Antimicrobial Update. Vicky Dudas, Pharm.D. Associate Clinical Professor of Pharmacy Director, Antimicrobial Management Program UCSF Medical Center

Transcription

1 Antimicrobial Update Vicky Dudas, Pharm.D. Associate Clinical Professor of Pharmacy Director, Antimicrobial Management Program UCSF Medical Center

2 Objectives Discuss treatment of acute bacterial rhinosinusitis Review treatment of UTIs Review new antibiotics with gram-negative activity Review treatment options for MRSA Discuss C.difficile

3 Case presentation 45 year old woman with mild asthma had rhinorrhea and nasal congestion 12 days prior to presentation. The last 3 days she has clinically worsened with headache, nasal congestion and purulent nasal secretions. NKDA

4 What is the treatment of choice for acute bacterial rhinosinusitis (ABRS)? 1. Augmentin 875 mg po bid 2. Amoxicillin 500mg po tid 3. Moxifloxacin 400 mg po qd 4. Clarithromycin 500 mg po bid 5. No antibacterials

5 Bacterial Etiology of ABRS S.pneumoniae 30-35% With 20-30% intermediate and high level resistance to penicillin H.influenzae 15-25% With 30-40% β-lactamase producers M.catarrhalis 5-10% With 99% β -lactamase producers

6 Benefit of antibiotics for therapy of acute bacterial rhinosinusitis The cumulative randomized, double-blind trials suggest that antibiotics are significantly more effective than placebo in decreasing or eliminating symptoms, but the effect is small 81% of those treated and 66% of placebo treated responded at days

7 Clinical Practice Guideline on Adult Sinusitis If a decision is made to treat ABRS with an antibiotic, the clinician should prescribe amoxicillin as first line therapy for most adults (PCN allergic macrolides) Otolaryngology-head and neck surgery 2007;137:365

8 Antibiotics and Topical Nasal Steroid for Treatment of Acute Maxillary Sinusitis Double-blind, randomized placebo controlled trial of 240 adults with acute sinusitis Randomized to: 1. Amoxicillin 500mg TID and nasal steroid 2. Nasal steroid and placebo amoxicillin 3. Amoxicillin and placebo steroids 4. Placebo amoxicillin and placebo steroids JAMA 2007;298:

9 Primary Outcome: proportions of patients with symptoms lasting 10 days Amoxicillin: 29/100 (29%) No amoxicillin: 36/107 (33.6%) Nasal steroid: 32/102 (31.4%) No nasal steroid: 33/105 (31.4%) JAMA 2007; 298:

10 Case presentation A 27 year old woman presents with acute onset of dysuria, urgency and frequency. Which antibiotic would you start? 1. Amoxicillin 2. Nitrofurantoin 3. Trimethoprim- sulfamethoxazole 4. Ciprofloxacin

11 Etiology of UTI Outpatient E.coli 75-90% Staphylococcus saprophyticus 5-15%, mainly in younger women Klebsiella, Proteus, Enterococcus Nosocomial E. coli, Klebsiella, Proteus, Enterococcus Pseudomonas, Citrobacter, Enterobacter

12 Susceptibility of E.coli Urinary Isolates North American Urinary Tract Infection Collaborative Alliance (NAUTICA) 40 medical centers (30 US/ 10 Canada) April outpatient midstream isolates 1142 isolates collected (76% US) TMP-SMX 21% resistance Ampicillin 38% resistance Ciprofloxacin 5 % Levofloxacin 5 % Nitrofurantoin 1.1% resistance Zhanel et al. Int J Antimicrob Agents 2006; 27:468

13 IDSA Guidelines: Acute Uncomplicated UTI in Women Resistance to TMP-SMX is increasing In some areas, resistance as high as 20%-30% Resistance overestimated? Selection bias of treatment failures Still useful as empiric therapy If prevalence of resistance is 20% should be considered the current standard therapy

14 TMP-SMX in Tx of Women with Uncomplicated UTI Study patients: women with clinical symptoms and pyuria, bacteriuria Urine sent for C & S TMP-SMX DS BID x 5 days Culture + patients divided to 2 groups: TMP-SMX susceptible TMP-SMX resistant Clin Infect Dis 2002; 34: 1165

15 TMP-SMX in Tx of Women with Uncomplicated UTI Overall: 29% TMP-SMX resistance; E. coli: 19% TMP-SMX resistance Microbiological cure: TMP-SMX susceptible: 82% TMP-SMX resistant: 42% Clinical cure: TMP-SMX susceptible: 88% TMP-SMX resistant: 54%

16 Antibiotics for UTIs Fluoroquinolones ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin Active against most enteric gram-negatives Achieves high urine and tissue levels Can be given for 3 days Development of resistance is concern

17 Antibiotics for UTIs Nitrofurantoin Active against E.coli (> 95%) Less active against other GNR s and no activity against Pseudomonas and Proteus High levels in urine, but no tissue penetration Should be given for 7 days Fosfomycin Active against E.coli (> 90%) Approved as single dose treatment of uncomplicated cystitis (3gm sachet dissolved in 3-4 oz of water)

18 Case (Cont) After multiple treated UTIs patient diagnosed with pyelonephritis and is admitted to the hospital. You suspect a resistant organism and order a urine culture. 48 hours later you find out it s an extendedspectrum β-lactamase (ESBL) producing E.coli

19 β-lactamases Most important mechanism of resistance to β-lactams, especially in gram-negatives Hundreds of different enzymes Extended-spectrum β-lactamases (ESBLs) MICs unpredictable Paterson D. Resistance in gram-negative bacteria: enterobacteriaceae. American J Medicine 2006;S20.

20 ESBLs: Clinical Implications Found in E.coli, Klebsiella, Proteus Prevalence increasing (3-10%) Should be considered resistant to all penicillins, cephalosporins and aztreonam Carbapenems (ertapenem, meropenem, imipenem, doripenem) are the β-lactams of choice in serious infections ESBL strains are often sensitive to pip/tazo, but few clinical data to support efficacy Paterson D. Resistance in gram-negative bacteria: enterobacteriaceae. American J Medicine 2006;S20.

21 Carbapenems Imipenem, meropenem, doripenem active vs most gram-negative pathogens (including ESBL producers) gram positive pathogens (inclulding E. faecalis, MSSA), anaerobes (as good as flagyl) Weaknesses: pseudomonas (rapid emergence of resistance to imipenem), E.faecium, MRSA, MRSE

22 Carbapenems Ertapenem does not have activity against P. aeruginosa and Acinetobacter (otherwise it approximates meropenem spectrum of activity) Once daily dosing convenient for outpatient therapy Elimination: 80% in the urine (38% unchanged drug) Dose reduction by 50% in Clcr < 30 ml/min

23 Ertapenem: FDA Indications Intra-abdominal Urinary tract infection Skin and soft tissue infection including diabetic foot infection Acute pelvic infection Community acquired pneumonia

24 Tigecycline (Tygacil) Spectrum of Activity Gram negative: active vs most aerobic gram negative pathogens, including ESBLs Less active vs Proteus, Morganella, Providencia No activity vs Pseudomonas Gram positive: active vs MRSA, MRSE, enterococcus, streptococci, VRE Anaerobes: both gram positive and gram negative

25 Tigecycline (Tygacil ) Dosing: 100 mg LD, then 50 mg Q12h Low serum levels but high tissue levels (problem in bacteremia!!) No significant drug interactions Adverse events: High rate of upper GI side effects Tetracycline-like bone and teeth deposition: contraindicated in pregnancy and children <8 yo Development of resistance

26 Tigecycline: Place in Therapy FDA indications: Complicated SSTI (equal to vancomycin/aztreonam) and intra-abdominal infection (equal to imipenem) Despite limited clinical experience, will most likely be useful in the treatment of ESBLproducing organisms and multi-drug resistant acinetobacter especially in patients with β-lactam hypersensitivity Tigecycline s lack of Pseudomonas coverage and low serum concentrations will limit its use in septic patient populations

27 MRSA: CA-MRSA vs. HA-MRSA Clinical manifestations Resistance to non-b-lactams Communityacquired SSTI uncommon Healthcareassociated Nosocomial disease common SCC mec type IV I, II, III Genotype USA300 USA100 Virulence factors ACME, PVL(?)

28 Randomized, double-blind, placebo controlled trial of cephalexin for SSTI 166 outpatient subjects comparing placebo to cephalexin at 500 mg orally qid x 7days after I&D of skin and soft tissue abscesses Primary outcome: clinical cure or failure 7 days post I&D 88% MRSA isolates (93% + PVL gene) Clinical cure rates: 90.5% in placebo (n=84) 84.1% in cephalexin (n =82) Rajendran et al. Antimicrob Agents Chemo 2007; 51:4044

29 Oral Antistaphylococcal Agents TMP- SMX Most MRSA are susceptible (~95%) One comparative clinical trial showed it was slightly less efficacious than vancomycin (Markowitz et al. Annals of Internal Medicine 1992;117:390) Not much published, most experience in minor to moderate SSTI

30 Oral Antistaphylococcal Agents Clindamycin: FDA approved for staphylococcal infections Oral dose at mg tid Excellent coverage against GAS Major issue is cross-resistance with macrolides Can use if macrolide susceptible If macrolide resistant, but clindamycin susceptible, use of clindamycin depends upon whether inducible resistance exists. Requires D test to determine if inducible resistance is present

31 Inducible Resistance to Clindamycin: the D Test Deresinski. Clin Infect Dis 2005; 40: 562)

32 Oral Antistaphylococcal Agents Minocycline > doxycycline > tetracycline 90+ % of MRSA are susceptible, limited clinical data, but equal to vancomycin in animal model. Fluoroquinolones: rapid emergence of resistance for MRSA Rifampin: rapid emergence of resistance when used alone Tetracyclines as an oral treatment option for patients with community onset skin and soft tissue infections caused by MRSA. AAC 2007;51:3298

33 Oxazolidinones Linezolid Spectrum of activity Streptococcus pneumoniae (PCN-R) Methicillin-resistant S. aureus, MSSA Methicillin-resistant S. epidermidis, MSSA Enterococcus faecalis and faecium, VRE Group A Strep PO preparation with ~ 100% oral bioavailability (available IV)

34 Linezolid Adverse Effects Adverse effects: bone marrow suppression, particularly thrombocytopenia Mild MAO inhibitor effects and risk for serotonin toxicity Postmarketing adverse events: 29 cases of serotonin toxicity in patients receiving concomitant linezolid and other agents (mostly SSRIs), 13 required intervention 72 patients receiving linezolid and SSRI/venlafaxine of which 2 had high probability of serotonin syndrome. Clin Infect Dis 2006;42:1578, Clin Infect Dis 2006;43:180

35 Linezolid Adverse Effects Mitochondrial toxicity Lactic acidosis Optic neuropathy Patient with optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, renal failure after 4 months of linezolid. Biopsy of muscle, liver, kidney all demonstrated decreased mitochondrial chain enzyme activity Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy. 2007;27:1189

36 Daptomycin (Cubicin ) Lipopeptide antibiotic Do NOT use for pneumonia Toxicity: dose-dependent myopathy at >7 D; observed in 0.2% of patients in clinical trials Spectrum: MSSA, MRSA, MRSE, E. faecalis, VRE IV administration 4 mg/kg/d for skin and soft tissue infection ( 6 mg/kg/d for endocarditis and bacteremia) with Clcr > 30 ml/min

37 Daptomycin vs Standard Therapy for Bactermia Unblinded randomized trial of daptomycin 6 mg/kg versus anti-staphylococcal penicillin (MSSA) or vancomycin (MRSA) + low dose gentamicin 120 daptomycin-treated (75% definite or possible endocarditis ) 115 comparator treated (79% definite or possible endocarditis Fowler et al. New Engl J Med. 2006;355:653

38 Summary of Results Daptomycin N=120 Comparator N=115 Success, m-itt 44.2% 41.7% Success, MSSA 44.6% 48.6% Success, MRSA 44.4% 31.8% Failure, AE 8 (7%) 17 (15%) Failure: persistent infection, relapse 19 (16%)* 11 (10%)* 6/19 dapto and 1/9 vanco treated patients had increase in MIC

39 Clostridium difficile Rate and severity of Clostridium difficile associated diarrhea may be increasing Causes: toxins A and B Risks: age, hospitalization, antibiotic exposure During last few years, more frequent, more severe disease which is more refractory to standard treatment Clin Infect Dis 2008:46;S32

40 Which of the following is the therapy of choice for C.difficile associated diarrhea? 1. Vancomycin 2. Metronidazole 3. Nitazoxanide 4. Rifaximin

41 An Epidemic, Toxin Gene Variant Strain of Clostridium difficile L. Clifford McDonald et al NEJM 353:2433, 2005 A Predominantly Clonal Multi- Institutional Outbreak of Clostridium difficile Associated Diarrhea with High Morbidity and Mortality Vivian G. Loo et al. NEJM 353: 2442, 2005 Currently available assays do not miss these strains but cannot differentiate them from non-bi/nap1 strains

42 Treatment of Clostridium difficile Initial antibiotic therapy infection Moderate disease: metronidazole PO 250 mg qid or 500 mg tid x 10d Severe disease: vancomycin po mg qid x 10d Management of CDAD Stop offending antibiotic (~20% may resolve) Avoid antiperistaltics Hand hygiene Soap and water (hand gels ineffective) Clin Infect Dis 2008:46;S32

43 Oral vancomycin vs oral metronidazole, stratified by disease severity Prospective, randomized, double-blind, placebo controlled 172 CDAD patients randomized to MET or VAN Mild CDAD cure: MET 90%, VAN 98% (p=0.36) Severe* CDAD cure: MET: 76% VAN 97% (p=0.02) * WBC> 15,000, age > 60, temp > 38.3, albumin <2.5, toxic megacolon, treatment in the ICU Zar et al. Clin Infect Dis 2007; 45: 302-7

44 Clostridium difficile Frequency of relapse (15-30% of patients) Retreat relapse with the same agent Treatment of recurrent disease (anecdotal or limited data) Probiotics Intercolonic delivery of vancomycin Immune globulin Saccharomyces boulardi Vancomycin with tapering or pulse doses

45 Clostridium difficile Investigational therapies Ramoplanin Rifaximin, rifalazil Nitazoxanide Tolevamer C.difficile vaccine

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