Antibiotics: What You Need to Know in 2017 Alyssa R. Letourneau, MD, MPH Instructor in Medicine, Harvard Medical School Director, MGH Antimicrobial Stewardship Program
Disclosures No financial disclosures I will discuss the use of medications for non- FDA approved indications This review is not all encompassing 2
Objectives Provide a framework to think about initial antibiotic therapy Review general spectrum of activity for antibiotic classes Review common antibiotics and how they are used for common infectious disease syndromes 3
4
Selecting an Antibiotic Name the Syndrome/Infection What am I treating? Sepsis / Fever Syndrome Meningitis Bacteremia Pneumonia Intra-abdominal infection Cellulitis UTI How broad or narrow do I need to be? 5
What are the most likely pathogens? What resistance may exist? Do I need to be worried about colonization? Methicillin-resistant Staphylococcus aureus Vancomycin-resistant Enterococcus Multidrug-resistant gram-negatives 6
Who is the host? HIV/AIDS, immunodeficiency Chemotherapy, transplant recipient TNF alpha inhibitors, steroids Any exposures? Sick contacts, children, animals Any animal bites (or human) Travel history, recent or remote 7
Where is the Infection? Is the antimicrobial getting to the pathogen? Serum Cerebral spinal fluid Tissues Body fluid concentration Dosing Appropriately Renal function Body weight Organism 8
Antibiotic allergies Take a history! 80 yo with penicillin allergy as a teenager She will likely tolerate a penicillin or cephalosporin 10% report penicillin (PCN) allergy 90-99% with reported allergy tolerate PCNs 9 Blumenthal KG et al. Ann Allergy Asthma Immunol 2015:115;294
10 Blumenthal KG et al. Ann Allergy Asthma Immunol 2015:115;294
11 Blumenthal KG et al. Ann Allergy Asthma Immunol 2015:115;294
Can I Give the Antimicrobial? Toxicity Renal failure Mental status changes Clostridium difficile Formulation/bioavailability Intravenous Oral Inhaled Adherence/convenience Daily 3 times/day 5 times/day 12
Duration / Cost / Availability Duration Shortest duration with best therapeutic effect Cost/Availability Formularies Shortages 13
Antimicrobial Timeout Obtain cultures before starting antimicrobials Use rapid diagnostics Reassess at 48-72 hours Response to therapy should not be the only guide for therapeutic decisions Have the courage to make a diagnosis Follow recommended guidelines 14
Stewardship All antibiotic use can lead to resistance Less can be more, narrow when you can Reassess at 48 to 72 hours Data, data, data Think before you send something What will you do with the test results? Can it help you narrow? Could a biopsy be more useful? Response to therapy should not be the only guide for therapeutic decisions 15
16 Letourneau AR and Calderwood MS. Scientific American Medicine 2016
Case 1 65yo man with diabetes, recently discharged from rehab after IV antibiotics for cellulitis Fevers, cough, shortness of breath Leukocytosis Chest x-ray with left upper lobe infiltrate Admitted to the medical intensive care unit What to start empirically? A. Cefepime B. Vancomycin + cefepime C. Vancomcyin + cefepime + metronidazole D. Piperacillin-tazobactam E. Vancomcyin + meropenem 17
Case 1 Answer 65yo man with diabetes, recently discharged from rehab Fevers, cough, shortness of breath Leukocytosis Chest x-ray with left upper lobe infiltrate Admitted to the medical intensive care unit What to start empirically? B. Vancomycin + cefepime Answers will also depend on local resistance pattern! Kalil AC et al. CID 2016;63(5):e61-e111. 18
Case 1 Answer Reasoning Hospital-acquired pneumonia IV antibiotics in last 90 days Methicillin-resistant Staph aureus (MRSA) and Pseudomonas aeruginosa Kalil AC et al. CID 2016;63(5):e61-e111. 19
Case 1 Answer Reasoning A. Cefepime alone No MRSA therapy Methicillin-susceptible Staph aureus (MSSA), Streptococcus, Gram-negative rods (GNRs) Treats Pseudomonas aeruginosa B. Vancomycin + cefepime Best Answer Adding MRSA therapy with vancomycin Kalil AC et al. CID 2016;63(5):e61-e111. 20
Case 1 Answer Reasoning C. Vancomycin + cefepime + metronidazole Too broad. No aspiration mentioned, adding anaerobic therapy with metronidazole not needed D. Piperacillin-tazobactam No MRSA therapy, treats Pseudomonas Similar therapy as cefepime + metronidazole Anaerobic therapy not necessary too broad Kalil AC et al. CID 2016;63(5):e61-e111. 21
Case 1 Answer Reasoning E. Vancomcyin + meropenem Too broad No mention of multi-drug resistant pathogens necessitating a carbapenem Adding anaerobic therapy as well, unnecessary Although may vary by local resistance patterns Kalil AC et al. CID 2016;63(5):e61-e111. 22
Vancomycin (IV) Spectrum: most gram-positive organisms Streptococcus species, including penicillin resistant Enterococci, including penicillin resistant Staph aureus including MRSA Coagulase-negative staphylococci Clostridia species Clostridium difficile (oral formulation only) Bacillus species 23
Vancomycin (IV) Indications: MRSA bacteremia Resistant gram-positive infection Skin and soft tissue infections (MRSA) Suspected bacterial meningitis Severe beta-lactam allergy Adverse events: red man/woman syndrome Nephrotoxicity, leukopenia, thrombocytopenia 24
Cefepime (IV) 4 th generation cephalosporin Spectrum: Streptococcus species, MSSA (not drug of choice) Enteric gram-negative rods H. influenza, Neisseria Pseudomonas species Treats some AmpC over-producers Serratia, Proteus (indole+), Citrobacter, Enterobacter, Morganella (SPICE-M) Treats some extended-spectrum beta-lactamase (ESBL) Depends on MIC and resistance pattern 25
Cefepime (IV) Indications: Pseudomonas aeruginosa Not FDA approved for CNS infections, but is used Fever and neutropenia Dependent on local resistance for P. aeruginosa Healthcare-associated pneumonia, UTI Intra-abdominal infection including cholangitis and pancreatitis 26
Piperacillin-tazobactam (IV) Beta-lactam/beta-lactamase inhibitor Spectrum: Broad gram-positive, GNRs, anaerobes Streptococcus species, MSSA Ampicillin-susceptible Enterococcus Enteric GNRs Pseudomonas Anaerobes including Bacteroides 27
Piperacillin-tazobactam (IV) Indications: similar to cefepime Empiric therapy for healthcare-associated pneumonia, UTI, sepsis Empiric therapy to treat for Pseudomonas Empiric therapy for fever and neutropenia Dependent on local resistance for P. aeruginosa Intra-abdominal infections NOT meningitis 28
Metronidazole (IV/PO) Spectrum: Some gram-positive anaerobes, most gram-negative anaerobes Bacteroides species Clostridium species including C. difficile Gardnerella vaginitis Helicobacter pylori, Campylobacter fetus Anti-parasitic: Giardia, Entamoeba, Trichomonas Indications: C. difficile colitis, intra-abdominal infections, brain abscess, pulmonary abscess, vaginitis Excellent oral bio-availability 29
Carbapenems (IV) Spectrum: Very broad spectrum Some gram-positive including MSSA, Strep species Gram-positive rods, including Listeria Resistant GNRs including extended-spectrum betalactamases (ESBLs), P. aeruginosa Anaerobes, including B. fragilis Indications: infection with resistant pathogens Not Active Against: MRSA, Corynebacterium JK, Enterococcus faecium Stenotrophomonas maltophilia, Burkholderia cepacia 30
Carbapenems (IV) - Characteristics Doripenem Not recommended for vent-associated pneumonia Ertapenem Narrower spectrum Does not treat Enterococcus or Pseudomonas aeruginosa Good for home IV therapy of drug resistant organsims as it is once daily dosing 31
Carbapenems (IV) - Characteristics Imipenem/cilastatin May cause seizures if not renally dosed Not approved for meningitis Treats some non-tuberculous mycobacteria Meropenem Preferred for CNS infections 32
Case 1 - Review 65yo man with diabetes, recently discharged from rehab Fevers, cough, shortness of breath Leukocytosis Chest x-ray with left upper lobe infiltrate Admitted to the medical intensive care unit What to start empirically? A. Cefepime B. Vancomycin + cefepime C. Vancomcyin + cefepime + metronidazole D. Piperacillin-tazobactam E. Vancomcyin + meropenem 33
Case 2 25yo F who injects drugs presents with fevers, fatigue, sweats MSSA growing in multiple blood cultures No neurologic deficits What do you start? A. Nafcillin (naf) B. Cefazolin C. Vancomycin (vanc) D. Naf + gentamicin E. Cefazolin + gentamicin 34
Case 2 - Answer 25yo F who injects drugs presents with fevers, fatigue, sweats MSSA growing in multiple blood cultures No neurologic deficits What do you start? A. Nafcillin (naf) OR B. Cefazolin Beta-lactam therapy for Staph aureus No need for gentamicin or rifampin (no prosthetic valve) 35
Anti-Staph Penicillins Nafcillin (IV), Oxacillin (IV), Dicloxacillin (PO) Spectrum: MSSA infections Indications: Beta-lactam therapy preferred for MSSA IV therapy for bacteremia PO therapy for skin and soft tissue infections 36
Cefazolin (IV), Cephalexin (PO) 1 st generation cephalosporin Spectrum: Gram-positives and some GNRs Gram-positive cocci, MSSA Most community-acquired E. coli, Proteus, Klebsiella Some anaerobes (not Bacteroides) Indications: Bacteremia without CNS involvement (IV) MSSA infections (bone, jt, endocarditis) (IV) Surgical prophylaxis (IV) Cellulitis (IV or PO) 37
Aminoglycosides (IV) Spectrum: Drug-resistant GNRs, mycobacteria Amikacin Broadest spectrum Treats gentamicin-resistant GNRs Gentamicin Most commonly used Synergistic for enterococci or staph in endocarditis Tobramycin Slightly more active than gent for Pseudomonas Streptomycin primarily for TB 38
Case 2 Review 25yo F who injects drugs presents with fevers, fatigue, sweats MSSA growing in multiple blood cultures No neurologic deficits What do you start? A. Nafcillin (naf) B. Cefazolin C. Vancomycin (vanc) D. Naf + gentamicin E. Cefazolin + gentamicin 39
Case 3 67 yo M with fevers and headache Leukocytosis CSF Value Normal Glucose 10 50-75 Protein 150 5-55 What to start empirically? A. Ceftriaxone B. Vanc + ceftriaxone C. Vanc + ceftriaxone + ampicillin D. Vanc + ceftazidime WBC 500 0-5 Polys 99% 0-6% Gram stain Neg Neg 40
Case 3 - Answer 67 yo M with fevers and headache Leukocytosis CSF Value Normal Glucose 10 50-75 Protein 150 5-55 WBC 500 0-5 Polys 99% 0-6% Gram stain Neg Neg What to start empirically? C. Vanc + ceftriaxone + ampicillin Resistant Streptococcus pneumoniae Neisseira meningitidis Haemophilus influenzae Listeria monocytogenes 41
Ceftriaxone (IV) 3 rd generation cephalosporin Spectrum: Gram-positives, gram-negatives Gram-positives including penicillin-intermediate Streptococcus pneumonia, other Strep species Enteric gram negative rods Neisseria, Haemophilus influenzae NOT active against enterococci, Listeria, MRSA, Pseudomonas, AmpC or extended-spectrum betalactamase (ESBL) producing GNRs 42
Ceftriaxone (IV) Indications Community-acquired and aspiration pneumonia Community-acquired infections/syndromes Sepsis Intra-abdominal infections UTIs, pyelonephritis Cellulitis Bacterial meningitis Endocarditis Lyme disease (CNS, cardiac, arthritis) Gonorrhea 43
Ceftazidime (IV) 3 rd generation cephalosporin Spectrum: Enteric gram-negative rods (same as ceftriaxone) Pseudomonas aeruginosa Poor activity for gram positives Indications: P. aeruginosa infections including hospital-acquired pneumonia and UTI Fever and neutropenia CNS infection after CNS surgery FDA-approved for meningitis 44
Ampicillin (IV), Amoxicillin (PO) Spectrum: Gram-positive cocci, some enterococci Drug of choice for Listeria (IV) Gram-negative rods such as E. coli, P. mirabilis H. influenzae (non-beta-lactamase producing) Indications: IV Listeria bacteremia or meningitis PO Outpatient pneumonia, UTI, otitis, cellulitis 45
Case 3 - Reasoning 67 yo M with fevers and headache Leukocytosis CSF Value Normal Glucose 10 50-75 Protein 150 5-55 WBC 500 0-5 Polys 99% 0-6% Gram stain Neg Neg What to start empirically? A. Ceftriaxone B. Vanc + ceftriaxone C. Vanc + ceftriaxone + ampicillin D. Vanc + ceftazidime Resistant Strep pneumoniae Neisseira meningitidis Haemophilus influenzae Listeria monocytogenes 46
Case 4 45 yo man with diverticulitis No abscess on imaging 2 of 4 blood cultures with E. coli Started on ceftriaxone and metronidazole Blood cultures are slow to clear E. coli is pan-susceptible What do you send him home on? A. IV ceftriaxone and oral metronidazole B. Oral amoxicillinclavulanic acid C. IV ertapenem D. Oral ciprofloxacin and metronidazole 47
Case 4 - Answer 45 yo man with diverticulitis No abscess on imaging 2 of 4 blood cultures with E. coli Started on ceftriaxone and metronidazole Blood cultures are slow to clear E. coli is pan-susceptible What do you send him home on? D. Oral ciprofloxacin and metronidazole *Bacteremia Want good oral bioavailability of drug Narrowest spectrum for what we are treating 48
Case 4 Reasoning A. IV ceftriaxone and oral metronidazole IV drug, will need PICC line Good coverage of pathogens B. Oral amoxicillin-clavulanic acid Oral regimen, but would not use for bacteremia C. IV ertapenem IV drug, will need PICC line Broader regimen than needed 49
Ampicillin-sulbactam (IV) Amoxicillin-clavulanic acid (PO) Beta-lactmase inhibitor extends spectrum Spectrum: MSSA, H. influenzae, some enteric gram negative rods, anaerobes Indications: Pneumonia, UTI, intra-abdominal infections, chronic sinusitis, otitis media Would not use oral form for bacteremia 50
Fluoroquinolones (IV or PO) Ciprofloxacin, Levofloxacin, Moxifloxacin Spectrum: Relatively broad-spectrum Gram-negative rods, Pseudomonas aeruginosa Streptococcus pneumoniae (Levo/Moxi) Legionella, Mycoplasma, Chlamydia Some gram-positive cocci Some mycobacteria (Levo/Moxi) Anaerobes (Moxi) 51
Fluoroquinolones (IV or PO) Indications: Levofloxacin and Moxifloxacin -> community acquired pneumonia Intraabdominal infections Pyelonephritis, Prostatitis Osteomyelitis, Prosthetic joint infection Typhoid and enteric fever 52
Fluoroquinolones (IV or PO) Advantages: Good oral bioavailability Once-daily dosing (Levo/Moxi) Well tolerated Disadvantages: Overused, some emerging resistance Tendonitis + rupture, esp Achilles QTc prolongation C. difficile infection Increase INR when on warfarin FDA warning 53
Case 4 - Review 45 yo man with diverticulitis No abscess on imaging 2 of 4 blood cultures with E. coli Started on ceftriaxone and metronidazole Blood cultures cleared E. coli is pan-susceptible What do you send him home on? A. IV ceftriaxone and oral metronidazole B. Oral amoxicillinclavulanic acid C. IV ertapenem D. Oral ciprofloxacin and metronidazole 54
To Review All antibiotic use can lead to resistance Less can be more, narrow when you can Reassess at 48 to 72 hours Data, data, data Think before you send something What will you do with the test results? Can it help you narrow? Could a biopsy be more useful? Response to therapy should not be the only guide for therapeutic decisions 55
Where s the infection? 56 Raff AB and Kroshinsky D. JAMA 2016;316:325
Where s the infection? 57 Raff AB and Kroshinsky D. JAMA 2016;316:325
Failure to Respond Presence of a nonbacterial infection or a non-infectious process mimicking infection Inadequate dosing of antimicrobials Incorrect drug for site of infection Antimicrobial resistance Failure of source control Drain an abscess, relieve an obstruction, remove a foreign body Superinfection Adverse drug reaction Impairment of host defense local or systemic 58
Take Home Points Understand the host and infectious risk Is the drug getting to where it should be to be effective More antibiotics is not necessarily better! 59
Resources This is by no means all encompassing Multiple online and smartphone based apps to help with antimicrobial choices Up-to-Date Johns Hopkins Guides The Sanford Guide to Antimicrobial Therapy 60
Acknowledgements Thank you to Michael Calderwood M.D., M.P.H. and David Hooper, M.D. for sharing slides from previous talks
ADDITIONAL SLIDES *AGAIN, NOT ALL INCLUSIVE 62
Drugs for Gram-positive Therapy Penicillin/Ampicillin Group A Streptococcus, susceptible Enterococcus and Strep pneumonia, Clostridia, Listeria (amp) Nafcillin/oxacillin/dicloxacillin/cefazolin Preferred MSSA therapy Clindamycin To inhibit toxin production (Strep toxic shock) 63
Drugs for Gram-positive Therapy Ceftriaxone Intermediately resistant Strep pneumoniae or other resistant Strep spp Vancomycin MRSA, severe penicillin allergy Levofloxacin Penicillin or ceftriaxone-resistant Strep pneumoniae 64
Drugs for Gram-positive Therapy Linezolid (IV or PO) VRE, MRSA Daptomycin MRSA, alternative to vancomycin) Ceftaroline MRSA, resistant Strep pneumoniae 65
Drugs for Gram-negative Therapy Coming from the community Ceftriaxone, ciprofloxacin Concern for Pseudomonas aeruginosa Cefepime, ceftazidime, or piperacillin-tazobactam Concern for multidrug resistant GNRs Carbapenem Severe penicillin allergy -> aztreonam Carbapenem resistant Colistin/polymyxin, tigecycline, extended-infusion carbapenem + aminoglycoside 66
Drugs for Anaerobic Therapy Clindamycin Metronidazole Ampicillin-sulbactam, piperacillin-tazobactam Carbapanems 67
Other Antibiotics Penicillin (IV or PO) Still drug of choice for Group A Streptococcus and for Syphilis Prophylaxis for recurrent cellulitis 68
2 nd Generation Cephalosporins Cefuroxime (PO), Cefoxitin (IV), Cefotetan (IV) Cefazolin/cephalexin coverage + H. influenzae, Moraxella PO for pneumonia or UTI as alternative to amoxicillin-clavulanic acid IV has anaerobic therapy and used for GI/GYN surgical prophylaxis 69
Ceftaroline (IV) 5 th Generation cephalosporin Spectrum: Similar to ceftriaxone + MRSA No activity against Pseudomonas aeruginosa Indications: FDA approved for skin and soft tissue infections Off label for complicated MRSA infections 70
Aztreonam (IV) Monobactam Similar mechanism as beta-lactam Spectrum: Aerobic gram-negative rods, Pseudomonas aeruginosa No gram-positives Indications: Severe beta-lactam allergy, if no ceftazidime allergy as they can cross react 71
Clindamycin Treats most oral anaerobes including in anaerobic pulmonary infections Intra-abdominal and/or pelvic polymicrobial infections Some Bacteroides fragilis resistance High risk for C. diff infection Inhibits toxin formation in toxic shock for Group A Streptococcus pyogenes Excellent oral bioavailability Anti-parasitic: malaria, babesia, toxoplasmosis 72
Linezolid and Tedizolid Spectrum: VRE and MRSA Indications: Infections with VRE, MRSA PO = IV Some non-tuberculous mycobacteria Warnings: Cytopenias when used for > 2 weeks Optic and peripheral neuropathy when used for > 28 days Potential for serotonin syndrome with SSRIs Bacteriostatic 73
Daptomycin (IV) Spectrum: VRE and MRSA (bactericidal) Indications: VRE and MRSA infections Not for pneumonia as inactivated by surfactant Warnings: MRSA with vancomycin MIC > 1.5 may have similar creep in daptomycin MIC while on therapy Myopathy/myositis -> follow CPK weekly 74
Other Gram Positive Agents Telavancin Similar to vancomycin Oritavancin and Dalbavancin Once weekly infusions marketed for MRSA skin and soft tissue infections 75
Doxycycline (IV or PO) Spectrum: Broad spectrum, bacteriostatic Aerobic gram-positive bacteria, including MRSA Aerobic gram-negative bacteria (not P. aeruginosa) Atypical respiratory pathogens Rickettsia spp Spirochetes including Borrelia, leptospirosis, and treponemes Coxiella burnetti, brucella spp., Francisella tularensis Vibrio cholerae and Vibrio vulnificus 76
Doxycycline (IV or PO) Indications: as in spectrum MRSA skin infections Community-acquired pneumonia Bone and joint infections as suppressive therapy STDs (gonorrhea, chlamydia) Tick-borne illnesses (not babesiosis) Rocky mountain spotted fever Leptospirosis, Q-fever, brucellosis Warnings: phototoxicity, GI upset 77
Trimethoprim-Sulfamethoxazole (IV or PO) Spectrum: MSSA, MRSA Poor for Streptococcus species Does not treat Enterococcus or Pseudomonas GNRs including enterics, Stenotrophomonas and Burkholderia Nocardia, Listeria, Pneumocystis jirovecii, Toxoplasmosis, Cyclospora and Isosopora Indications: UTI (depending on local resistance) Above infections Prophylaxis against Pneumocystis jirovecii Warnings: Rash, hyperkalemia, aseptic meningitis, bone marrow suppression 78
Macrolides Azithromycin, Clarithromycin, Erythromycin Spectrum: Legionella (azithro or fluoroquinolone) Mycoplasma pneumoniae Chlamydia pneumoniae Chlamydia trachomatis Pertussis, Diptheria Non tuberculosis mycobacteria (azithro/clarithro) 79
Macrolides Indications: Campylobacter jejuni gastroenteritis Bartonellosis H. pylori (clarithromycin in combination) Atypical mycobacteria (azithro/clarithro in combination with other drugs) 80