Zain Chagla Sea Courses Patagonia. Drug resistant infections

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1 Zain Chagla Sea Courses Patagonia Drug resistant infections

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3 Agenda Review drug resistant infections and their management How did we get here? MRSA ESBL VRE Carbapenemase Other drug resistant infections on the horizon

4 Certain interesting facts emerge from these Tables. It is clear that penicillin contains bacterioinhibitory substance which is very active towards some microbes while not affecting others. The members of the coli-typhoid group are unaffected Fleming, A Bull. World Health Organ. 79, (2001).

5 Suspension of lysed E. coli mixed with Penicillium extract Incubated with Staphylococcus aureus - instead of bacterial killing penicillin is inhibited This effect is reversed by heating the substance to 90 degrees (denaturing protein) Therefore an enzyme - penicillinase exists Abraham, E. P. & Chain, E Rev. Infect. Dis. 10, (1988).

6 The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily undergoes himself and by exposing his microbes to non-lethal quantities of the drug make them resistant. Alexander Fleming, Nobel Prize Speech 1945

7 Inducible Penicillin Resistance Growth of S. aureus in low dose penicillin leads to penicillin resistance (1942) Identification of a similar inhibitor to E. coli found and able to inhibit growth of further S. aureus First demonstration of acquired resistance to a Betalactam, only a few years after introduction of penicillin 1. Rammelkamp CH, Maxon T. Proc. Royal Soc. Exper. Biol. Med. 1942;51: Kirby WMM. Extraction of a higly potent penicillin inactivator from penicillin resistant staphylococci. Science. 1944;99:

8 History continued 1960 s-70 s - resistance elements on extrachromosomal elements, able to be transferred horizontally between bacterium - TEM/SHV-1 Often lead to use of polymyxin or aminoglycosides for these infections Rise of B-lactamases in clinical infections, development of third generation cephalosporins As with every antimicrobial, development of further resistance

9 Mandell, Douglas, and Bennett s principles and practice of infectious diseases. (Elsevier/Saunders, 2015).

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11 Methicillin Resistant Staphylococcus aureus Methicillin introduced in 1959 MRSA first described in 1960! Outbreaks amongst European / North American Hospitals Detroit in 1980 s --> MRSA seen in a group of non hospitalized marginalized individuals Two recognized pheno/genotypes HA-MRSA - affect ill patients, those with lines, more resistant, less virulent CA-MRSA - SSTI, more virulent, less resistant Risk factors - Athletes, homeless, marginalized, jails, reserves, barracks

12 MRSA

13 What does this mean PBP2a essentially negates the effects of ALL B-lactam antibiotics Ceftaroline only B-lactam specifically developed for this Therapeutic options quite limited CA-MRSA also has added virulence factors (panton valentin leukocidin) - predisposition to necrotic / purulent infections Can replace normal flora quite effectively Lots of issues with household contacts + pets becoming colonized + symptomatic Delay to effective antimicrobial therapy in some Reservoirs in rectum, nares, oropharynx make eradication difficult

14 Who to suspect MRSA Family member/contact with MRSA Recent or prolonged hospitalization Long term care Hemodialysis Incarcerated Indigenous people on reserve IVDU Homeless High level athletes - particularly in USA? Health care workers - evidence is mixed

15 Clinical manifestations

16 Basic principles - ER/Inpatient Look out for purulent infections or sepsis in high risk individuals (particularly IVDU) Always start empiric anti MRSA antibiotics Vancomycin 15-20mg/kg BID renally adjusted Daptomycin 8-12mg/kg daily renally adjusted (except pulmonary) If there is pus then drain it! Often need repeated I+D of infected sites

17 Advice when discharged into community Practice safe hand hygiene Avoid sharing anything that comes into contact with skin Undergarments Sporting / other equipment Toiletries/Shaving supplies Gym mats Risk of transmission to all household contacts Babies even within 24 hours of delivery Watch for recurrent furunculosis - warn patients to report family history to HCP

18 Basic principles - outpatient Consider in those at risk or refractory skin and soft tissue infections Drain what can be drained Consider treatment for those unwell, large abscesses, recurrent disease, non response to drainage alone Septra 2 ds PO BID Clindamycin mg PO TID (Some rate of resistance so should get culture before starting) Doxycycline 100mg PO BID Linezolid 600mg PO BID Vancomycin Delayed acting once weekly injectable (Dalbavancin etc)

19 Long term management Unfortunately a chronic issue for many Up to 60% of purulent SSTI showing up to emergency room in USA Community carriage variable depending on demographics - up to 10% in marginalized cities Using close contact swabs of low sensitivity - colonization can be intermittent Decolonization Aim to decolonize reservoir Multiple regimens described in the literature Loeb et. Al 2003 (Cochrane) - no difference in oral/topical/combination Ammerlan et al 2009 (CID) - topical mupirocin most benefit - 90% short term, 60% long term No real study if the failures do better than placebo patients

20 My decolonization protocol Day -7 Day 0 Day Figure out EVERYTHING in house that touches skin and wash it or throw it away Nasal treatment - mupirocin ointment 2% apply under nails and in nares BID x 5 days Oral treatment - Chlorhexidine MW swish and spit BID Body/Scalp treatment (Avoid face) - Chlorhexidine 2-4% body wash / shampoo OR bleach (2.63%, 1 teaspoon in 1 gallon of H20) x 7 days ALL FAMILY MEMBERS DO THIS - consider using the baths / mupirocin on dogs/cats Rewash everything from day -7

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22 Summary MRSA infections growing in prevalence Hospital and community acquired different entity (although now mixing quite a bit) Treatment options limited for inpatients and outpatients Source control a big deal - very necrotizing/pyogenic Consider family wide decolonization

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24 VRE Vancomycin resistant enterococci Colonization of those chronically hospitalized, long term care, or in settings with high prevalence of these (ex. Reservations) Very little clinical disease Some hospitals have decided against routine screening Precautions for home - good stool and hand hygiene Occasional infections - urinary tract Very low virulence - unlikely to be ill Consider doxycycline, fosfomycin For seriously ill (line infections, bacteremia) - Daptomycin/Linezolid

25 Case 2 55 year old female from Interior BC Lives on reserve, past medical history diabetes, CKD, HTN, Depression Presents with dysuria, fever, very positive urinalysis (WBC, protein, nitrates) Allergy to macrobid (Swelling/rash) Given Septra for 2 days, no response - changed to Cipro Urine culture sent

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27 What to do now?

28 What are ESBL s? Heterogenous group of enzymes derived from point mutations from original Beta-lactamases Fall into major categories either based on biochemistry or by functional activity Most are plasmid mediated but some related to chromosome These plasmids can accumulate other drug resistant elements can be transferred

29 Antimicrobial defintion Resistance to Penicillins First, second, and third generation cephalosporins Monobactams Sensitive to Cefamycins (cefoxitin) Carbapenems Reversed by Clavulinic acid (? clinically relevant) Tend to be Klebsiella sp. and E. coli, occasionally other enterobacteraciae Paterson, D. L. & Bonomo, R. A. Extended-Spectrum -Lactamases: a Clinical Update. Clinical Microbiology Reviews 18, (2005).

30 Mandell, Douglas, and Bennett s principles and practice of infectious diseases. (Elsevier/Saunders, 2015).

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32 Closely related AmpC producing organisms (aka SPICE) Have a chromosomal extended spectrum beta-lactamase that is induced in the presence of antibiotic Serratia, Providencia, Proteus vulgaris, Citrobacter, Enterobacter Carbapenemase producing organisms Hydrolyze carbapenems - two major types NDM-1, and KPC Typically related to geographical pockets

33 Paterson, D. L. & Bonomo, R. A. Extended-Spectrum -Lactamases: a Clinical Update. Clinical Microbiology Reviews 18, (2005). Epidemiology Initial outbreaks in France, Germany Now a global disease Up to 8-17% of Klebsiella from France Up to 6% in USA isolates Up to 40% of isolates from ICU from Brazil Up to 36% of Klebsiella in South Africa 5% in Australia 30% in China, 5-15% in South East Asia

34 Intraabdominal isolates 1. Hawser et al., Int J Antimicrob Agents Mar;41(3): Hawser et al., Antimicrobial agents and chemotherapy 2011:

35 Canadian epidemiology Denisiuk AJ et al. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 9-12, 2012

36 Risk factors Ostholm-Balkhed, A. et al. Travel-associated faecal colonization with ESBL-producing Enterobacteriaceae: incidence and risk factors. J. Antimicrob. Chemother. 68, (2013).

37 Clinical Manifestations The antimicrobial flora is replaced by the ESBL phenotype Think of where you typically find E. coli / Klebsiella clinically UTI Pneumonia Intraabdominal sepsis Wound infections

38 I have always stuck up for Western medicine. You can chew all the celery you want, but without antibiotics, three quarters of us would not be here. -Hugh Laurie

39 Therapeutic options Complicated Quinolone Carbapenem? Amino glycosides + TMP-SMX Uncomplicated - all of above plus TMP-SMX Fosftomycin Nitrofurantoin No change in duration of treatment other than perhaps VAP

40 Fosfomycin Old drug, used in 1970 s predominantly for gram negative infections Lost from market secondary to toxicity and better gram negative drugs out there Reformulated into orally available powder with high bioavailability and high levels in urinary tract Indication is similar to Nitrofurantoin Not covered by ODB - $30 a sachet

41 Fosfomycin Use in complicated infections is growing a number of cases reported in the literature and posters suggesting a role in ESBL prostatitis, epidymitis Likely reasonable in complicated lower tract, no data in upper tract infection Efficacy may be reduced in people with underlying hardware (stents), and possibly transplant However, with limited oral options it is a reasonable tool to try 1.Neuner, E. A.,et al. Antimicrobial Agents and Chemotherapy 56, (2012). 2. Grayson, M. L. et al. Clin. Infect. Dis. 61, (2015).

42 Patients being discharged home Part of fecal flora Need to keep this in medical records for empiric therapeutic choices particularly when ill Can be transmitted person to person Good toilet hygiene + hand hygiene Regular cleaning of bathroom Avoid sharing intimate objects

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44 Carbapenem resistance Growing trend globally Big outbreaks in India now involving middle east, Pakistan, SE Asia NDM phenotype KPC phenotype through European ICU s disseminated into North America Large outbreak at NIH in Maryland This is here to stay - consider in people who have had exposure to the medical system abroad (Ex. Hemodialysis while visiting India) Very transmissible to family (Similar to ESBL) Therapeutic options limited - Fosfomycin (IV formulation available in Europe), Colistin, Aminoglycoside, Newer cephalosporin?

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46 12% of isolates contained gene mutation for resistance

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49 Bottom Line More and more drug resistance noted VRSA, XDR TB, Fully drug resistant pseudomonas/acinetobacter, penicillin resistant Streptococcus pneumonaie Disseminating into community and acquiring virulence Now a part of global health in general Very few antimicrobials in the pipeline - pricing models will be similar to targeted chemotherapy Much more research and collaboration needed - both with medical and veterinary world

50 Summary ESBL s and carbapenemases are COMMON Consider in anyone - particularly with risk factors or travellers/from abroad For non serious infections get cultures For serious infections warn patients of their status and need for empiric drugs Drug resistance is rising and the pipeline is getting much more thin

51 Questions?