Two4 55C Infections of Urinary Tract - Sepsis, Antibiotic resistance

  1. Changing Definition of Sepsis: Sepsis-3, 2016, new vs old definition?
    Old definition

    Sepsis: Suspected Infection + ≥ 2 SIRS criteria: Temp >38°C or < 36°C, HR > 90/min, RR > 20/min. or PaCO₂ < 32 mm Hg, WBC count > 12,000/mm³, < 4,000/mm³, or > 10% bands

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    Severe sepsis  -  Sepsis  + ≥ 1 organ dysfunction

    Septic shock - Sepsis + Persistent Hypotension (SBP<90 mm Hg or MAP <70 requiring vasopressor after adequate fluid resuscitation)

    New definition: 

    Sepsis: Suspected Infection  + ≥ 2 SOFA score: PaO2/FiO2 ratio, platelets, serum bilirubin, hypotension, GCS, serum creatinine and urine output

    Severe sepsis - Catagory removed 

    Septic shock - Sepsis + Persistent Hypotension requiring vasopressors to maintain MAP> 65mmHg + Lactate level ≥ 2 mmol/L  (both after adequate fluid resuscitation)
  2. Q-SOFA score?
    • qSOFA Score include 
    • - Hypotension :SBP<100 mmHg
    • - Altered mental status (GCS score <15)
    • - Tachypnea: >22/min

    • 0 or 1 points - Not high risk, continue management as appropriate 
    • 2 or 3 points - High risk of poor outcome, access for evidence of organ dysfunction 

    —Positive qSOFA should create a suspicion of sepsis and organ dysfunction.
  3. Operationalization of Clinical Criteria Identifying Patients With Sepsis and Septic Shock - JAMA 2016
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    • 6 systems - respiratory, hepatic, neurological, renal, coagulation, cardiovascular 
    • Each system - 0-4 
    • SOFA score - 0-24
  4. Describe predisposing factors, prevention and management of urosepsis related to endourological management of nephrolithiasis. (TU 75,2+2+3)
    • Urosepsis is a consequence of urinary tract infection. Enterobacteria are the most common pathogens:
    • E. coli (52%)
    • Proteus spp.
    • Enterobacter spp.
    • Klebsiella spp.
    • P. aeruginosa
    • and Gram-positive bacteria, such as enterococci (5%)

    • Risk factors for urosepsis
    • Age (≥ 65 years (38)
    • Diabetes mellitus
    • Immune suppression (organ transplantation, chemotherapy, corticosteroid treatment, AIDS) - Candida spp., Pseudomonas spp., and coagulase-negative staphylococci are more common pathogens than in non-immunosuppressed patients
    • Nosocomial urinary tract infection acquired on a urology ward - Among patients with nosocomial urinary tract infections (UTIs) acquired on urology wards, the prevalence of urosepsis is 12%. In contrast, patients with nosocomial UTIs acquired on non-urological wards have a 2% prevalence of severe sepsis and a 0.3% prevalence of septic shock
    • Prior urological interventions
  5. What is Urosepsis?
    Urosepsis is defined as life threatening organ dysfunction caused by a dysregulated host response to infection originating from the urinary tract and/or male genital organs.
  6. Pathophysiology of urosepsis?
    • In infection, bacteria or bacterial cell wall components act as pathogen-associated molecular patterns (PAMP) that bind to pattern-recognition receptors (PRR) on the surface of macrophages, neutrophils, and endothelial or urothelial cells.
    • Infection activates the complement system and the native immune system, leading to a massive initial pro-inflammatory response
  7. Treatment of urosepsis
    • In general, there are three categories of treatment for urosepsis:
    • - Cause-directed (antibiotic treatment and elimination of foci of infection)
    • - Supportive (hemodynamic and pulmonary stabilization)
    • - Adjunctive (glucocorticoid and insulin treatment)
  8. Cause-directed management of urosepsis?
    • - Antibiotic treatment should be begun as soon as possible (within an hour) after diagnosis, but only after blood and urine cultures have been obtained (recommendation grade B, evidence level Ic). The antibiotic(s) should be chosen in the light of local resistance rates and the expected pathogen spectrum. In view of the presence of capillary leakage leading to edema formation and lower volumes of distribution, as well as increased clearance because of the hyperdynamic circulatory situation or low clearance rates because of multiple organ dysfunction, antibiotics should generally be given initially at high doses, which are reduced later on in the course of treatment.
    • - Source localization – Microbiology, Imaging- Bedside USG (preferred), CT KUB
    • - Elimination of foci of infection - infected kidney above an obstruction is managed by internal ureteral stenting or percutaneous nephrostomy. Urosepsis due to a high residual urine volume or acute urinary retention (even without pyuria) is best treated with a transurethral bladder catheter. Abscesses or infected lymphoceles requiring treatment can be drained with a pigtail catheter inserted under ultrasonographic (or other radiological) guidance. Bowel Injury- Debridement, diversion
  9. Supportive (hemodynamic and pulmonary stabilization) in urosepsis?
    Based on Early Goal Directed Therapy (EGDT) 2018. 

    Within 6 hours of presentation to the Emergency Department intensive monitoring of specific circulatory parameters with the aggressive management of 5 key parameters to specified targets. Hemodynamic stabilization promotes the delivery of an adequate oxygen supply to the tissues.

    • Parameters
    • CVP  8-12 mmHg
    • MAP 65 – 90 mmHg
    • Urine output >0.5 ml/kg/hr
    • Mixed venous oxygen saturation >65% / Central venous oxygen saturation (ScvO2) >70%
    • Haematocrit >30%

    • Interventions
    • Reduce work of breathing by early use of mechanical ventilation at low tidal volumes (6 mL/kg of body weight) and peak pressures no higher than 30 mbar, whenever adequate oxygenation (>90% by pulse oximetry) cannot be achieved by hemodynamic stabilization and mask oxygen administration alone
    • Fluid resuscitation - isotonic crystalloid solution should be begun within 15 minutes, with the goal of adminstering at least 30 mL/kg of body weight in the first hour (proceed with caution in case of congestive heart failure).
    • Apply vasopressors if patient is hypotensive during or after fluid resuscitation to maintain MAP >65mmHg. Norepinephrine is the vasopressor drug of first choice. If the cardiac output is low despite volume therapy, the positive inotrope dobutamine (20 μg/kg/min) is the catecholamine of the first choice.
    • Once tissue perfusion is normal, and in the absence of coronary heart disease, anaemia with haemoglobin values under 7 g/dL should be treated with erythrocyte concentrate transfusion.

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  10. Give an outline of surviving sepsis campaign. (TU 75,3) 

    Management of urosepsis : Hour-1 Surviving Sepsis Campaign Bundle of Care 2018 Update?
    • 1. Measure lactate level - Remeasure if initial lactate is >2 mmol/L within 2-4 hours to guide resuscitation
    • 2. Blood and urine culture - Take a urine culture and two sets of blood cultures before starting antimicrobial treatment.  If catheter >2 weeks, replace catheter and send urine CS. 
    • 3. Antibiotics-Broad spectrum 
    • 4. Begin rapid administration of 30ml/kg crystalloid for hypotension or lactate ≥4 mmol/L - to be given within the first 3 hours/ ? first one hour 
    • 5.Vasopressors - Apply vasopressors if patient is hypotensive during or after fluid resuscitation to maintain MAP >65mmHg
  11. Adjunctive therapy in urosepsis?
    • - Only in septic shock with treatment-resistant hypotension despite vasopressor administration and volume substitution can the administration of hydrocortisone (200 mg/d) be considered as a last resort
    • - glycemic target should be set between 110 mg/dL and 180 mg/dL, with regular blood sugar measurement every 1 to 2 hours
  12. Mechanism of antibiotic resistance in gram-negative bacteria?
    • Mechanism of intrinsic resistance
    • 1.Impermeability - Influx(entry) of antibiotics through the cell wall depends on the chemical nature of the antibiotic and the structural characteristics of the cell wall
    • - gram-negative bacteria are intrinsic resistance to vancomycin bacause their outer membrane protein(porin) is impermeable to large, rigid, and hydrophobic glycopeptide molecule of vancomycin
    • - Pseudomonas aeruginosa is intrinsically resistant to β-lactams, β-lactam inhibitors, sulfonamides, trimethoprim, tetracycline, and chloramphenicol due to impermeable OMP.

    2. Biofilm - decreased penetration of antibiotics into the physical or chemical barriers of biofilm

    3.Efflux pump - transporter proteins for the extrusion of toxic substances and antibiotics from the interior of the cell to the external environment

    • 4.Enzymatic inactivation
    • - β-Lactamases

    Mechanism of acquired resistance

    1.Efflux - Although efflux plays a major role in intrinsic resistance, changes in these cell wall proteins can also result in novel acquired traits

    • 2.Target site modification - Modification of a target can reduce the binding affinity of the antibiotic to the target. Modification of target sites occurs primarily by chromosomal mutation, and enzymatic alteration of target sites
    • A. Chromosomal mutation:
    • - Quinolones target DNA gyrase and topoisomerase IV, inhibit DNA synthesis. Mutation in GyrA and ParC gene result in DNA topoisomerases that have low affinity to quinolones.
    • - β-Lactam antibiotics kill S. pneumoniae by targeting endogenous high-molecular-weight PBPs :-PBP1A, -1B, -2A, -2B, and -2X. Mutations in these PBPs lead to alteration of PBPs, which result in reducing affinity to β-lactam antibiotics.
    • B. Enzymatic alteration of target site

    3.Acquisition of new target site

    • 4. Enzymatic inactivation and destruction of drugs
    • - Class A β-lactamases are primarily penicillinases produced by gramnegative and gram-positive bacteria capable of hydrolyzing penicillin class antibiotic substrates
    • - ESBLs can hydrolyze specific sets of penicillins, cephalosporins, and monobactams, although not all ESBLs are capable of hydrolyzing all cephalosporins equally well.

    5. Adaptation of alternative metabolic pathway

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  13. Common resistant Pathogens
    • ESCAPE 
    • Enterococcus fecium 
    • Staph aureus 
    • Clostridium difficile 
    • Acinatobacter 
    • Pseudomonas auriginosa 
    • Enterobacteriaceae
  14. Multidrug resistant bugs and their treatment
    MRSA methicillin-resistant Staphylococcus aureus (MRSA) Vancomycin

    WHO priority list of antibiotic resistant bacteria - 2017 

    ESBL (Extended Spectrum Beta Lactamase)  - Carbapeneme 

    CRE-KPC (Carbpenam Resistant Enterococci - Klebsiella pneumoniae carbapenemase) - Ceftazidime avibactam 

    CRE MBL(Carbpenam Resistant Enterococci - Metallobeta Lactamase) - Aztreonam 

    CRAB (Carbapenem Resistant Acinetobacter Baumanni)  - Polymyxin 

    CRPA (Carbapenem Resistant Pseudomonas Aeruginosa)- Ceftazidime avibactam
  15. Cefiderocol
    • Also called trojon horse 
    • Activity against CRE and CRPA
  16. Polymyxin B Vs Colistin (Polymyxin E), which is preferred in urinary tract infection?
    • Colistin is preferred, nephrotoxicity 
    • Loading dose - 9 millions IU infused over 1 hour
    • Maintainence dose - 9-10.9 IU in 2 divided doses, every 12 hour over 1 hour 
    • Needs renal adjustment 

    • Polymyxin B 
    • Loading dose - 2-2.5mg/kg 
    • Maintainence dose - 1.25-1.5 mg/kg 
    • Dose maintainence is not required, even if patient has renal impairment
  17. Fosfomycin?
    For uncomplicated cystis, re-emerged drug
  18. Imipenem?
    • Imipenem/cilastatin - 500mg/500mg - 500mg of Imipenam every 6 hourly
    • Imipenem inhibits cell wall synthesis by binding with penicillin-binding proteins 
    • Cilastatin prevents renal metabolism of imipenem
    • Meropenem is more stable with renal enzymes, need not be co-administered with cilastatin
  19. Anitbiotic stewardship?
    Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms
  20. Antibiotic prophylaxis?
    • Cystoscopy -
    • Neither EAU or AUA recommends antimicrobial prophylaxis for routine diagnostic cystoscopy in the absence of patient-related risk factors. The AUA recommends prophylaxis lasting less than 24 hours for therapeutic lower urinary tract procedures such as transurethral resection of the bladder and prostate.

    • Risk factors that require antibiotics (EAU)
    • Older age
    • Diabetes mellitus
    • Impaired immune system
    • Malnutrition
    • Extreme weight
    • History of urinary tract infectionVIndwelling
    • catheters/bacterial burden
    • Previous instrumentation
    • Genetic factors

    The AUA recommends either a fluoroquinolone or  trimethoprimsulfamethoxazole as the prophylactic agent of choice. Alternative agents include an aminoglycoside with or without ampicillin, a first- or second-generation cephalosporin, or amoxicillin/clavulanate .

    • Ureteroscopy - 
    • According to the AUA Best Practice Policy Statement, all patients undergoing upper-tract endoscopy should receive antibiotic prophylaxis. Agents of choice include a fluoroquinolone or trimethoprim-sulfamethoxazole with an aminoglycoside plus or minus ampicillin; a first- or second-generation cephalosporin; or amoxicillin/clavulanate
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Two4 55C Infections of Urinary Tract - Sepsis, Antibiotic resistance