InInfectious Diseases I: Background & Antibiotics by Drug Class Gram Stain ● Gram positive (+): thick cell wall & stain dark purple or bluish from the crystal violet stain ● Gram negative (-): thin cell wall & take up the safranin counterstain → pink or reddish color ● Atypical: do not have a cell wall & do not stain well Gram positive (+) Cocci (Clusters) Cocci (Pairs & chains) • Staphylococcus sp. (MSSA, MRSA) • Streptococcus pneumoniae (diplococci) • Streptococcus sp. (Strep. pyogenes) • Enterococcus sp. (VRE) Rods • Listeria monocytogenes Anaerobes • Peptostreptococcus • Clostridioides difficile Gram negative (-) Cocci • Neisseria sp. Coccobacilli • Acinetobacter baumannii • Bordetella pertussis • Moraxella catarrhalis Rods Colonize gut “enteric” • PEK: Proteus mirabilis, E. coli, Klebsiella • CapES: Citrobacter, Enterobacter, Serratia sp. Rods Do not colonize gut • Pseudomonas aeruginosa • Haemophilus influenzae • Providencia sp. Curved or spiral shaped rods • H. pylori Antibiotic PK/PD Hydrophilic & Lipophilic Drugs Hydrophilic Agents Beta-lactams AMGs Vancomycin Daptomycin Polymyxins • Small volume of distribution → less tissue penetration • Mostly renally eliminated → drug accumulation & side effects can occur if not dose adjusted • Low intracellular concentrations → Not active against atypical (intracellular) pathogens • Poor/moderate bioavailability → IV:PO ratio is not 1:1 Lipophilic Agents Quinolones Macrolides Rifampin Linezolid Tetracyclines • Large volume of distribution → better tissue penetration • Mostly hepatically metabolized → potential for hepatotoxicity & drug-drug interactions • Achieve intracellular concentrations → Active against atypical (intracellular) pathogens • Excellent bioavailability → IV:PO ratio is often 1:1 Dose Optimization ABX Time > MIC Goal Dosing Strategies Maintain drug level > MIC for most of dosing interval Shorter dosing interval, extended or continuous infusion AMGs, Quinolones, Daptomycin High peak (⇧ killing), Low trough (⇩ toxicity) Large dose, long interval Vancomycin, Macrolides, Tetracyclines, Polymyxins Exposure over time Variable Beta-lactams Time-dependent CMAX: MIC Concentration-dependent AUC: MIC Exposure-dependent Key Features of Beta-Lactams Penicillins Class Effects • All PCNs increase risk of seizures if accumulation occurs (ex. failure to dose adjust renally) • Hemolytic anemia (+ Coombs test) • Type I - Immediate Hypersensitivity Reactions • SJS/TEN can occur Penicillin VK • First line for pharyngitis (strep throat) & mild nonpurulent skin infections • G+ anaerobes (mouth flora) Outpatient (PO) Amoxicillin • First line for acute otitis media (peds dose: 80-90 mg/kg/day) • DOC: infective endocarditis PPX before dental procedures (2 grams PO x 1, 30-60 min before) • Used in H. Pylori treatment • Take on empty stomach 1H before or 2H after meals • Comes in chewable tablet • G+ anaerobes (mouth flora) Amoxicillin/Clavulanate (Augmentin) • First line for acute otitis media (peds dose: 90 mg/kg/day) • First line for bacterial sinusitis (if ABX indicated) • Comes in chewable tablet • G+ anaerobes (mouth flora), G- anaerobes: B. fragilis Dicloxacillin • Covers MSSA only • No renal dose adjustment needed Inpatient (Parenteral) Penicillin G Benzathine (Bicillin L-A) • DOC for syphilis (IM: 1.2-2.4 million units x 1) • Not for IV use – can cause death • G+ anaerobes (mouth flora) Amoxicillin, Amp/Sulbactam (Unasyn) • Diluted in NS ONLY • G+ anaerobes (mouth flora), G- anaerobes: B. fragilis Nafcillin & Oxacillin • Covers MSSA only • No renal dose adjustment needed • Nafcillin = vesicant – central line preferred - If extravasation occurs, use cold packs & hyaluronidase Piperacillin/Tazobactam (Zosyn) • Only PCN active against Pseudomonas • Extended infusions (4 hours) can be used to maximize T > MIC • G+ anaerobes (mouth flora), G- anaerobes: B. fragilis Cephalosporins Class Effects Outpatient (PO) • All should be avoided in patients with a beta-lactam allergy (even PCN allergy) - Exceptions: pediatric patients with acute otitis media & mild PCN allergy • Risk of seizures if accumulation occurs (ex. failure to dose adjust renally) • Hemolytic anemia (+ Coombs test) • SJS/TEN possible Cephalexin (Keflex) (1st gen) • Common uses: skin infections (MSSA), pharyngitis (strep throat) • 250-500 mg PO Q6-12H • G+ anaerobes (mouth flora) Cefuroxime (Ceftin) (2nd gen) • Common uses: acute otitis media, community acquired pneumonia (CAP) • Separate from antacids by 2 hours • NO anaerobic coverage • Separate by 2 hours with short-acting antacids; avoid H2RAs & PPIs Cefdinir (Omnicef) (3rd gen) • Common uses: acute otitis media • DO NOT REFRIGERATE • G+ anaerobes (mouth flora) • Separate by 2 hours with short-acting antacids; avoid H2RAs & PPIs Cefixime (Suprax) (3rd gen) • Comes in chewable tablet Cefazolin (1st gen) • Common uses: surgical prophylaxis Cefotetan (Cefotan), Cefoxitin (2nd gen) • G+ anaerobes (mouth flora), G- anaerobes: B. fragilis • Common uses: surgical prophylaxis (GI procedures) • Cefotetan can cause increased bleeding & disulfiram-like reaction with alcohol ingestion Inpatient (Parenteral) Ceftriaxone (Rocephin), Cefotaxime (3rd gen) • Common uses: CAP, meningitis, spontaneous bacterial peritonitis, pyelonephritis • Ceftriaxone: Do not use in neonates (age 0-28 days) or calcium-containing IV products - No renal dose adjustment Ceftazidime (Fortaz, Tazicef) (3rd gen) // Cefepime (4th gen) • Active against Pseudomonas Ceftolozane/tazobactam (Zerbaxa), Ceftazidime /avibactam (Avycaz) • Used for MDR Gram negative organisms (including Pseudomonas) • G+ anaerobes (mouth flora), G- anaerobes: B. fragilis - Must be given with metronidazole for adequate anaerobic coverage • Ceftazidime/avibactam active against some Carbapenem-resistant G- rods (CRE) Ceftaroline (Teflaro) (5th gen) • Only β- lactam active against MRSA • Common uses: CAP, SSTIs Carbapenems Class Effects • All active against ESBL-producing organisms & Pseudomonas (except ertapenem) • All area active against G+ & G- anaerobes • Seizure risk (with higher doses, failure to dose adjust renally, or use of imipenem/cilastatin) Do NOT Cover • Atypicals, MRSA, VRE, C. difficile, Stenotrophomonas • ErtAPenem does not cover PEA: Pseudomonas, Enterococcus, or Acinetobacter Common Uses • Polymicrobial infections (ex. severe diabetic foot infections) • Empiric therapy when resistant organisms are suspected • ESBL-positive infections • Resistant Pseudomonas or Acinetobacter (except Ertapenem) • ALL are IV only – Ertapenem must be diluted in normal saline (NS) Key Features of Other Antibiotics Aminoglycosides Class Effects Risks • Kill Gram - pathogens & are synergistic with 𝜷-lactams for some Gram + - Generally have low resistance & drug cost • Post-antibiotic effect: Bacterial killing continues after serum level drops below MIC • Notable toxicities that require monitoring: nephrotoxicity & ototoxicity, neuromuscular blockade - Hearing loss, tinnitus, balance problems – may be irreversible • Fetal harm Concentration-dependent killing → give larger doses less frequently (extended interval dosing) - Gives kidneys time to recover between doses (post-antibiotic effect) Dosing Strategy • If underweight: use ABW for dosing // If obese: use AdjBW for dosing • Traditional Dosing: Gentamicin/Tobramycin: 1-2.5 mg/kg/dose Q8H (CrCl > 60: Q8H) • Extended Interval Dosing: Gentamicin/Tobramycin: 4-7 mg/kg/dose Drug Peak Trough Gentamicin (G + synergy) 3-4 mcg/mL < 1 mcg/mL 5-10 mcg/mL < 2 mcg/mL 20-30 mcg/mL < 5 mcg/mL Gentamicin (G -) Tobramycin Amikacin Quinolones Common Uses Respiratory Quinolones Antipseudomonal Quinolones • Varies by agent – pneumonia, UTIs, intra-abdominal infections, travelers’ diarrhea • Covers atypicals • Levofloxacin (Levaquin), Moxifloxacin (Avelox) • Reliable Strep. Pneumo activity (in pneumonia) • Ciprofloxacin (Cipro), Levofloxacin (Levaquin) • Used for Pseudomonas infections (including pneumonia) • DO NOT REFRIGERATE PO solution/suspension Moxifloxacin • ONLY one that is not renally adjusted (do not use for UTIs) • DO NOT REFRIGERATE IV formulation IV to PO ratio • 1:1 → Levofloxacin (Levaquin), Moxifloxacin (Avelox) Profile Review Tip Counseling • Caution with CVD, ⇩ K/Mg & with other QT prolonging drugs - Azole antifungals, antipsychotics, methadone, macrolides • Avoid in patients with seizure history or if using seizure drugs • Avoid systemic quinolones in kids & pregnancy/breastfeeding • Causes: - Photosensitivity - Hypo or hyperglycemia - CNS effects – Seizures, Psychiatric disturbances - QT prolongation - Tendon rupture - Peripheral neuropathy • Avoid sun exposure, separate from polyvalent cations, monitor BG • Cipro PO susp: shake for 15 seconds – do NOT put through NG or other feeding tube • Cipro: strong CYP1A2 inhibitor Macrolides Common Uses • All macrolides: CAP, an alternative to beta-lactams for pharyngitis • Covers atypicals • Azithromycin: COPD exacerbations, pertussis, chlamydia (pregnant patients), prophylaxis for MAC – mycobacterium avium complex, severe travelers’ diarrhea (including dysentery, diarrhea w/ blood) • Clarithromycin (Biaxin): H. Pylori treatment regimens • Erythromycin (E.E.S): ⇧ gastric motility → used for gastroparesis Z-Pak dose • Two 250 mg tablets PO x 1, then 250 mg PO daily x 4 days QT Prolongation • Caution with CVD, ⇩ K/Mg & with other QT prolonging drugs - Azole antifungals, antipsychotics, methadone, quinolones • Clarithromycin: caution in patients with CAD Drug Interactions • Clarithromycin, Erythromycin: strong CYP3A4 inhibitor - Simvastatin & Lovastatin = contraindicated (⇧ risk of muscle toxicity) • Azithromycin, Erythromycin – No renal dose adjustments Counseling • Causes: QT prolongation, Hepatotoxicity, GI upset (take with food) • Azithromycin, Clarithromycin - DO NOT REFRIGERATE PO suspension Tetracyclines Common Uses • Covers atypicals • Doxycycline (Vibramycin), Minocycline (Minocin, Solodyn): CA-MRSA skin infections, acne • Doxycycline (Vibramycin): - First line for tick borne illness (Lyme disease, Rocky Mountain Spotted Fever) & chlamydia - Option for: CAP, COPD exacerbations, bacterial sinusitis, VRE UTI • Tetracycline: H. Pylori treatment regimens Risks • Do NOT use in children < 8 YO, pregnancy/breastfeeding • Causes: Photosensitivity, drug interactions due to binding • Doxycycline: take with full glass of water & remain upright for 30 min after to avoid GI irritation - DO NOT REFRIGERATE PO suspension • Minocycline: drug-induced lupus erythematosus (DILE) Profile Review Tip • Doxycycline (Vibramycin) – No renal dose adjustments • IV:PO ratio = 1:1 (Doxycycline, Minocycline) Sulfonamides Common Uses • CA-MRSA skin infections, UTI, Pneumocystis Pneumonia (PCP) Ratio/Dosing • 5:1 ratio of SMX/TMP → Dose based on TMP • SS tablet: 80 mg TMP • DS tablet: 160 mg TMP – usual dose = 1 tablet BID • Dilute IV in D5W only (not NS) • Uncomplicated UTI: 1 DS tab PO BID x 3 days • Pneumocystis Pneumonia (PCP) PPX: 1 DS or SS tablet daily Sulfa allergy • Most sulfa allergies occur with SMX/TMP (rash/hives common) • Skin reactions: (SJS/TEN, Thrombotic thrombocytopenic Purpura (TTP)) can occur - If rash is accompanied by fever or systemic symptoms, seek emergency care Risks • ⇧ INR with warfarin → use alternative ABX when possible • Strong CYP2C9 inhibitor (warfarin = substrate) • Avoid in sulfa allergy, pregnancy/breastfeeding • Causes: Photosensitivity, ⇧ K (hyperkalemia risk), crystalluria (take with 8 oz of water) • Hemolytic anemia + Coombs test OR G6DP deficiency • DO NOT REFRIGERATE Vancomycin Common Uses • First line for mod/severe MRSA infections - Use alternative when MRSA MIC > 2 mcg/mL Dosing • Systemic infections (IV only): 15-20 mg/kg Q8-12H - Dose based on ABW - CrCl 20-49: Q24H • C. difficile infections (PO only): 125 mg QID x 10 days Risks • Nephrotoxicity, Ototoxicity • Vancomycin infusion reaction (red man syndrome) • Serious MRSA infections (bacteremia, sepsis, endocarditis, pneumonia, osteomyelitis, meningitis: - AUC/MIC ratio 400-600 or trough 15-20 mcg/mL Lipoglycopeptides ALL • Concentration-dependent killing Telavancin (Vibativ) • Boxed Warnings - Fetal risk – obtain pregnancy test prior to therapy - Nephrotoxicity • CI with concurrent use of IV UFH • Can falsely ⇧ aPTT/PT/INR • Renal dose adjustments required Oritavancin (Orbactiv, Kymyrsa) • CI – Do NOT use IV UFH for 120H (5 days) after • Can falsely ⇧ aPTT/PT/INR • Dosing (SSTIs): Single-dose IV: 1200 mg Dalbavancin (Dalvance) • Dosing (SSTIs): Single-dose IV: 1500 mg • Renal dose adjustments required Daptomycin (Cubicin, Cubicin RF) Profile Review Tip • Concentration-dependent killing • Covers VRE • Causes: Myopathy & rhabdomyolysis - ⇧ CPK – monitor weekly • Can falsely ⇧ aPTT/PT/INR • Do not use to treat pneumonia – inactivated in lungs by surfactant • Cubicin: compatible with NS & LR (not D5W – dextrose) • Cubicin RF: compatible with NS (not D5W – dextrose) Linezolid (Zyvox) Profile Review Tip Risks • Bacteriostatic killing → not good for bacteremia • Covers VRE • IV:PO ratio = 1:1 • No renal dose adjustments • CI – Do not use with or within 2 weeks of MAO-Is - Serotonin syndrome • Duration-related myelosuppression (thrombocytopenia – ⇩ platelets) - Monitor weekly CBC • Peripheral & optic neuropathy when used > 28 days • Hypoglycemia • Do NOT shake linezolid suspension – DO NOT REFRIGERATE Quinupristin + Dalfopristin (Synercid) Profile Review Tip • Covers VRE E. faecium, NOT E. faecalis • Causes: Arthralgias/myalgias, infusion reactions, hyperbilirubinemia • Dilute in D5W only (not NS) • Administer via central line (ex. PICC) Tigecycline (Tygacil) Profile Review Tip • Covers Atypicals & ESBL-bacteria, VRE • Boxed Warnings: ⇧ risk of death – only use when others not suitable • Do NOT use for bloodstream infections • Reconstituted solution should be yellow/orange – discard if not Polymyxins Profile Review Tip • Used primarily for MDR G - infections • Boxed Warnings: - Dose-dependent nephrotoxicity - Neurotoxicity – can result in respiratory paralysis Clindamycin (Cleocin) Profile Review Tip • Used primarily for Gram + including some CA-MRSA & G+ anaerobes • Boxed Warnings: Colitis (C. difficile) • An induction test (D-test) should be performed on Staph aureus that’s susceptible to clinda but resistant to erythromycin - Flattened zone (+ D-test) indicates clindamycin resistance • No renal dose adjustments • DO NOT REFRIGERATE PO suspension Metronidazole (Flagyl) Profile Review Tip • Covers G- anaerobes: B. fragilis, & Protozoal organisms • Used primarily for Bacterial vaginosis, trichomoniasis, C. difficile, intra-abdominal infections • Available PO, Topical, Vaginal, IV • CI - Pregnancy (1st trimester) - Use of alcohol or propylene glycol-containing products during treatment or within 3 days of DC (disulfiram reaction) • Causes: Metallic taste • IV:PO ratio = 1:1 • No renal dose adjustments • DO NOT REFRIGERATE • CYP2C9 inhibitor – Warfarin - ⇧ INR, ⇧ risk of bleeding → will need to ⇩ dose Nitrofurantoin(Macrobid, Macrodantin) Key Features • DOC for Uncomplicated UTI - Macrobid: 100 mg PO BID x 5 days • CI when CrCl < 60 • Dosing: MacroBID = BID; Macrodantin = QID • Counseling: Take with food to prevent nausea, cramping; can discolor urine – brown • G6PD deficiency (hemolytic anemia) Summary Tables MRSA Methicillin-resistant staph aureus MSSA Methicillin-susceptible staph aureus Pseudomonas • Vancomycin (use alt. if MIC > 2) • Daptomycin (not in pneumonia) • Linezolid, Ceftaroline • SMX/TMP (CA-MRSA SSTIs) • Doxycycline, Minocycline (CA-MRSA SSTIs) • Clindamycin (CA-MRSA SSTIs) • Dicloxacillin, Nafcillin, Oxacillin • Amoxicillin/Clavulanate, Ampicillin/Sulbactam • Cefazolin, Cephalexin (other 1st & 2nd gen) • Piperacillin/Tazobactam • Ceftazidime (3rd) • Cefepime (4th) • Ceftolozane/Tazobactam • Ceftazidime/Avibactam • Carbapenems (except ertapenem) • Aztreonam • Ciprofloxacin, Levofloxacin • Tobramycin • Colistin, Polymyxin B • Penicillin G, Ampicillin (E. faecalis only) • Linezolid, Daptomycin Cystitis only ↓ Doxycycline, Nitrofurantoin, Fosfomycin HNPEK • Beta-lactam/beta-lactam inhibitors • Cephalosporins (except 1st gen) • Carbapenems • Aminoglycosides, Quinolones, SMX/TMP CAPES • Piperacillin/Tazobactam • Cefepime (4th) • Carbapenems • Aminoglycosides • Colistin, Polymyxin B Atypicals • Azithromycin, Clarithromycin • Quinolones • Doxycycline, Minocycline • Beta-lactam/beta-lactam inhibitors • Cefotetan, Cefoxitin • Carbapenems • Moxifloxacin (reduced activity) • Metronidazole • Ceftazidime/Avibactam • Colistin, Polymyxin B • Meropenem/Vaborbactam • Imipenem/Cilastatin/Relebactam VRE Vancomycin-resistant Enterococcus G- anaerobes (B. fragilis) CRE Carbapenem-resistant G- rods ESBL Extended-spectrum 𝛽-lactam producing G- rods (E.coli, Klebsiella, Proteus mirabilis) C. difficile • Carbapenems • Ceftolozane/Tazobactam • Ceftazidime/Avibactam • Vancomycin (oral) • Fidaxomicin • Metronidazole Storage Requirements Liquid ABX Refrigeration REQUIRED After Reconstitution Penicillin VK Ampicillin Amoxicillin/Clavulanate Cefadroxil Cefpodoxime Cephalexin Cefprozil Cefuroxime Cefaclor Vancomycin (oral) Valganciclovir Refrigeration Recommended Amoxicillin – improves taste Do NOT Refrigerate Cefdinir Azithromycin Clarithromycin Doxycycline Ciprofloxacin Levofloxacin Clindamycin Linezolid SMX/TMP Acyclovir Fluconazole Posaconazole Voriconazole Nystatin Storage Requirements IV ABX Do NOT Refrigerate Metronidazole Moxifloxacin SMX/TMP Acyclovir No renal dose adjustments Dicloxacillin, Nafcillin, Oxacillin Ceftriaxone Doxycycline Moxifloxacin Azithromycin, Erythromycin Clindamycin Metronidazole Linezolid Special Requirements Take with/without food • Most antibiotics can be take with food to decrease stomach upset • Take on empty stomach → Penicillin VK, Ampicillin, Levofloxacin, Rifampin, Isoniazid, Itraconazole, Voriconazole 1:1 PO to IV Dosing Levofloxacin, Moxifloxacin, Doxycycline, Minocycline, Linezolid, Tedizolid, Metronidazole, SMX/TMP Fluconazole, Isavuconazonium, Posaconazole, Voriconazole Light Protection During Administration Doxycycline, Micafungin, Pentamidine Diluent Compatibility Dextrose Only Quinupristin + Dalfopristin, SMX/TMP, Amphotericin B, Pentamidine Saline Only Ampicillin, Ampicillin/Sulbactam, Ertapenem, Daptomycin (Cubicin RF) NS/LR Only Daptomycin (Cubicin), Capsofungin Drug-Lab Interactions G6PD Deficiency Coombs test, positive DILE False + Urine Glucose SMX/TMP, Nitrofurantoin, Dapsone SMX/TMP, Penicillins, Cephalosporins, Rifampin Minocycline PCNs, Cephalosporins Infectious Diseases II: Bacterial Infections Perioperative Antibiotic Selection Surgical Procedure Recommended ABX Cardiac or vascular Cefazolin or cefuroxime Orthopedic Cefazolin Beta-lactam allergy Clindamycin or Vancomycin (ex. joint replacement, hip fracture) GI (ex. appendectomy, colorectal surgery) Cefazolin + Metronidazole or Cefotetan or Cefoxitin or Ampicillin/Sulbactam Clindamycin or Metronidazole + AMGs or Quinolone Meningitis Most common bacteria: Neisseria meningitidis Streptococcus pneumoniae Listeria monocytogenes G- diplococci 2nd most common cause in adults G+ diplococci Most common cause in adults G+ bacilli (rods) Neonates, age > 50 YO & immunocompromised 7 days ABX duration 10-14 days ABX duration At least 21 days ABX duration Age 1 month to 50 years Age > 50 YO or immunocompromised Meningitis: Empiric therapy Age < 1 month (neonates) Ampicillin (for Listeria coverage) + Cefotaxime (no ceftriaxone) or Gentamicin Ceftriaxone or Cefotaxime + Vancomycin Ampicillin (for Listeria coverage) + Ceftriaxone or Cefotaxime + Vancomycin Acute Otitis Media (AOM) Observation for 48-72 hours for patients > 6 months with non-severe AOM - Non-severe: otalgia < 48H, no otorrhea, temperature < 102.2℉ (39℃) and: - Age 6-23 months: symptoms in one ear only - Age > 2 years: symptoms in one or both ears - If symptoms do not improve, or worsen, use ABX Acute Otitis Media (AOM) ABX Treatment ● First line: Amoxicillin or Amoxicillin/clavulanate 90 mg/kg/day in 2 divided doses ● Mild PCN allergy: Cefdinir, Cefuroxime, Cefpodoxime, Ceftriaxone ● Treatment Failure: Amoxicillin/clavulanate (if amox used first); Ceftriaxone Other Upper Respiratory Tract Infections ● Pharyngitis – Rapid antigen test positive for S. pyogenes ○ Penicillin or Amoxicillin (Macrolide if severe allergy) ● Acute Sinusitis ○ > 10 days of persistent symptoms OR > 3 days of severe symptoms, temp > 102℉ ○ Amoxicillin/clavulanate Lower Respiratory Tract Infections Acute Bronchitis ● Non-productive or productive cough lasting 1-3 weeks ● Antibiotics are not recommended – managed with supportive care Pertussis Acute Bronchitis caused by Bordetella pertussis ● Known as whooping cough ● Highly contagious → treated with macrolides (azithromycin, clarithromycin) COPD Exacerbation – Increase in symptoms that worsen over < 14 days ● Worsened dyspnea, Increased sputum volume, Increased sputum purulence ● Preferred ABX: Amoxicillin/clavulanate; Azithromycin, Doxycycline, Moxifloxacin, Levofloxacin Outpatient CAP Step 1: Comorbidities (chronic heart, lung, liver, renal disease; DM, alcoholism, malignancy, asplenia) Step 2: Decide if the patient falls into the category of “Healthy” or “High-Risk” Step 3: Choose regimen – look for allergies, drug-disease interactions, DDIs & culture results Patient Characteristics Healthy No comorbidities Recommended Empiric Therapy • Amoxicillin high dose: 1 gram TID OR • Doxycycline OR • Azithromycin, Clarithromycin (if local pneumococcal resistance is < 25%) High-Risk • Amoxicillin/clavulanate, Cefpodoxime or Cefuroxime PLUS • Azithromycin, Clarithromycin or Doxycycline OR With comorbidities • Moxifloxacin, Levofloxacin (monotherapy) Usual duration of treatment: 5-7 days Inpatient CAP Empiric therapy Non-severe • Ampicillin/Sulbactam, Cefotaxime, Ceftriaxone, or Ceftaroline PLUS • Azithromycin, Clarithromycin or Doxycycline OR • Moxifloxacin, Levofloxacin (monotherapy) Empiric therapy Severe • Ampicillin/Sulbactam, Cefotaxime, Ceftriaxone, or Ceftaroline PLUS • Azithromycin, Clarithromycin OR • Ampicillin/Sulbactam, Cefotaxime, Ceftriaxone, or Ceftaroline PLUS • Moxifloxacin, Levofloxacin ADD ON THERAPY FOR RISKS MRSA risk ADD Vancomycin or Linezolid (Prior respiratory isolation) Pseudomonas risk (Prior respiratory isolation) Hospitalization + use of IV ABX in past 90 days Use IV beta-lactam with activity against Pseudomonas - Piperacillin/tazobactam, Cefepime, Meropenem, Ceftazidime, Imipenem/cilastatin Use regimen with ABX active against both MRSA & Pseudomonas Drug-specific risks when evaluating CAP therapy - Macrolides: QT prolongation, CVD, DDI with clarithromycin (strong CYP3A4 inhibitor) - Doxycycline: avoid in pregnancy/breastfeeding - Quinolones: QT prolongation, seizure, tendonitis, CVD, avoid in pregnancy/breastfeeding HAP/VAP MRSA risk factors MDR G - pathogens + MRSA risk factors • IV ABX use within 90 days • MRSA prevalence in hospital unit > 20% or unknown • Prior MRSA infection or positive MRSA nasal swab • IV ABX use within 90 days • Prevalence of G - resistance in hospital unit > 10% • Hospitalized > 5 days prior to onset of VAP Treatment Empiric therapy Pseudomonas + MSSA • Piperacillin/tazobactam OR • Cefepime OR • Levofloxacin OR MRSA risk ADD Vancomycin or Linezolid Pseudomonas risk / MDR risk • Meropenem OR • Aztreonam OR • Imipenem/cilastatin Double coverage for pseudomonas with 2 of the following: PLUS Vancomycin or Linezolid (1): Piperacillin/Tazobactam, Cefepime, Ceftazidime, Aztreonam, Imipenem/cilastatin, Meropenem (2): Levofloxacin, Ciprofloxacin, Tobramycin, Amikacin, Gentamicin Tuberculosis (TB) Caused by mycobacterium tuberculosis (aerobic, non-spore forming bacillus) - Hospitalization require isolation in a single negative-pressure room - Healthcare workers must wear a respirator mask (N95 mask) Latent TB Active TB Overall Immune system contains infection Transmitted by aerosolized droplets Symptoms None Cough/hemoptysis, fever, night sweats, weight loss Contagious No Yes – highly Detected Positive skin test (TST, PPD) Positive blood test (IGRA) Positive skin test, positive blood test Chest X-ray Normal Abnormal – cavitation, nodules Latent TB Treatment Latent TB Goal of treatment Treatment advantages Regimen options Reduce lifetime risk of reactivating TB Shorter regimens (3 or 4 months) are preferred in most adults due to: ● Higher completion rates & less risk of hepatotoxicity Drug interactions = biggest barrier to rifampin, & rifapentine-based regimens Isoniazid (INH) + Rifapentine once weekly x 3 months via directly observed therapy (DOT) - Do not use in pregnancy Isoniazid (INH) + Rifampin daily x 3 months Rifampin 600 mg daily x 4 months Isoniazid (INH) 300 mg daily x 6 or 9 months - May be preferred in HIV-positive patients taking antiretroviral therapy Active TB - M. tuberculosis (MTB) is an acid-fast bacilli (AFB) – detected with an AFB smear - This is still not definitive - Definitive diagnosis must be made with a PCR or sputum culture Active TB Treatment – Divided into two phases: intensive & continuation Intensive phase Preferred to avoid resistance 4 drugs x 2 months (until cultures & susceptibilities are available) RIPE: Rifampin + Isoniazid (INH) + Pyrazinamide (PZA) + Ethambutol: Daily or 5x per week → Duration: 2 months (8 weeks) Continuation phase 2 drugs x 4 months (based cultures & susceptibilities results) INH + Rifampin: Daily, 5x per week, or 3x per week → Duration: 4 months (18 weeks) Key Points for RIPE therapy for TB Monitor Infection • Sputum sample (for culture), symptoms & chest X-ray (are lungs clearing up?) ALL RIPE Drugs • ⇧ LFTs, including total bilirubin – monitor baseline & monthly Rifampin • Orange bodily secretions • Strong CYP450 inducer (1A2, 2C8, 2C9, 2C19, 3A4 & P-gp) – use rifabutin if unacceptable DDIs • Flu-like symptoms • Hemolytic anemia (+ Coombs test) Isoniazid (INH) • Peripheral neuropathy: give with pyridoxine 25-50 mg PO QD • DILE • Hemolytic anemia (+ Coombs test) Pyrazinamide • ⇧ uric acid – do not use with acute gout Ethambutol • Visual damages (requires baseline & monthly vision exams) • Confusion, hallucinations Infective Endocarditis Treatment – 4-6 weeks of IV ABX Organism Preferred Regimen Viridans group streptococci • Penicillin or Ceftriaxone • + Gentamicin If beta-lactam allergy: • Vancomycin monotherapy Staphylococci (MSSA) • Naficillin or Cefazolin PLUS • Gentamicin and Rifampin (if prosthetic valve) If beta-lactam allergy: • Vancomycin PLUS • Gentamicin and Rifampin (if prosthetic valve) Staphylococci (MRSA) • Vancomycin PLUS Gentamicin and Rifampin (if prosthetic valve) Enterococci - Native & prosthetic valve: • Penicillin or Ampicillin OR • Gentamicin or Ampicillin If beta-lactam allergy: • Vancomycin PLUS Gentamicin Both PLUS high dose Ceftriaxone If VRE: • Daptomycin or Linezolid Daptomycin monotherapy is an alternative for MSSA & MRSA when patient has a beta-lactam allergy & no prosthetic valve Rifampin is added for staphylococci prosthetic valve infection Infective Endocarditis DENTAL Prophylaxis Patients at High Risk for IE Dental work needed, such as a root canal, tooth extracting, abscess draining, etc. Adult PPX Regimens All given as a single dose 30-60 minutes before procedure First line: Amoxicillin 2 grams PO PLUS Select cardiac conditions including: - Artificial (prosthetic) heart valve or heart valve repaired with artificial material - History of endocarditis - Heart transplant with abnormal heart valve function - Certain congenital heart defects including heart/heart valve disease If unable to take PO medication: Ampicillin 2 grams IM/IV or Cefazolin or Ceftriaxone 1 gram IM/IV If able to take PO medication but allergic to penicillin: Azithromycin or Clarithromycin 500 mg or Doxycycline 100 mg Intra-Abdominal Infections Spontaneous Bacterial Peritonitis ● Empiric therapy: Ceftriaxone x 5-7 days ○ Meropenem can be used in critically ill patients or those at risk for MDR pathogens ● Secondary PPX: SMX/TMP or a Quinolone (ciprofloxacin) Other Intra-Abdominal Infections ● Appendicitis, Cholecystitis, Cholangitis, Secondary peritonitis, Diverticulitis – 4-5 days ● If ABX selection doesn’t cover anaerobic coverage, add metronidazole Community-Acquired (Low-Risk) Risk for Resistant or Nosocomial Pathogens* PEK, anaerobes, streptococci PEK, Pseudomonas, Enterobacter, anaerobes, streptococci + Enterococci • Ertapenem • Moxifloxacin • Metronidazole + Cefuroxime or Cefotaxime or Ceftriaxone • Metronidazole + Ciprofloxacin or Levofloxacin • Carbapenem (except ertapenem) • Piperacillin/tazobactam • Metronidazole + Cefepime or Ceftazidime SSTIs Summary Superficial SSTI Impetigo Honey-colored crusts S. pyogenes, S. aureus Superficial SSTI Folliculitis/furuncle/ carbuncle S. aureus (including CA-MRSA) Mild Cellulitis (Non-Purulent) Localized pain, swelling, redness, warmth • Limited lesions: Topical Mupirocin • Numerous lesions: Cephalexin, Dicloxacillin • Folliculitis & small furuncle may require only warm compresses • Large furuncles & carbuncles: I/D + SMX/TMP, Doxycycline S. pyogenes (Group A strep), S. aureus • Cephalexin, Dicloxacillin • Beta-lactam allergy: clindamycin 300 mg PO QID Mild/Moderate Abscess (Purulent) S. aureus (including CA-MRSA) Severe Purulent SSTI S. aureus – MRSA Necrotizing Fasciitis S. pyogenes (Group A strep), S. aureus – MRSA, anaerobes (Clostridium), E. coli • I/D + SMX/TMP, Doxycycline • Cultures show MSSA: Cephalexin • Vancomycin, Daptomycin, Linezolid → 7-14 days • Urgent surgical debridement + • Vancomycin or Daptomycin + • Piperacillin/tazobactam or Meropenem + • Clindamycin DFI Treatment Type of Regimen MSSA coverage MRSA coverage needed (ex. prior infection, colonization) Treatment Duration of Treatment • Ampicillin/Sulbactam or • Piperacillin/tazobactam or • Carbapenem (meropenem, ertapenem) or • Moxifloxacin or • Metronidazole + Ceftriaxone, Cefepime, Levofloxacin, Ciprofloxacin ADD Vancomycin, Daptomycin, or Linezolid to one of the regimens above • 7-14 days • More severe, deep tissue infection: 2-4 weeks • Severe, limb-threatening or bone/joint infection: 4-6 weeks • Osteomyelitis: requires longer courses of therapy Urinary Tract Infections (UTIs) Cystitis Lower UTI (bladder & urethra) • Urgency & frequency; nocturia • Dysuria (painful/burning urination) • Suprapubic tenderness • Hematuria (blood in urine) Pyelonephritis Upper UTI (kidneys) • Flank/costovertebral angle pain • Abdominal pain, N/V Acute Uncomplicated Cystitis ● Nitrofurantoin (Macrobid) 100 mg PO BID x 5 days (CI if CrCl < 60) ● SMX/TMP DS 1-2 tablets PO BID x 3 days (CI if sulfa allergy) ● Fosfomycin 3 grams x 1 dose ● Pregnancy: Amoxicillin, Cephalexin ● Do not choose the same agent if it’s been used in last 3 months Acute Pyelonephritis ● Moderately ill outpatient (PO): 5-7 days ○ If local quinolone resistance < 10%: Ciprofloxacin 500mg, Levofloxacin 750 ○ If local quinolone resistance > 10%: Ceftriaxone, Ertapenem, AMG ○ Concern for quinolone AE: SMX/TMP ● Severely ill hospitalized patient (IV): 5-10 days ○ Ceftriaxone OR Ciprofloxacin, Levofloxacin ○ Concern for resistance: Piperacillin/tazobactam OR Carbapenem (ESBL) • Fever, chills & malaise Bacteriuria & Pregnancy - Must be treated even if asymptomatic - Beta-lactams = preferred (Amoxicillin + clavulanate or PO cephalosporin) - Fosfomycin, Nitrofurantoin, SMX/TMP, can be used if there is a beta-lactam allergy - Avoid agents in first trimester (especially Nitrofurantoin, SMX/TMP DS) - Quinolones should be avoided C. Difficile Treatment - 10 days Initial, non-severe/severe Fidaxomicin 200 mg PO BID x10D (pref) Non-severe: WBC < 15,000 & SCr < 1.5 Metronidazole 500 mg PO TID x10D (non-severe only & if other options not available) 2nd Episode (first recurrence) Fidaxomicin 200 mg PO BID x10D Vancomycin 125 mg PO QID x10D followed by tapered & pulsed regimen Second/subsequent recurrence Vancomycin in tapered & pulsed regimen Fidaxomicin 200 mg PO BID x10D Vancomycin 125 mg PO QID x10D followed by Rifaximin 400 mg PO TID x20D Fecal microbiota transplantation Fulminant/Complicated Disease Vancomycin 125 mg PO QID x10D Vancomycin 500 mg PO/NG/PR QID PLUS Metronidazole 500 mg IV Q8H Hypotension, shock, ileus, toxic megacolon Sexually-Transmitted Infections STI Symptoms Treatment Chlamydia Discharge or asymptomatic Not pregnant: Doxycycline 100 mg PO BID x 7 days Pregnancy: Azithromycin 1 gram PO x 1 Gonorrhea Discharge or asymptomatic Ceftriaxone < 150 kg: 500 mg IM x 1 > 150 kg: 1 gram IM x 1 Chlamydia not excluded: add doxycycline (see above) Treatment = same for pregnancy Genital Warts Single or multiple pink/skin-toned lesions Imiquimod cream (Aldara, Zyclara) Syphilis (Primary, Secondary or Early Latent) Painless, smooth genital sores (chancre) Penicillin G benzathine (Bicillin L-A) 2.4 million units IM x 1 Beta-lactam allergy Doxycycline 100 mg PO BID x 14 days If pregnant/nonadherent, desensitize & treat with Bicillin L-A Acquired within past year Latent Syphilis (Late Latent or Tertiary) Acquired > 1 year or unknown Asymptomatic Penicillin G benzathine (Bicillin L-A) 2.4 million units IM QW x 3 weeks Beta-lactam allergy Doxycycline 100 mg PO BID x 28 days Neurosyphilis Trichomoniasis Penicillin G aqueous IV Beta-lactam allergy Desensitization → Penicillin G aqueous IV Yellow/green, frothy vaginal discharge with pH > 4.5; soreness, pain with intercourse Metronidazole Pregnancy Metronidazole is CI in 1st trimester per package labeling, but CDC recommends metronidazole for trichomoniasis in all trimesters Bacterial Vaginosis Clear, white/gray vaginal discharge with fishy odor with pH > 4.5; little or no pain Metronidazole 500mg BID x 7 days Metronidazole 0.75% gel x 5 days Clindamycin 2% cream x 7 days Syphilis: PCN Desensitization Syphilis must be treated with PCN in select patients with an allergy because doxycycline, is not suitable ● A pregnant patient cannot take doxycycline due to the adverse effects on the fetus ○ Suppressed bone growth & skeletal development ● A patient with poor compliance/follow-up is at risk for treatment failure with a twice-daily regimen that must be taken for 14-28 days ● Neurosyphilis Per CDC, follow these steps: 1. Confirm allergic reaction with a skin test 2. Temporarily desensitize the patient with an approved desensitization protocol 3. Treat with IM Penicillin G benzathine (Bicillin L-A) Infectious Diseases III: Antifungals & Antivirals Key Pearls with Azole Antifungals Class Effects Fluconazole (Diflucan) Itraconazole • ⇧ LFTs • Hypokalemia • QT prolongation (except Isavuconazonium – causes QT shortening) • Vaginal candidiasis: 150 mg PO x 1 • Also available PO/IV • Only azole that requires renal adjustments • Penetrates CNS – treats fungal meningitis • Resistant to: C. krusei, C. glabrata • Uses: Yeast infections (oral, esophageal, vaginal), onychomycosis • DO NOT REFRIGERATE - suspension • Boxed Warning - Can worsen HF; do not use to treat onychomycosis in history of HF - QT prolongation & ventricular tachyarrhythmias (including TdP) • Activity against: dimorphic fungi (Blastomycosis & Histoplasma) • Uses: Nail bed infections (onychomycosis) • Tablets: Take with food • Solution: Take on empty stomach Ketoconazole • Boxed Warnings: Hepatotoxicity, QT prolongation Voriconazole (Vfend, Vfend IV) • Uses: Aspergillus (treatment of choice) • Penetrates CNS – treats fungal meningitis • Warnings/Side effects ● Hepatotoxicity ● Phototoxicity ● Visual changes ● CNS toxicity (hallucinations) • Vfend: take on empty stomach (at least 1 hour before or after meal) • CrCl < 50: IV vehicle SBECD accumulates – PO = preferred • DO NOT REFRIGERATE - suspension Posaconazole (Noxafil) Isavuconazonium (Cresemba) IV Administration • CrCl < 50: IV vehicle SBECD accumulates – PO = preferred • Tablet dose DOES NOT EQUAL suspension dose (different bioavailability) • Take with food • DO NOT REFRIGERATE - suspension • QT shortening, not prolongation • Requires a filter • Prodrug of isavuconazole • IV to PO ratio = 1:1 • Drugs with SBECD vehicle: voriconazole & posaconazole Azole Antifungals Drug Interactions All Azoles • Moderate/strong CYP3A4 inhibitors • Can ⇧ concentrations of apixaban & rivaroxaban • Caution use in combo with other QT prolonging drugs Fluconazole • Inhibit CYP2C9 → ⇧ effects of warfarin Voriconazole • Inhibit CYP2C9 → ⇧ effects of warfarin • Concentrations can ⇧ dangerously when given with drugs that inhibit CYP2C19, 2C9, or 3A4 • Do not use with long-acting barbiturates, carbamazepine, efavirenz, ergot alkaloids, pimozide, quinidine, rifabutin, rifampin, ritonavir, sirolimus, SJW Ketoconazole, Itraconazole • Inhibit P-gp • Requires acidic gut → ⇧ pH will ⇩ absorption - Separate antacids 2 hours before or after Posaconazole • PPIs & cimetidine can ⇩ absorption Other Systemic Antifungals Amphotericin B • Deoxycholate = Conventional • Liposomal (AmBisome)= Lipid form – less toxicities • Conventional AmpB doses should NOT exceed 1.5 mg/kg/day - Premedicate: APAP or NSAID // Diphenhydramine + hydrocortisone • Causes: - Infusion-related: fever, chills, headache, malaise, rigors - ⇩ K, ⇩ Mg, nephrotoxicity • Compatible with D5W only – Lipid form must be filtered • Yellow-orange in color Coverage: ● Yeasts: most Candida species and Cryptococcus neoformans ● Molds: Aspergillus species and Zygomycetes ● Dimorphic fungi: Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis Flucytosine, 5-FC • Dose-related myelosuppression • Should not be used alone – only used in with AmpB for invasive cryptococcal meningitis Echinocandins • Caspofungin (Cancidas), Micafungin (Mycamine), Anidulafungin (Eraxis) • Histamine-mediated symptoms • Only available as injections • All are given once daily – do not require dose adjustment for renal • Micafungin: requires light-protection during administration Nystatin Griseofulvin Terbinafine (Lamisil AT - topical) • Used for: Oral Candidiasis, Intestinal Infections • Suspension: swish in the mouth & retain for as long as possible - Several minutes before swallowing • DO NOT REFRIGERATE (comes in tablet & suspension) • Indicated for fungal infection of skin, hair & nails • Contraindications: Pregnancy • Photosensitivity, ⇧ LFTs, • Take with a fatty meal to ⇧ absorption or with food/milk • Hepatotoxicity • Headache, ⇧ LFTs Clotrimazole • Used for: Oral Candidiasis • Troche/lozenge Miconazole • Used for: Oral Candidiasis Empiric Treatment for Select Fungal Pathogens/Infections Pathogen Preferred Regimen Alternative Regimen Candida albicans Oropharyngeal (thrush) Mild disease: Clotrimazole, Miconazole Mod/severe disease or HIV: Fluconazole Nystatin Candida albicans Esophageal Fluconazole Echinocandin Candida krusei & glabrata All Candida species bloodstream infection Echinocandin Amphotericin B or High-dose fluconazole Aspergillus Invasive Voriconazole Amphotericin B or Isavuconazonium Cryptococcus neoformans Meningitis Amphotericin B + Flucytosine (5-FC) High-dose fluconazole + Flucytosine (5-FC) Dermatophytes Nail bed infection Terbinafine or Itraconazole Fluconazole Influenza All should be started within 48H of illness onset Neuraminidase inhibitors Oseltamivir (Tamiflu) • Treatment, age > 12 YO: 75 mg BID x 5 days • PPX, age > 12 YO: 75 mg BID x 10 days • Comes in capsules & suspension • Neuropsychiatric events, Headache, GI: N/V/D • Preferred in pregnancy Zanamivir (Relenza) • Treatment, age > 7 YO • PPX, age > 5 YO • Dosed as inhalations • Bronchospasm – Do NOT use in asthma/COPD Endonuclease inhibitor Baloxavir (Xofluza) • Treatment & PPX, age > 5 YO: PO x 1 dose Herpes Viruses Acyclovir (Zovirax, Sitavig) • Caution with renal impairment, elderly and/or those receiving nephrotoxic drugs • Acyclovir dose based on IBW, including obese patients • Valacyclovir = Prodrug of acyclovir • Famciclovir = Prodrug of penciclovir Valacyclovir (Valtex) Herpes Simplex Labialis (Cold Sores) Docosanol (Abreva) OTC cream Apply 5x daily at 1st sign of outbreak, continue until healed Acyclovir (Zovirax) Rx cream Apply 5x daily x 4 days (can be used on genital sores) Systemic Treatment for Herpes Simplex Labialis (Cold Sores) Episode Acyclovir Valacyclovir Famciclovir Initial (treat 7-10 days) 200 mg 5x daily or 400 mg TID 1 gram BID 250 mg TID or 500 mg BID Recurrence 400 mg TID x 5-10 days 2 grams BID x 1 day 1.5 grams x 1 dose Chronic suppression 400 mg BID 500 mg or 1 gram QD Systemic Treatment for HSV-2 (Genital Herpes) Episode Acyclovir Valacyclovir Famciclovir Initial (treat 7-10 days) 400 mg TID or 200 mg 5x daily 1 gram BID 250 mg TID or 500 mg BID Recurrence 400 mg TID x 5 days or 800 mg BID x 5 days or 800 mg TID x 2 days 500 mg BID x 3 days or 1 gram QD x 5 days 125 mg BID x 5 days or 500mg x 1 then 250 mg BID x 2 days or 1 gram BID x 1 day Chronic suppression 400 mg BID 500 mg or 1 gram QD 250 mg BID Herpes Zoster (Shingles) Treatment Drug Pearls Description Acyclovir (Zovirax) 800 mg PO 5x daily x 7 days (or 10 days) Valacyclovir (Valtex) 1 gram PO TID x 7 days A cluster of fluid-filled blisters, often in a band around one side of the waist, forehead, or around an eye or neck Famciclovir 500 mg PO TID x 7 days Cytomegalovirus (CMV) ● Occurs in severely immunocompromised states (AIDS, transplanet) & most commonly causes: ○ Retinitis, colitis or esophagitis ● Ganciclovir & valganciclovir = treatments of choice ○ Causes myelosuppression ○ Hazardous agents: special handling required ○ Solution: refrigerate ● Foscarnet & cidofovir = reserved for refractory cases Infectious Diseases IV: Opportunistic Infections Immunocompromised states include: Diseases that destroy key components of immune response, primarily HIV with CD4 T lymphocyte count < 200 Use of systemic steroids for > 14 days at prednisone dose > 20 mg/day or > 2 mg/kg/day Asplenia due to sickle cell disease or splenectomy Use of immunosuppressants for autoimmune conditions or post-transplant Use of cancer chemotherapy agents that destroy WBCs, particularly with severe neutropenia (ANC < 500) Primary Prophylaxis OI Criteria for Starting Pneumocystis jirovecii pneumonia (PJP) CD4 count < 200 or AIDS Toxoplasmosis gondii encephalitis Primary PPX Regimen Preferred: SMX/TMP DS or SS QD Alternatives: SMX/TMP DS 3x/week or Dapsone or Dapsone + Pyrimethamine + Leucovorin or Atovaquone or Atovaquone + Pyrimethamine + Leucovorin or Inhaled pentamidine Toxoplasma IgG positive and CD4 count < 100 Preferred: SMX/TMP DS QD Alternatives: Criteria for DCing CD4 count > 200 for > 3 months on ART Consider when CD4 count 100-200 & viral load undetectable for > 3-6 mo CD4 count > 200 for > 3 months on ART Mycobacterium avium complex (MAC) ● ● ● SMX/TMP DS 3x/week or SS QD or Dapsone + Pyrimethamine + Leucovorin or Atovaquone or Atovaquone + Pyrimethamine + Leucovorin Consider when CD4 count 100-200 & viral load undetectable for > 3-6 mo Not recommended if ART is started ASAP Preferred: Azithromycin 1200 mg weekly Taking fully suppressive ART If not taking ART & CD4 count < 50 Alternatives: Azithromycin 600 mg twice weekly Clarithromycin 500 mg BID Atovaquone, Dapsone, Pentamidine – options in setting of sulfa allergy Atovaquone, Pentamidine – options in setting of G6PD deficiency Leucovorin is added to all pyrimethamine-containing regimens as rescue therapy to reduce risk of pyrimethamine-induced myelosuppression Treatment of Opportunistic Infections Opportunistic Infection Preferred Regimen Alternative Regimen Secondary PPX Candidas (thrush) Fluconazole Oropharyngeal: Itraconazole, posaconazole Esophageal: Voriconazole, isavuconazonium or Echinocandin Not usually recommended Cryptococcal meningitis Amphotericin B + Flucytosine (5-FC) Fluconazole + Flucytosine (5-FC) or Amphotericin B + Fluconazole Fluconazole (low-dose) Cytomegalovirus (CMV) Valganciclovir or Ganciclovir If toxicities to ganciclovir or resistant strains: foscarnet or cidofovir None; maintain CD4 > 100 Mycobacterium avium complex (MAC) Clarithromycin or Azithromycin + Ethambutol Add 3rd or 4th agent using: Rifabutin, Amikacin, Streptomycin, Moxifloxacin, or Levofloxacin Same as treatment Pneumocystis jirovecii pneumonia (PJP) SMX/TMP (high dose) + prednisone or methylprednisolone Duration: 21 days Atovaquone or Pentamidine IV or Clindamycin + primaquine or Dapsone + trimethoprim Same as primary PPX Toxoplasmosis gondii encephalitis Pyrimethamine + Leucovorin + sulfadiazine SMX/TMP or Clindamycin + Pyrimethamine + Leucovorin or Atovaquone or Atovaquone + sulfadiazine or Atovaquone + Pyrimethamine + Leucovorin Same as treatment (but with reduced doses) Risks: undercooked/raw meat, cat feces/litter Human Immunodeficiency Virus HIV Replication States & Antiretroviral Sites of Action Stage & Description Drugs/Drug Classes Stage 1: Binding/Attachment HIV attaches to a CD4 receptor & the CCR5 and/or CXCR4 coreceptors on the surface of the CD4 host cell CCR5 antagonist: Maraviroc Attachment inhibitor: Fostemsavir Post-attachment inhibitor: Ibalizumab-uiyk Stage 2: Fusion Fusion inhibitor: Enfuvirtide HIV viral envelope fuses with the CD4 membrane → HIV enters host cell & releases HIV RNA, viral proteins & enzymes needed for replication Stage 3: Reverse Transcription HIV RNA is converted to HIV DNA by reverse transcriptase. HIV DNA can the enter the CD4 cell nucleus Stage 4: Integration Once inside the CD4 cell nucleus, integrase is released & used to insert HIV DNA into the host cell DNA Nucleoside reverse transcriptase inhibitors (NRTIs): Emtricitabine, Tenofovir Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Efavirenz, Rilpivirine Integrase Inhibitors (INSTIs): Bictegravir, Dolutegravir, Raltegravir Stage 5: Replication None Host cell machinery is used to transcribe & translate HIV DNA into HIV RNA & long-chain proteins (the HIV building blocks) Stage 6: Assembly None New HIV RNA, proteins, & enzymes (including protease) move to the cell surface & assemble into immature HIV Stage 7: Budding & Maturation Protease Inhibitors (PIs): Atazanavir, Darunavir Immature HIV pushes out of the CD4 cell & protease breaks up long viral protein chains, creating mature virus that can infect other cells Antiretroviral Therapy (ART) Preferred initial ART regimens in treatment-naive adults Brand Generic Components One Pill, Once Daily (Single Tablet Regimens) Biktarvy Tenofovir AF/Emtricitabine/ Bictegravir Triumeq Dolutegravir/Lamivudine/ Abacavir Dovato Dolutegravir/Lamivudine Two Pills, Once Daily (for most) Tivicay + Truvada Dolutegravir/Emtricitabine/ Tenofovir DF Pearls Most preferred regimens contain 2 NRTIs & 1 INSTI • Emtricitabine/TAF (Descovy) or Emtricitabine/TDF (Truvada) make up the NRTI backbone in most regimens • Lamivudine & Emtricitabine are interchangeable but should not be used together (both are cytosine analogs & are therefore antagonistic) Dovato (1 NRTI & 1 INSTI) is an exception to the above • Do not use in treatment naive patients if HIV RNA > 500,000 copies/mL, there is known HepB co-infection (or status unknown) or HIV genotypic testing is not available Triumeq contains abacavir – extra testing required • Test for HLA-B*5701 allele before using – positive result indicates higher risk for severe hypersensitivity reaction & any abacavir-containing product is contraindicated Fixed-dose combos have less flexibility with renal dosing • Bikarvy, Triumeq, Dovato, Truvada, Descovy Tivicay + Descovy Dolutegravir/Emtricitabine/ Tenofovir AF - Do not use if CrCl < 30 mL/min Bikarvy – individual components of these drugs can be given separately to allow for more flexible renal-dose adjustments Key Features of Drugs used in ART Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) All NRTIs • Warnings: lactic acidosis & hepatomegaly with steatosis (fatty liver) - Boxed Warning for zidovudine • Common side effects: nausea, diarrhea, headache, ⇧ LFTs HBV & HIV Coinfection Boxed Warnings • Severe acute HBV exacerbation can occur if emtricitabine, lamivudine, & tenofovir-containing products are DC’d • Do not use Epivir-HBV for HIV (contains a ⇩ dose of lamivudine) Abacavir (Ziagen) • Boxed Warning: risk for hypersensitivity reaction (HSR) - Screen for HLA-B*5701 allele before starting - Contraindicated if positive (higher risk of HSR) - Epzicom (Abacavir/Lamivudine) - Triumeq (Dolutegravir/Lamivudine/Abacavir) - Ziagen (Abacavir) - Patients must carry a medication card indicating that HSR (ex. fever, rash, N/V/D, fatigue, dyspnea, cough) is an emergency - Never re-challenge patients with a history of HSR • Consider avoiding with CVD due to potential ⇧ risk of MI Emtricitabine (Emtriva) Tenofovir formulations (⇧ risk with TDF) • Hyperpigmentation of the palms of the hands or soles of the feet • Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury & electrolyte abnormalities) • ⇩ dose with renal impairment & avoid other nephrotoxic drugs (ex. NSAIDs) • ⇩ bone mineral density: consider calcium/vitamin D supplementation & DEXA scan if at risk • Monitor lipids if switching from TDF to TAF for an improved side effect profile - TAF has a higher risk of lipid abnormalities • TDF: do not start if CrCl < 50 - Cimduo (TDF/Lamivudine) - Destrigo (TDF/Lamivudine/Doravirine) - Symfi, Symfi Lo (TDF/Lamivudine/Efavirenz) - Truvada (TDF/Emtricitabine) - Atripla (TDF/Emtricitabine/Efavirenz) - Complera (TDF/Emtricitabine/Rilpivirine) - Stribild (TDF/Emtricitabine/Elvitegravir/Cobicistat) • TAF: do not start if CrCl < 30 - Biktarvy (TAF/Emtricitabine/Bictegravir) - Descovy (TAF/Emtricitabine) - Odefsey (TAF/Emtricitabine/Rilpivirine) - Genvoya (TAF/Emtricitabine/Elvitegravir/Cobicistat) - Symtuza (TAF/Emtricitabine/Darunavir/Cobicistat) Zidovudine (Retrovir) • Hematologic toxicity: neutropenia & anemia (⇧ MCV is a sign of adherence) • Myopathy Didanosine & Stavudine • Pancreatitis, peripheral neuropathy (can be irreversible) Integrase Strand Transfer Inhibitors (INSTIs) Side effects & Warnings • All INSTIs: HA, insomnia, diarrhea, weight gain, rare risk of depression & suicidal ideation in pateints with pre-existing psychiatric conditions • Bictegravir, Dolutegravir: ⇧ SCr (by inhibiting tubular secretion) with no effect on GFR • Raltegravir, Dolutegravir - ⇧ CPK, myopathy & rhabdomyolysis - Hypersensitivity reaction: syndrome of rash, fever & symptoms of allergic reaction • Dolutegravir: - Preferred drug treatment of HIV during pregnancy - Hepatotoxicity (especially if coinfection with hepatitis B or C) • Cabotegravir IM: injection site reactions Drug Interactions with Polyvalent Cations • Take INSTIs 2 hours before or 6 hours after: Al, Ca, Mg, iron-containing products • Exceptions: - Dolutegravir & Bictegravir can be taken with oral calcium or iron if also taken with food - Dose separation with raltegravir may not be effective – avoid polyvalent cations if possible Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) All NNRTIs • Hepatotoxicity & rash, including SJS/TEN: highest risk with nevirapine Efavirenz • Psychiatric symptoms (depression, suicidal thoughts) • CNS effects (impaired concentration, abnormal dreams, confusion) – generally resolve in 2-4 weeks • ⇧ total cholesterol & triglycerides Rilpivirine • Depression • ⇧ SCr with no effect on GFR • Do not use if viral load > 100,000 copies/mL and/or CD4 count < 200 (higher failure rate) Drug Interactions • Major CYP3A4 substrates - Rilpivirine & doravirine: do not use with strong CYP3A4 inducers - Phenytoin, Rifampin, Rifapentine, Carbamazepine, Oxcarbazepine, Phenobarbital, SJW • Efavirenz & etravirine: moderate CYP3A4 inhibitors • Rilpivirine & acid suppressants - Do not use with PPIs - Separate H2RAs – take H2RAs at least 12 hours before or 4 hours after - Separate antacids – take antacids at least 2 hours before or 4 hours after Protease Inhibitors (PIs) All PIs • Metabolic Syndrome: hyperglycemia/insulin resistance, dyslipidemia (⇧ LDL, ⇧ TGs), ⇧ body fat - ⇧ CVD risk (lower risk with atazanavir & darunavir) • Hepatic dysfunction: ⇧ LFTs, hepatitis and/or exacerbation of preexisting hepatic disease • Hypersensitivity reactions: rash (including SJS/TEN), angioedema, bronchospasm, anaphylaxis • Common side effects: diarrhea, nausea Atazanavir • Hyperbilirubinemia – “Bananavir” (jaundice or scleral icterus): reversible, does not required DC • Requires acidic gut for absorption - Antacids: take 2 hours before or 1 hour after - H2RAs: avoid or take 2 hours before or 10 hours after - PPIs: avoid with unboosted; take boosted at least 12 hours after - Dose should not exceed omeprazole 20 mg or equivalent Darunavir, Fosprenavir, • Caution with sulfa allergy Tipranavir Lopinavir/Ritonavir Tipranavir CYP3A4 Drug Interactions • PO solution contains 42% alcohol: can cause disulfiram reaction with metronidazole • Intracranial hemorrhage All PIs are major CYP3A4 substrates – most are strong CYP3A4 inhibitors Do not use with PIs: • Alfuzosin • Colchicine • Dronedarone • Lovastatin & Simvastatin • CYP3A4 Inducers - Phenytoin, Rifampin, Rifapentine, Carbamazepine, Oxcarbazepine, Phenobarbital, SJW • Anticoagulants/antiplatelets: Apixaban, Rivaroxaban, Edoxaban, Ticagrelor - Warfarin is not CI but monitor INR closely • Direct-acting antivirals (DAAs) for hepatitis C - NS3/4A Protease Inhibitors: Glecaprevir, Grazoprevir, Voxilaprevir - NS5A Replication Complex Inhibitors: Elbasvir, Ledipasvir, Pibrentasvir, Velpatasvir, - NS5B Polymerase Inhibitors: Sofosbuvir • Some hormonal contraceptives • Steroids (systemic, intranasal, inhaled – increased risk of Cushing’s syndrome) Pharmacokinetic Boosters (Enhancers) All PK Boosters • CYP3A4 inhibitors – inhibit ART metabolism, which ⇧ (boosts) ART level & therapeutic effects • Ritonavir & Cobicistat are not interchangeable – do not use both together Ritonavir • Is a PI but is used as a booster because it is a strong inhibitor & not very well tolerated at higher doses needed for antiretroviral activity - Booster dosing is lower than treatment dosing • PO solution contains 43% alcohol: can cause disulfiram reaction with metronidazole Cobicistat • ⇧ SCr with no effect on GFR Drug Interactions Strong CYP3A4 inhibitors, also inhibit CYP2D6, P-gp and OAT transporters Do not use with PK Boosters: • Alfuzosin, Tamsulosin • Colchicine (with hepatic or renal impairment) • Lovastatin & Simvastatin • Tyrosine Kinase inhibitors (TKIs) (“nibs”) • CYP3A4 Inducers - Phenytoin, Rifampin, Rifapentine, Carbamazepine, Oxcarbazepine, Phenobarbital, SJW • Azole antifungals (especially isavuconazonium, itraconazole, voriconazole) • CV drugs: Amiodarone (ritonavir only), Dronedarone, Eplerenone, Ivabradine, Ranolazine • PDE-5 Inhibitors used for pulmonary HTN (Tadalafil, Sildenafil) • Any narrow therapeutic index drug that is highly dependent on CYP3A4 for clearance Combination ART Products Agents Descovy TAF/Emtricitabine Biktarvy TAF/Emtricitabine + Bictegravir First line Complera TAF/Emtricitabine + Rilpivirine Genvoya TAF/Emtricitabine + Elvitegravir + Cobicistat Regimen/Pearls • Lactic acidosis & hepatomegaly with steatosis (fatty liver) • Nausea, diarrhea, headache, ⇧ LFTs • Hyperpigmentation of palms of the hands or soles of the feet • Renal impairment - acute renal failure & Fanconi syndrome • ⇩ BMD - Both ⇩ than TDF • Monitor lipids • Do not start if CrCl < 30 Above PLUS: Bictegravir: • HA, insomnia, diarrhea, weight gain, depression & suicidal ideation in pateints with pre-existing psychiatric conditions • ⇧ SCr (by inhibiting tubular secretion) with no effect on GFR • Take 2H before or 6H after: Al, Ca, Mg, iron-containing products - Can be taken with PO calcium or iron if also taken with food Above PLUS: Rilpivirine: • Hepatotoxicity & rash, including SJS/TEN • Depression • ⇧ SCr with no effect on GFR • Do not use if viral load > 100,000 copies/mL and/or CD4 < 200 • Do not use with strong CYP3A4 inducers • Do not use with PPIs • Separate H2RAs – take H2RAs at least 12H before or 4H after • Separate antacids – take antacids at least 2H before or 4H after Above PLUS: Elvitegravir: • HA, insomnia, diarrhea, weight gain, depression & suicidal ideation in pateints with pre-existing psychiatric conditions Cobicistat: • ⇧ SCr with no effect on GFR •Take with food • Strong CYP3A4 inhibitor, also inhibit CYP2D6, P-gp & OAT Do not use with • Alfuzosin, Tamsulosin • Colchicine (with hepatic or renal impairment) • Lovastatin & Simvastatin • Tyrosine Kinase inhibitors (TKIs) (“nibs”) • CYP3A4 Inducers - Phenytoin, Rifampin, Rifapentine, Carbamazepine, Oxcarbazepine, Phenobarbital, SJW • Azole antifungals (especially isavuconazonium, itraconazole, voriconazole) • CV drugs: Dronedarone, Eplerenone, Ivabradine, Ranolazine • PDE-5 Inhibitors used for pulmonary HTN (Tadalafil, Sildenafil) • Any narrow therapeutic index drug highly dependent on CYP3A4 for clearance Symtuza: TAF/Emtricitabine + Darunavir + Cobicistat Above PLUS: Darunavir: • Metabolic Syndrome: hyperglycemia/insulin resistance, dyslipidemia (⇧ LDL, ⇧ TGs), ⇧ body fat - ⇧ CVD risk (lower risk) • Hepatic dysfunction: ⇧ LFTs, hepatitis and/or exacerbation of preexisting hepatic disease • Hypersensitivity reactions: rash (including SJS/TEN), angioedema, bronchospasm, anaphylaxis • Caution with sulfa allergy Cobicistat: • ⇧ SCr with no effect on GFR •Take with food Darunavir & Cobicistat: Do not use with • Alfuzosin, Tamsulosin • Colchicine • Lovastatin & Simvastatin • Tyrosine Kinase inhibitors (TKIs) (“nibs”) • CYP3A4 Inducers - Phenytoin, Rifampin, Rifapentine, Carbamazepine, Oxcarbazepine, Phenobarbital, SJW • Anticoagulants/antiplatelets: Apixaban, Rivaroxaban, Edoxaban, Ticagrelor - Warfarin is not CI but monitor INR closely • Direct-acting antivirals (DAAs) for hepatitis C - NS3/4A Protease Inhibitors: Glecaprevir, Grazoprevir, Voxilaprevir - NS5A Replication Complex Inhibitors: Elbasvir, Ledipasvir, Pibrentasvir, Velpatasvir, - NS5B Polymerase Inhibitors: Sofosbuvir • Azole antifungals (especially isavuconazonium, itraconazole, voriconazole) • CV drugs: Dronedarone, Eplerenone, Ivabradine, Ranolazine • PDE-5 Inhibitors used for pulmonary HTN (Tadalafil, Sildenafil) • Any narrow therapeutic index drug highly dependent on CYP3A4 for clearance • Some hormonal contraceptives • Steroids (systemic, intranasal, inhaled – ⇧ risk of Cushing’s syndrome)