Urinary tract infection sepsis ANTIBIOTICS

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1. TREATMENT OF URINARY TRACT INFECTION Presenter: Dr. JAHANGIR

2. Treatment ANTIBIOTICS COMMONLY USED IN UROLOGY Source control Management of Sepsis

3. Introduction: definitions Urinary tract infections (UTI) symptomatic urothelial inflammation secondary to bacterial adhesion and internalization with in the urinary tract - Symptoms: frequency, urgency, dysuria, suprapubic pain/pressure, fever, flank pain -Positive urine culture: > 10 5 CFU/ml or >10 2 cfu/ml VS. Asymptomatic bacteriuria Two consecutive midstream urine specimens with isolation of the same bacterial strain in quantitative counts ≥ 10 5 CFU/ml Absence of symptoms

4. Pyuria is the presence of white blood cells (WBCs) in the urine,is generally indicative of infection and/or an inflamatory response of the urothelium to the bacterium,stones , or other indwelling foreign body. Bacteriuria without pyuria is generally indicative of bacterial colonization without infection of the urinary tract. Pyuria without bacteriuria warrants evaluation for tuberculosis, stones, or cancer.

5. Classification of urinary tract infections Anatomical - Lower: bladder &/or urethra “CYSTITIS” - Upper : kidney &/or ureters “PYELONEPHRITIS” Degree of complexity - Uncomplicated describes an infection in a healthy patient with a structurally and functionally normal urinary tract. - complicated infection is associated with factors that increase the chance of acquiring bacteria and decrease the efficacy of therapy . The urinary tract is structurally or functionally abnormal, the host is compromised, and/or the bacteria have increased virulence or antimicrobial resistance.

6. Complicated UTI General Male gender Children Diabetes mellitus Pregnancy Immunosuppression Renal insufficiency Neurologic disease or injury Urological Nosocomial UTI Foreign body (indwelling catheter or bladder /renal calculi) Anatomical abnormalities Polycystic or medullary sponge kidney Diverticuli Vesicoureteric reflux Ureteral or urethral obstruction Renal artery stenosis or thrombosis Voiding Dysfunction Surgery of the urinary tract Antimicrobial resistance

7. UTIs may also be defned by their relationship to other UTIs: Isolated - UTI: an interval of at least 6 months between infections. Recurrent – UTI: 2 culture proven infections within 6 months or ≥ 3 culture proven infection within 12 months. Recurrent UTI may be due to -Re-infection (i.e. infection by different bacteria, negative culture b/w infection or infection occurs >2 weeks after successful treatment) -persistence (recurrence of infection within 2 weeks of treatment by the same organism originating from a focus within the urinary tract).

8. Pathogenesis Route of infection Ascending infection ( From extra urinary sources such as distal gut or veginal epithelium) Hematogenous spread ( uncommon, but is seen with staphylococcus aureus, candida & mycobacterium tuberculosis) Lymphatogenous spread Direct extension from other organs (intraperitoneal abscesses, or vesicointestinal or vesicovaginal fistulas, Relapsing infection from an inadequately treated focus in the prostate or kidney may seed other parts of the urinary tracts). Host factors Bacterial pathogenic factors

9. Diagnosis History and physical exam Laboratory testing Urinalysis : - E & N can be detected by a urine dipstick and are more reliable when the bacterial count is >100,000 colony-forming units (CFU)/ml - Microscopic examination of the urine for WBCs & bacteria is performed after centrifugation. When bacteria counts are >100,000 CFU/ mL. >3 WBCs/HPF suggests a possible infection .

10. Diagnosis Lab testing con’t -Urine C/S (Gold standard) Obtain prior to initiation of empiric therapy if -atypical symptoms -negative urinalysis -recent antibiotic use -complicated ≥ 10 5 cfu /ml urine is the classic definition of a positive urine culture ≥ 10 2 cfu /ml can be used for UTI diagnosis in a symptomatic pt.

11. Diagnosis Additional investigation Upper tract imaging, cystoscopy, urodynamics -generally unnecessary during initial diagnostic testing Indication -complicated UTI -urinary retention -persistent fever (72 hours after initiation of Tx ) -unexplained/persistent hematuria -bacterial persistence -suspected urolithiasis (H/O calculi, urine PH ≥8.0)

12. Treatment with antimicrobial agents has minimized the morbidity and mortality associated with UTIs. The goal in treatment is to eradicate the infection by selecting the appropriate antibiotics that would target specific bacterial susceptibility. It is therefore fundamental to have a specific working knowledge of the various antibiotic choices available and an understanding of their mode of action and possible adverse side effects.

13. ANTIBIOTICS COMMONLY USED IN UROLOGY Mechanism of action Spectrum of activity Side effect Contraindications Antimicrobials in pregnancy Potential side effects applicable to all -Allergic reaction, hypersensitivity, rash, yeast infection, GI upset, pseudomembranous colitis

14. SULFONAMIDES Sulfonamides act by inhibiting the synthesis of tetrahydrofolic acid, necessary for subsequent DNA synthesis. Commonly used drugs are TRIMETHOPRIM TRIMETHOPRIM-SULFAMETHOXAZOLE These are bacteriostatic drug, inexpensive, and has minimal effect on normal gut flora. Effectiveness: gram positive organism (Streptococcus, Staphylococcus) Gram neg organism (Most Enterobacteriaceae like E.coli and klebsiella spp )

15. limitation: Enterococcus and Pseudomonas spp Side effects: include allergic reactions, rash, fever, renal and liver damage, hemolytic anemia in pt with G6PD deficiency, photosensitivity and vasculitis . Contraindications: folic acid deficiency state, glucose-6-phosphate dehydrogenase deficiency, acquired immunodeficiency syndrome( AIDS) or in pregnant pts

16. Dosage TMP-SMX is a fixed dose combination of 80mg TMP and 400mg SMX or double strength tablet of 160mg TMP and 800mg SMX . TRIMETHOPRIM 100 mg PO bid

17. Beta-lactams Penicillin, cephalosporin, aztreonam: beta-lactam ring Inhibit bacterial cell wall synthesis (by irreversible binding of the β-lactam ring to the enzyme transpeptidase ) Bacterial resistance: beta –lactamase production (an enzyme which breaks the β-lactam ring) Ampicillin & amoxicillin often good activity against Enterococci, streptococcus and Proteus mirabilis. However Limitation: Gram negative bacteria can quickly develop resistance. The addition of β- lactamase inhibitors such as clavulanic acid renders the aminopenicillins more active against the gram negative bacteria.

18. Methicillin, nafcillin , augmentin are resistant to beta-lactamase 1 st generation cephalosporin have good activity against gram positive bacteria (except MRSA), E. coli , proteus and klebsiella spp 2 nd generation have increased activity against anaerobes and haemophilus influenza . 3 rd & 4 th generation have broader coverage against gram negative with less gram positive effectiveness.

19. Side effects PENICILLINS : allergic reactions, rash, diarrhea, and anaphylaxis . CEPHALOSPORINS : allergic reactions, rash, fever, anaphylaxis, and synergistic toxicity with aminoglycosides Contraindications: hypersensitivity to penicillins ; may use with caution in patients with delayed hypersensitivity

20. AMINOGLYCOSIDES Aminoglycosides are a group of bactericidal antibiotics which act by inhibiting bacterial protein synthesis ( inhibit bacterial DNA and RNA synthesis). Effectiveness: against most gram negative urinary tract pathogens including E. coli, Enterobacter, Klebsiella, Proteus and Pseudomonas spp The drug is excreted in the urine by glomerular filtration .

21. Gentamicin or Tobramycin is a good first choice for most serious gram negative infections (febrile UTI) . Amikacin is effective for gentamicin or tobramycin resistant organisms. Limitation: avoid in pregnant patients, in patients with Severely impaired renal function, diabetes, or hepatic failure. Use with caution in myasthenia Gravis patients, and with other ototoxic and Nephrotoxic drugs .

22. Side effects: include ototoxicity ,nephrotoxicity (non- oliguric renal failure after 5-10 days of therapy) and Neuromuscular blockade. Nephrotoxicity is potentiated by hypovolemia, cephalosporins , and furosemide (Lasix). Serum levels should be monitored and adjusted for renal insufficiency. Peak levels (30-60 min after infusion) should be in the range of 15 to 20 mg/L for amikacin. Trough levels are taken just prior to the next dose Dosage: gentamicin 7mg/kg or tobramycin 5 to 7 mg/kg

23. TETRACYCLINES Bacteriostatic antibiotics which interfere with bacterial protein synthesis (inhibit ribosomal function) Wide spectrum, good for STD Excretion in the urine is mainly by glomerular filtration. Side effects: photosensitivity, hepatic toxicity, and staining of the teeth in children(can not use in pregnancy or in children) GI absorption is decreased if taken with food. (tetracycline, doxycycline ( Vibramycin ), and minocycline)

24. CLINDAMYCIN Clindamycin inhibits bacterial protein synthesis and is effective against most gram positive organisms and anaerobic infections including Bacteroides fragilis. Side effects include GI disturbances, mostly diarrhea and pseudomembranous enterocolitis secondary to Clostridium difficile. Dosage - 600-900 mg iv q6h (Adjust dosage for hepatic dysfunction.)

25. VANCOMYCIN Vancomycin is a bactericidal antibiotic which inhibits cell wall synthesis. It is active against gram positive bacteria and Clostridium difficile and is excreted by the kidneys unchanged. Side effects include ototoxicity, fever, phlebitis, and nephrotoxicity. Dosage - 500 mg q6h IV. (Adjust dosage for renal insufficiency.)

26. Fluoroquinolones (CIPROFLOXACIN, NORFLOXACIN) Mechanism : inhibit DNA gyrase (inhibits bacterial DNA synthesis Preventing bacterial replication ) It has a broad spectrum of coverage including most gram negative and gram positive organisms, particularly Pseudomonas and group D streptococcus. Avoid in pregnancy or under 16 (cartilage binding) Concomitant antacid, iron, zinc, or sucralfate use dramatically decreases oral absorption

27. Side effects: dizziness, seizures, confusion, insomnia, photosensitivity, - tendon ruptures , anxiety/depression, hallucinations, confusion , and suicidal thoughts Hepatic & renal clearance: mild renal dosing adjustments FDA warning issued in 2018 warns against the development of mental health side effects, specifically agitation, disorientation, delirium, memory impairment

28. Fosfomycin Fosfomycin, a bactericidal antibiotic that interferes with cell wall synthesis by inhibiting the initial step involving phosphoenolpyruvate synthetase . It is highly active against Gram-positive pathogens such as Staphylococcus aureus and Enterococcus, and against Gram-negative bacterias . Its major benefit is its limited cross-resistance as well as its efficacy against the majority of gram-negative organism & vancomycin-resistant enterococcus(VRE)

29. Fosfomycin is mainly used in the treatment of UTI, particularly those caused by E.coli (most Enterobacteriaceae, not p.aeruginosa ) & Enterococci . Effective as a single-dose agent when used as an empirical treatment for uncomplicated cystitis . Side effect : headache, GI upset & vaginitis . Contraindications : hypersensitivity to fosfomycin

30. NITROFURANTOIN Nitrofurantoin is a synthetic bacteriostatic agent (inhibit bacterial enzymes and DNA activity). Its only effective in the urine where therapeutic levels are achieved. It should not be used in patients with renal impairment as the drug may not reach adequate concentrations in the urine and thus, it is not recommended in patients with a creatinine clearance below 50 ml/min . Never use in treating tissue infections such as pyelonephritis or prostatitis (poor tissue penetration).

31. Many urinary pathogens are sensitive; however, Proteus and Pseudomonas are usually resistant. Side effects: pulmonary hypersensitivity from acute to chronic with chronic use, hemolytic anemia in G6PD . Peripheral neuropathy, GI upset Dosage - 100 mg q6h PO.

32. general principles for selecting the appropriate Antibiotics include consideration of the Age, gender, pregnancy or nursing home status  Anatomical site of infection: potential pathogens   community-acquired vs hospital-acquired acquired infections   immuno-competent vs immuno-compromised   susceptibility patterns of potential pathogens in the community/hospital   recent hospitalization   chronic diseases

33. recent antibiotic treatment   travel   colonisation with resistant bacteria Remove foreign materials, debride necrotic tissue, drain abscesses, and relieve obstruction   contact with potential resistant bacteria (human, animal source) the dosing interval, maintenance dosing: pharmacodynamic of the antibiotic, excretion problems (kidney function etc ). Adjust antibiotic dosages as necessary for renal or hepatic dysfunction .

34. Monitor therapy( i.e temperature curve, white count, signs of inflammation and follow-up cultures). Only use antibiotics when necessary. Avoid use of newer agents when available agents are effective. Use intravenous administration for any serious infections, at least initially. Short course (3 to 5-day) therapy for uncomplicated infections • Longer duration (10-14 days) for complicated infection (e.g. pyelonephritis) Revise antibiotic choice to reflect culture and sensitivity results.

35. ANTIBIOTIC CHOICES IN PREGNANCY All antibiotics cross the placental barrier to various degrees . Penicillin derivatives and cephalosporins have been shown to have minimal toxic effects to both mother and fetus and are therefore commonly utilized. Nitrofurantoins are also highly effective for simple urinary tract infections of pregnancy but can cause nausea and vomiting. Aminoglycosides can be used for pyelonephritis in pregnancy when other less toxic choices are unsuitable. Tetracyclines have numerous side effects, such as teratogenic potential and staining of the teeth , and should be avoided. Trimethoprim-sulfa combinations are effective but should be avoided near term.

36. Treatment of Asymptomatic Bacteriuria Pregnant women . Patients with neurological or structural abnormality of the urinary tract . Patients undergoing urologic surgery.

37. TREATMENT OF ASYMPTOMATIC BACTERIURIA IN PREGNANCY

38. TREATMENT OF UNCOMPLICATED CYSTITIS IN A NONPREGNANT WOMAN Most cases of uncomplicated cystitis occur in women. Each year , approximately 10% of women report having had a UTI, and more than 50% of all women have at least one such infection in their lifetime

39. Regimens in uncomplicated cystitis

40. TREATMENT OF UNCOMPLICATED CYSTITIS IN A NONPREGNANT WOMAN

41. Recurrent UTIs Risk factors for recurrent uncomplicated UTI Young and pre-menopausal women Sexual intercourse Use of spermicide A new sexual partner A mother with a history of UTI History of UTI during childhood Blood group antigen secretory status Post-menopausal and elderly women History of UTI before menopause Urinary incontinence Atrophic vaginitis due to oestrogen deficiency Cystocele Increased post-void urine volume Blood group antigen secretory status Urine catheterisation and functional status deterioration in elderly institutionalised women

42. Management of rUTIs Behavioral modifications (Postcoital voiding, increased fluid intake, wiping from front to Back, avoid douching and occlusive underwear. Use vaginal estrogen replacement in post-menopausal women . Use immunoactive prophylaxis, (OM-89 has been shown to be more effective in female patients ) Prophylaxis with vaginal probiotics (Lactobacillus spp ) has a beneficial clinical impact on restoration of vaginal flora and rUTI prevention Efficacy of cranberry products is unclear

43. Endovesical instillations: of hyaluronic acid (HA) and chondroitin sulphate (CS) have been used for glycosaminoglycan (GAG) layer replenishment in the treatment of interstitial cystitis, overactive bladder, radiation cystitis , and for prevention of rUTI Antibiotic prophylaxis antibiotic prophylaxis is the most effective approach against UTI Recurrences Continuous or post-coital antimicrobial prophylaxis to prevent recurrent UTI when non-antimicrobial interventions have failed . For patients with good compliance self-administered short-term antimicrobial therapy should be considered.

44. Uncomplicated Pyelonephritis Uncomplicated pyelonephritis is defined as pyelonephritis (inflammation of the kidney and renal pelvis) limited to non-pregnant, pre-menopausal women with no known relevant urological abnormalities or comorbidities.

45. Regimens for oral treatment

46. Regimens for empirical parenteral Treatment in uncomplicated pyelonephritis

47. Complicated UTIs A complicated UTI are believed to result in an infection that will be more difficult to eradicate than an uncomplicated infection.

48. Complicated UTIs Treatment

49. Catheter-associated UTIs Catheter-associated UTI refers to UTIs occurring in a person whose urinary tract is currently catheterized or has been catheterized within the past 48 hours. Do not use pyuria as sole indicator for catheter-associated (CA-UTI ). Do not use the presence or absence of cloudy urine alone to differentiate catheter-associated asymptomatic bacteriuria from CA-UTI . limiting catheterisation in nursing home patients reported successful CA-UTI reduction and reduced catheter usage.

50. Management and prevention of CA-UTI

51. Urosepsis Definition: Life-threatening organ dysfunction caused by a dysregulated host response to infection originating from the urinary tract and/or male genital organs. criteria of sepsis: SIRS and infection either documented or strongly suspected For rapid identification a quick SOFA score was developed i.e respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of100 m mHg or less . Severe sepsis: sepsis plus sepsis-induced organ dysfunction

52. Recommendations for the diagnosis and treatment of urosepsis Perform the quick SOFA score to identify patients with potential sepsis. Take a urine culture and two sets of blood cultures before starting antimicrobial treatment. Administer parenteral high dose broad spectrum antimicrobials within the first hour after clinical assumption of sepsis. Adapt initial empiric antimicrobial therapy on the basis of culture results. Initiate source control including removal of foreign bodies, decompression of obstruction and drainage of abscesses in the urinary tract. Provide immediate adequate life-support measures.

53. regimens for antimicrobial therapy for urosepsis

54. Septic shock Septic shock is a condition characterized by abnormal circulatory function secondary to overwhelming infection. Gram negative bacteria were predominant organisms isolated in 30% to 80% of cases & gram-positive bacteria in 5% to 24%. E.coli is the most common organism causing gram-negative bacteremia.

55. The classic bedside findings include a warm patient, brisk capillary refill & a bounding pulse reflecting pyrexia, peripheral vasodilation & decreased systemic vascular resistance. Other diagnostic criteria include evidence of organ dysfunction such as hypotension, oliguria or ileus . laboratory abnormalities including leukocytosis or leukopenia, hyperbilirubinemia, hyperlactatemia, hyperglycemia, coagulation abnormalities & elevated CRP and procalcitonin .

56. PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS Septic shock is thought to result from the release of vasoactive substances such as bradykinin, prostaglandins, histamine, and catecholamines . Profound tissue hypoxia is a cardinal feature. Phase 1: The initial hyperdynamic state or warm shock is characterized by increased cardiac output, decreased peripheral vascular resistance, low central venous pressure, and warm extremities. Phase 2 : Eventually cardiac decompensation will result in the hypodynamic state or cold shock characterized by decreased cardiac output, increased peripheral vascular resistance, and cool extremities. Fever, leukocytosis, and a profound metabolic acidosis are usual.

57. DIAGNOSIS Septic shock presents initially as altered mental status, hyperventilation, and respiratory alkalosis. It can easily be confused with other conditions, The differential diagnosis includes atelectasis , pulmonary embolus , pneumonia , acute hemorrhage , and myocardial infarction . Workup should begin with history, physical examination, urinalysis, CBC, LFT and electrolytes. Patients should be pan-cultured including blood, urine, sputum, and wounds prior to starting antibiotic therapy. Arterial blood gases (ABGs) and serum lactate dehydrogenase levels should be followed to monitor the patient's progress. Imaging investigations such as sonography and CT-scan should be performed early, X-Ray chest is mandatory and plain films of the abdomen and IVU scan may help identify the source of infection.

58. MANAGEMENT GUIDELINES The most important aspect of management is to eliminate the source of infection. 1. An abscess must be drained, obstructive uropathy must be relieved, and wounds should be debrided if necessary. 2. Broad spectrum antibiotic therapy should be immediately started either alone or in combination with an aminoglycoside, without waiting for culture results. 3. If infection is hospital acquired or if the pt has had multiple infections or is immunocompromised or severely ill,an aminoglycoside & anti-pseudomonas beta lactam or a 3 rd generation cephalosporin should be used. 4. A central line should be placed for access and monitoring the central venous pressure (CVP).

59. 5. Fluid resuscitation is best done using crystalloid & or colloid/blood products. 6.If additional blood pressure support is needed , vasoactive agents including phenylephrine, norepinephrine, vasopressin, & dopamine can be instituted. 7. Maintenance of blood glucose levels bellow 110mg/dl with intensive insulin therapy 8. Intubation with mechanical ventilation and positive end expiratory pressure (PEEP) are important for patients developing respiratory failure and shock lung. 11. Monitor patient's progress with ABGs and serum lactate.

60. Take-home Message when prescribing antibiotics, ‘ Start Smart —Then Focus’; use the right drug at the right time at the right dose for the right duration . In this way we might be able to preserve the utility of antibiotics.

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