Antimicrobial Update

Vicky Dudas, Pharm.D.Associate Clinical Professor of Pharmacy

Director, Antimicrobial Management ProgramUCSF Medical Center

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

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

What is the treatment of choice for acute bacterial rhinosinusitis (ABRS)?

1. Augmentin 875 mg po bid2. Amoxicillin 500mg po tid3. Moxifloxacin 400 mg po qd4. Clarithromycin 500 mg po bid 5. No antibacterials

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

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 10-14 days

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

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 steroid2. Nasal steroid and placebo amoxicillin3. Amoxicillin and placebo steroids4. Placebo amoxicillin and placebo steroidsJAMA 2007;298:2487-2496

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; 298:2487-96

Case presentation

A 27 year old woman presents with acute onset of dysuria, urgency and frequency. Which antibiotic would you start?

1. Amoxicillin2. Nitrofurantoin3. Trimethoprim- sulfamethoxazole4. Ciprofloxacin

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

Susceptibility of E.coli Urinary Isolates

• North American Urinary Tract Infection Collaborative Alliance (NAUTICA) – 40 medical centers (30 US/ 10 Canada)

• April 2003-2004 – 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

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

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

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%

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

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)

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 extended- spectrum β-lactamase (ESBL) producing E.coli

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.

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.

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

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

Ertapenem: FDA Indications

• Intra-abdominal• Urinary tract infection• Skin and soft tissue infection including

diabetic foot infection• Acute pelvic infection• Community acquired pneumonia

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

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

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 ESBL- producing 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

MRSA: CA-MRSA vs. HA-MRSACommunity-

acquiredHealthcare- associated

Clinical manifestations

SSTI Nosocomial disease

Resistance to non-B-lactams

uncommon common

SCC mec type IV I, II, IIIGenotype USA300 USA100Virulence factors

ACME, PVL(?)

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

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

Oral Antistaphylococcal Agents

• Clindamycin:– FDA approved for staphylococcal infections– Oral dose at 300-450 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

Inducible Resistance to Clindamycin: the “D” Test

Deresinski. Clin Infect Dis 2005; 40: 562)

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

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)

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

Linezolid Adverse EffectsMitochondrial 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

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

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 endocarditisFowler et al. New Engl J Med. 2006;355:653

Summary of ResultsDaptomycinN=120

ComparatorN=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

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

Which of the following is the therapy of choice for C.difficile associated diarrhea?

1. Vancomycin2. Metronidazole3. Nitazoxanide4. Rifaximin

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

Treatment of Clostridium difficile infection

• Initial antibiotic therapy– Moderate disease: metronidazole PO 250 mg qid or 500

mg tid x 10d – Severe disease: vancomycin po 125-500 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

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 ICUZar et al. Clin Infect Dis 2007; 45: 302-7

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

Clostridium difficile

• Investigational therapies– Ramoplanin– Rifaximin, rifalazil– Nitazoxanide– Tolevamer– C.difficile vaccine