Multidrug resistant bacteria in critically ill patients

1. Multidrug resistant bacteria in critically ill patients Rania M Ali Ass. Professor of Anesthesia, intensive care and pain management Faculty of medicine Ain Shams university

2. A 66-year-old man (BW, 100 kg; BMI, 35) was admitted to the ICU for septic shock following gastric perforation PCT and CRP were elevated and cultures from the drainage fluid showed Klebsiella ESBL which was sensitive only to meropenem and Imipenem and Acinetobacter which was sensitive only to colistin

3. A blood culture was withdrawn on day 4 and its results was negative After treatment with meropenem (1 g every 8 h) and colistin (3 × 106 IU every 8h) for 7days, the patient clinically improved so antibiotic was discontinued

4. Four days later the patient's clinical and hemodynamic condition worsened and become feverish. Both TLC and CRP were elevated again Treatment was changed to Imipenem high dose 1gm/6hr extended infusion over 3 hrs and Colistin high dose loading 9 ml and maintenance 4-5 ml/12hr

5. Four days later the patient's clinical and hemodynamic condition worsened and become feverish. Both TLC and CRP were elevated again Treatment was changed to Imipenem high dose 1gm/6hr extended infusion over 3 hrs and Colistin high dose loading 9 ml and maintenance 4-5 ml/12hr

6. The patient's clinical status improved, vasopressors could be stopped, and inflammatory parameters decreased. He was treated for 12 days and finally returned home at day 48 with no further antimicrobial treatment

7. Is antibiotic resistance truly a serious health threat? Should you stop antibiotics if symptoms resolve? How to monitor the response antibiotics to ensure that patients are treated adequately and infection relapses are prevented?

8. ICU patients are particularly likely to develop infection • infection is a reason for admission • immunosuppression associated with critical illness • large number of invasive devices used in these patients • Correct and adequate antibiotic coverage is essential but can be complex • delayed identification of microorganisms • the impact of critical illness and therapy on PK and PD of antibiotics • the high prevalence of antibiotic-resistant strains

9. Multidrug-resistant pathogens • (ESKAPE) pathogens account for more than 80 % of infectious episodes in the ICU • E. Faecium • S. Aureus • K. Pneumoniae • A. Baumannii • P. aeruginosa • Enterobacter spp.

10. Multidrug-resistant pathogens • “ESCAPE” • E. Faecium • S. Aureus • C. difficile • A. baumannii • P. aeruginosa • Enterobacteriaceae spp. • Incorporate not only Enterobacter spp. but also other Enterobacteriaceaespp. (namely, Escherichia coli and Proteus spp.) • Because of the increasing levels of antibiotic resistance (including extended-spectrum β-lactamases, carbapenemases and aminoglycoside resistance) and decreasing levels of fluoroquinolone susceptibility among these organisms

12. Diagnosis • Typical clinical signs of infection, such as fever or  WBC count (non-specific) • Many biomarkers, e.g., CRP and procalcitonin (PCT) (non-specific) • Culture-based techniques • Take several days for a positive result to be available • In patients already receiving antibiotics, cultures may be negative • PCR and mass spectrometry with or without electrospray ionization are more rapid microbiological identification methods

13. Antibiotic stewardship (AMS) and infection control strategies • Aim • Provide assistance with • In order to • Optimal choice • Dosage • PK/PD characteristics • Duration of antibiotics  costs  adverse events  development of resistance

14. The adaptation to Standard 1-hour bundle in patients with sepsis or septic shock sustained by MDR infections The evidence-based guidelines of the Surviving Sepsis Campaign in 2018

15. Biomarkers, such as CRP and the procalcitonin • Unlike CRP, procalcitonin is more specific to bacterial infections • Use of the procalcitonin-guided algorithm has been shown to reduce the duration of exposure to antibiotics by ≤25%

16. Using Procalcitonin to Guide Antibiotic Therapy • If PCT levels do not decline despite therapy, consider treatment failure (e.g., inadequate antibiotic therapy or source control) • PCT algorithms apply to patients with clinically confirmed infections as well as those in whom infection was never proven • PCT algorithms can be used as a clinical decision aid but should never override clinical judgment

17. Rapid methods to diagnose multidrug resistance • One of the key aspects of avoiding the spread of resistant strains is early detection • traditional culture-plate methods  4days • immunocapture-coupled PCR (qMRSA)  1day • Carbapenemase-producing organisms (CROs) • Colistin-resistant isolates • Microdilution are time-consuming • Chromogenic agar  16 h less

18. Rapid methods to diagnose multidrug resistance • Blood culture • Matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF MS)

19. This spreading antibiotic resistance is not matched by development of equally effective antibiotics This demands for effective utilization of old antibiotics that are possibly active against multidrug and extremely drug resistant (MDR and XDR) bacteria

21. International health organizations • The European Centre for disease prevention and control (ECDC) • The Centers for Disease Control and Prevention (CDC) • Use these terms to highlight the rapid emergence and spread of antibiotic resistance “Crisis” “Catastrophic consequences” “Nightmare scenario”

22. MDR have been divided depending on their resistance profile • Multidrug-resistant organisms (MDR) • non-susceptible to at least 1 agent in 3 antimicrobial categories • Extensively drug-resistant (XDR) • non-susceptible to at least 1 agent in all but 2 or fewer antimicrobial categories • Pan-drug-resistant (PDR) • non-susceptible to all agents in all antimicrobial categories

23. Staphylococcus aureus; antimicrobial categories and agents used to define MDR, XDR and PDR MRSA is always considered MDR by virtue of being an MRSA

24. Enterococcus spp.; antimicrobial categories and agents used to define MDR, XDR and PDR When a species has intrinsic resistance to an antimicrobial category, that category must be removed from the list in this table prior to applying the criteria for the definitions

25. Enterobacteriaceae; antimicrobial categories and agents used to define MDR, XDR and PDR

26. Enterobacteriaceae; cont.

27. Pseudomonas aeruginosa; antimicrobial categories and agents used to define MDR, XDR and PDR

28. Acinetobacter spp.; antimicrobial categories and agents used to define MDR, XDR and PDR

29. Pseudomonas aeruginosa; examples of antimicrobial susceptibility profiles

31. Polymyxins (including colistin) • Reserve intravenous colistin for infections due to polymyxin-susceptible multiresistant bacteria and preferably use in combination with other agents • Give careful consideration to use of higher dosage regimens in critically ill patients

32. Polymyxins (including colistin) • To treat susceptible KPC-producing Klebsiella spp • If the meropenem MIC is ≤ 8 mg/L  Use colistin with meropenem • If the meropenem MIC is > 8 and ≤ 32 mg/L  consider higher meropenem dose by continuous infusion • If the meropenem MIC > 32 mg/L  Consider colistin with aminoglycosides or tigecycline in infections with strains producing KPC or other carbapenemases, which are susceptible to these

33. Polymyxins (including colistin) • Closely monitor renal function • Elderly • Those receiving high intravenous doses for prolonged periods • Those on concomitant nephrotoxic agents, e.g. Aminoglycosides

34. Polymyxins (including colistin) • Standard dose: 2MU q8h • Evidence is emerging that higher-dose regimens may be more appropriate in the ICU setting (with therapeutic drug monitoring: to target a peak of 5–15mg/L and a trough of 2–6mg/L)

35. In life-threatening infections caused by Gram-negative bacteria susceptible only to colistin, a loading dose of 9MU followed by 4.5MU q12h (reduced in renal impairment) was effective (23/28 responses) and resulted in a reversible mild renal injury in only five patients

37. Imipenem and meropenem • Use meropenem or imipenem or ertapenem to treat serious infections with ESBL and AmpC- producing Enterobacteriaceae • Apply antibiotic stewardship to use of all carbapenems to minimize the risk of developing resistance either by acquisition of carbapenemase-producing strains or, with ertapenem, by porin loss • Do not use imipenem to treat susceptible Pseudomonas infections

38. Imipenem and meropenem • Test all meropenem- or imipenem- resistant isolates of Enterobacteriaceae immediately for the precise level of resistance and for an indication of the responsible class of carbapenemase • Submit to agreed reference laboratories to determine susceptibility to a wide range of potentially active agents, including, as appropriate, colistin, ceftazidime/avibactam, temocillin, aminoglycosides, fosfomycin and tigecycline • Consider use of continuous infusion meropenem in combination at dose determined by nomogram if infection with KPC carbapenemase-producing Klebsiella with MIC of > 8 and < 64mg/L.

39. Time-dependent antibiotics • Exhibit maximum bactericidal activity when unbound concentrations of the drug exceed the minimum inhibitory concentration (MIC) of the bacterial pathogen • The main classes of antibiotics in this group include • β-lactams (penicillins, cephalosporins, carbapenems, monobactams) • lincosamides (clindamycin and lincomycin)

40. Prolonged infusions of beta-lactam antibiotics Beta-lactam antibiotics demonstrate a time-dependent effect on bacterial eradication Prolonged infusion administration strategy may improve microbiologic and clinical cure, especially when pathogens demonstrate higher minimum inhibitory concentrations (MIC) Continuous infusion (over the entire dosing interval) or an extended infusion (over 2 to 4 hours).