenopathy-related reactions, myocarditis/pericarditis. Sinusitis 1. Definition and etiology a. Inflammation of the mucosal lining of the nasal passage and paranasal sinuses lasting up to 4 weeks b. Many different causes, including viruses, bacteria, and fungi c. Viruses account for more than 90% of cases, whereas bacteria account for less than 10%. 2. Diagnosis a. Presence of at least two major symptoms or one major and two or more minor symptoms (Table 7) 40  Pharmacology-IV b. Viral or bacterial? (Table 8) 3. Treatment a. Begin antibiotics as soon as bacterial sinusitis is diagnosed b. First-line therapy i. Amoxicillin/clavulanate ii. High-dose amoxicillin/clavulanate (2 g /125 mg twice daily in adults or 90/6.435 mg/kg/day divided twice daily) in: (a) Geographic regions with high endemic rates (greater than 10%) of invasive penicillin nonsusceptible S. pneumoniae 41  Pharmacology-IV (b) Those with a severe infection (e.g., evidence of systemic toxicity with a temperature of 102.2°F (39°C) or higher and a threat of suppurative complications) (c) Attendance at day care (d) Age younger than 2 years or older than 65 years (e) Recent hospitalization (f) Antibiotic use within the past month (g) Those who are immunocompromised c. Second-line therapy i. Respiratory fluoroquinolone (including children with type I hypersensitivity to penicillin) – Because of serious adverse effects, avoid if there are other treatment options. ii. Doxycycline iii. Cefixime or cefpodoxime proxetil with clindamycin (for children with non–type I hypersensitivity to penicillin) iv. Intranasal saline irrigation as adjunctive therapy v. Intranasal corticosteroids as adjunctive therapy in patients with allergic rhinitis d. Therapy duration i. Adults: 5–7 days ii. Children: 10–14 days URINARY TRACT INFECTIONS A. Introduction 1. Most common bacterial infection in humans: 7 million office visits per year; 1 million hospitalizations 2. Many women (15%–20%) will have a urinary tract infection (UTI) during their lifetime 3. 1–50 years of age: UTIs occur predominantly in women. 42  Pharmacology-IV after 50: men are increasingly affected because of prostate problems. B. Microbiology (Table 8) C. Predisposing Factors 1. Age 2. Female sex 3. Diabetes mellitus 4. Pregnancy 5. Immunosuppression 6. Urinary tract instrumentation 7. Urinary tract obstruction 8. Renal disease, renal transplantation 9. Neurologic dysfunction D. Clinical Presentation 1. Lower UTI: Cystitis (older adults may have only nonspecific symptoms, such as mental status changes, abdominal pain, and decreased eating or drinking) a. Dysuria b. Frequent urination c. Urgency d. Occasionally, gross hematuria 43  Pharmacology-IV 2. Upper UTI: Pyelonephritis (older adults may have only nonspecific symptoms, such as mental status changes, abdominal pain, and decreased eating or drinking) a. Frequency, dysuria, hematuria b. Suprapubic pain c. Costovertebral angle tenderness; flank pain d. Fever, chills e. Elevated WBC f. Nausea, vomiting 3. Factors associated with or used to define complicated UTI (UTI involving a structural or functional abnormality) a. Male sex b. Hospital acquired c. Pregnancy d. Anatomic abnormality of the urinary tract e. Poorly controlled diabetes mellitus f. Recent antimicrobial use g. Indwelling urinary catheter h. Recent urinary tract instrumentation i. Immunosuppression 4. Recurrent cystitis a. Relapse: Infection with the same organism within 14 days of discontinuing antibiotics for the preceding UTI b. Reinfection: Infection with a completely different organism; most common cause of recurrent cystitis E. Diagnosis: Urinalysis (blood cultures will be positive in 20% of patients with upper UTIs) 44  Pharmacology-IV 1. Pyuria (WBC greater than 10 cells/mm3 ) 2. Bacteriuria (more than 102 colony-forming units per milliliter is diagnostic) in symptomatic patients or those with catheters 3. Red blood cells 4. Cloudiness 5. Nitrite positive (E. coli, Proteus, Klebsiella) 6. Leukocyte esterase positive 7. Casts (if pyelonephritis) 8. Note: patient must also have symptoms; diagnosis cannot be made on urinalysis results alone F. Asymptomatic Bacteriuria 1. Asymptomatic bacteriuria should only be screened for and treated in -pregnant women, -patients undergoing endoscopic urologic procedures, -and renal transplant recipients in the first 30 days after transplantation. a. Pregnant women should be treated for 4–7 days. b. Patients undergoing endoscopic urologic procedures should be treated with one or two doses of antibiotics. 2. Patients with functional and/or cognitive impairment should not be treated for asymptomatic bacteriuria solely on the basis of a history of falls or mental status changes/confusion. Patients must have local urinary symptoms or systemic signs of infection. G. Therapy 1. Uncomplicated cystitis a. Recommended therapy i. Trimethoprim/sulfamethoxazole 160 mg/800 mg twice daily for 3 days. 45  Pharmacology-IV -Avoid if resistance prevalence is known to exceed 20% or -if used for UTI in previous 3 months. ii. Nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for 5 days (ineffective in patients with a CrCl less than 30 mL/minute/1.73 m2 ) iii. Fosfomycin tromethamine 3 g, one dose b. Alternatives i. Fluoroquinolones (not moxifloxacin) for 3 days – Because of serious adverse effects, avoid fluoroquinolones if there are other treatment options. ii. β-Lactams (amoxicillin-clavulanate, cefdinir, cefaclor, cephalexin, and cefpodoxime proxetil) for 5–7 days 2. Uncomplicated pyelonephritis a. Outpatient therapy (if patient is not immunocompromised or does not have nausea and vomiting) i. Trimethoprim/sulfamethoxazole 160 mg/800 mg twice daily for 14 days ii. Levofloxacin 750 mg orally daily for 5 days or ciprofloxacin 500 mg orally twice daily for 7 days (not moxifloxacin) – Because of serious adverse effects, avoid fluoroquinolones if there are other treatment options. iii. β-Lactams (see above) for 10–14 days (less effective than first two options) b. Uropathogen resistance greater than 10%: Use initial dose of an intravenous, long- acting β-lactam (e.g., ceftriaxone) or once-daily aminoglycoside. 46  Pharmacology-IV 3. Complicated UTIs a. Outpatient therapy i. Trimethoprim/sulfamethoxazole 160 mg/800 mg twice daily for 7-14 days ii. Levofloxacin 750mg oral daily for 5 days or ciprofloxacin 500mg oral twice daily for 7 days (not moxifloxacin) iii. β-Lactams (see above) for 7–14 days b. Inpatient therapy i. Fluoroquinolone ii. Aminoglycoside iii. Ceftriaxone (consider a β-lactam with antipseudomonal activity in patients recently hospitalized or with urinary catheters or living in nursing homes) iv. Therapy duration: 5–14 days (5 days with levofloxacin) 4. Pregnancy (pregnant women should be screened for bacteriuria and treated, even if asymptomatic) a. Antibiotic options i. Amoxicillin/clavulanate for 3-7 days ii. Nitrofurantoin (avoid in the first trimester and at term if other options available) for 5-7 days iii. Cephalexin or cefpodoxime proxetil for 3-7 days iv. Fosfomycin tromethamine single dose b. Antibiotics to avoid i. Fluoroquinolones ii. Tetracyclines iii. Aminoglycosides iv. Trimethoprim/sulfamethoxazole (used frequently but avoidance recommended, especially during the late third trimester) 47  Pharmacology-IV 5. Recurrent cystitis a. Relapse i. Assess for pharmacologic reason for treatment failure. ii. Longer treatment (for 2–6 weeks, depending on length of initial course) b. Reinfection (reassess need for continuous prophylactic antibiotics every 6–12 months) i. If patient has two or fewer UTIs in 1 year, use patient-initiated therapy for symptomatic episodes (3-day treatment regimens). ii. If patient has three or more UTIs in 1 year and they are temporally related to sexual activity, use postintercourse prophylaxis with trimethoprim/sulfamethoxazole single strength, cephalexin 250 mg, or nitrofurantoin 50–100 mg and counsel on voiding after intercourse. iii. If patient has three or more UTIs in 1 year that are not related to sexual activity, -use daily or three times per week prophylaxis with trimethoprim 100 mg, trimethoprim/sulfamethoxazole single strength, cephalexin 250 mg, or nitrofurantoin 50–100 mg. 6. Catheter-related UTIs a. Short-term indwelling catheters i. Risk of bacteriuria is 5% for each day of catheterization. ii. By 30 days, 75%–95% of patients with an indwelling catheter will have bacteriuria. iii. Preventive antimicrobial therapy is not recommended; it only increases the chance of selecting out resistant organisms. iv. Asymptomatic patients with bacteriuria should not be treated. 48  Pharmacology-IV v. Symptomatic patients with bacteriuria should be treated with 7 days of antibiotics -if symptoms resolve promptly and with 10–14 days of antibiotics if there is a delayed response (both durations whether or not catheter removed). -Treat for 5 days with levofloxacin if the patient is not severely ill; treat for 3 days in women 65 years and younger who have their catheters removed and who do not have upper urinary tract symptoms. vi. The most common organisms are E. coli (21.4%), Candida spp. (21.0%), Enterococcus spp. (14.9%), P. aeruginosa (10.0%), K. pneumoniae (7.7%), and Enterobacter spp. (4.1%). b. Long-term indwelling catheters i. Almost all patients will be bacteriuric with two to five organisms. ii. Asymptomatic patients should not be treated. Catheters do not need to be replaced. iii. Symptomatic patients should be treated for a short period (7 days) to prevent resistance, and catheter replacement may be indicated. 7. Prostatitis a. Acute bacterial prostatitis i. Primarily gram-negative organisms ii. Therapy duration 2–4 weeks, can extend for an additional 2 weeks if patient remains symptomatic (a) Trimethoprim/sulfamethoxazole (b) Fluoroquinolones b. Chronic bacterial prostatitis i. Difficult to treat ii. Therapy duration 1–4 months (a) Trimethoprim/sulfamethoxazole 49  Pharmacology-IV (b) Fluoroquinolones 8. Epididymitis a. Sexually transmitted (most likely caused by C. trachomatis or N. gonorrhoeae) i. Ceftriaxone 500 mg (1000 mg if weight greater than 150 kg) intramuscularly once plus doxycycline 100 mg twice daily ii. Use levofloxacin 500 mg daily instead of doxycycline in men who practice insertive anal sex. iii. Duration: 10 days b. Non-sexually transmitted (most likely caused by enteric gram-negative organisms): i. Men with bladder outlet obstruction (benign prostatic hyperplasia) or who have undergone prostate biopsy, vasectomy, or other urinary tract instrumentation procedures ii. Levofloxacin 500 mg daily iii. Duration: 10 days Otitis media: Clinical Presentation 1. Definitions a. Acute otitis media (AOM): I. Presence of middle ear effusion and evidence of middle ear inflammation. II. Middle ear effusion may be indicated by: i. Bulging tympanic membrane. ii. Decreased or no mobility of the tympanic membrane. iii. Purulent fluid in the middle ear. 50  Pharmacology-IV III. Inflammation of the middle ear may be indicated by erythema of the tympanic membrane or otalgia. b. Otitis media with effusion (OME): Fluid in the middle ear without evidence of local or systemic illness. c. Recurrent AOM: Three or more episodes of acute otitis within 6 months or four episodes within 1 year with at least 1 episode within the most recent 6 months. 2. Risk factors a. Younger age (generally less than school age) b. Day care attendance. c. Absence of breastfeeding d. Family history of AOM. e. Positioning during feeding (e.g., supine position during bottle-feeding allows reflux into eustachian tubes). f. Lower socioeconomic status. g. Smokers in the household. h. Craniofacial abnormalities or cleft palate. i. Immune deficiencies j. Cochlear implants k. Siblings in the home l. Seasonal cooler months (winter) 3. Incidence a. AOM in first year of life: 25% b. AOM by 5 years of life: 60% c. Peak incidence at 6 to 12 months of age Common Pathogens 51 Pharmacology-IV 1. Viral. 2. S. pneumoniae. 3. Nontypeable H. influenzae. 4. Moraxella catarrhalis C. Signs & Symptoms: 1. Otorrhea 2. Erythema 3. Tugging or pulling of ears (otalgia) 4. Fever 5. Irritability/sleep changes Treatment 1. General principles a. Clinical resolution may occur without antibiotic therapy. b. Immediate antibiotic therapy is warranted for AOM with bulging tympanic membrane, perforation, or otorrhea. c. Delayed antibiotic prescribing (if otalgia persists for > 2-3 days or temperature >39°C in the past 2 days) is an acceptable strategy in children > 2 years with AOM without severe systemic symptoms. d. Analgesics are more beneficial than antibiotics for relieving otalgia within the first 24 hours. e. Antibiotics also may be deferred (delayed) in otherwise healthy children between 6 months and 2 years of age if their symptoms are mild and otitis media is unilateral (as opposed to bilateral). f. Caregiver must be reliable to recognize worsening of condition and gain immediate access to medical care, if needed. g. Delayed antibiotic prescribing is not recommended for infants younger than 6 months 52 Pharmacology-IV h. Persistence of middle ear fluid is likely after treatment for AOM and does not warrant repeated treatment. i. Antibiotics are not generally warranted for OME because of the high rate of spontaneous resolution. 1. Antibiotics are recommended only if bilateral effusions persist for more than 3 months. 2. Corticosteroids, antihistamines, and decongestants are not recommended. 53 Pharmacology-IV 54  Pharmacology-IV E. Complications of AOM: Incompletely treated or untreated: 1. Hearing loss 2. Mastoiditis 3 Tympanic membrane perforation 4. Otorrhea Prevention Strategies 1. Antibiotic prophylaxis a. Not recommended. b. The risk of promoting bacterial resistance may outweigh the slight benefit. 2. Immunization: using pneumococcal and influenza vaccines. 3. Modification of risk factors OPHTHALMIC INFECTIONS A. External eye anatomy: 55  Pharmacology-IV B. Infectious Conjunctivitis (Pink Eye): a. Definition: inflammation of the bulbar and/or palpebral conjunctiva. Bulbar conjunctiva: the transparent lubricating mucous membrane that covers the surface of the eye. Palpebral conjunctiva: the transparent lubricating mucous membrane that covers the lining of the undersurface of the eyelids. b. Etiologies: 1. Bacterial (30% of cases), fungal, and viral infections. 2. The bacterial etiology often depends on geography and age. 3. The most common bacterial pathogens include: Staph., Strept., Corynebacterium, Haemophilus, Pseudomonas, and Moraxella species. c. Complications: Range from mild corneal irritation to severe visual loss, which develops in cases caused by extremely pathogenic bacteria, such as Chlamydia trachomatis or Neisseria gonorrhoeae. d. Signs and symptoms: 1.Follicles: more common in ocular viral infections; affects mainly the lower eyelid 56 Pharmacology-IV 2.Papillae: more common in ocular bacterial infections; affects mainly the upper eyelid and bilateral. 3. Discharge: More purulent in bacterial than in viral conjunctivitis, with more mattering (generally white, green, or yellow mucous discharge) of the eyelid margins; patients may report waking up with their eyes “glued” shut 4. Enlarged preauricular lymph node: Common in viral conjunctivitis and unusual in bacterial conjunctivitis, although found in severe bacterial conjunctivitis caused by N gonorrhoeae. 5. Eyelid edema: Often present in bacterial conjunctivitis, but mild in most cases; severe eyelid edema in the presence of copious purulent discharge raises the suspicion of N gonorrhoeae infection 57  Pharmacology-IV E. Pathophysiology 1. The surface tissues of the eye are colonized by normal flora (strept., staph, etc) 2. Alterations in: - The host defenses. - The bacterial titer. - Or the species of bacteria can lead to clinical infection. 3. Alteration in the flora can also result from: - External contamination (eg, contact lens wear, swimming). - Use of topical or systemic antibiotics. - Spread from adjacent infectious sites (eg: rubbing of the eyes). 4. The primary defense against infection is the epithelial layer covering the conjunctiva. 5. Disruption of this barrier can lead to infection. 6. Secondary defenses include: - Hematologic immune mechanisms carried by: The conjunctival vasculature. Tear film immunoglobulins and lysozyme. - The rinsing action of lacrimation and blinking. E. Diagnosis: Bacterial culture is recommended in the following conditions: a. Neonatal conjunctivitis 58  Pharmacology-IV b. Hyperacute conjunctivitis suggestive of N gonorrhoeae c. Extremely elderly patients d. Nursing home patients e. Immunocompromised patients: HIV infection, chemotherapy, immunosuppressive therapy f. Recurrent (recalcitrant) conjunctivitis g. Corneal allograft recipients h. Patients who have undergone recent intraocular surgery: cataract, glaucoma shunt i. Patients with a thinning or damaged trabeculectomy (glaucoma surgery) filtering bleb (blister) j. Methicillin-resistant Staphylococcus aureus (MRSA) or methicillin- resistant Staphylococcus epidermidis (MRSE) carriers - Samples are collected by conjunctival scrapings using topical anesthetic and platinum spatula. - Gram stain is useful for identifying bacterial infections. - Giemsa stain is helpful in screening for intracellular inclusion bodies of Chlamydia. - Fungal culture would be unusual except in the setting of a corneal ulcer or in the case of known contamination of a contact lens solution. - The cellular response in conjunctivitis differs according to the cause, as follows: Bacterial infections: Neutrophils predominate Viral infections: Lymphocytes predominate F. Management: a. Non-pharmacological: 1. Good hygiene (eg, washing hands with soap and water). 59  Pharmacology-IV 2. Avoidance of touching the eyes, especially after exposure to potentially infectious sources. 3. Proper contact lens care includes avoidance of contact lens wear while sleeping and proper cleaning and discarding of both lenses and contact lens cases. 4. Avoid sharing fomites. 5. Discontinue contact lens use and discard: - The used contact lenses. - Open contact lens solutions. - Used contact lens cases. - Used makeup and makeup brushes. b. Pharmacological: The mainstay of treatment for bacterial conjunctivitis is topical (administered as eye drops or ointment) antibiotic therapy. 1. Systemic antibiotics are indicated for gonorrhea and chlamydial infections. 2. Under certain circumstances, topical antibiotics may be considered of limited benefit and, considering the risks of widespread antibiotic resistance, should be withheld while the disease course resolves without treatment. 3. For mild and non–vision-threatening bacterial conjunctivitis, older-generation antibiotics should be used (Trimethoprim + polymyxin B, Azithromycin, Gentamicin, Tobramycin, Neomycin, Ciprofloxacin, Ofloxacin, Gatifloxacin, Erythromycin, Bacitracin). 4. For moderate and severe bacterial conjunctivitis, the latest fluoroquinolones, including moxifloxacin, besifloxacin, and levofloxacin, are generally effective. 5. Rare severe infections may also require patient hospitalization to ensure consistent administration of fortified aminoglycoside-cephalosporin combination 60  Pharmacology-IV therapy, fortified topical vancomycin, or topical fluoroquinolone monotherapy treatment every 15 minutes to hourly. 6. All are effective treatments, although fortified antibiotics must be prepared without preservatives in compounding pharmacies and must remain refrigerated because of their shorter shelf life. 7. Fortification means preparation of highly concentrated medications to achieve higher efficacy against resistant strains of bacteria. 8. Steroid use is controversial. 9. Povidone-iodine 1.25% ophthalmic solution may be a safe and viable alternative to topical antibiotics for treating bacterial conjunctivitis, especially in resource- poor countries, where antibiotics may be scarce and/or expensive. c. Neonatal Chlamydial and Gonococcal Infection 1. Chlamydial infection of the newborn requires systemic treatment of the neonate, the mother, and at-risk contacts. 2. The neonate may be treated with erythromycin orally in liquid form for 2 weeks. 3. Some newborns also require a second dose. 4. The mother and at-risk contacts may be treated with doxycycline for 7 days. 5. N. gonorrhoeae infection of the newborn also requires systemic treatment of the neonate, the mother, and at-risk contacts. 6. The neonate may be treated with IV. penicillin G for 1 week. 7. The mother and at-risk contacts may be treated with a single dose of intramuscular ceftriaxone followed by oral doxycycline for 7 days. 8. Strict daily attention to the peripheral cornea, conjunctival scarring, and membrane formation allows timely surgical action. 61 Pharmacology-IV 9. Prophylaxis against ophthalmia neonatorum is a major force in the worldwide effort to prevent blindness. 10. Common prophylaxis regimens are the instillation of 1% silver nitrate solution, 1% tetracycline ointment, or 0.5% erythromycin ointment. 11. Relatively inexpensive povidone iodide is also gaining popularity in this role. 62 Pharmacology-IV Part III Ass. Prof. Islam Ahmed Elazizy 63  Pharmacology-IV SKIN AND SKIN STRUCTURE INFECTIONS A. Cellulitis 1. Description a. Acute spreading skin infection that involves primarily the deep dermis and subcutaneous fat. b. Non-elevated, poorly defined margins. c. Warmth, pain, erythema and edema, and tender lymphadenopathy. d. Malaise, fever, and chills. e. Usually, patient has had previous minor trauma, abrasions, ulcers, or surgery (could be tinea infections, psoriasis, or eczema). f. Often, patients have impaired lymphatic drainage. 2. Microorganism: Usually Streptococcus pyogenes and occasionally S. aureus (rarely other organisms); blood cultures are rarely positive and not routinely recommended unless severe systemic symptoms are present or the patient is immunosuppressed. 3. Treatment: 5–10 days (may extend therapy if infection has not improved) a. Penicillin G if definitively streptococcal b. First-generation cephalosporin (cefazolin, cephalexin) c. Ceftriaxone 64 Pharmacology-IV d. Clindamycin e. Treat empirically for MRSA if associated with penetrating trauma, injection drug use, purulent drainage, nasal colonization with MRSA, concurrent evidence of MRSA infection elsewhere or systemic inflammatory response syndrome (SIRS) criteria (severe nonpurulent). i. Outpatient: Clindamycin, trimethoprim/sulfamethoxazole (add β-lactam for Streptococcus), doxycycline (add β-lactam for Streptococcus). ii. Inpatient: Vancomycin, linezolid, daptomycin, or telavancin. B. Erysipelas 1. Description a. Acute spreading skin infection that involves primarily the superficial dermis. b. Spreads rapidly through the lymphatic system in the skin (patients may have impaired lymphatic drainage) c. Usually occurs in infants and older adults d. Usually occurs on the legs and feet (facial erysipelas can occur, but this is less common) e. Warmth, erythema, and pain 65 Pharmacology-IV f. Edge of infection is elevated and sharply demarcated from the surrounding tissue. g. Systemic signs of infection are common, but blood cultures are positive only 5% of the time. 2. Microorganism: Group A Streptococcus (S. pyogenes), but occasionally groups G, C, and B are seen. 3. Treatment: 5 days (may extend therapy if infection has not improved) a. Penicillin G. b. Cefazolin C. Clindamycin. C. Necrotizing Fasciitis 1. Description a. Acute, necrotizing cellulitis that involves the subcutaneous fat and superficial fascia b. Infection extensively alters surrounding tissue, leading to cutaneous anesthesia or gangrene. c. Very painful (pain out of proportion to appearance) 66 Pharmacology-IV d. Streptococcal infection: Either spontaneous or attributable to varicella, minor trauma (cuts, burns, and splinters), surgical procedures, or muscle strain; mixed infection generally secondary to abdominal surgery or trauma e. Significant systemic symptoms, including shock and organ failure 2. Microorganisms a. S. pyogenes b. Mixed infection with facultative and anaerobic bacteria 3. Treatment a. Surgical debridement: Most important therapy and often repeated debridement is necessary b. Antibiotics are not curative; given in addition to surgery (if used early, may be effective alone) c. Empiric therapy: Vancomycin or linezolid plus piperacillin/tazobactam or a carbapenem or ceftriaxone with metronidazole d. If group A streptococci, S. aureus, or clostridia suspected, clindamycin should be included in the empiric regimen to suppress streptococcal toxin and cytokine production e. Streptococcal necrotizing fasciitis: High-dose intravenous penicillin plus clindamycin 67 Pharmacology-IV DIABETIC FOOT INFECTIONS A. Epidemiology 1. 25% of people with diabetes develop foot infections. 2. 1 in 15 needs amputation. B. Etiology 1. Neuropathy: Motor and autonomic a. Mechanical or thermal injuries lead to ulcerations without patient knowledge. b. Gait disturbances and foot deformities; maldistribution of weight on the foot c. Diminished sweating, causing dry, cracked skin 2. Vasculopathy: Decreased lower limb perfusion 3. Immunologic defects: Cellular and humoral C. Causative Organisms: In general, polymicrobial (average, 2.1–5.8 microorganisms) 1. S. aureus 2. Group A and B Streptococcus 68 Pharmacology-IV 3. Enterococcus 4. Proteus 5. E. coli 6. Klebsiella 7. Enterobacter 8. P. aeruginosa 9. Bacteroides fragilis 10. Peptostreptococcus D. Therapy 1. Preventive therapy a. Examine feet daily for calluses, blisters, trauma, and so forth. b. Wear properly fitting shoes. c. Do not walk barefoot. d. Keep feet clean and dry. e. Have toenails cut properly. 2. Antimicrobial therapy a. Mild infections (and no antibiotics in the past month), defined as local infection involving only the skin and the subcutaneous tissue, with no SIRS criteria and erythema of 2 cm or less i. No MRSA risk factors: Dicloxacillin, nafcillin, cephalexin, cefazolin, levofloxacin or clindamycin ii. MRSA risk factors: Doxycycline or trimethoprim/sulfamethoxazole b. Moderate to severe infections, defined as local infection with erythema greater than 2 cm, or involving structures deeper than skin and subcutaneous tissues without (moderate) or with (severe) 2 or more SIRS criteria 69 Pharmacology-IV i. Ampicillin/sulbactam ii. Ertapenem iii. Cefoxitin iv. Moxifloxacin alone or ciprofloxacin/levofloxacin plus clindamycin v. Tigecycline vi. If risk of P. aeruginosa (uncommon in diabetic foot infections and often a nonpathogenic colonizer), use piperacillin/tazobactam, ceftazidime, cefepime, or carbapenem. Risk factors for Pseudomonas include high local prevalence of Pseudomonas infection, warm climate, frequent exposure of the foot to water, a severe infection, and failure of previous therapy with non-pseudomonal antibiotics. vii. If risk of MRSA, use vancomycin, linezolid, or daptomycin. Risk factors for MRSA include history of MRSA infection or colonization, high local prevalence of MRSA, or a severe infection. c. Treatment duration: 1–2 weeks for mild infections and 2–3 weeks for moderate to severe infections. Extended duration is needed for osteomyelitis; after amputation treatment, duration is 2–5 days if there is no remaining infected tissue or 4 weeks or more if infected tissue remains. E. Surgical Therapy 1. Drainage and debridement (appropriate wound care) are very important. 2. Amputation is often necessary; if infection is discovered early, can maintain structural integrity of the foot. 70 Pharmacology-IV IMPETIGO - The most common bacterial infection in children. - Acute, highly contagious infection of the superficial layers of the epidermis. - Primarily caused by S. pyogenes or S. aureus. - Secondary skin infections of existing skin lesions (eg: cuts, abrasions, insect bites, chickenpox) can also occur. - Methicillin-resistant S aureus (MRSA) and gentamicin-resistant S. aureus strains have also been reported to cause impetigo. - Classified as either nonbullous (impetigo contagiosa, about 70% of cases) or bullous. Signs and symptoms Nonbullous impetigo: - Multiple lesions (usually merged) on face (perioral, perinasal) and extremities or in areas with a break in the natural skin defense barrier. - The initial lesions are small vesicles or pustules (< 2 cm) that rupture and become a honey-colored crust with a moist erythematous base. - Pharyngitis is absent, but mild regional lymphadenopathy is commonly present. - Usually, a self-limited process that resolves within 2 weeks. Bullous impetigo: - Less contagious than the nonbullous form. - Affect the face, extremities, axillae, trunk, and perianal region of neonates, but older children and adults can also be infected. 71 Pharmacology-IV - The initial lesions are fragile thin-roofed, flaccid, and transparent bullae (< 3 cm) with a clear, yellow fluid that turns cloudy and dark yellow. - Once the bullae rupture, they leave behind a rim of scale around an erythematous moist base but no crust, followed by a brown- lacquered or scalded-skin appearance. - Bullous impetigo also differs from nonbullous impetigo in that bullous impetigo may involve the buccal mucous membranes, and regional adenopathy rarely occurs. - Extensive lesions in infants may be associated with systemic symptoms such as fever, malaise, generalized weakness, and diarrhea. - Rarely, infants may present with signs of pneumonia, septic arthritis, or osteomyelitis. Diagnosis - Usually based on history and physical examination. - Bacterial culture and sensitivity are recommended in the following scenarios: - When MRSA is suspected. - In the presence of an impetigo outbreak - In the presence of poststreptococcal glomerulonephritis (PSGN); in such cases, urinalysis is also necessary. - Biopsy may be appropriate in doubtful or refractory cases of impetigo. 72  Pharmacology-IV Management: Localized, uncomplicated impetigo - Gentle cleansing, removal of the honey-colored crusts of nonbullous impetigo using antibacterial soap and a washcloth, and frequent application of wet dressings to areas affected by lesions are recommended. - Good hygiene with antibacterial washes, such as chlorhexidine or sodium hypochlorite baths, may prevent the transmission of impetigo and prevent recurrences. - Duration of treatment with topical antibiotics: 5 days. - Antibiotics: mupirocin, retapamulin, ozenoxacin (quinolone), fusidic acid. - Hydrogen peroxide 1% cream, has bactericidal activity, used for a maximum of 3 weeks. Widespread (complicated) impetigo - Systemic treatment is necessary using oral route. - Duration of treatment is 7 days. - Antibiotics: cephalexin1st, dicloxacillin, amoxicillin/clavulanate Widespread (complicated) impetigo with confirmed MRSA - Systemic treatment is necessary using oral route. - Treatment duration 7 days. - Antibiotics: clindamycin, trimethoprim-sulfamethoxazole and doxycycline. In patients with bullous impetigo who present to the emergency department with large areas of involvement resulting in denuded (exposed) skin from ruptured bullae, management also includes intravenous fluid resuscitation. 73  Pharmacology-IV Inpatient care is required for infants at risk of sepsis and/or dehydration due to skin loss. If inpatient care is warranted in the child with untreated impetigo, contact isolation is recommended. OSTEOMYELITIS A. Introduction 1. Infection of the bone with subsequent bone destruction 2. About 20 cases per 100,000 people B. Characteristics: 74 Pharmacology-IV CABG = coronary artery bypass graft; IV = intravenous; IVDU = intravenous drug use; PVD = pulmonary vascular disease; URI = upper respiratory infection. C. Clinical Presentation 1. Signs and symptoms a. Fever and chills b. Localized pain, tenderness, and swelling c. Neurologic symptoms if spinal cord compression 2. Laboratory tests a. Elevated WBC b. Elevated erythrocyte sedimentation rate c. Elevated C-reactive protein 3. Diagnostic tests a. Radiographic tests: Positive results lag behind infectious process. b. Computed tomography and magnetic resonance imaging scans 75 Pharmacology-IV c. Radionuclide imaging: Positive as soon as 24–48 hours after infectious process begins. D. Empiric Therapy 1. Pediatric (neonate therapy should be tailored to the patient) a. Cefazolin b. Nafcillin, oxacillin c. Clindamycin (use if prevalence of MRSA in community is 10% or more) d. Vancomycin (use if prevalence of MRSA and clindamycin-resistant S. aureus in community is 10% or more) 2. Adults a. Nafcillin, oxacillin, cefazolin, ceftriaxone, clindamycin, or vancomycin (alternatives linezolid or daptomycin) b. Choose additional antibiotics according to patient-specific characteristics. 3. Patients with sickle cell anemia: Ceftriaxone/cefotaxime or ciprofloxacin/levofloxacin (no studies assessing best empiric therapy) 4. Prosthetic joint infections a. Debridement and retention of prosthesis or one-stage exchange of prosthesis i. Staphylococcal: Pathogen-specific intravenous therapy plus rifampin 300– 450 mg twice daily for 2–6 weeks, followed by rifampin plus ciprofloxacin or levofloxacin for 3 months (hip, elbow, shoulder, ankle prosthesis) or 6 months (knee prosthesis) ii. Non-staphylococcal: Pathogen-specific intravenous (or highly bioavailable oral) therapy for 4–6 weeks, followed by indefinite oral suppression therapy b. Resection of prosthesis with or without planned reimplantation or amputation 76 Pharmacology-IV i. Pathogen-specific intravenous (or highly bioavailable oral) therapy for 4–6 weeks ii. Only 24–48 hours of antibiotic therapy after amputation if all infected tissue is removed E. Therapy Length 1. Acute osteomyelitis: 4–6 weeks 2. Chronic osteomyelitis: 6–8 weeks of parenteral therapy and 3–12 months of oral therapy F. Criteria for Effective Oral Therapy for Osteomyelitis 1. High bioavailability antibiotic is available. 2. Adherence. 3. Identified organism that is highly susceptible to the oral antibiotic used. 4. C-reactive protein less than 2.0 mg/dL. 5. Adequate surgical debridement. 6. Resolving clinical course. CENTRAL NERVOUS SYSTEM INFECTIONS A. Meningitis: Introduction 1. Incidence: About 8.6 cases per 100,000 people. 2. Occurs more often in male than in female patients. 3. More common in children. B. Microbiology 1. Bacterial (septic meningitis). 77 Pharmacology-IV 2. Other causes (aseptic meningitis) a. Viral b. Fungal c. Parasitic d. Tubercular e. Syphilis f. Drugs (e.g., trimethoprim/sulfamethoxazole, ibuprofen) C. Predisposing Factors 1. Head trauma. 2. Immunosuppression. 3. CNS shunts. 4. Cerebrospinal fluid (CSF) fistula or leak. 5. Neurosurgical patients. 6. Alcoholism. 7. Local infections. a. Sinusitis. b. Otitis media. c. Pharyngitis. 78 Pharmacology-IV d. Bacterial pneumonia. 8. Splenectomized patients 9. Sickle cell disease 10. Congenital defects D. Clinical Presentation 1. Symptoms a. Fever, chills b. Headache, backache, nuchal rigidity, mental status changes, photophobia c. Nausea, vomiting, anorexia, poor feeding habits (infants) d. Petechiae or purpura (Neisseria meningitidis meningitis) 2. Physical signs a. Brudzinski sign b. Kernig sign 79 Pharmacology-IV c. Bulging fontanel 2. Early versus late neonatal sepsis a. Onset I. Early: Within 3 days of birth II. Late: After the first 3 days of life b. Risk factors I. Early: i. Very low birth weight. ii. Prolonged rupture of amniotic membranes (greater than 18 hours). iii. Prolonged labor. iv. Maternal genitourinary tract colonization with group B Streptococcus. v. Maternal endometritis. vi. Chorioamnionitis. II. Late: i. Unrelated to obstetric risk factors. ii. Usually related to iatrogenic factors (e.g., endotracheal tubes, central venous catheters). c. Incidence I. Early 80  Pharmacology-IV i. 0.7–3.7 of 1000 live births (8 of 1000 very-low-birth- weight) ii. Meningitis occurs in less than 10% of cases. II. Late i. 0.5–1.8 of 1000 live births ii. Meningitis occurs in 60% of cases. E. Diagnosis 1. History and physical examination 2. Blood cultures 3. Lumbar puncture a. Elevated opening pressure b. Composition in bacterial meningitis. CSF = cerebrospinal fluid. c. CSF stains and studies i. Gram stain (microorganisms): Helps identify organism in 60%–90% of cases ii. Latex agglutination: High sensitivity, 50%–100%, for common organisms (a) Not recommended routinely 81 Pharmacology-IV (b) Most useful in patients pretreated with antibiotics with subsequent negative CSF Gram stains and cultures iii. Acid-fast staining (tubercular meningitis) iv. Cryptococcal antigen v. Herpes simplex virus polymerase chain reaction 4. Laboratory findings a. Elevated WBC b. CSF Gram stain c. CSF cultures (positive in 75%–80% of bacterial meningitis cases) d. Blood cultures (±) e. C-reactive protein concentrations: High F. Empiric Therapy 1. Neonates younger than 1 month a. Ampicillin plus aminoglycoside or b. Ampicillin plus cefotaxime 2. Infants (1–23 months): Ceftriaxone plus vancomycin 3. Children and adults (2–50 years): Ceftriaxone plus vancomycin 4. Older adults (50 years and older): Ceftriaxone plus vancomycin* plus ampicillin 5. Penetrating head trauma, neurosurgery, or CSF shunt: Vancomycin plus cefepime, ceftazidime, or meropenem *Vancomycin added for activity against highly drug resistant S. pneumoniae. G. Therapy for Common Pathogens 1. S. pneumoniae a. An MIC to penicillin of 0.1 mcg/mL or less 82 Pharmacology-IV i. Penicillin G 4 million units intravenously every 4 hours ii. Ampicillin 2 g intravenously every 4 hours iii. Alternative: ceftriaxone 2 g intravenously every 12 hours or chloramphenicol 1–1.5 g intravenously every 6 hours b. An MIC to penicillin of 0.1–1.0 mcg/mL i. Ceftriaxone ii. Alternative: Cefepime 2 g intravenously every 8 hours or meropenem 2 g intravenously every 8 hours c. An MIC to penicillin of 2.0 mcg/mL or greater i. Vancomycin 15–20 mg/kg intravenously every 8–12 hours plus ceftriaxone ii. Alternative: Moxifloxacin 400 mg intravenously every 24 hours iii. If cephalosporin resistant: Vancomycin plus rifampin, vancomycin plus moxifloxacin, linezolid 2. N. meningitidis a. An MIC to penicillin of less than 0.1 mcg/mL i. Penicillin G ii. Ampicillin iii. Alternative: Third-generation cephalosporin (cefotaxime or ceftriaxone) or chloramphenicol b. An MIC 0.1–1.0 mcg/mL i. Ceftriaxone ii. Alternative: Chloramphenicol, fluoroquinolone, or meropenem 3. H. influenzae a. β-Lactamase negative i. Ampicillin 83 Pharmacology-IV ii. Alternative: Third-generation cephalosporin (cefotaxime or ceftriaxone), cefepime, chloramphenicol, or fluoroquinolone b. β-Lactamase positive i. Third-generation cephalosporin (cefotaxime or ceftriaxone) ii. Alternative: Cefepime, chloramphenicol, or fluoroquinolone 4. Streptococcus agalactiae a. Penicillin G b. Ampicillin c. Alternative: Third-generation cephalosporin (cefotaxime or ceftriaxone) 5. Listeria monocytogenes a. Penicillin G b. Ampicillin c. Alternative: Trimethoprim/sulfamethoxazole 5 mg/kg intravenously every 6–12 hours or meropenem H. Therapy Length: Based on clinical experience, not on clinical data 1. N. meningitidis: 7 days 2. H. influenzae: 7 days 3. S. pneumoniae: 10–14 days 4. S. agalactiae: 14–21 days 5. Listeria monocytogenes: 21 days or more I. Adjunctive Corticosteroid Therapy 1. Risks and benefits a. Significantly less hearing loss and other neurologic sequelae in children receiving dexamethasone for H. influenzae meningitis 84 Pharmacology-IV b. Significantly improved outcomes, including decreased mortality, in adults receiving dexamethasone for S. pneumoniae meningitis c. May decrease antibiotic penetration (decreased penetration of vancomycin in animals after dexamethasone) 2. Dosage and administration a. Give corticosteroids 10–20 minutes before or at same time as antibiotics. b. Dexamethasone 0.15 mg/kg every 6 hours for 2–4 days c. Use in children with H. influenzae meningitis or in adults with pneumococcal meningitis; however, may need to initiate before knowing specific causative bacteria. J. Chemoprophylaxis 1. N. meningitidis For close contacts (household or day care) and exposure to oral secretions of index case a. Rifampin i. Adults: 600 mg every 12 hours, four doses ii. Children: 10 mg/kg every 12 hours, four doses iii. Infants (younger than 1 month): 5 mg/kg every 12 hours, four doses b. Ciprofloxacin 500 mg orally, one dose (adults only) c. Ceftriaxone 125–250 mg intramuscularly, one dose 2. H. influenzae For all close contacts in households with unvaccinated or immunocompromised children a. Adults: Rifampin 600 mg/day for 4 days b. Children (1 month to 12 years): Rifampin 20 mg/kg/day for 4 days c. Infants younger than 1 month: Rifampin 10 mg/kg/day for 4 days 85 Pharmacology-IV K. Brain Abscess 1. Pathophysiology a. Direct extension or retrograde septic phlebitis from otitis media, mastoiditis, sinusitis, and facial cellulitis b. Hematogenous: Particularly lung abscess or infective endocarditis: 3%–20% have no detectable focus. 2. Signs and symptoms a. Expanding intracranial mass lesion: Focal neurologic deficits b. Headache c. Fever d. Seizures e. Mortality is about 50%. 3. Microbiology a. Usually polymicrobial b. Streptococcus spp. in 50%–60% c. Anaerobes in about 40% 4. Therapy a. Incision and drainage: By craniotomy or stereotaxic needle aspiration 86  Pharmacology-IV b. Suggested empiric regimens based on source of infection i. Otitis media or mastoiditis: Metronidazole plus third-generation cephalosporin ii. Sinusitis: Metronidazole plus third-generation cephalosporin iii. Dental sepsis: Penicillin plus metronidazole iv. Trauma or neurosurgery: Vancomycin plus third-generation cephalosporin v. Lung abscess, empyema: Penicillin plus metronidazole plus sulfonamide vi. Unknown: Vancomycin plus metronidazole plus third-generation cephalosporin c. Corticosteroids if elevated intracranial pressure PERITONITIS AND INTRA-ABDOMINAL INFECTIONS A. Introduction 1. Definition: Inflammation of the peritoneum (serous membrane lining the abdominal cavity) 2. Types a. Primary: Spontaneous or idiopathic, no primary focus of infection b. Secondary: Occurs secondary to an abdominal process B. Primary Peritonitis: Spontaneous Bacterial Peritonitis C. Secondary Peritonitis 1. Etiology: 87 Pharmacology-IV a. Peptic ulcer perforation b. Perforation of a GI organ c. Appendicitis d. Endometritis secondary to intrauterine device e. Bile peritonitis f. Pancreatitis g. Operative contamination h. Diverticulitis i. Intestinal neoplasms j. Secondary to peritoneal dialysis 2. Microbiology of intra-abdominal infections a. Stomach and proximal small intestine: Aerobic and facultative gram-positive and gram-negative organisms b. Ileum: E. coli, Enterococcus, anaerobes c. Large intestine: Obligate anaerobes (i.e., Bacteroides, Clostridium perfringens), aerobic and facultative gram-positive and gram-negative organisms (i.e., E. coli, Streptococcus, Enterococcus, Klebsiella, Proteus, Enterobacter) 3. Clinical manifestations and diagnosis a. Fever, tachycardia b. Elevated WBC c. Abdominal pain aggravated by motion, rebound tenderness d. Bowel paralysis e. Pain with breathing f. Decreased renal perfusion g. Ascitic fluid 88 Pharmacology-IV i. Protein: High (more than 3 g/dL); exudate fluid ii. WBCs: Many, primarily granulocytes D. Therapy: Secondary Peritonitis 1. Therapy or prophylaxis should be limited in a. Bowel injuries caused by trauma that are repaired within 12 hours (treat for less than 24 hours) b. Intraoperative contamination by enteric contents (treat for less than 24 hours) c. Perforations of the stomach, duodenum, and proximal jejunum (unless patient is on antacid therapy or has malignancy) (prophylactic antibiotics for less than 24 hours) d. Acute appendicitis without evidence of perforation, abscess, or peritonitis (treat for less than 24 hours) 2. Mild to moderate community-acquired infection a. Cefoxitin b. Cefazolin, cefuroxime, ceftriaxone, or cefotaxime plus metronidazole c. Ertapenem d. Moxifloxacin e. Ciprofloxacin or levofloxacin plus metronidazole f. Tigecycline 3. High-risk or severe* community-acquired or health care–acquired infection a. Piperacillin/tazobactam b. Ceftazidime or cefepime plus metronidazole c. Imipenem/cilastatin, meropenem d. Ciprofloxacin plus metronidazole or levofloxacin plus metronidazole (not for health care–acquired infections) 89  Pharmacology-IV e. Consider adding an aminoglycoside when extended-spectrum β-lactamase– producing Entero-bacteriaceae or P. aeruginosa is of concern (health care– acquired infections only). f. Consider adding vancomycin for MRSA (health care–acquired infections only) g. Add antifungal therapy if candida spp. Grown for intra-abdominal cultures h. Consider using antibiotics effective against Enterococcus (especially if patient has received cephalosporin, has valvular disease, is immunocompromised or post-operative) i. Therapy duration: 4 days (when source control is complete) * High-risk or severe is defined as APACHE II score greater than 15, advanced age, poor nutritional status/low albumin concentration, comorbidities and organ dysfunction, an inability to achieve adequate source control, presence of malignancy, severe physiologic disturbance or immunosuppression. 4. Therapy duration: 4–7 days (when source control is complete) CLOSTRIDIUM DIFFICILE INFECTION A. Introduction 1. Clostridium difficile is transmitted by the fecal-oral route. 2. Overgrowth in the GI tract occurs after antibiotic therapy. 3. Risk factors: Hospital stays, medical comorbidities (e.g., oncology, inflammatory bowel disease, chronic kidney disease, organ transplant), extremes of age, immunodeficiency states, use of broad-spectrum antibiotics, use of proton pump inhibitors 4. Production of endotoxins A and B causes pathogenesis. 90  Pharmacology-IV 5. Symptoms: Watery diarrhea, abdominal pain, leukocytosis, GI tract complications 6. Disease severity: a. Non-severe: Leukocytosis with WBC 15 x 103 cells/mm3 or less and SCr less than 1.5 mg/dL b. Severe: Leukocytosis with WBC 15 x 103 cells/mm3 or greater or SCr greater than 1.5 mg/dL c. Fulminant: Hypotension or shock, ileus, megacolon 7. BI/NAP1 strain produces more enterotoxin, produces binary toxin, has increased sporulation capacity, and is resistant to fluoroquinolones. Increased risk of metronidazole failure, morbidity, and mortality B. Therapy 1. Initial episode a. Nonsevere infection i. Vancomycin 125 mg orally four times a day for 10 days ii. Fidaxomicin 200 mg orally twice daily for 10 days. No difference in clinical cure rates compared with vancomycin but lowered incidence of recurrence iii. Metronidazole may be used if the above two agents are not available (500 mg orally three times daily for 10 days) b. Severe infection i. Vancomycin 125 mg orally four times a day for 10 days ii. Fidaxomicin 200 mg orally twice daily for 10 days c. Fulminant infection: Vancomycin 500 mg orally four times a day plus metronidazole 500 mg intravenously every 8 hours (if complete ileus, add vancomycin per rectum 500 mg in 100-500 mL of saline as an enema four times a day) 91  Pharmacology-IV 2. First recurrence a. Following metronidazole: Vancomycin 125 mg orally four times daily for 10 days b. Following vancomycin: i. Vancomycin prolonged taper and pulsed dosing: 125 mg orally four times daily for 10-14 days, then twice daily for a week, then daily for a week then every 2-3 days for 2-8 weeks ii. Fidaxomicin 200 mg orally two times daily for 10 days c. Following fidaxomicin: Vancomycin prolonged taper and pulsed dosing 3. Second and subsequent recurrences a. Vancomycin prolonged taper and pulsed dosing b. Vancomycin 125 mg orally four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days c. Fidaxomicin 200 mg orally twice daily for 10 days d. Fecal microbiota transplantation 4. Recurrence prevention with bezlotoxumab a. Human monoclonal antibody that binds to C. difficile toxin B preventing recurrent infections. b. Indicated in patients who are at high risk of recurrence (older than 65, one or more prior episodes within the previous 6 months, immunocompromised, clinically severe CDI at presentation, or virulent strain [ribotype 027, 078 or 244]). c. Dose: 10 mg/kg intravenously as a single 60-minute infusion given during standard antibiotic therapy (does not replace standard antibiotic therapy) d. Lower incidence of recurrent C. difficile infection in 12 weeks (17% versus 27%). 92 Pharmacology-IV 93