Infectious Diseases PDF

Introduction to Antimicrobial Therapy Martin Price Spring 2025 Hem/Onc/ID Some Semantics Antibiotics: any substance that inhibits the growth or kills a pathogen Antibacterial Drugs Antifungal Drugs Antiviral Drugs What is Empir...

Introduction to Antimicrobial Therapy Martin Price Spring 2025 Hem/Onc/ID Some Semantics Antibiotics: any substance that inhibits the growth or kills a pathogen Antibacterial Drugs Antifungal Drugs Antiviral Drugs What is Empiric Therapy? Empiric Therapy Infection is present but the causative agent is not known Therapy started prior to Culture and Sensitivity results are known Antibiotic selection is based on knowledge of the typical pathogens associated with a particular infection Empiric therapy is the most common use of antibiotics in clinical medicine Definitive identification of a causative organism takes up to 48 hours Delay in treatment is harmful to the patient in many cases Combination therapy may be common Treating most common pathogens Broader spectrum antibiotics are often used Definitive Therapy Therapy that is tailored to culture and sensitivity results Provider knows exactly which antibiotics will work for the infection May require an adjustment to empiric therapy Monotherapy is preferred Narrow spectrum antibiotics are preferred to help minimize resistance Gram Stain vs. Bacterial Culture Gram Stain Bacterial Culture Indicates where there is a possible Results can take up to 24-48 hours bacterial cause for an illness or not Organism specific criteria allow for Differentiation of bacteria based definitive diagnosis on characteristics of their cell-wall Allows for guided or definitive Quicker Results therapy targeted against a specific Does not definitively identify an organism organism Helps in guiding EMPIRIC Therapy Bacteria Review Gram Positive Gram Negative Atypical Spirochetes Rickettsia Mycobacteria Mycoplasma Legionella Gram Positive Cocci Staphylococcus S. aureus S. epidermis Streptococcus S. pneumonia S. pyogenes (GAS) S. agalactiae (GBS) Enterococci E. faecalis Gram Positive Rods Clostridia C. tetani C. botulinum C. difficile Oral vancomycin Corynebacterium C. diphtheria Get the vaccine Anti-toxin for those with disease Listeria L. monocytogenes Concerns in pregnancy Ampicillin  Gram Negative Bacteria Enterobacteriaceae E. coli, Proteus, Klebsiella, Shigella, Salmonella, Yersinia, Citrobacter UTI, Pneumonia, Diarrhea, Sepsis Nitrite producers Non-fermenters Moraxella Pseudomonas Antibiotic Resistance Neisseria Chlamydia Haemophilus H. pylori How are they different? What is the difference between bactericidal and bacteriostatic? Bactericidal Kills Bacteria Can eradicate bacteria even if immune system is ineffective Better for immunocompromised patients PCN and Cephalosporins Are Very Cidal For Microbes PCN Cephalosporins Aminoglycosides Vancomycin Fluoroquinolones Metronidazole Generally, drugs that interrupt cell wall or DNA synthesis are bactericidal Bacteriostatic Inhibit Bacterial Proliferation Cannot eliminate bacteria on their own Designed to give the immune system an upper hand Requires a competent immune system Tetracyclines (Doxycycline) Macrolides (Azithromycin) Bactrim Linezolid Chloramphenicol What type of patient should not receive a bacteriostatic antibiotic? Spectrum of Activity Broad Spectrum Covers a wide range of bacteria – gram +, gram -, and often atypicals Good for empiric therapy Increased risk of adverse effects, superinfections, and resistance Examples Fluoroquinolones Carbapenems Some Penicillins – Augmentin, Piperacillin-Tazobactam, Ampicillin- Sulbactam Some Cephalosporins – Ceftriaxone, Cefepime, etc. Tetracyclines Bactrim Spectrum of Activity Narrow Spectrum Targeted therapy – covers fewer organisms Preferred when the causative organism is known Lower risk of superinfections and resistance Examples Penicillins – PCN V, PCN G, Nafcillin Cephalosprorins – Cefazolin Vancomycin Clindamycin Metronidazole Keys to Effective Antibiotic Use What organism is causing the disease I am trying to treat? Is the drug I am using effective at treating the organism that is causing the disease? Will drug harm the patient along with the organism I want to treat? Can the drug get to where I need it to get to in the body? Does the drug stay where I want it long enough to work effectively? Antibiotic Targets Cell Wall Synthesis Bacitracin Beta-Lactams Penicillin Cephalosporins Carbapenems Monobactams (Aztreonam) Vancomycin Protein Synthesis Aminoglycosides Tetracyclines DNA Synthesis and Repair Fluoroquinolones Metronidazole Mechanisms of Antibiotic Resistance Enzymatic or Metabolic Inactivation of Antibiotic Very common Examples Beta-Lactamase Production Aminoglycoside-modifying enzymes Alteration of Target Site Examples MRSA – alters Beta-lactam binding protein Rifampin resistance – binding site on RNA polymerase Efflux Pumps Actively expel antibiotic from cell Examples Multidrug resistance (MDR) efflux pumps Mechanisms of Antibiotic Resistance Reduced Permeability – Porin Channel Mutations Common in gram-negative bacteria – especially pseudomonas Often works synergistically with efflux pumps Often affects beta-lactams, fluoroquinolones, and aminoglycosides Alteration of Metabolic Pathways Bacterial develop alternate metabolic pathways Allow bacteria to continue vital process despite antibiotics Example Sulfonamide resistance – Bactrim Biofilms formation Horizontal Gene Transfer Very Important to Remember Which Antibiotics are Effective Against MRSA Very Important to Remember Which Antibiotics are Effective Against Pseudomonas  Systematic Approach to Selection of Antimicrobial Agents Identification of Selection of Confirmation Monitor therapeutic causative presumptive of infection response pathogen therapy Antibiograms Help Guide Empiric Therapy Sepsis What is Sepsis? “Life threatening organ dysfunction caused by a dysregulated host response to infection” Infection leads to uncontrolled systemic inflammation This can lead to vasodilation and increased capillary permeability Organ failure and death may occur if this process is left unchecked  Basic Definition of Shock  Hypotension Elevated Lactate Signs of Tissue Hypoperfusion Oligouria Elevated Liver Enzymes Types of Shock Hypovolemic Loss of fluid → Inadequate venous return → Low Cardiac Output (CO) ”The Tank is Empty” Cardiogenic Decreased cardiac contractility → loss of pump function → Low CO ”Pump Doesn’t Work” Obstructive Extracardiac obstruction of blood flow into and out of heart → Low CO ”The Pipes are Clogged” Distributive/Vasodilatory Loss of vascular tone → vasodilation → hypoperfusion despite normal CO ”The Container is Too Big” Sepsis is the Most Common Cause of Distributive Shock What is Septic Shock? Persistent hypotension (MAP < 65) requiring the use of vasopressors in a patient with sepsis Sepsis induced hypotension that is refractory to adequate fluid resuscitation Continued signs of tissue hypoperfusion despite fluid resuscitation Treatment of Sepsis Early Recognition Fluid Resuscitation Culture All The Things – Blood, urine, sputum, etc. -- preferably before antibiotic therapy Empiric Antibiotic Therapy Vasopressors if shock is present Directed Therapy once culture results are back Fluid Resuscitation in Sepsis Aggressive Fluid Administration is a Key Treatment strategy in septic patients Rapid Large Volume Infusions of IV Fluids 30mL/kg Completed within the first 3 hours of presentation Typically given in 500mL boluses Evaluate for clinical and hemodynamic response after each bolus Evaluate the patient for the presence of pulmonary edema before fluid resuscitation and after each bolus Continue boluses until tissue perfusion improves, pulmonary edema develops, or it is evident that the patient is refractory to fluid resuscitation Isotonic Crystalloid Solutions Sodium Containing Solutions Sodium Concentration similar to Serum Concentrations Less fluid shifts Types Normal Saline -- 0.9% Saline Lactated Ringer’s Solution Most common type of IVF used for treatment of Sepsis and Shock that is not due to bleeding Does not transport Oxygen Normal Saline Major Components are Sodium and Chloride Hyperchloremic in relation to plasma Used for volume expansion, but fluid leaves vasculature quickly after administration Most commonly used solution for treatment of sepsis and shock not due to bleeding Especially when volumes of less than 2 liters are to be administered Concerns with use Fluid Overload and Dilution Coagulopathy Hyperchloremic Metabolic Acidosis Hypernatremia Lactated Ringer’s Solution Contains additional electrolytes in addition to sodium and chloride Potassium, Calcium, Lactate Lower amounts of chloride compared to Normal Saline Less risk of Hyperchloremic Metabolic Acidosis Lower amounts of sodium compared to Normal Saline Hyponatremia is a risk May be preferred over Normal Saline when very large amounts of fluid are to be administered (over 2 liters) Other Types of Crystalloid Solutions These are not used in the treatment of sepsis Hypertonic Saline (3%) Causes rapid volume expansion through fluid shifts from intracellular to extracellular Extremely dangerous – only used in specific circumstances Hypotonic Saline (0.45%) aka Half Normal Saline Mainly used in the treatment of Hypernatremia D5W 5% Dextrose in Water Many others Colloid Solutions Large Molecule containing solutions Hold onto fluid in the vascular space Less fluid is lost to interstitial spaces Requires less amounts of fluid to be given – beneficial in patients at risk for volume overload – CHF, Cirrhosis More Expensive than Crystalloid Solutions Have not demonstrated a benefit over crystalloids in the treatment of sepsis or shock Considered Second-Line Major Concerns Anaphylaxis – Larger Molecules Renal Dysfunction Major Colloid Solutions Albumin Hyperoncotic Starch – should not be used in sepsis or shock Significant risk of Kidney Injury Pentastarch, Hydroxyethyl Starch Major Takeaways Early Fluid Resuscitation is key in the treatment of sepsis and septic shock Recommendation is for 30mL/kg Monitor for fluid overload and for patient response and adjust fluid resuscitation accordingly Isotonic Crystalloids are First-Line Choose based on underlying patient characteristics and labs Re-evaluate choice frequently and change if necessary Empiric Antibiotic Therapy Preferably initiated within 1 hours of patient presentation Things to Consider Recent Antibiotic Use Comorbidities Immune Defects Community Acquired vs. Hospital Acquired Infection Site of Infection Presence of any Invasive Devices Gram Stain Local Antibiogram Principles of Empiric Therapy Broad Spectrum – cover both Gram+ and Gram- bacteria Carbapenems Piperacillin-tazobactam Most common organisms causing sepsis E. coli, S. aureus, K. pneumoniae, S. pneumoniae Don’t Forget to Cover for MRSA Vancomycin is a part of most Empiric Therapy Do you need to consider Pseudomonas? No Concern for Pseudomonas Vancomycin plus one of the following Third Generation Cephalosporin Ceftriaxone Cefotaxime Beta-lactamase resistant beta-lactam Piperacillin-tazobactam Carbapenem Imipenem Meropenem Concern for Pseudomonas Vancomycin plus one or even two of the following Antipseudomonal Cephalosporin Ceftazidime Cefepime Antipseudomonal Carbapenem Imipenem Meropenem Piperacillin-tazobactam Ciprofloxacin Aztreonam Viral Illnesses What is a Virus? Obligatory Intracellular Microorganism Relies on host biosynthetic mechanism to reproduce Basic Structure Double or Single Stranded DNA or RNA Protein Coat – Capsid Envelope – derived from infected host’s cell membrane Viral Replication Cycle (Potential Targets for Antivirals) Attachment and penetration of the virus into the host cell Uncoating of the virus inside the host cell Synthesis of viral components within the host cell Assembly of viral particles Release of virus from host cell to invade other cells DNA Viruses Smallpox, Herpesviruses, Adenoviruses, Hepatitis B Virus, HPV Enter host cell nucleus and transcribe viral DNA into mRNA using host cell mechanisms mRNA is translated into viral proteins New viruses are assembled in the cytoplasm and released from host cell RNA Viruses Rubella, Influenza, Hepatitis A and C, Coronavirus, Zika, Retroviruses Synthesize mRNA from viral RNA mRNA is used to create viral proteins and more genomic viral RNA Virus is packaged and released from the cell in a similar fashion as DNA viruses Influenza RNA Virus – Orthomyxoviridae Family Two virus Types infect humans – Influenza A and B Influenza A is subdivided based on surface antigens – hemagglutinin and neuraminidase (H1N1, H3N2, etc.) Causes upper respiratory and GI symptoms Acute fever, sore throat, headache, cough, rhinitis, nausea, and vomiting Causes more deaths than any other vaccine-preventable illness Effects the old and very young the most Prevention is our most effective way of managing influenza – Vaccine Anti-viral therapy does exist, but its use and effectiveness is limited Resistance is rising due overuse and misuse of these drugs No Lasting Immunity to Influenza Immunity to one subtype does not confer immunity to other types Antigenic Drift Small changes to the surface antigens of a specific subtype due to point mutations Leads to seasonal epidemics, changes in annual flu vaccine, need for annual vaccination Antigenic Shift Large changes to surface antigens that leads emergence of a new (novel) influenza virus (H#N#) Leads to potential for a pandemic Vaccination Recommended for all persons aged 6 months and older Patients from 6 months to less than 2 years should only receive the inactivated influenza vaccine (IIV) Vaccine works best when seasonal influenza virus is well matched with strains in the vaccine Two Types Inactivated Influenza Vaccine (IIV) Trivalent (IIV3) and Quadrivalent Forms (IIV4) Live Attenuated Influenza Vaccine (LAIV) Quadrivalent Ideally given from October to November Patients with severe allergic reactions to eggs should not receive these two types of flu vaccines Inactivated Influenza Vaccine (Fluzone) Approved for ages 6-months and older May be given to Immunocompetent and Immunocompromised patients Quadrivalent version contains Flu A H3N2 and H1N1 and two types of Flu B viruses Intramuscular Injection Patients 65 and older should get IIV4 High Dose (Fluzone HD) Adverse Effects Injection site soreness Fever and Malaise Allergic Reaction – mostly in those with egg allergies Possible link to Guillain-Barre Syndrome – avoid in patients who have experienced GBS following previous flu vaccine Live Attenuated Influenza Vaccine (FluMist) Approved for ages 2-49 Not approved in immunocompromised patients Contains same flu types as IIV Vaccines Administered Intranasally Causes immune system to mount an IgG and IgA response Do not use during Pregnancy Adverse Effects Runny nose, sore throat, congestion Same concerns regarding GBS and egg allergies as with IIV Antiviral Treatment of Influenza Early Identification of Influenza is Key Antiviral Drugs are most effective if started within 48 hours of onset of symptoms The sooner antiviral drugs are started the more effective they are Antivirals may shorten the duration of symptoms Other medications such as acetaminophen and antihistamines may be used with antivirals to help with symptoms of influenza Neuraminidase Inhibitors Impairs viral replication and spread by inhibiting release of virus from infected cells Drugs Oseltamivir (Tamiflu) Zanamivir (Relenza) Peramivir (Rapivab) Administer within 48 hours of symptom onset May reduce duration of illness by approximately 1-2 days Reduces risk of complications and hospitalizations by about 50% Oseltamivir Approved for use in patients 14 days and older Administered orally for 5 days Preferred influenza antiviral in pregnancy Most common adverse effect – nausea and vomiting Adverse Effect to be aware of Neuropsychiatric effects – confusion, delirium, and hallucinations Reported primarily in children and adolescents Direct causation has not been established May be used prophylactically as well Some types of Influenza are nearly 100% resistant to oseltamivir  Zanamivir and Peramivir Zanamivir Administered via Inhalation Poor oral bioavailability Consider patient’s ability to use device Not recommended for patients with asthma or COPD Approved for ages 7 and older Dosed for 5 days Peramivir Administered IV Approved for ages 2 and older Administered as a single dose Cap-Dependent Endonuclease Inhibitor Blocks viral replication by interfering with viral RNA Transcription Drug – Baloxavir (Xofluza) Approved for patients 12 years and older Especially in patients at high risk for developing complications Asthma, Diabetes, Heart Disease, etc. Is used in younger patients Best when used within 48 hours of symptom onset Decreases duration of illness by 2.5 days Effective against variants that are resistant to Oseltamivir Avoid use with dairy products or cation containing substances Do NOT use in pregnancy or breastfeeding Adverse Effects – Nausea, Diarrhea, Elevated Liver Enzymes Adamantanes Inhibit the virus’s ability to uncoat and replicate Blocks M2 ion channel Only effective against Influenza A H1N1 New H1N1 variant that appeared in 2009 and is now the predominant seasonal influenza A is resistant to these drugs CDC does not recommend the use of these drugs for treatment of influenza Drugs Amantadine Rimantadine Dose reductions are required for reduced kidney function and in elderly patients Especially with Amantadine Prophylaxis in certain patient situations Major Adverse Effects of Amantadine Neurotoxicity – delirium, hallucinations, seizures, coma Cardiac Arrythmias Herpes Viruses Common Pathogenic Herpes Viruses HSV-1 and HSV-2 – mucocutaneous, PNS, and CNS Varicella Zoster – Chicken Pox Cytomegalovirus Epstein-Barr Virus -- Mononucleosis Pharmacotherapy of HSV Infections Therapy suppresses viral replication, but does not cure the patient of the virus Virus remains latent within neuronal cell bodies Oral therapy is most common IV therapy is available for most agents for severe life-threatening infections and for immunocompromised patients Topical forms of some agents are available, but are less effective than systemic therapy Daily Suppressive Therapy may be used in patients with frequent HSV outbreaks Commonly used Antivirals for HSV Infections Acyclovir and Valacyclovir Famciclovir and Penciclovir Ganciclovir and Valganciclovir Acyclovir Protype drug for a class of antivirals used in to treat Herpes viruses Inhibits viral DNA Synthesis through inhibition of Viral DNA Polymerase Prevents elongation of Viral DNA strand Drug only becomes active inside cells infected with herpes virus Does not appreciably affect Human DNA Synthesis Less Side Effects Poor Oral Bioavailability – Requires more frequent dosing Distributes widely in body fluids – Can treat infections in many areas of the body including CNS Resistance can occur Only effective against Herpes Viruses Most effective against HSV-1 Effective against HSV-2 Less effective against Varicella Zoster and EBV Least effective (ineffective) against Cytomegalovirus Acyclovir Adverse Effects Generally well tolerated Common – nausea, diarrhea, rash, and headache Considered safe for use in pregnancy Rare but potentially more serious (more common with IV dosing) Nephrotoxicity Usually resolves with drug cessation and fluid administration CNS Symptoms – confusion and hallucinations Drug Interactions to be Aware of Other Nephrotoxic Agents increase the risk of nephrotoxicity Probenecid decreases renal clearance of acyclovir May be used to prolong the duration of the drug Valacyclovir Prodrug of Acyclovir Improved oral bioavailability over Acyclovir – Less Frequent Dosing Rapidly converted to Acyclovir in the body Drug Characteristics including adverse effects are the same as with Acyclovir More effective against Varicella Zoster Infections Clinical Uses Genital HSV Infections Herpetic Gingivostomatitis Recurrent Herpes Cold Sores Topical Acyclovir/Hydrocortisone Combination Herpetic Keratoconjunctivitis or Herpes Ophthalmicus Herpes Zoster (Shingles) Suppressive Therapy Bell’s Palsy Herpetic CNS Infections IV Chronic Suppressive Therapy Who should receive Suppressive Therapy Patients with severe or frequent recurrences – 6 or more episodes per year Patients who want reduce risk of transmission to uninfected sexual partner Regimens Acyclovir – 400mg BID Famciclovir – 250mg BID Valacyclovir – 500mg once a day or 1000mg once a day for patients who had 10 or more outbreaks in a year Considered safe Patients have taken chronic suppressive therapy safely for up to 10 years Ganciclovir and Valganciclovir Same Mechanism of action as Acyclovir Effective against all herpes viruses Especially active against CMV Ganciclovir has poor oral bioavailability Only used in IV form and occasionally as an ophthalmic gel Valganciclovir is the prodrug of Ganciclovir and has better oral bioavailability Available in Oral Form Major Clinical Use is the Treatment and Prevention of CMV Infections Prevention of CMV infection and Treatment of Retinitis reactivation in patient due to CMV receiving organ and bone marrow transplants Adverse Effects Black Box Warnings Myelosuppression – Neutropenia Pancytopenia has been reported Most common during 2nd week of therapy Improves within a week of drug cessation Granulocyte Colony Stimulating Factors may be needed – Filgrastim and Lenograstim May cause infertility in both males and females May be teratogenic Use is not recommended in pregnancy If treatment is necessary, Valganciclovir is the preferred agent May be carcinogenic COVID-19 SARS Coronavirus 2 (SARS-CoV-2) Older adults and those with certain comorbidities are at risk for severe complications from the virus Current Drugs Targeting Virus that Causes COVID-19 Remdesivir Nirmatrelvir/Ritonavir (Paxlovid) Other Drugs and Therapies used in the treatment of COVID-19 Oxygen Glucocorticoids – Dexamethasone Various Immune Modulators Anticoagulants Nebulized Respiratory Drugs Monoclonal Antibodies Convalescent Plasma Remdesivir Developed to treat RNA viruses that presented a threat of pandemic Ebola, MERS, SARS FDA granted emergency use authorization in 2020 Inhibits RNA synthesis by binding to RNA Polymerase Indicated for patients 12 years and older with severe COVID-19 requiring hospitalization Infused over 30-120 minutes Initial loading dose followed by maintenance doses Clinical Trials have shown that the drug has marginal clinical benefit Most common adverse effects Nausea, vomiting, elevated LFTs Anemia, Acute Kidney Injury, Fever, and Hyperglycemia have also been reported Paxlovid Combination of two antiviral drugs Nirmatrelvir and Ritonavir Ritonavir helps to slow the metabolism of Nirmatrelvir Protease Inhibitors Indicated for treatment of mild to moderate COVID-19 Especially in patients at high risk for progression to severe disease Approved for patients 12 years and older Mainly designed to prevent hospitalization and death from COVID-19 in high-risk patients Used in outpatient setting Administer as soon as possible after diagnosis Should be within 5 days of symptom onset Dose depends on kidney function Half dose of Nirmatrelvir in moderate kidney dysfunction Not recommended in severe kidney dysfunction (GFR less than 30) Many important drug interactions – be sure to use a drug interaction checker to check Paxlovid against any drug the patient is taking HIV Infection and Treatment Three Main Routes of Infection – Sexual, Parenteral, and Perinatal HIV infects immune cells that express the CD4 Receptor T-helper lymphocytes Monocytes Macrophages Dendritic cells Untreated HIV Infection → Severe Depletion of CD4 T- Cells → AIDs Increased infections from normally nonpathogenic organisms → Opportunistic Infections Anti-Retroviral Therapy (ART) is the mainstay of treatment Goal of therapy is suppression of viral load and prevention of depletion of CD4 cells Facts About HIV Enveloped single-stranded RNA Virus Retrovirus Two Types HIV-1 HIV-2 Suppression of viral load is important not only for patient survival, but to prevent transmission Patients with early and late HIV are more likely to transmit the disease Of the 1.2 million individuals living with HIV in the U.S. only about 13% are aware that they have the disease. What is a Retrovirus? Normal production of essential cellular proteins DNA is converted to an RNA strand (transcription) RNA is used as a blueprint for creation of an end product – usually a protein (translation) A retrovirus works backward Uses RNA as a template to create DNA. DNA is then transcribed into m-RNA which is translated into viral proteins and a new virus What does this mean for the treatment of HIV? Pharmacological Implications of a Retrovirus An enzyme unique to retroviruses is required to make DNA from RNA RNA-Dependent DNA Polymerase (aka Reverse Transcriptase) Major target of ART in HIV patients Reverse Transcriptase is not very good at its job Many mistakes are made during transcription → Rapid Mutation of HIV Enables virus to evade immune response Makes it hard to create a vaccine against HIV Leads to Drug Resistance Integrase – another enzyme unique to HIV Integrates HIV viral DNA into host cell’s chromosome Establishes a persistent latent infection inside the patient’s body Reason we have not been able to cure HIV Reason ART must be taken continuously Antiretroviral Therapy Goals – Restore and Preserve Immune Function; Prevent Transmission How do we meet these goals? Maximal suppression of HIV replication → Undetectable Levels of HIV-RNA Why maximal suppression? HIV infection is always harmful → Immune System Damage HIV-RNA levels represent the amount of HIV replication More HIV replication – more CD4 cell destruction Maximal suppression → less potential for selection of resistant HIV variants All patients with HIV should receive ART regardless of CD4 count Urgent indications – pregnancy, AIDs defining illness, CD4 count less than 200, HIV and hepatitis coinfection Principles of Antiretroviral Therapy Patients with HIV should be on 2-3 antiretroviral agents from at least 2 different pharmacologic classes Patients should be started on ART as soon as the diagnosis of HIV is made Better patient outcomes and less risk of transmission Antiretroviral medications are the only FDA approved treatment for HIV Many drug-to-drug interactions exist with these medications Always check against the patient’s medication list 5 Classes of Antiretrovirals Entry Inhibitors Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Integrase Strand Transfer Inhibitors (InSTIs) HIV Protease Inhibitors Newer agents from each class are better than older agents Better Efficacy Fewer Adverse Effects More Tolerable Nucleotide Reverse Transcriptase Inhibitors Reverse Transcriptase – important viral enzyme that allows HIV to turn RNA into DNA NRTIs terminate DNA elongation by binding to Reverse Transcriptase Effective against both HIV-1 and HIV-2 Most patients starting ART take at least 1 drug from this class Drugs Tenofovir Abacavir Emtricitabine Lamivudine Most newer NRTIs are cleared through the kidney – renally adjust dose Exception is Abacavir which is metabolized by the liver – avoid in advanced hepatic impairment Tenofovir also has activity against Hepatitis B – should be used in patients that are co-infected with both viruses Non-nucleotide Reverse Transcriptase Inhibitors Cause a change in the shape of Reverse Transcriptase Not effective against HIV-2 Drugs – have –vir in the middle (all newer agents) Doravirine Etravirine Rilpivirine Delavirdine Any mutation that changes the binding site of reverse transcriptase may cause resistance Development of resistance is common with all drugs in this class except Etravirine and Rilpirvirine Must be combined with other ART drugs to prevent resistance Major Class Adverse Effects Rash (rarely leading to DRESS or SJS) Hepatoxicity HIV Protease Inhibitors Inhibit a protein involved in viral maturation Production of immature non-infectious viruses Active against HIV-1 and HIV-2 Drugs Atazanavir Darunavir Adverse Effects GI Distress Increased Lipids Insulin Insensitivity Almost always used with low doses of certain CYP3A Inhibitor → Increase Drug Concentration Ritonavir (Older HIV PI) or Cobicistat Darunavir must be taken with either Ritonavir or Cobicistat HIV Entry Inhibitors Block entry of HIV into cells Usually used in patients who have been on other ART for long periods of time Used in patients with multidrug resistant HIV-1 infections Drugs Enfuvirtide – subcutaneous injection BID; expensive Maraviroc – only effective against viral forms that bind to CCR5 coreceptor Ibalizumab – IV infusion every 2 weeks Fostemsavir (Temsavir) – May cause elevations in LFTs; high doses may cause prolonged QT interval Each drug in this class has individual characteristics All drugs in the class are generally well tolerated Integrase Inhibitors (InSTI) Inhibits HIV DNA from being added to the patient’s DNA Active against both HIV-1 and HIV-2 Produce more rapid decline HIV viral RNA than other ART Drugs Bictegravir, Cabotegravir, Dolutegravir, Raltegravir Cation containing antacids reduce bioavailability Generally, better tolerated than other ART Less risk of developing resistance than other ART Adverse Effects Nausea, Rash, Headache Psychiatric Effects – Insomnia, Depression, Increased risk of Suicide Weight Gain Recommended Regimen for most patients with HIV 2 NRTIs – 1 InSTI – Plus Tenofovir and Bictegravir Emtricitabine Management of Opportunistic Infections Opportunistic Infection may be the presenting symptom of a patient with HIV/AIDs Probability of developing a specific opportunistic infection is closely related to CD4 count Once a patient reaches a specific CD4 count initiation of prophylactic therapy against common OI may be necessary The best way to prevent OI is to suppress HIV viral load and preserve immune function Management Principles Prevent Exposure to Opportunistic Pathogens Ensure patient is properly vaccinated Use primary chemoprophylaxis at certain CD4 thresholds to prevent initial episode of OI Treat any OI that arises Use secondary chemoprophylaxis to prevent disease recurrence Discontinue chemoprophylaxis when patient is on sustained ART and immune system has recovered Management of Pneumocystis jirovecii PCP pneumonia is the most common life-threatening OI in patients with AIDs Fungus that has protozoan characteristics Present in most humans – only causes disease in immunosuppression Occurs when CD4 count is less than 200 Untreated the mortality rate is nearly 100% Treatment of choice – Trimethoprim-sulfamethoxazole (Bactrim) Given IV Duration is usually 21 days Corticosteroids should be administered within 72 hours of starting Bactrim ART should be started within 2 weeks of PCP therapy Bactrim also used for primary and secondary prophylaxis Trimethoprim-Sulfamethoxazole (Bactrim) Both are antibacterial agents Both drugs individually are bacteriostatic, but together may have bactericidal action Both drugs inhibit the pathway involved in the synthesis of folate Affect DNA synthesis Has a wide range of clinical use including GI infections, Respiratory Infections, UTI, and PCP Bacterial Resistance is a concern Obtain sensitivity reports Resistance has limited its use as empiric therapy for many diseases including UTI and respiratory infections Effective against most MRSA infections Not effective against Pseudomonas Major Adverse Effects of Bactrim Rash – SJS Monitor patients who develop a rash during therapy for progression to SJS Certain drugs used in ART can also cause rash Fever Leukopenia Thrombocytopenia Elevated LFTs Hyperkalemia May lead to a hemolytic anemia in patients with G6PD Deficiency – rare Inhibits warfarin metabolism – may cause increased bleeding – inhibits CYP2C9 These adverse reactions are more common in patients with HIV Prophylaxis Primary Prophylaxis Any patient with HIV and a CD4 count less than 200 or a history of oral pharyngeal candidiasis Secondary Prophylaxis Any patient with HIV who have had a previous episode of PCP Preferred Agent – Bactrim Cost Effective Provides additional protection against Toxoplasmosis and other bacterial infections 1 double strength tablet daily May discontinue when CD4 count is above 200 Antifungals Fungi – Key Facts Eukaryotes – more biologically complex than bacteria Share many cellular characteristics with human cells May be unicellular or multicellular Lack chlorophyll – must acquire nutrients from external environment Key Differences from Human Cells Have a cell wall Composed of Chitin Composition of Cytoplasmic Membrane Ergosterol (fungi) vs. Cholesterol (human) Fungal Disease in Humans Pathogenic Fungi – can cause disease in immunocompetent humans Histoplasmosis Coccidiodomycosis Cryptococcosis Blastomycosis Paracoccidiodomycosis Sporotrichosis Commensal Fungi – part of normal flora Candida Opportunistic Fungi – cause infection in immunocompromised hosts Aspergillus  Fungal Cells are Similar to Human Cells Structure of ergosterol is very similar to cholesterol Fungal Many fungal infections occur in poorly vascularized tissues Infections Superficial Layer of Skin Nails Can Be Hair Many Drugs are poorly soluble Challenging Have trouble reaching site of infection Slow growing to Treat Targeting cell division is more challenging Opportunistic Infections Many therapies are dependent on a properly functioning host immune system Clinical Pearls for Antifungal Treatment Most drugs are designed to slow the growth of the fungus Requires immune system to eradicate the infection Clinical Resistance vs. Microbial Resistance Just because a drug has effectiveness in laboratory testing doesn’t mean it will be effective in a particular patient and vice versa Antifungal Therapy may require weeks to months and may require repeated courses Many Adverse Effects Many Drug-to-Drug Interactions Antifungal Resistance Most often occurs with Candida albicans Most often occurs with –azole antifungals Four different mechanisms of –azole resistance Upregulation of Ergosterol Biosynthesis Multidrug Efflux Pump Alteration of Drug Target Proteins Alteration of Membrane Proteins Types of Antifungal Drugs Topical – will discuss more in dermatology Systemic Some can be used as topical and systemic agents Best classified by mechanism of action Azoles Polyenes Echinocandins Miscellaneous Polyenes Amphotericin B Broadest Spectrum of any antifungal drug Most commonly used to treat serious fungal infections in immunocompromised patients Active against all pathogenic and Opportunistic fungi including Candida Limited Activity against some Protozoan species No activity against bacteria Fungicidal MOA -- removes ergosterol from fungal cell membrane Leads to fungal cell death Must be administered IV for systemic use Is not absorbed from GI tract Available in Conventional (C-AMB) and Lipid (ABCD, ABLC, L-AMB) Forms Resistance is rare Adverse Effects Infusion reactions including anaphylaxis (rare) can occur Fever and Chills are the most common reaction Most common with ABCD form Pretreatment with ibuprofen, acetaminophen, or a steroid can lessen the reaction Resolves spontaneously in 30-45 minutes Nephrotoxicity Greatest with C-AMB (occurs in 80% of patients) Avoid use with other nephrotoxic agents (aminoglycosides) Permanent Renal Impairment is rare Cumulative doses exceeding 3-5g may lead to permanent renal damage Administering 1 liter of Normal Saline on day of drug administration can decrease nephrotoxicity Renal Potassium Wasting 1/3 of patients will require potassium supplementation if on prolonged therapy C-AMB is tolerated by premature neonates better than older children and adults Nystatin Same mechanism of action as Amphotericin B Only used Topically Extremely toxic if taken systemically Not absorbed from GI tract Only used to treat Candidiasis Not effective for treating fungal nail infections Powder form is best for moist lesions – diaper rash Oral suspension is used for oral candidiasis Patient should swish and swallow Azole Antifungals Azole Antifungals MOA – impair the biosynthesis of ergosterol Fungistatic – arrest the growth of the fungus Triazoles – fewer side effects and drug interactions than imidazoles Systemic drugs Imidazoles – mostly topical with a few exceptions Have clinical activity against many fungal species Many types of Candida Histoplasmosis Blastomyces Dermatophytes Aspergillus is less susceptible Many Drug Interactions Strong Inhibitors of CY-P450 Enzymes Other Drugs may decrease plasma concentrations of Azoles Itraconazole Triazole Most often used clinically as oral treatment for fungal skin and nail infections May be used to treat various mild to moderate systemic fungal infections Effective against Aspergillosis particularly after Amp B has been administered Also used in therapy for Histoplasmosis Black Box Warning – May cause or worsen heart failure; QT Prolongation Hepatoxicity is a concern Discontinue if signs appear (Jaundice, etc.) Be cautious in patients with pre-existing liver dysfunction Major drug interactions exist with all azole antifungals Fluconazole Triazole Extremely Versatile Antifungal Drug Excellent Bioavailability and Distribution Effective Oral Therapy for Candidiasis Oral Candidiasis – 100 to 200mg daily for 7 to 14 days Vulvovaginal Candidiasis – 150mg single dose patient may repeat in 72 hours if symptoms persist Part of management of Cryptococcosis Meningitis AIDs patients – 2 weeks of Amp B followed by 8 weeks of 400mg Fluconazole Then 200mg of Fluconazole indefinitely First-line choice for treatment of Coccidioidal Meningitis Not effective against Histoplasmosis, Sporotrichosis, or Aspergillosis Fluconazole Adverse Effects Hepatotoxicity – range from mild to hepatic failure Alopecia – prolonged high dose therapy SJS and TEN – rare QT Prolongation (all azole antifungals) Avoid in Pregnancy Increased incidence of Tetralogy of Fallot Voriconazole Triazole IV or Oral Forms Extended Spectrum of Activity compared to Fluconazole Should be given 1 hour before or 1 hour after meals Primary Clinical Use – Invasive Aspergillosis Also approved for esophageal candidiasis Contraindicated in pregnancy Hepatotoxicity is a concern – monitor liver function Can prolong QT interval like all azoles Renal toxicity with IV formulation Monitoring of drug levels is often done Drug follows nonlinear metabolism Ketoconazole Imidazole Antifungal activity similar to itraconazole except lacks activity against Aspergillus Used mostly topically Use as an oral antifungal has mostly been replaced by itraconazole except when a lower cost option is needed Echinocandins Echinocandins MOA – Inhibit synthesis of an essential fungal cell wall component 1,3-B-D-glucan Activity against 2 types of Fungi Candida – Fungicidal Aspergillus – Fungistatic Resistance is a concern 3 Available Drugs Caspofungin – decrease dose in moderate hepatic impairment Anidulafungin – no dosage adjustments in hepatic or renal impairment Micafungin – no dosage adjustments in hepatic or renal impairment First-line drugs for Candidemia (sepsis due to Candida) Do not penetrate CSF Lack oral bioavailability → must be given IV Well Tolerated → major adverse effect is redness and inflammation at infusion site Contraindicated in Pregnancy Other Systemic Antifungal Agents Flucytosine Related to Fluorouracil Used in the treatment of some invasive fungal infections Penetrates well into many areas of the body including the CSF and Aqueous Humor Fungus converts the drug to 5-FU – inhibits DNA synthesis Human cells lack the enzyme (cytosine deaminase) that converts flucytosine to 5-FU Most often used in combination with Amp B to treat severe cryptococcal infections of the nervous system Gold Standard Therapy for Cryptococcal Meningitis High rates of resistances limits its use as a single agent Combination with Amp B has led to improved survival over Amp B monotherapy Dosage must be renally adjusted Bacteria in the GI tract may convert Flucytosine to 5-FU which can lead to some adverse effects Bone Marrow Suppression → Leukopenia and Thrombocytopenia Vomiting and Diarrhea Antimalarial Drugs Artemisinin Fast acting Designed to treat severe malaria due to P. falciparum Extract of Sweet Wormwood plant (Artemsia annua) Effective against multi-drug resistant strains of the parasite Generally, not used as monotherapy Combined with other drugs in Artemisinin Combination Therapy First-Line Therapy Treatment of Malaria Parental Artesunate was approved for treatment of severe P. falciparum in 2020 Not recommended in 1st trimester of pregnancy or for children weighing 5kg or less  Quinine Quinolines Chloroquine Hydroxychloroquine Chloroquine Long-standing antimalarial drug First developed in 1943 Widespread resistance among P. falciparum Agent of choice for P. ovale and P. malariae Very Narrow Therapeutic Index A dose of 30mg/kg may be fatal Hypotension, Cardiac Arrythmias, Cardiac Arrest Common adverse effects – headache, visual disturbances, urticaria May cause hemolysis in patients with G6PD deficiency Quinine More toxic and less effective than chloroquine Can produce respiratory distress and dysphagia in patients with Myasthenia Gravis Adverse Effects are many Tinnitus and other hearing impairments Visual disturbances Headache Postural Hypotension Hypoglycemia – can be severe and life-threatening Hypersensitivity Reaction can lead to Hemolysis Safe in pregnancy Primaquine Effective against Liver Stage of parasite Used to prevent relapse in malarial species that have a dormant liver stage P. vivax P. ovale Must rule out G6PD deficiency prior to administration Not used in pregnancy Second-Line Drugs Aminoglycosides Streptomycin, Amikacin, Capreomycin Rarely used due to side-effects with prolonged use – hearing loss Clofazamine A Primary agent for treatment of MDR-TB Cycloserine Neuropsychiatric effects are a serious concern Seizures, Psychosis, and Suicidal Ideations Avoid in patients with history of seizures or depression Fluoroquinolones Moxifloxacin Helminth Infections Flatworms, Tapeworms, and Roundworms Cause of extensive disease burden worldwide Drugs used to treat these infections are among the most commonly used worldwide Many drugs exist, but only a few are commonly used Benzimidazoles Albendazole Mebendazole Ivermectin Praziquantel Benzimidazoles Albendazole and Mebendazole Considered very safe when administered in short courses May lead to abdominal pain, distention, and diarrhea if patient has large worm burden Generally, not recommended during pregnancy There is limited data for use in children less than 2-years old Recommended dose is 200mg for children between 1 and 2 years Use in children less than 1 may be appropriate in certain circumstances Praziquantel Causes paralysis of adult worms Relatively ineffective in early infections Drug of choice for treating Schistosomiasis May cause drowsiness Should not attempt to drive or attempt other task that require mental alertness Need to reduce dose in hepatic impairment WHO recommends use during any trimester of pregnancy Ivermectin Derived from the the mold Streptomyces avermitilis Hyperpolarizes nerve and muscle cells of of invertebrates → paralysis Effective against a variety of helminth infections Intestinal nematodes – ascariasis, trichurasis, enterobiasis Drug of choice for treatment of onchocerciasis and strongyloidiasis Effective against ectoparasitic infections – scabies and head lice Possibly has some antiviral activity Adverse Effects Dizziness, Nausea, Fatigue, Pruritis Mazzotti Reaction – inflammatory reaction due to death of certain helminths Fever, Rash, Swollen Lymph Nodes, Tachycardia, Hypotension Risk of encephalopathy in patients with severe Loa loa infections Use caution in patients with meningitis Avoid in pregnancy and breastfeeding Questions???