Antibiotic Workshop Part 1: Antibiotic Basics. Jennifer Primeggia, MD Infectious Diseases, Hospitalist Department of Medicine Inova Fairfax Hospital

Transcription

1 Antibiotic Workshop Part 1: Antibiotic Basics Jennifer Primeggia, MD Infectious Diseases, Hospitalist Department of Medicine Inova Fairfax Hospital

2 Lecture Overview Definitions/ Key Concepts Empiric Therapy: Key Lists to Memorize Antibiotic Classes

3 Key Concepts Related to Antimicrobials Patterns of Antimicrobial Killing Time dependent v. concentration dependent Post-Antibiotic Effect Static v. Cidal MICs Synergy Empiric versus Narrow Spectrum/ Targeted

4 Patterns of Microbial Killing Concentration independent (time dependent) Rate and extent of microorganism killing remain unchanged regardless of antimicrobial concentration. Examples: beta-lactams, vancomycin, macrolides, aztreonam, carbapenems, clindamycin, tetracyclines, quinupristin/dalfopristin Concentration dependent (time independent) Rate and extent of microorganism killing are a function of the antimicrobial concentration (increase as the concentration increases). Examples: fluoroquinolones, aminoglycosides, Metronidazole, Daptomycin, Colistin

5 Figure 2: Principal PK-PD characteristics of antimicrobial drugs Left: Time-dependent antibiotics (beta-lactams, including penicillins and penems, glycopeptides, linezolid, macrolides, etc.). The time that the concentration of a drug remains above the MIC (T > MIC) is the PK-PD index correlating with efficacy. The post-antibiotic effect (PAE) can be absent (macrolides), minimal (betalactams, including penicillins and penems), or moderate (glycopeptides, linezolid). Right: Concentration-dependent antibiotics (aminoglycosides, fluoroquinolones). The peak concentration/minimum inhibitory concentration (C max /MIC) ratio and/or the area under the concentration-time curve at 24 h/mic (AUC 0-24/MIC) ratio are the best PK-PD modeling and simulation correlating with efficacy. Moreover, there is a prolonged PAE with the concentration-dependent antibiotics.

6 Post-Antibiotic Effect Post-Antibiotic Effect (PAE) Persistent suppression of bacterial regrowth after the antibiotic is removed or levels decrease to below the MIC for the organism Varies with the particular organism-drug combination May be influenced by: concentration of the antimicrobial used, duration of the exposure to the antimicrobial, inoculum of organisms, combination of antimicrobials used, growth rate of the organisms, and host defenses

7 Patterns of Microbial Killing Bacteriostatic activity versus bactericidal activity Bacteriostatic activity refers to the inhibition of bacterial growth, while bactericidal activity refers to killing the bacteria.

8 MIC s Minimum inhibitory concentration (MIC) the lowest concentration of antibiotic that completely inhibits growth of the specific organism being tested. Minimum bactericidal concentration (MBC) the lowest concentration of antibiotic at which bacteria are killed.

9 Synergy Occurs when inhibitory or bactericidal activity of combination therapy is greater than would be expected from the sum of the activities of the individual agents Synergy for gram - infections is of major value only when the bacterium is resistant to one or both of the drugs in the combination. Synergy has been best established for B-lactam and aminoglycoside combinations. Ex. Unasyn + Gent for native valve endocarditis (enterococcus) Synergy between other drug combinations is less predictable and has unclear clinical significance. Daptomycin + B-lactams for VRE?

10 Empiric v Targeted Therapy Empiric Antibiotic Therapy Narrow Spectrum Antibiotic Therapy

11 Empiric v Targeted Therapy Empiric therapy is a medical term referring to the initiation of treatment prior to determination of a firm diagnosis It is most often used when antibiotics are given to a person before the specific bacterium causing an infection is known When more information is known, treatment may be changed to a narrow-spectrum antibiotic which more specifically targets the bacterium known to be causing disease

12 Empiric Therapy Initiation of therapy may be necessary for unstable or high-risk patients while the diagnostic evaluation is ongoing Antibiotic therapy should begin within 1 hour after the diagnosis of sepsis is considered The choice of regimen depends of the suspected infectious etiology, whether the infection is community or health care acquired and whether the patient is immunocompromised No need to cover everything Most likely, (not every) organisms implicated in the disease O Grady et al. Crit Care Med. 2008

13 How to Learn Antibiotics Key lists to memorize Think Clinically Don t forget your micro!

14 Devising an Empiric Regimen What Covers Pseudomonas MRSA Enterococcus Anaerobes Key Lists to Memorize

15 What Covers Pseudomonas? Piperacillin-Tazo, Ticarcillin- Clav Cefepime, Ceftazidime Imipenem, Meropenem Cipro, Levaquin Aztreonam Aminoglycosides Polymixin B (Colistin)

16 What Covers MRSA? IV Vancomycin Linezolid Daptomycin Clindamycin* Ceftaroline Synercid (quinupristindalfopristin) (Tigecycline) Oral Bactrim Clindamycin* Linezolid (Doxycycline) (Minocycline)

17 Clindamycin Excellent tissue penetration, particularly in bone and abscess Limited CNS penetration Bacteriostatic Not recommended for endovascular infections Also, Great Anaerobic coverage In addition to MRSA, covers Gas Gangrene/ Necrotizing Fasciitis Used in Toxic Shock Syndrome (TSS) to inhibit toxin synthesis SE: Most commonly associated with C. diff, but all Abx can cause it Steward et al. Testing for Induction of Clindamycin Resistance in Erythromycin-Resistant Isolates of Staphylococcus aureus. Journal of Clinical Microbilogy, April

18 Clindamycin* CA-MRSA is defined by inducible-clinda resistance If an organism is S to Clinda but R to erythromycin, it is likely to have inducible form of macrolide resistance so choose another Abx

19 Vancomycin IV vancomycin mg/kg/dose (actual body weight) q 8-12 hours (B-III) NOT to exceed 2 g per dose In seriously ill patients (sepsis, meningitis, PNA, IE), a LD of mg/kg x 1 may be considered (C-III) Infuse over 2 hours given increased risk of red man syndrome Consider use of antihistamine Troughs are the most accurate and practical method of guiding dosing (B-II) Should be obtained prior to the 4th or 5th dose Monitoring peaks is not recommended (B-II) For serious infections trough concentrations of are recommended (B-II)

20 Vancomycin

21 Vancomycin Adverse Effects Nephrotoxicity and Ototoxicity rare with monotherapy, more common when administered with other nephro- or ototoxins risk factors include renal impairment, prolonged therapy, high doses,? high serum concentrations, other toxic meds Dermatologic rash, bullous lesion Hematologic - neutropenia and thrombocytopenia with prolonged therapy Thrombophlebitis

22 Daptomycin Lipopeptide class: Disrupts cell membrane function via calcium-depended binding Bactericidal, concentration-dependent No Lung Coverage (inactivated by surfactant) Gram + Coverage FDA approved: S. aureus bacteremia, R-sided endocarditis, cssti Nonsuceptible isolates have emerged Risk factors: Prior exposure to vancomycin Elevated vancomycin MICs (? Cross-resistance) CPK monitoring: Weekly More frequently in those receiving statins, with renal insufficiency Elevations in CPK are not seen in those receiving 4 mg/kg/day

23 Linezolid Synthetic oxazolididone MOA: Inhibits initiation of protein synthesis at the 50S ribosome Gram + coverage, some atypicals Used for MRSA and VRE Mycoplasma, Chlamydia, Legionella Atypical mycobacteria Side effects: Thrombocytopenia > anemia/ neutropenia (Usually reversible) Peripheral and optic neuropathy (Partially reversible) Lactic acidosis Some data demonstrates increased mortality if used in critically ill patients with MRSA/ VRE bacteremia so use Vanc/Dapto instead

24 Linezolid: Drug Drug/Food interactions Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Tyramine rich foods, adrenergic drugs and serotonergic drugs should be avoided due to the potential drug-food and drug-drug interactions Foods high in tyramine content are those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor

25 Tyramine Rich Foods Aged cheeses (0 to 15 mg tyramine per ounce) Fermented or air-dried meats such as pepperoni (0.1 to 8 mg tyramine per ounce) Sauerkraut (8 mg tyramine per 8 ounces) Soy sauce (5 mg tyramine per 1 teaspoon) Tap beers (4 mg tyramine per 12 ounces) Red wines (0 to 6 mg tyramine per 8 ounces).

26 Quinupristin-Dalfopristin A combination of 2 streptogramin antibiotics Inhibits protein synthesis Used as salvage therapy for invasive MRSA infections in the setting of vancomycin treatment failure Toxicity: arthraligas, myalgias, nausea, infusion-related reactions

27 Bactrim: TMP-SMZ Not FDA approved for treatment of any staph infection Used for outpt SSTI as % of CA-MRSA strains are susceptible A few studies have suggested a role in bone and joint infections A few case reports indicate potential efficacy in treatment of bacteremia and endocarditis Toxicities: Hypersensitivity reactions, nephrotoxicity, myelosuppression, hyperkalemia MOA: interferes with folic acid synthesis

28 What Covers Enterococcus Enterococcus Vancomycin Ampicillin Amoxicillin Pipercillin-Tazobactam Imipenem > Meropenem +/- Cipro -/- Specific for VRE Linezolid Daptomycin Tigecycline Quinupristin-dalfopristin As a class, cephalosporins do NOT cover Enterococcus

29 A glycylcycline Tigecycline 9-t-butylglycylamido derivative of minocycline Enables the drug to overcome the 2 major mechanisms of tetracycline resistance: tetracycline-specific efflux pump acquisition and ribosomal protection Activity against: csssi, ciai, CABP G+, G-, anaerobes. Several multidrug-resistant bacteria: VRE, ESBL s, MRSA, carbapenemresistant Acinetobacter Does not cover Proteus and Pseudomonas (intrinsic resistance)

30 Tigecycline Bacteriostatic, caution with use in bacteremia Adverse effects: NAUSEA FDA warning to consider alternative agents in patients with serious infections because of phase III/VI clinical trials that noted an increase in all-cause mortality

31 FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning This update is in follow-up to the FDA Drug Safety Communication: Increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections1 issued on September 1, Safety Announcement [ ] The U.S. Food and Drug Administration (FDA) is warning that an additional analysis shows an increased risk of death when intravenous (IV) Tygacil (tigecycline) is used for FDA-approved uses as well as for non-approved uses. As a result, we approved a new Boxed Warning about this risk to be added to the Tygacil drug label and updated the Warnings and Precautions and the Adverse Reactions sections. A Boxed Warning is the strongest warning given to a drug. These changes to the Tygacil label are based on an additional analysis that was conducted for FDA-approved uses after issuing a Drug Safety Communication2 (DSC) about this safety concern in September Health care professionals should reserve Tygacil for use in situations when alternative treatments are not suitable. Tygacil is FDA-approved to treat complicated skin and skin structure infections (csssi), complicated intra-abdominal infections (ciai), and community-acquired bacterial pneumonia (CABP). Tygacil is not indicated for treatment of diabetic foot infection or for hospital-acquired or ventilator-associated pneumonia. Patients and their caregivers should talk with their health care professionals if they have any questions or concerns about Tygacil.

32 What Provides Good Anaerobic Coverage? PCN Clindamycin Metronidazole (Flagyl) Moxifloxacin Augmentin Unasyn Pip-Tazo Carbapenems Tigecycline FLAGYL CLINDA FLAGYL

33 What Covers Pseudomonas MRSA Enterococcus Anaerobes Key Lists to Memorize

34 The Classes Penicillins Cephalosporins Carbapenems Fluoroquinolones Macrolides Aminoglycosides

35 Penicillins MOA: bind to PBPs in the cell wall and inhibit cross-linking, thus inhibiting cell wall synthesis Natural Penicillins Aminopenicillins Penicillinase-resistant PCNs anti-staph PCNs Carboxypenicillins & Urediopenicillins anti-pseudomonal PCNs PCN G PCN V Ampicillin, Amoxicillin Amp-sulbactam (Unasyn), Amoxicillin- clavulanate (Augmentin) Nafcillin Oxacillin Dicloxacillin Ticarcillin, Piperacillin Ticarcillin-clavulanate (Timentin), Piperacillin-tazobactam (Zosyn)

36 What do PCNs cover? Overall great Gram + Coverage Natural Penicillins Aminopenicillins Penicillinase-resistant PCNs anti-staph PCNs Carboxypenicillins & Urediopenicillins anti-pseudomonal PCNs Gram + Minimal Gram - anaerobes Some Gram No Enterobacter, Serratia Anaerobes Narrow spectrum Gram + coverage No gram -, enterococcal, or anaerobic coverage Gram +, Gram - aerobes, anaerobes Pseudomonas!

37 Natural Penicillins (penicillin G, penicillin VK) Gram-positive pen-susc S. pneumoniae Group A/B/C/G strep viridans streptococci Enterococcus Other Treponema pallidum (syphilis) Gram-negative Neisseria sp. Anaerobes Above the diaphragm Clostridium sp.

38 Penicillinase-Resistant Penicillins (nafcillin, oxacillin, methicillin) Developed to overcome the penicillinase enzyme of S. aureus which inactivated natural penicillins Gram-positive Methicillin-susceptible S. aureus Penicillin-susceptible strains of Streptococci

39 Aminopenicillins (ampicillin, amoxicillin) Developed to increase activity against gram-negative aerobes Gram-positive pen-susc S. aureus Pen-susc streptococci Viridans streptococci Enterococcus sp. Listeria monocytogenes Gram-negative Proteus mirabilis Salmonella, some E. coli L- H. influenzae

40 Carboxypenicillins (carbenicillin, ticarcillin) Developed to further increase activity against resistant gram-negative aerobes Gram-positive marginal Gram-negative Proteus mirabilis Salmonella, Shigella some E. coli L- H. influenzae Enterobacter sp. Pseudomonas aeruginosa

41 Ureidopenicillins (piperacillin, azlocillin) Developed to further increase activity against resistant gram-negative aerobes Gram-positive viridans strep Group strep some Enterococcus Anaerobes Fairly good activity Gram-negative Proteus mirabilis Salmonella, Shigella E. coli L- H. influenzae Enterobacter sp. Pseudomonas aeruginosa Serratia marcescens some Klebsiella sp.

42 -Lactamase Inhibitor Combos (Unasyn, Augmentin, Timentin, Zosyn) Developed to gain or enhance activity against - lactamase producing organisms (some better than others). Provides some or good activity against: Gram-positive Gram-negative S. aureus (MSSA) H. influenzae Anaerobes E. coli Proteus sp. Bacteroides sp. Klebsiella sp. Neisseria gonorrhoeae Moraxella catarrhalis

43 Common Uses of PCNs PCN G Syphilis Nafcillin (IV) DOC for MSSA bacteremia/ endocarditis Dicloxacillin (PO) Cellulitis (outpatient) Pip-Tazo Broad coverage Urinary/ GI/ Lung Augmentin (Amox/Clav) PO Sinusitis, OM, UTI Aspiration PNA (when discharging patients) Unasyn (Amp/ Sulbactam) IV Cellulitis/ bites Ampicillin DOC for Enterococcus, Listeria

44 Cephalosporins 1 st Generation Cefazolin (IV) Cefadroxil (PO) Cephalexin (PO) 2 nd Generation Cefotetain (IV) Cefoxitin (IV) Cefuroxime (IV, PO) Cefaclor (PO) Cefprozil (PO) 3 rd Generation Cefotaxime (IV) Ceftriaxone (IV) Ceftazidime (IV) Cefixime (PO) Ceftibuten (PO) Cefpodoxime(PO) Cefdinir (PO) 4 th Generation Cefepime (IV) 5 th Generation Ceftaroline (IV)

45 1 st Generation 2 nd Generation Cefotetain (Lorabid) Cefoxitin (Mefoxin) Cefuroxime (Zinacef)) Cefaclor (Celor) Cefprozil (Cefzil) Cephalosporins 3 rd Generation Cefazolin (Ancef) Cefotaxime (Claforan) Cefadroxil (Duricef) Ceftriaxone (Rocephin) Cephalexin (Keflex) Ceftazidime (Fortaz) Cefixime (Suprax) Ceftibuten (Cedax) Cefpodoxime (Vantin) Cefdinir (Omnicef) 4 th Generation Cefepime (Maxipime) 5 th Generation Ceftaroline (Teflaro)

46 Cephalosporins Overview Divided into 4 (or 5) major groups called Generations Are divided into generations based on Antimicrobial activity Resistance to beta-lactamase MOA: bind to PBPs in the cell wall and inhibit crosslinking, thus inhibiting cell wall synthesis

47 Cephalosporin Overview Good gram + Coverage As a class, they do NOT cover Enterococcus, Listeria, or Corynebacterium As you increase through the generations, you gain better gram negative coverage Only Cefepime and Ceftazidime cover Pseudomonas 2 nd, 3 rd, 4 th generations cover some anaerobes, but don t think of them routinely as good anaerobic antibiotics

48 1st Generation Cephalosporins Best activity against gram + aerobes, with limited activity against a few gram - aerobes Gram-positive meth-susc S. aureus pen-susc S. pneumoniae Group A/B/C/Gstreptococci viridans streptococci Gram-negative E. coli K. pneumoniae P. mirabilis

49 2nd Generation Cephalosporins Spectrum of Activity Gram-positive meth-susc S. aureus pen-susc S. pneumoniae Group A/B/C/G strep viridans streptococci Gram-negative E. coli K. pneumoniae P. mirabilis H. influenzae M. catarrhalis Neisseria sp.

50 2nd Generation Cephalosporins Spectrum of Activity The cephamycins (cefoxitin and cefotetan) are the only 2nd generation cephalosporins that have activity against anaerobes Anaerobes Bacteroides fragilis Bacteroides fragilis group Useful for OB and colorectal surgery PPX, for treatment of CA abdominal infections and PID * There is some B. fragilis resistance

51 3 rd Generation Cephalosporins Spectrum of Activity Gram-negative aerobes E. coli, K. pneumoniae, P. mirabilis H. influenzae, M. catarrhalis, N. gonorrhoeae (including betalactamase producing); N. meningitidis Citrobacter sp., Enterobacter sp., Acinetobacter sp. Morganella morganii, Serratia marcescens, Providencia Pseudomonas aeruginosa (ceftazidime)

52 4 th Generation Cephalosporin 4th generation cephalosporins for 2 reasons Extended spectrum of activity Gram +: similar to ceftriaxone Gram - : similar to ceftazidime, including Pseudomonas aeruginosa; also covers beta-lactamase producing Enterobacter sp. Stability against -lactamases Only cefepime is currently available

53 Ceftaroline 5 th generation (advanced generation) cephalosporin Indications: CAP, csssis Spectrum of activity: Gram+ and Gram, including MRSA, multidrug- resistant S. pneumoniae, S. pyogenes, E coli, Klebsiella Activity against extended-spectrum β-lactamaseproducing bacteria is limited

54 Common Uses of Cephalosporins 1 st Generation Cefazolin (IV) = Ancef Surgical PPX Cephalexin (PO) = Keflex Cellulitis, UTI, URI 2 nd Generation Cefotetan (IV) Surgical PPX Cefuroxime (IV, PO) = Ceftin Cellulitis, URI 3 rd Generation Cefotaxime (IV) Surgeons like it better than ceftriaxone!- less biliary sludging Ceftriaxone (IV) PNA, Meningitis, UTI Lyme, Gonorrhea Ceftazidime (IV) Neutropenic Fever 4 th Generation Cefepime (IV) Neutropenic Fever

55 Carbapenems Great Broad Spectrum Antibiotics Covers Gram + s, Gram s and Anaerobes All cover E. faecalis Bacteria not covered: MRSA, VRE, coagulasenegative staph, C. difficile, Nocardia, Stenotrophomonas DOC for ESBL Organisms Some differences between the different drugs to be aware of

56 Carbapenems Imipenem The only one that covers E. faecium Highest risk of Seizures as a SE, but the whole class does it Meropenem The only one approved for meningitis The only one that covers Burkholdaria Ertapenem Advantage of once daily dosing (great for outpatient IV infusion) Does NOT cover Pseudomonas or Acinetobacter Doripenem Least likely to cause seizures

57 Bacterial Resistance Issues Gram Negatives Extended-Spectrum B-Lactamase-Producing (ESBL) Gram-negative Bacilli ampc-mediated Resistance in Gram-negative bacilli Carbapenem-Resistant Enterobacteriaceae (CRE) Klebsiella pneumoniae Carbapenemase (KPC)

58 Extended-spectrum betalactamases (ESBLs) ESBLs are enzymes that confer resistance to most B-lactam antibiotics Infections with these organisms have been associated with poor outcomes Carbapenems are the best antimicrobial agent for infections caused by these organisms

59 Beta-Lactamases Beta-lactamases are enzymes that open the beta-lactam ring, inactivating the antibiotic Beta lactamases hydrolyze PCNs and narrow spectrum cephalosporins (ex. cefazolin), but are not effective against higher generation cephalosporins with an oxyiamino side chain (ex. Cefotaxime, ceftazidime, ceftriaxone, cefepime) Core structure of penicillins (top) and cephalosporins (bottom). β-lactam ring in red.

60 Schematic representation of ceftazidime with the R1 side chain at C7 and the R2 side chain at C3. Jacoby G A Clin. Microbiol. Rev. 2009;22:

61 Extended Spectrum Beta-Lactamases Soon after cefotaxime came into clinical use in Europe, Klebsiella strains were discovered in Germany with transferable resistance to the oxyimino-cephalosporins (ex. Cefotaxime, ceftazidime, and ceftriaxone) TEM-related ESBLs were discovered in France in 1984 and the US in 1988

62 ESBLs ESBLs Family is Heterogeneous TEM Beta-lactamases SHV beta-lactamases CTX-M beta-lactamases OXA beta-lactamases PER-1 VEB-1 GES-1/2 BES SFO TLA The predominant ESBL type in the US Increasing prevalence in the US: A single clonal group of E. coli may have accounted for a large proportion of antimicrobial resistance to E coli infections in the US in 2007 Name derived from greater activity against cefotaxime

63 ESBLs ESBLs vary in activity against different oxyimino-beta-lactam substrates but cannot attack the cephamycins (cefoxitin, cefotetan) and the carbapenems They are generally susceptible to betalactamase inhibitors, such as clavulanate, sulbactam, and tazobactam These are combined with beta-lactam substrates to test for the presence of the resistance mechanism

64 ESBL Lab Detection Detection of ESBLs is based on the resistance they confer to oxyimino-beta-lactam substrates (ex. Cefotaxime, ceftazidime, ceftriaxone, cefepime) and the ability of B- latamase inhibitor (usu. Clavulanate) to block this resistance

65 ampc-mediated Resistance Confers resistance to: The S.P.A.C.E Organisms Cephamycins (cefotetan and cefoxitin) Oxyimino-B lactams (ceftriaxone, cefotaxime, ceftazidime) Chromosomal in SPACE organisms and is inducible Plasmid mediated in other gram-negatives and is not inducible

66 ampc-mediated Resistance The S.P.A.C.E Organisms Generally avoid 2 nd and 3 rd generation cephalosporins even if organism is reported susceptible, because of the potential for induction or selection of AmpC type b-lactamase Serratia Pseudomonas Acinetobacter Citrobacter Enterobacter

67 ESBL v ampc Resistance ESBL Encoded by genes located on plasmids, resulting in easy XFR to other bacterial species Well inhibited by B- lactamase inhibitors and retain sensitivity to cephalomycins ampc Encoded by genes located on chromosomes; often inducible but not often transferable Weakly inhibited by B- lactamase inhibitors (clavulanic acid) and confer resistance to cephamycins

68 Carbapenem-Resistant Enterobacteriaceae (CRE) Carbapenem-hydrolyzing B-lactamases that confer resistance to a broad spectrum of B- lactam substrates, including carbapenems Most important is KPC (Klebsiella pneumoniae carbapenemase group) Enzymes reside of transmissible plasmids Treatment: limited options Combination therapy with 2+ agents Colsitin, aztreonam, tigeycline, fosfomycin

69 Fluoroquinolones Cipro, Moxifloxacin, Levaquin are most commonly used All have IV and PO forms Most FQs have good bioavailability after oral administration Some differences among them Uses: Cipro Moxi Levaquin UTI/ GC Lung Penetrates CNS SBP ppx Respiratory FQ - Covers atypicals Covers Anaerobes NO Urinary Penetration Lung (CAP) GI infections Respiratory FQ - covers atypicals Covers some anaerobes UTI/ Chlamydia/ GC Lung (CAP) Osteomyelitis

70 FQs Spectrum of Activity Gram + Gram - Atypicals MSSA S. Pneumo Limited Activity Group A/B/C/G and Viridans strep Enterococcus Enterobacteriacae (E coli, Klebsiella, Enterobacter, Proteus, Salmonella, Shigella, Serratia) H. Flu M. Catarrhalis Neisseria Increasing Resistance Pseudomonas Legionella Chlamydia Mycoplasma Ureaplasma Others M.TB Bacillus anthracis

71 FQ: Adverse Effects Gastrointestinal 5 % Nausea, vomiting, diarrhea, dyspepsia Central Nervous System Headache, agitation, insomnia, dizziness, rarely, hallucinations (elderly) Seizures in predisposed patients, esp without dose adjustment for renal function Hepatotoxicity LFT elevation (led to withdrawal of trovafloxacin) Cardiac Variable prolongation in QTc interval Musculoskeletal Cartilage erosion, tendinitis and tendon rupture Dysglycemia (drug removed from market) Hyper or hypoglycemia

72 Macrolides What are they? Azithromycin, Erythromycin, Clarithromycin What do they cover? Some gram negatives, including Atypicals and Gonorrhea Mycobacterium Avium What are they used for? Erythromycin Not much- diarrhea such as severe SE, more often used as a promotility agent in the ICU Chlamydia Clarithromycin (Biaxin) CAP, MAC Tx Azithromycin CAP, MAC ppx, Chlamydia

73 Aminoglycosides MOA is Multifactorial, but ultimately involves inhibition of protein synthesis Are bactericidal Examples: Gentamicin Tobramycin Amikacin Streptomycin

74 Aminoglycosides Spectrum of Activity Spectrum of Activity: Gram + Aerobes: most S. aureus and coagulase-negative staph (but not DOC), viridans streptococci (in combination with a cell-wall agent), Enterococcus sp. (only in combination with a cell-wall agent) Gram - Aerobes (not streptomycin): E. coli, K. pneumoniae, Proteus sp. Acinetobacter, Citrobacter, Enterobacter sp. Morganella, Providencia, Serratia, Salmonella, Shigella, Pseudomonas aeruginosa (amik>tobra>gent) Mycobacteria tuberculosis - streptomycin atypical - streptomycin or amikacin

75 Aminoglycosides Adverse Effects Nephrotoxicity Nonoliguric azotemia due to proximal tubule damage; increase in BUN and serum Cr; reversible if caught early Risk factors: prolonged high troughs, long duration of therapy (> 2 weeks), underlying renal dysfunction, elderly, other nephrotoxins Ototoxicity CN 8 damage - vestibular and auditory toxicity; irreversible Vestibular: dizziness, vertigo, ataxia Auditory: tinnitus, decreased hearing Risk factors: same as for nephrotoxicity

76 Traditional Dosing Aminoglycosides Extended Interval Dosing Maximizes pharmacodynamics by providing high serum levels compared with MIC Decreased nephrotoxicity by allowing a drug-free interval between doses

77 Colistin IV or inhalation MOA: colistimethate is converted to colistin, which disrupts the permeability of bacterial membrane, leading to leakage of the cell contents and cell death Spectrum of activity: broad against gram aerobes, including: MDR Acinetobacter, P. aeruginosa, K. pneumoniae Toxicities: Nephrotoxicity (usually reversible), Neurotoxicity (paresthesias, vertigo, neuromuscular blockade)

78 Lecture Overview Definitions/ Key Concepts Empiric Therapy: Key Lists to Memorize Pseudomonas MRSA, Enterococcus (VRE) Anaerobes Antibiotic Classes: Penicillins, Cephalosporins, Carbapenems, Fluoroquinolones, Macrolides, Aminoglycosides

79 Why does this matter? Few new antibiotics are in the drug development pipeline Few antibiotics in development have documented in vitro activity against antibioticresistant gram-negative bacteria The arsenal of available antimicrobial drugs is becoming smaller because older drugs are disappearing from the market or are temporarily unavailable. Pulcini et al. Forgotten Antibiotics. CID 2012

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