LRTI.pdf

Lower Respiratory Tract Infections LRTI Maram Ahmed Alzahrani PGY2, Infectious Diseases Pharmacy Resident King Faisal Specialist Hospital and Research Centre, Riyadh Dr. Abdullah Almohaizeie, PharmD, ID Clinical Pharmacist Consultant....

Lower Respiratory Tract Infections LRTI Maram Ahmed Alzahrani PGY2, Infectious Diseases Pharmacy Resident King Faisal Specialist Hospital and Research Centre, Riyadh Dr. Abdullah Almohaizeie, PharmD, ID Clinical Pharmacist Consultant. LEARNING OBJECTIVES: To be able to assess the pharmacotherapy and the classification of LRTI To be able to describe the clinical presentation and diagnosis of LRTI To be able to recognize the causative pathogens and the recommended treatment  ANTIBIOTIC CLASSIFICATION AND PHARMACOLOGY Beta-lactam penicillins Cephalosporines Carbapenem Monobactam Natural penicillins 1st generation Meropenem Penicillin G 4th generation Aztreonam Cefazolin Cefepime Imipenem Penicillin V Cephalexine Ertapenem Procaine penicillin 5th generation Cefadroxil Ceftaroline Doripenem Benzathine penicillin 2nd generation penicillinase-resistant penicillin Ceftobiprole Cefaclor Nafcillin Cefotetan Methicillin Cefuroxime Cloxacillin Cefoxitin Oxacillin 3rd generation Flucloxacillin Ceftriaxone Side effect: gastrointestinal side effects, such as diarrhea, nausea, and constipation; Aminopenicillins Cefotaxime nervous system effects such as headaches, insomnia, and seizures; hematological Amoxicillin Ceftazidime effects such as impaired platelet function; allergic reactions including anaphylaxis; pain Ampicillin Cefdinir Dose adjustment: Renal except Ceftriaxone, penicillinase-resistant penicillin b-Lactam/b-Lactamase Inhibitor Ampicillin/sulbactam Amoxicillin/clavulanic acid Piperacillin/tazobactam  ANTIBIOTIC CLASSIFICATION AND PHARMACOLOGY Other classes Macrolides Tetracycline Fluoroquinolones Azithromycin Tetracycline Levofloxacin Clarithromycin Doxycycline Ciprofloxacin Erythromycin Moxifloxacin SE: GI disturbance Deposition in SE: Tendon rupture,QT SE: GI disturbance QT bone and teeth, nausea and vomiting, prolongation, aortic prolongation photosensitivity dissection, Clostridioides Dose adjustment: non hepatic Contraindication: In pregnancy and difficile associated diarrhea, nor renal is requried children 65 years Diabetes mellitus Asplenia Chronic cardiovascular and pulmonary Smoking and/or alcohol abuse Hospital-acquired pneumonia (HAP ) COPD, ARDS, or coma Enteral nutrition, nasogastric tube Ventilator-associated pneumonia (VAP) Reintubation, tracheostomy, or patient transport COMMUNITY-ACQUIRED PNEUMONIA (CAP) Community-Acquired Pneumonia (CAP)  Sever ICU In-patient Disease Severity and Non-Sever Site of Care General Ward Out- patient  Disease Severity and Site of Care Commonly used indices Pneumonia severity index (PSI) (Scoring system to determine severity of disease and probability of poor outcome used to determine inpatient vs. outpatient treatment) CURB-65 score C: confusion U: uremia (BUN > 20 mg/dL) R: respiratory rate (>30 br/min) B: blood pressure low 90/60 65: Age more than 65 years Scores: 1 = outpatient treatment 2 = inpatient treatment ≥3 = ICU admission Disease Severity and Site of Care IDSA–ATS guidelines define severe CAP as the presence of one major or 3 or more minor criteria.  Case 1 A 67-year-old woman with mild Alzheimer’s disease A 2-day history of productive cough, fever, and increased confusion is transferred from home to the ED No recent hospitalizations or recent use of antibiotic agents Her T 38.4°C, BP145/85 mm Hg, the RR is 30, HR 120, and the O2 is 91% (room air) Crackles are heard in both lower lung fields Oriented to person only WBC 4000 Na 130 mmol/L BUN 25 mg/dL (9.0 mmol/L) A radiograph of the chest shows infiltrates in both lower lobes Based on the clinical condition of MA in the ED, where should her care be continued? A. Outpatient B. Inpatient-general ward C. Inpatient-ICU admission  Case 2 JL is an 84 Y.O. who was brought in the ED this morning by her husband who stated in the last day she had become very confused. Relevant patient data includes: T 101.4, WBC 13.2, Hct 34, Na 137, K 3.9, BUN 17, Cr 1,CO 220, Glu 91, BP 108/76, HR 78, RR 24, O2Sat 92% on RA. She is diagnosed with CAP. Calculate the CURB 65 score? A. 1 B. 2 C. 3 D. 4 E. 5 Treatment Principles Empiric Treatment: Outpatient Macrolide (azithromycin 500 mg on first day then 250 mg daily or clarithromycin 500 mg twice daily only in areas with pneumococcal resistance to macrolides ,25% Empiric Treatment: Hospitalized, Non-ICU Empiric Treatment: Hospitalized, ICU Treatment of CAP is generally a minimum of 5 days Exceptions: P. aeruginosa 7days MRSA 7 days When to D/C therapy? Afebrile x 48-72 h Clinical stability Criteria for switching from IV to PO: Tolerating PO or enteral nutrition or other medications with no contraindications to oral therapy  Positive Influenza Test Adjunctive Corticosteroids Give neuraminidase inhibitor regardless of time since symptom Do not routinely add adjunctive corticosteroids onset or treatment setting (inpatient/outpatient) Add if shock refractory to fluid resuscitation and vasopressor support Continue antibiotics, consider discontinuing if negative cultures, No benefit in non-severe CAP low procalcitonin, and early clinical stability Conflicting mortality benefit data in severe CAP HAP/VAP Microbiology Staphylococcus aureus (MRSA) Pseudomonas aeruginosa Acinetobacter Stenotrophomonas Maltophilia Enterobacteriaceae group Pneumonia HAP Treatment  Empirical antibiotics should provide coverage for S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli.  (piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem)  Adding an agent active against MRSA (vancomycin OR linezolid) for the empiric treatment in the following: Pneumonia HAP Treatment Pseudomonas covarege: Adding antibiotics from 2 different classes with activity against P. aeruginosa empirically if: Prior intravenous antibiotic use within 90 days High risk for mortality (Risk factors for mortality include need for ventilatory support due to HAP and septic shock)  structural lung disease All other patients with HAP who are treated empirically may be prescribed a single antibiotic with activity against P. aeruginosa. Pneumonia VAP Treatment  Empirical antibiotics should cover S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli.  (piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem) Adding an agent active against MRSA (vancomycin or linezolid )for the empiric treatment only in patients with any of the following: Prior intravenous antibiotic use within 90 days Epidemiologic data show that more than 10% -20% of all S. aureus isolates are methicillin-resistant or data are unavailable Pneumonia VAP Treatment Dual antipseudomonal therapy from different classes for the empiric treatment of suspected VAP only in patients with any of the following: Risk factors for antimicrobial resistance (IV antibiotics use within 90 days) Patients being treated in units where >10% of gram-negative isolates are resistant to for monotherapy Patients in an ICU where local antimicrobial susceptibility rates are not available Patient with structural lung disease (ie, bronchiectasis or cystic fibrosis) Antibiotic Therapy De-escalated The therapy is recommended after culture results (refers to changing an empiric broad-spectrum antibiotic regimen to a narrower antibiotic regimen by changing the antimicrobial agent or changing from combination therapy to monotherapy Duration of Therapy (HAP/CAP): 7-day course of antimicrobial therapy is recommended Inhaled Antibiotics It is reasonable to consider adjunctive inhaled antibiotic therapy as a treatment of last resort for patients who are not responding to intravenous antibiotics alone, whether the infecting organism is or is not multidrug-resistant (MDR) (suggest both inhaled and systemic anti-biotics, rather than systemic antibiotics alone) For patients with VAP due to gram-negative bacilli that are susceptible to only aminoglycosides or polymyxins use both inhaled and systemic antibiotics, rather than systemic antibiotics alone DIRECTED THERAPY IN ADULT PATIENTS Pathogen Preferred Antibiotic Therapy Alternate Antibiotic Therapy Macrolide, cephalosporin, S. pneumoniae Penicillin G OR amoxicillin clindamycin, doxycycline, Penicillin-susceptible fluoroquinolonea MIC < 2 Penicillin-resistant MIC >8 Cefotaxime, ceftriaxone, Vancomycin, linezolid, high-dose fluoroquinolonea amoxicillin (3 g/day) if MIC ≤ 4 mg/L H. influenzae Fluoroquinolone, doxycycline, Amoxicillin non-β-lactamase producing azithromycin, clarithromycin 2nd OR 3rd generation Fluoroquinolone, doxycycline, β-lactamase producing cephalosporin azithromycin, clarithromycin Legionella spp. Fluoroquinolone, macrolide Doxycycline MRSA Vancomycin, linezolid TMP-SMX Clindamycin MSSA Antistaphylococcal penicillin Cefazolin, clindamycin TUBERCULOSIS Tuberculosis (TB) is caused by Mycobacterium tuberculosis  It primarily infects the lungs but can disseminate (spread) to other organs.  TB can be fatal if not treated properly.  The disease has two phases: latent and active.  Mycobacterium tuberculosis characteristic: Rod-shaped thin aerobic bacterium  Definitions Pulmonary TB: TB disease that occurs in the lungs Open TB: when there are lesions in the lungs +Cough+ sputum Extra-pulmonary TB: TB diseases affect any body part other than the lungs. Disseminated TB: TB infection has spread from the lungs to other parts of the body, with multiple organs affected Miliary TB: the acute form of TB in which minute nodules are formed in several organs of the body through the dissemination of the bacilli throughout the body by the bloodstream Drug-resistant TB: Multi-drug resistance TB (MDR-TB): TB with resistance to At Least Isoniazid and Rifampin, the 2 most important 1st- line drugs. Extensive drug resistance TB (XDR-TB): MDR-TB with additional resistance to fluoroquinolone, and second-line injectable Sites involved: Pulmonary TB Extrapulmonary sites - Lymph nodes - Genitourinary tract - Bones and joints - Meninges - Intestine - Skin Risk factors Diseases that weaken the immune system such as HIV Person on immunosuppressant like steroids Healthcare workers travel in a country with a high incidence of TB disease Alcoholism Transplantation Low body weight Injection drug users Diabetes mellitus, Severe kidney disease, leukemia, lymphoma, Head and neck cancer Clinical Presentations Pulmonary TB In the pictures Extrapulmonary TB Bones: pain in the bones or back Joints: pain, redness, swelling Kidney: painful peeing (urination), cloudy pee (urine) Brain: headaches, stiff neck, hurts to move head or eyes Latent TB No symptoms Transmission Airborne. However, not all forms of TB are contagious, and the most contagious ones are pulmonary TB Other common extrapulmonary sites include lymph nodes, pleura, and osteoarticular system, all reputed to be noninfectious. ISOLATION Diagnosis latent TB: Classification of the Tuberculin Skin Test Reaction. Induration of ≥5ml Induration of >10 Induration of >15 Latent disease can be diagnosed using the tuberculin People living with People born in countries any one without skin test (TST), also called a purified protein derivative HIV where TB disease risk factor (PPD) test. The test read 48 to 72 hours after injection by Health care provider measuring the diameter of the zone induration A false-positive TST can occur in those who have received the bacille Calmette-Guerin (BCG) vaccine (used in areas of the world with high TB rates). Injection of PPD containing five unit/0.1 ml Diagnosis latent TB: interferon-gamma release assay (IGRA), is available and can be used in patients who have received the BCG vaccine It does not require a follow-up visit. If an IGRA is not available, the TST is acceptable Diagnosis Active TB 1- Using sputum from patients: 3 consecutive sputum samples (early morning) Acid-fast bacilli smear Culture (2-4 weeks or 8 weeks) 2- Chest radiography 3- Nucleic acid ampliation RNA and DNA TREATMENT  Pharmacology of TB Treatments Anti-TB Mechanism : Adverse effects: Comment Isoniazid inhibits the synthesis of mycoloic Peripheral neuropathy The highest risk to induce acids, an essential component of Peripheral neuropathy Persons with risk factors hepatotoxicity 5 mg/kg the bacterial cell wall for neuropathy (e.g., diabetes, uremia, (typically, 300 alcoholism, malnutrition, HIV infection), Pyridoxine only for high- mg) pregnant women, and persons with seizure risk patients disorder may be given pyridoxine (vitamin B6) 10–50 mg/day with INH, as this may prevent neuropathy. -Hepatotoxicity -CNS effects(seizures, paresthesia) -GI upset Anti-TB Mechanism : Adverse effects: Comment Rifampicin Inhibits bacterial RNA synthesis Discoloration (reddish-orange) of body fluids Potent CYP3A4 Inducer. by binding to the beta subunit of Flu like symptoms 10 mg/kg DNA-dependent RNA polymerase, Hepatotoxicity (typically 600 blocking RNA transcription Dose dependent thrombocytopenia mg) GI upset  Pharmacology of TB Treatments Anti-TB Mechanism : Adverse effects: Comment Pyrazinamide Converted to pyrazinoic acid in - Hepatotoxicity Contraindication :acute gout 40 to 55 kg: susceptible strains - Malaise and arthralgia Sever hepatic damage 1,000 mg of Mycobacterium which lowers - Acute gouty arthritis the pH of the environment; exact mechanism of action has not been elucidated Anti-TB Mechanism : Adverse effects: Comment Ethambutol Inhibits cell wall synthesis - Optic neuritis, reversible after Is only safe for people with liver disease stopping the medications CSF penetration is poor 40–55 kg: 800 - Cutaneous reactions (dermatitis and Perform bassline and monthly visual mg skin rash) acuity and color discrimination monitoring  TREATMENT OF ACTIVE TB INFECTION The preferred regimen for treating TB remains a regimen consisting of: An intensive phase of 2 months of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) followed by a maintenance phase of 4 months of INH and RIF. If TB isolate is susceptible to both INH and RIF, then ETHAMBUTOL can be dropped from the intensive phase.  Latent TB Treatment: Patients who are co-infected with HIV: Isoniazid 300 mg/day for 9 months Alternative: Isoniazid 900 mg twice weekly for 9 months with directly observed therapy Patients who are not infected with HIV: Isoniazid 300 mg/day or 900 mg twice weekly for 6–9 months (9 months preferred , especially for children and pregnant women) Rifampin 600 mg/day for 4 months Rifapentine 900 mg plus isoniazid 900 mg/week for 12 weeks (with directly observed therapy) Directly Observed Therapy (DOT) MANAGEMENT OF TREATMENT INTERRUPTIONS:  Extrapulmonary TB Extra-pulmonary TB: TB diseases affect any body part other than the lungs. Typically presents as a slowly progressive decline in organ function. Patients may have low-grade fever and symptoms related to the part of the body that is affected.  Treatment of Extrapulmonary TB Isoniazid Extrapulmonary TB is treated with conventional regimens Pyrazinamide The FOUR first-line medications are used for the 2 Ethionamide Ethambutol months intensive phase followed by a variable duration of Levofloxacin streptomycin continuation phase depending on the site or organ affected Rifampicin Duration of therapy: Extra-pulmonary TB with central nervous system (CNS) infection: 9–12 months Extra-pulmonary TB with bone or joint involvement: 6–9 months Extra-pulmonary TB in other sites: 6 months Pregnancy Latent TB Active TB 4-month daily regimen of rifampin (RIF) (4R) isoniazid, rifampin and ethambutol for 2 month 3-month daily regimen of isoniazid (INH) and then INH,RIF for daily for 7 month RIF (3HR) 6- or 9-month daily regimen of INH (6H or 9H) (9 months of INH, RIF, and EMB, IDSA).  Pregnancy Pregnancy and Breastfeeding women taking INH should also take pyridoxine (vitamin B6) 25mg-50mg/daily. Inclusion of PZA in the treatment regimen for pregnant women is controversial in the United States. Expert opinion is that in pregnant women with tuberculosis and HIV, extrapulmonary or severe tuberculosis, it is more beneficial to include PZA in the treatment regimen than to not include PZA. Second line: Cycloserine, fluoroquinolones, aminoglycosides and Ethionamide are not recommended during pregnancy  Corticosteroids in TB Meningitis In TB meningitis, corticosteroids significantly decrease mortality thus, adjunctive corticosteroids (either dexamethasone or prednisolone) are recommended The recommended dosage regimens of corticosteroids are dexamethasone 12 mg/day or 0.4 mg/kg/day for the first 3 weeks in adults, with tapering over the next 3-5 weeks with monitoring of the improvement Lee JY. Diagnosis and treatment of extrapulmonary tuberculosis. Tuberc Respir Dis (Seoul). 2015;78(2):47-55. TREATMENT TB SECOND LINE:  Management of Common Adverse Effects  Hepatotoxicity (INH, RIF, and PZA can cause drug-induced liver injury) Suspected when  ALT level is ≥ 3 X ULN in the presence of hepatitis symptoms  Or ≥ 5 X ULN in the absence of symptoms Severity  Mild toxicity: If the ALT level is < 5 X ULN  Moderate toxicity: if ALT level 5–10 X ULN  Severe toxicity: if ALT level > 10 X ULN EMB RIF INH PZA Hepatotoxicity  Management of Common Adverse Effects Stop anti-TB drugs immediately: If ALT levels are ≥ 5 X ULN (with or without symptoms) OR If ALT ≥ 3 X ULN in the presence of symptoms In smear positive TB cases or where discontinuation of therapy is deemed unsafe due to severity of the illness, a non-hepatotoxic anti-TB treatment (2nd line) could be considered American Thoracic Society, United States Centers for Disease Control and Prevention, and Infectious Disease Society of America 2018 HEPATOTOXICITY RE-CHALLENGE  Management of Common Adverse Effects Rash All antituberculosis drugs can cause a rash, the severity of which determines management If the rash is mainly itchy without mucous membrane involvement or systemic signs such as fever, treatment is symptomatic with antihistamines, and all antituberculosis medications can be continued. A petechial rash is more concerning and suggests thrombocytopenia from a rifamycin (ie, RIF, RFB, RPT) hypersensitivity If the platelet count is low, the rifamycin is permanently stopped and the platelet count closely monitored until definite improvement is noted. Drugs are also stopped if the patient has a generalized erythematous rash.  Management of Common Adverse Effects Peripheral neuropathy Pyridoxine (VIT-B6) Dose: - 25 to 50 mg/day is given with isoniazid to individuals at risk for neuropathy (eg, pregnant women, breastfeeding infants, and individuals with HIV infection, diabetes, alcoholism, malnutrition, chronic renal failure, or advanced age,Malnourshi). - For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day.  Management of Common Adverse Effects Optic Neuritis EMB-related visual impairment during treatment of active tuberculosis has been estimated to occur in 22.5 per 1000 persons (2.25%) receiving EMB at standard doses The onset of optic neuritis is usually >1 month after treatment initiation but can occur within days. The opinion of experts is that baseline 1)visual acuity (Snellen test) and 2)color discrimination tests followed by monthly 1)color discrimination tests are performed during EMB use. To avoid permanent deficits, EMB is promptly discontinued if visual abnormalities are found. If vision does not improve with cessation of EMB, experts recommend stopping INH as well, as it is also a rare cause of optic neuritis  Candidates considered for latent TB treatment: People in these groups should be given high priority for LTBI People in these group should be given high priority for LTBI treatment if they have positive IGRA result or a TST reaction treatment if they have positive IGRA result or a TST reaction that is more than 5 or more milimeters that is more than 10 or more milimeters Recent contacts of people with infectious TB diseae People born in countries where TB disease is common People living with HIV People who abuse drugs People with chest x-ray findings suggestive of previous TB People who live or work in high-risk setting disease People who work in mycobacteriology lab Patients with organ transplant People with diseases that increase the risk of TB (eg. Other immunosepressed patients (eg. Prolong use of steroids Scilicosis, DM, severe kidney disease , certain types of equivalent or greater to 15mg/day for one month) cancer) Children younger than 5 years Infants, children and adolescents exposed to adults in high risk group