Health Care Associated Infections on the NICU aka: Nosocomial infections

1. Health Care Associated Infections on the NICU(aka: Nosocomial infections) Catherine M. Bendel, MD Associate Professor of Pediatrics Director, Neonatal-Perinatal Medicine Fellowship Program

2. Objectives Define and differentiate between early-onset, late-onset and health-care associated (nosocomial) infections on the NICU. List the major micro-organisms responsible for each of these types of infection. Understand the risk factors for NICU nosocomial infections. Understand what laboratory tests are important in making the diagnosis of each of these infections. Understand the primary prevention strategies

3. “Prematurity is an infectious disease.” - James Todd, M.D.

4. Definitions Early Onset Neonatal Sepsis (EONS) Late Onset Neonatal Sepsis (LONS) Nosocomial or Health Care Associated Neonatal Infections (HCANI) <5 days old (prenatal or peripartum) 5 days to 3 months old (peripartum) Any infection that develops while a patient is in the hospital (peripartum or postnatal)

5. Microbes Early Onset Neonatal Sepsis (EONS) Late Onset Neonatal Sepsis (LONS) Nosocomial or Health Care Associated Neonatal Infections (HCANI) Maternal normal GU flora (GBS/ E. coli) Maternal flora and pathogens (GBS/Chlamydia/MRSA/HSV/HepB/ CMV/ HIV/Candida….) Skin/GI/Resp - self/others/equipment (CoNS/ gram negs/Candida/RSV)

6. Microbes - HCANI #1 Coagulase-negative Staphylococcus Infant skin or GI tract Care-provider hands #2 Gram-negative bacilli Infant skin, respiratory or GI tract Care-provider hands (artificial nails) Medical equipment #3 Candida spp (C. albicans, C. parapsilosis, ?C. glabrata) Infant skin or GI tract Care-provider hands Medical equipment/treatments

7. Incidence Early Onset Neonatal Sepsis (EONS) Late Onset Neonatal Sepsis (LONS) Nosocomial or Health Care Associated Neonatal Infections (HCANI) 1-10/1,000 live births 15-25/1000 premies 0.5/1,000 live births (GBS) ~5% of all NICU admissions 11-32% of all VLBW (<1500)

8. Why are infants, especially premies, more susceptible to infections?

9. Risk Factors for HCANI: Intrinsic Prematurity ELBW > VLBW Immunology of the neonate Mechanical barrier to infection Severity of illness Abnormal microbial flora

10. Prematurity Risk of infection inversely related to BW/GA VO study looking only at bacterial sepsis: 26% if 501-750 grams 22% if 751-1000 grams 15% if 1001-1250 grams 8% if 1251-1500 grams Most likely a surrogate marker for immunologic immaturity, immature barrier function and severity of illness

14. Premature Antibody levels Extremely low production, reduced opsonic activity Primary source - active placental transfer of maternal antibodies Most maternal antibody transferred in the 3rd trimester Maternal antibody concentrations low for 1o pathogens So smaller and earlier = lowest levels and least effective antibody

16. Neonatal Neutrophils (PMNs) Immature ? Chemotaxis ? Deformability ? Phagocytosis ? Storage pool Adults 14-fold > circulating pool Neonates only 2-fold

20. Neonatal Neutropenia Prematurity Maternal Hypertension IUGR Sepsis

21. Neonatal Barriers to Infection

22. Impairments/alterations in Neonatal Natural Barriers Immature Skin Thin, lacking multiple layers/keritin Easily damaged by Drying (phototherapy/open warmer) Adhesive tape/ monitor leads Handling / phlebotomy/ surgery Surgical wounds heal more slowly

23. Invasive Fungal Dermatitis in a VLBW infant Figure 1. Invasive fungal dermatitis in an extremely low birth weight infant. Note the erosions and crusts. Blood cultures were also positive. Figure 2. Skin biopsy from a neonate with invasive fungal dermatitis. Gomori methenamine silver stain shows a cluster of hyphal forms in the dermi Figure 1. Invasive fungal dermatitis in an extremely low birth weight infant. Note the erosions and crusts. Blood cultures were also positive. Figure 2. Skin biopsy from a neonate with invasive fungal dermatitis. Gomori methenamine silver stain shows a cluster of hyphal forms in the dermi

24. Impairments/alterations in Neonatal Natural Barriers Umbilicus - colonization of devitalized tissue GI tract Increased gastric pH with drip feeds/H2 blockers Mucosal damage with NEC

25. Severity of Illness Direct correlation with rate of HCANI: Increased LOS Higher severity of illness scores Congenital anomalies Potential correlation: Prenatal insults/stress

26. Abnormal Microbial Flora Altered maternal transmission of normal flora due to C/S, prenatal antibiotics, etc Altered neonatal colonization due to Broad-spectrum antibiotics (favors Candida) Delayed enteral feeds

27. Risk Factors for HCANI: Extrinsic Catheters UAC, UVC, PICC, ETT, Foley, CT, Peritoneal drains, etc Hyperalimentation / intralipids Medications Understaffing / overcrowding Care-giver to patient transmission of flora/pathogens

28. Central Venous/Arterial Catheters Life-saving tools on the NICU Necessary evil Stasis, thrombin formation Hyperal /IL Length between tubing changes 72 hours significantly higher risk than <24 hours

29. Central Venous/Arterial Catheters Skin bugs colonize the hub or exit-site, migrate up the catheter and enter the bloodstream or infect a clot at the tip UVC > PICC / Broviac UAC > perc A-line Transient bacteremia results in tip infection (GI) Increased incidence of infection with time UVC > UAC > PICC / Broviac Minimally at 7 days Significantly at 10-14 days or if clot present

30. Catheters Micro-organisms love to stick to plastic ANY CATHETER IS AT RISK!! ETT, Foley, CT, Peritoneal drains, etc

31. Hyperalimentation / Intralipids Associated with increased risk of CoNS, Candida spp and Malassezia spp Exact etiology unclear Inhibition of IL-2 and lymphocytes Hyperglycemia Sugar and fat source that promotes growth of select microbes Affects of delayed enteral nutrition on GI flora/anatomy

32. Medications Broad spectrum antibiotics Alter normal flora (>5 days increases risk of candidemia) Select for resistant microbes -- super bugs! Third generation cephalosporins (Cefotaxime) Emergence of beta-lactamase producing Klebseilla pneumoniae Vancomycin - VRE

33. Antibiotic-resistant microbes Vancomycin- resistant enterococcus (VRE) Theoretic risk on NICU ? risk with multiple course of vanco Strict contact isolation Methicillin-resistant Staphylococcus aureus (MRSA) Real risk on NICU Community / maternal acquired Vanco use required Strict contact isolation

34. Medications H2- blockers (ranitidine/Zantac) associated with increased bacterial and fungal infections Steroids Immunosuppression Hyperglycemia Skin compromise fragility Poor healing Topical petrolatum ointment (aquaphor) associated with increased fungal infections

35. Incidence of Systemic Candidiasis associated with TPO in infants with BW = 1500 grams

36. Understaffing and Overcrowding Understaffing / increase in census associated with Decreased handwashing Epidemics of Staphylococcus aureus MRSA Multi-drug resistant Enterobacter cloacae Multi-drug resistant K. pneumoniae Candida albicans

37. Care-giver to patient transmission of flora/pathogens Hands of healthcare workers (HCW) a reservoir for pathogens - controlled with adequate hand washing Persistent organisms on HCW hands due to: Omitting or inadequate handwashing Contaminated antimicrobial washes Persistent organisms not addressed with antiseptic: Candida Artificial, painted and long natural nails, hand jewelry associated with infectious outbreaks

38. Health care associated infections on the NICU:Presentation and Diagnosis

39. Neonatal Infections

40. Signs/Symptoms ?

41. Laboratory Evaluation ? Cultures ? Complete Blood Cell Count CSF glu, protein, WBC Glucose Bilirubin Liver Function Tests Coagulation studies C-reactive Protein (CRP) Chest Radiograph Abdominal X-ray Cardiac ultrasound Catheter ultrasound Renal ultrasound (fungal balls) Ophthalmologic exam Head ultrasound/ CT

42. Cultures -- Who and Which? Blood culture -- indicated in ALL infants with suspected sepsis. Repeat cultures indicated if initial culture positive. ETT culture (with gram stain)-- indicated in all intubated patients Urine culture -- more helpful in LONS/HCANI + in 1.6% EONS compared to 7.47% LONS

43. Cultures -- Who and Which? CSF culture -- should always be considered Meningitis frequently accompanies sepsis Infants do not localize infections well 50-85% meningitis cases have + blood culture Specific signs & symptoms occur in less than 50% of infants with meningitis Using “selective criteria” for obtaining CSF may result in missed or delayed diagnosis in up to 37% of infants with meningitis

44. Laboratory Diagnosis of Neonatal Meningitis

45. Complete Blood Cell Counts Is the CBC helpful as an indicator of nosocomial neonatal sepsis? Thrombocytopenia frequently associated with sepsis WBC may be high, low or “normal” Persistent low WBC more predictive of sepsis than elevated WBC (ANC < 1200) I:T quotient unreliable

46. C-Reactive Protein Elevated CRP, > 10 mg/L (>1 mg/dl), highly associated with sepsis --- but NOT diagnostic Limited by lack of “normal” reference values for preterm infants Normal CRP in “rule-out NEC” evaluation correlates with absence of infection Trend with multiple samplings correlates with persistence (?CRP) or resolution (?CRP) of infection May be useful tool in determining the endpoint for antibiotics

47. C-Reactive Protein

48. C-Reactive Protein CRP levels <10mg/L, determined >24 hours after beginning therapy correctly identified 99% of infants not needing further therapy. CRP-guided determination of length of therapy, shortened the treatment course for most infected infants without increasing the rate of relapse. Limitations: no studies evaluating meningitis or infections other than bacterial sepsis.

49. Specific Signs/Symptoms NEC - ?risk of CoNS GI perforation - ?risk of Candida /GI organisms/ anaerobes Liver Dysfunction - ?risk of virus Respiratory decompensation - ?risk GI bugs or respiratory virus (influenza, RSV-especially with apnea) Renal insufficiency - ?risk of Candida CNS involvement - anything Thrombocytopenia - ?risk of Candida / HSV/ CMV

50. Empiric Therapy Vancomycin IV - gram positive coverage - treats CoNS, MRSA, GBS, Group D enterococcus Cefotaxime IV - gram negative coverage -treats Klebsiella spp, E.coli Tailor therapy when culture results known

51. Additional Empiric Therapy Add Clindamycin when ?risk of anaerobes (GI perforation) Acyclovir when ?risk of HSV Amphotericin when ?risk of Candida

52. Yeast SusceptibilitiesFairview-University Medical Center – 2006

53. Health care associated infections on the NICU:Prevention!!!!!

54. Strategies for prevention: Eliminate/reduce risk factors - intrinsic Prematurity - not likely/beyond our control Low IgG - IVIG not successful Low ANC - Granulocyte stimulating factor (GCSF) moderate success Immature skin - Aquaphor not successful, use extreme care with adhesives/handling Severity of illness - ????

55. Strategies for prevention: Eliminate/reduce risk factors - extrinsic Catheters Insert only when indicated/remove promptly when no longer required Utilize protocols for sterile insertion and maintenance (chlorhexidine, transparent dressings, etc) Minimize manipulations Remove if evidence of infection or clot formation Replace UVC/UAC when required > 10-14 days PICC / broviac / percutaneous a-line

56. Strategies for prevention: Eliminate/reduce risk factors - extrinsic Antibiotics Judicious use Avoid prolonged courses of BSA Avoid prolonged and frequent courses of 3rd generation cephalosporins or vancomycin Nystatin prophylaxis - prevents fungal overgrowth

57. Strategies for prevention: Eliminate/reduce risk factors - extrinsic Hyperalimentation Advance enteral feeds as rapidly as possible Minimize handling/breaks in line Medications Avoid rantidine (zantac) Avoid/shorten courses of steroids Avoid topical petrolatum

58. Strategies for prevention: Eliminate/reduce risk factors - extrinsic #1 Preventative Measure: GOOD HAND-WASHING!!!!!

60. Miscellaneous

61. Human papillomavirus (HPV) HPV causes both common skin warts (benign) and cervical/vaginal warts in the female (precursor to cervical dysplasia/cancer) Generally asymptomatic Infection can be passed to the infant during vaginal delivery Symptoms usually occur between 2-5 years of age Respiratory tract Mouth Eye Difficult to treat -- vaccine might prevent

62. Respiratory Syncytial Virus (RSV) Causes an acute respiratory illness Infants prone to severe bronchiolitis and apnea, often requiring hospitalization with ventilation Preterm infants at high risk for complications May be associated with the development of asthma as an older child Transmission is by direct or close contact with contaminated secretions Good handwashing best prevention Virus can live on environmental surfaces for hours

63. Respiratory Syncytial Virus (RSV) Diagnosis Classic symptoms - respiratory with apnea Culture or rapid test on nasopharyngeal swab Treatment Symptomatic Supplemental oxygen or respiratory support Prevention Palivizumab (Synagis) - monoclonal antibody Passive immunization - monthly injections during RSV season (roughly Nov - March)

64. Indications for Synagis Infants <24 mo with chronic lung disease who have required therapy within the last 6 months Infants <24 months with hemodynamically significant heart disease Infants born <32 weeks GA <28 weeks GA up to 12 mo 28-32 weeks GA up to 6 mo

65. Indications for Synagis Infants 32 - 35 weeks GA with risk factors Child-care attendance School-age siblings Exposure to environmental air pollutants Congenital abnormalities of the airway Infants with severe neuromuscular disorders Synagis is not indicated for the treatment of RSV disease

66. Candida Treatment — Parenteral Amphotericin B - mainstay of therapy Daily dosage: No “test dose” required in neonates Initial dose 0.5 mg/kg IV over 2-6 hours Increase by 0.25 mg/kg/d to goal of 0.75-1.0mg/kg/d Adjust for renal insufficiency

67. Candida Treatment — Ampho B Treatment Course 10-14 days for uncomplicated line sepsis 3- 6 weeks for disseminated or complicated sepsis. Cumulative dose of 30-35 mg/kg or clearance of disease — whichever comes first! Monitor systemic involvement for improvement/clearance — serial ultrasounds, repeat cx, etc.

68. Candida Treatment — Ampho B Complications of therapy: Renal insufficiency Monitor UOP, BUN,Cr qod initially; then q week if stable Renal failure reversible, but dialysis may be required Profound hypokalemia / hypomagnesemia Monitor K and Mg levels closely Hematologic - bone marrow suppression Monitor CBC and platelets qod initially and then q week Liver dysfunction

69. Candida Treatment — Alternatives Liposomal Amphotericin B (Ambisome) or Amphotericin B Lipid Complex (Ablecet) or Amphotericin B colloidal dispersion Dosing: 3-5 mg/kg/day IV over 2hours Appears to be safe and effective, but not superior to conventional Ampho B Diminished side effects, especially renal Limitations: Decreased renal absorption

70. Candida Treatment — Alternatives Fluconazole — IV (vorconazole next generation) Dosing, over 2-6 hours: Preterm = 29 weeks: 5-6 mg/kg/72 hours Preterm 30-36 weeks: 3-6 mg/kg/48 hours Term: 6-12 mg/kg/24-72 hours Monitor levels Side effects: renal, hepatic and hematologic, but less than Ampho B

71. Complement

74. Risk Factors #1 PREMATURITY ELBW > VLBW

75. Risk Factors for Neonatal Nosocomial Infections Prematurity ELBW > VLBW Increased LOS Abdominal surgery / NEC Hyperalimentation / Intralipids Neutropenia, Thrombocytopenia Catheters UAC, UVC, ETT, Foley, CT, Peritoneal drains, etc

76. Risk Factors for Neonatal Nosocomial Infections Prematurity ELBW > VLBW Increased LOS Abdominal surgery / NEC Hyperalimentation / Intralipids Neutropenia, Thrombocytopenia Catheters UAC, UVC, ETT, Foley, CT, Peritoneal drains, etc

77. Antibody

78. Neutrophils

79. Signs/Symptoms

80. Signs/Symptoms