Umayya Musharrafieh, MDAmerican University of Beirut Medical Center

10th Annual Family Medicine Conference October 14-16, 2011

Management of ESBL Urine Infection in Primary Care

Learning Objectives

• Expected to understand ESBL and appreciate their importance

• Understand the changing epidemiology of ESBL and how this affects patient therapy

• Know the available treatment options and optimize their use

• In March 1942, a 33-year-old woman lay dying ofstreptococcal sepsis in a New Haven, Connecticut, hospital,and despite the best efforts of contemporary medical science,her doctors could not eradicate her bloodstream infection

• Then they managed to obtain a small amount of a newlydiscovered substance called penicillin, which they cautiouslyinjected into her. After repeated doses, her bloodstream wascleared of streptococci, she made a full recovery, and shewent on to live to the age of 90

Sixty-six years after her startling recovery, a report described a 70-year-old man in San Francisco with endocarditis caused by vancomycin-resistant Enterococcus faecium (VRE)

Despite the administration, for many days, of the best antibiotics available for combating VRE, physicians were unable to sterilize the patient’s blood, and he died still bacteremic

Bad Bugs, No Drugs, No ESKAPE

Our Case • A 55-year-old woman with a history of flank pain started with symptoms of

cystitis of 10 days duration.

• Symptoms : fever, urgency, frequency and dysuria, without haematuria, flank pain and tenesmus. Recently returned from India. She was started on oral ciprofloxacin, 500 mg twice daily

• PE: febrile reaching 38deg,• Abdominal examination showed mild suprapubic

tenderness, mild CVA tenderness U/A : pyuria and occult haematuria, positive for nitrites.

Ultrasound : slightly enlarged rt kidney Urine culture: A prior had grown >108 cfu/L , E. coli with an ESBL phenotype

What are Extended Spectrum ß-Lactamases “ESBL” ?• The ESBL enzymes are plasmid - mediated enzymes produced by bacteria

• Breakdown the ß-lactam ring and inactivate a wide variety of ß- lactams, including 3rd

GC, penicillins and aztreonam.

• Caused by mutations of TEM-1 and TEM-2 and SHV-I

• Widespread use of 3rd GC and aztreonam is believed to be the major cause of the mutations in these enzymes

• They mediate R to cefotaxime, ceftazidime and other broad spectrum cephalosporins and to monobactams such as aztreonam,

• Have no detectable activity against cephamycins and imipenem and are inhibited by ß-lactamase inhibitors such as clavulanic acid

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Why are ESBLs a problem?

• Confer resistance to penicilins, cephalosporins and penicillinase inhibitors

• Co-resistance: harbor resistance genes to non-beta lactamslike Fluoro-quinolones, TMSMX ,tetracyclines , chloramphenicole, and aminoglycosides

• Spread to most common E.coli and klebsiella

• Problems in identification: ESBL isolates may appear susceptible to 3rd GC in vitro. However, RX of an ESBL-producing organism with 3rd GC may result in clinical failure

Clinical impact of infections owing to ESBLs

• ESBL-producing E. coli is an important cause of bacteraemiain hospitalized and non-hospitalized patients

• Inadequate initial antimicrobial therapy, may increase the rates of treatment failure and death

• ESBL-mediated resistance is not always obvious in vitro to all cephalosporins.

• Patients with bacteraemia episodes caused by ESBL-producers had higher mortality, morbidity and health associated costs

• longer duration hospital stay, and more admission to intensive care units

Traditional view and literature Who are predisposed to ESBLs?• Hospitalized patients,• ICU patients• Prolonged stays • Medical interventions • Nursing homes

ESBL in the community

• First became a problem in Canada, Spain and the United Kingdom

• While many “community-acquired” cases were actually from residential care homes or recently hospitalised patients, some were truly from the community

The Changing Epidemiology of Infections due to Enterobacteriaceae that Produce ESBLs: from hospital to community :

• Year 2000: identification of infections caused by bacteria harboring ESBLs in community dwellers

• These are typically UTIs caused by E. coli expressing CTX-M and R to quinolones, aminoglycosides, and sulfonamides

• In the Calgary, Canada, the clonal spread of two closely related strains harboring CTX-M-14, isolated most often from urine samples

• Later several types of ESBL (CTX-M) in UK , Italy Portugal and Spain were increasingly appearing in the community

J Clin Microbiol  2004 Mar;42(3):1089‐94.

Multivariate analysis of factors associated with increased risk of community-acquired infection due to ESBLEC

Risk factors of infections owing to extended-spectrum ß-lactamase-producing E. coli

• contact with healthcare centers (recent hospitalization, residence in a long-term care facility, catherization)

• recent use of antimicrobial agents (including aminopenicillins, cephalosporins, and fluoroquinolones

• recurrent UTIs and previous invasive procedures of the urinary tract

• presence of co- morbidities (older age, DM, etc).

• age at least 65 years old

• male sex

Risk factors of infections owing to extended-spectrum ß-lactamase-producing E. coli

• use of ß-lactam antibiotic in the preceding 3 months

• prostatic disease were found to be associated with ESBL-producing

• At least one overseas visit

• travellers to India

• No obvious risk factors

• Hematological malignancies

• Mechanical ventilation

What is the next step in management of our case?

• She was completing a 7 day course of oral ciprofloxacin, 250 mg twice daily. Her symptoms were not improving . Why?

• Looking back at the antibiogram revealed Intermediate sensitivity to Amoxicillin/clavulanic acid and susceptibility to Trimethoprin/sulfa

•

• Shall we start the patient on Trimethoprin/sulfa and , why if yes or no?

In vitro versus In vivo

• ESBL producing organisms produce more than one beta-lactamase in different amount. Hyperproducing strains may produce enough beta-lactamase to overcome the effect of the inhibitor

• Innoculum effect

• Beta-lactams need to traverse outer membrane proteins through porin channels in order to reach the PBP.

• Organisms such as K. pneumoniae may become deficient in these crucial outer membrane proteins

Treatment of infections caused by ESBL Enterobactariaceae

• Antimicrobials that are regularly used for empirical therapy are often not effective against ESBL –producing bacteria

• Challenge of choosing empiric RX and

• Empirical choices should be individualized based on institutional antibiograms that differ from hospital to hospital and city to city

• Carbapenems are the drug of choice : potential draw backs (cost, parenteral route, and selection for resistance)

Susceptibility of Enterobactaracea that produce ESBL • The CLSI from USA recommends that ESBL-

producing E.coli , k.pneumonia , k.oxytoca , P.mirabilis should be reported as resistant to penicillins , cephalosporins and monobactams regardless of data

• A frequent co-expression of resistance to classes other than beta-lactams (FQ, Aminoglycosides, cotrimoxazol & tetracycline) by these organisms

Outpatient parenteral antibiotic therapy (OPAT)• Management of systemically stable patients in hospital setting may

give rise to cross infection, escalated cost and increased morbidity

• Use of parenteral antimicrobial agents, which can effectively be administered in an OPAT, can minimize a lot of these problems and improve patient compliance and quality of life

• Availability of intravenous antibiotics like ertapenem and aminoglycosides (such as gentamicin) which can be administered once daily has given greater options in an OPAT setting

Tice AD. J Antimicrob Chemother 2004;53:83-6.

β-Lactam/β-Lactamase Inhibitor Combinations

• β-lactam inhibitors, such as sulbactam, clavulanate, and tazobactam, have variable inhibitory activity against ESBL enzymes

• Amoxicillin-clavulanic acid can be given in uncomplicated cystitis (consider high dose: 1gm PO TID for 5 days)

• Tazobactam, can be used for UTIs who need to be admitted pending cultures (in low inoculums and in urine)

Aminoglycosides (AG)

• No role in simple uncomplicated cystitis• In more complicated urinary infections can start

with 3GC plus an aminoglycoside (Amikacin) pending cultures and sensitivites

• Once recover ESBL , there is a need to shift to Carbapenems

Fluoroquinolones

• Resistance to FQ has reached immense in ESBL producing Enterobacteriaceae with rates of R ranging from 55% to 100%

• Limited role in treating infection caused by ESBL

• No more an option for uncomplicated cystitis

Cephalosporins

• No role in uncomplicated cystitis • Can be used along with Aminoglycosides in less sick

patients pending cultures

• Use of cephalosporins, including cephamycins and cefepime, is associated with a worse outcome compared with the use of carbapenems, despite apparent in vitro susceptibility

• Cephalosporins are therefore not recommended in patients with suspected or confirmed infections with ESBL-producing organisms

Nitrofurantoin• Nitrofurantoin is restricted to Rx or prevention of un-complicated cystitis; and is an

option for the Rx of uncomplicated UTI due to ESBL –producing bacteria

• For uncomplicated cystitis Nitrofurantoin can be used ( 100mg PO BID for 5 days)

• No role for complicated UTIs

• Because responses to this agent is less satisfactory and require longer courses of therapy, nitrofurantoin is considered to be an alternative rather than a 1st line therapeutic agent for this clinical syndrome

• Co-resistance between nitrofurantoin and fluoroquinolones in urinary isolates of E coli has also been noted

Clin microbiol infect 2008 ;14 supp. 1: 198-202

Fosfomycin

• Bactericidal antibacterial agent that continues to be active against most common uro-pathogens with very low incidence of resistantE .coli

• In one study resistance rate of ESBL-positive E.coli to fosfomycine was 0.3% vs. ESBL-positive K.pneumonia 7.2%

• Has become first choice for uncomplicated cystitis (3gm single dose)

• Low level of cross-resistance –not plasmid mediated

• It remains a viable option for treating UTIs due to ESBL –producing bacteria (1sachet QOD for one week, 1 sachet Q 2days for one week and then 1sachet /wk for 3 weeks

Antimicrob Agents Chemother 2007;51(4): 1281-6• Antimicrob Agents Chemother 2006;57(4):712-7

Carbapenems

• Carbapenems are the drug of choice against serious infections and ESBL

• For serious infections RX with carbapenemscan decrease mortality in hospitalized patients

• For outside patient management and stable patients can use Ertapenem which can be given IM 1 gm daily

Spread of OXA-48-mediated resistance to carbapenems in Lebanese Klebsiella

pneumoniae and Escherichia coli that produce extended spectrum β-lactamase

Matar, G. ; Dandache, I.; Carrër, A; Khairallah, M.-T.; Nordmann, P; Sabra, A ; Araj, G. F.

Annals of Tropical Mdicine and ParasitologyVolume 104, Number 3, April 2010 , pp, . 271-274(4)

Conclusion

• In uncomplicated UTIs nitrofurantoin, and Amoxcicllin /clavulanate are becoming drug of choice

• Highresistance to sulfa drugs and quinolones

• In less sick patients with urinary infections can use 3GC +AG, or Tazobactam pending cultures

• Carbapenems remain the drug of choice for documented ESBL

BIG CHALLENGE