Neonatal Sepsis by dr Hesham Tawakol, Consultant Neonatologist at Corniche Hospital, Abu Dhabi


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  • Twelve studies from eight Arabic countries including 2308 newborns with culture proven sepsis and clinical signs of sepsis reported that early onset sepsis ranged from 24 to 74%. Gram-negative organisms were the predominant pathogens in Libya, Egypt, Jordan, and Iraq (65–90% of all sepsis cases) with Klebsiella species (spp.), Serratia spp., Enterobacter spp., Escherichia coli, and Pseudomonas spp. being the most frequent bacteria. In Saudi Arabia, Bahrain and Kuwait, the Gram-positive microorganisms, coagulase negative Staphylocooci and Staphylococcus aureus were taking the lead (64–75%). Group B Streptococci were the predominant pathogen (24%) in the United Arab of Emirates (UAE). Candida species were emerging in Egypt, UAE, Bahrain, and Kuwait.
  • It is our practice to provide meningeal doses of ampicillin and gentamicin after a sepsis evaluation that does not include an initial LP. Blood culture can be negative in as many as 38 percent of infants with meningitis [5,47,48]. When CSF is obtained, it should be sent for Gram stain, routine culture, cell count with differential and protein and glucose concentrations
  • A complete blood count (CBC) obtained 6 to 12 hours after delivery may be helpful in the evaluation of early-onset sepsis. Although both the absolute neutrophil and the ratio of immature to total neutrophil counts (I/T ratio) have been used as markers for neonatal sepsis, they are more useful in identifying neonates who are unlikely to have sepsis than identifying those with sepsis
  • The clever bacteria met our challenge by creating beta lactamase, an enzyme that grants many bacteria immunity to penicillin-type antibiotics. In turn, we upped the ante by developing new kinds of antibiotics that trounced these beta lactamase-producing pathogens.But the bacteria weren't done yet. Some tricky little bugs had a trick up their metaphorical sleeves: Beta Lactamase model 2.0, known to us as extended-spectrum beta lactamase, or ESBL. This enzyme not only chops apart penicillins, but cephalosporin antibiotics, too New Delhi me New Delhi metallo-beta-lactamase 1 (NDM-1) is a newly-described metallo-beta-lactamase (MBL), first identified in 2008 in single isolates of Klebsiella pneumoniae and Escherichia coli, both recovered from a patient repatriated to Sweden after treatment in a hospital in New Delhi, IndiaMetallolactamase production can be detected by disk approximation test or Modified Hodge test and NDM -1 gene can be detected by polymerase chain reaction by the use of specific primer targeting the gene
  • While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a horizontal fashion by conjugation, transduction, or transformation.
  • Five Basic Mechanisms of Antibiotic Action against Bacterial Cells:Inhibition of Cell Wall Synthesis (most common mechanism)Inhibition of Protein Synthesis (Translation) (second largest class)Alteration of Cell MembranesInhibition of Nucleic Acid SynthesisAntimetabolite Activity
  • Neonatal Sepsis by dr Hesham Tawakol, Consultant Neonatologist at Corniche Hospital, Abu Dhabi

    1. 1. NEONATAL SEPSIS AND PREVENTION OF HEALTHCARE ASSOCIATED INFECTIONS Hesham Tawakol, MD, FAAP Consultant Neonatologist Al Corniche Hospital
    2. 2. Objectives  Neonatal sepsis  Drug Resistance  Prevention of Healthcare Associated Infections
    3. 3. Case    A preterm 28 weeks infant with history of RDS on nasal cannula 2 lpm 30% O2 has only PIV (DOL 20) Apnea – Bradycardia. Sepsis work up done. Vancomycin and amikacin. On CPAP (DOL 24) K. Pneumonia sensitive to meropenem, ciprofloxacin, amikacin and resistant to cefotaxime and ceftazidime. meropenem was initiated. Blood culture repeated, Baby on CMV 40% O2
    4. 4. Case   (DOL 26) blood culture +, baby deteriorating, Amikacin changed to ciprofloxacin. Blood culture repeated. , ECHO, head and abdominal US done with no focus (DOL 27) blood culture + Baby further deteriorates. On HFOV. Baby died secondary to DIC.
    5. 5. Do you think we have a problem?
    6. 6. Neonatal Sepsis  Bacterial  Viral Fungal 
    7. 7. Definition   In older medical literature, 1 week of age was considered the limit between EOS and LOS. More recently, EOS infection is any infection that manifest in the first 72 hours, LOS manifest after 72 hours of birth
    8. 8. Source of Infection   EOS is usually due to vertical transmission by ascending contaminated amniotic fluid or during vaginal delivery from bacteria colonizing or infecting the mother's lower genital tract LOS can be vertical from the mother or horizontal transmission from direct contact with care providers or environmental sources
    9. 9. Early Onset Sepsis in Full Term in USA 4 20 4 46 26 Soll PJ et al, Pediatr Infect Dis J. 2005;24(7):635–63 GBS Other Strept E coli Enterococcus S.Aureus
    10. 10. Early Onset Sepsis in VLBW in USA 9 11 49 14 17 E coli CONS GBS Other strept Other Gram pos Soll PJ et al, Pediatr Infect Dis J. 2005;24(7):635–63
    11. 11. Early Onset Sepsis in Developing Countries 9 10 35 21 25 Klebseilla S.Aureus E coli Pseudomonas GBS Ziadi et al, Pediatr Infect Dis J. 2009;28(suppl 1):S10–S18
    12. 12. Epidemiology    The overall incidence of neonatal sepsis ranges from 1 to 5 cases per 1000 live births. The estimated incidence is lower in term infants, with a reported rate of 1 to 2 cases per 1000 live births The incidence of early-onset sepsis has decreased primarily as a reduction of GBS infections due to the use of intrapartum antibiotic prophylaxis
    13. 13. Epidemiology CDC, GBS Prophylaxis guidelines 2010
    14. 14. Epidemiology CDC, GBS Prophylaxis guidelines 2010
    15. 15. Intrapartum Antibiotics Prophylaxis (IAP)      Penicillin or ampicillin Cefazolin Clindamycin Erythromycin Vancomycin
    16. 16. Epidemiology of LOS in Saudi Arabia CONS Staph aureus Enterococcus GBS E Coli Klebsiella Pseuomonas Enterobacter Serratia Candida Others K. Alfaleh Sultan Qaboos Univ Med J. 2010 August
    17. 17. Neonatal Sepsis in the Arab World  Twelve studies from eight Arabic countries including 2308 newborn with proven sepsis  Early onset sepsis ranged from 24 to 74%.  GBS in UAE 34 % early onset  Gram-negative organisms were the predominant pathogens in Libya, Egypt, Jordan, and Iraq Tosson et al, J Matern Fetal Neonatal Med. 2011
    18. 18. Risk Factors for LOS
    19. 19. Risk Factors for LOS A recent study showed that empiric antibiotic treatment resulted in a threefold increase in risk of infection from resistant bacteria for every day of ampicillin and gentamicin use and up to a 34fold increase with cephalosporin use in neonates previously exposed to antibiotics.  Le Jet all, Pediatr Infect Dis J. 2008
    20. 20. Clinical Presentation The primary clinical findings in a very low-birth weight infants     Apnea (55%) Feeding intolerance, abdominal distension or guaiac-positive stools (43%) Increased respiratory support (29%) lethargy and hypotonia (23%) Fanaroff et al, Pediatric Infect Dis J. Heart
    21. 21. Clinical Presentation   The most common clinical syndromes of early-onset disease are sepsis and pneumonia; less frequently meningitis. Late onset presents as sepsis and meningitis The case-fatality ratio of early-onset disease has declined from as high as 50% in the 1970 to 3-4 % in Full term and 20% in preterm infant
    22. 22. Diagnosis – Blood Culture    Positive blood culture is considered the gold standard in sepsis diagnosis. Positive results from blood culture depend on the technique used, microorganism density, previous antibiotic treatment, and sample volume. The automated method requires only 1.0 mL of blood and with the radiometric technique is very sensitive, with a high percentage of positive blood cultures, reaching 74% to 90.
    23. 23. Diagnosis – Blood Culture   Blood culture should be collected by peripheral venipuncture before beginning antibiotic treatment, and if positive, should be repeated during treatment to evaluate treatment effect. Patients who have central catheters can have blood obtained by this route, but another sample should be collected by peripheral access for better interpretation of results
    24. 24. Diagnosis – Blood Culture   Positive blood culture confirms sepsis, and when the blood culture is negative, the condition is considered as clinical sepsis An alarming fact in many neonatal intensive care units (NICUs) is that for each confirmed case of infection, between 11 and 23 uninfected newborns are treated
    25. 25. Diagnosis - Urine culture   Urine culture obtained by catheter or bladder tap should be included in the sepsis evaluation for infants >6 days of age. A urine culture need not be routinely performed in the evaluation of an infant ≤6 days of age because a positive urine culture in this setting is a reflection of high-grade bacteremia rather than an isolated urinary tract infection
    26. 26. Diagnosis – CSF Culture   The decision whether or when to perform a LP for CSF analysis and culture remains controversial As many as 25% of newborns who have sepsis have meningitis, and 15% to 55% of patients who have meningitis (positive CSF culture) have negative blood cultures.
    27. 27. Diagnosis – CSF Culture  The approach outlined by the 2012 AAP clinical report recommends that LP should be performed for an infant with any of the following clinical conditions  A positive blood culture  Clinical findings that are highly suggestive of sepsis  Laboratory data strongly suggestive of sepsis  Worsening clinical status while on antibiotic therapy
    28. 28. Diagnosis - CBC        CBC 6 to12 hours after delivery Total white count Absolute neutrophil count Ratio of immature to total neutrophil counts (I/T ratio) Both are more useful in identifying Platelets count
    29. 29. Diagnosis – Cytokines, Acute phase reactants and Surface Markers      IL 6 – IL 8 – IL 10 Tumor necrosis factor alpha CD64 CRP PCT
    30. 30. Diagnosis – CRP   C-reactive protein was the best single marker, with an overall sensitivity and specificity of 84% and 96%, respectively. At the beginning of sepsis, CRP concentrations are increased 1 mg/dL) in only 16% of cases, After 24 hours, positivity increases to 92%
    31. 31. Diagnosis – CRP   Performing IL-6 and C-reactive protein on day 0, together with either TNF alpha on day 1 or C-reactive protein on day 2, showed the best overall sensitivity (98%) and specificity (91%) for the diagnosis of late onset infection. CRP levels can be considered as a criterion for the discontinuation of antibiotic therapy to minimize antibiotic exposure and shorten hospital stay. Dia, HA et al,Pediatric Intern Child Health 2012
    32. 32. Diagnosis - Neutrophil CD64    Diagnostic Marker in Neonatal Sepsis. Can be incorporated as a valuable marker for excluding neonatal sepsis. A cut-point value ,sensitivity, specificity and a negative predictive values of 3.62, 75%, 77%, Streimish et al,. Pediatr Infect Dis J. 2012 Apr 4
    33. 33. Accuracy of diagnostic tests in Late onset Sepsis Test S% SP% Gram-specific PCR for Gram -ve 86 99 Gram-specific PCR for Gram +ve 74 98.5 Tumor necrosis factor -alpha 73-82 80-94 IL-6+CRP or PCT 100 96 IL-8+CRP 80 87 IL-8 urine 92 94 CD64+IL-6 or CRP 100 88
    34. 34. Diagnosis – Heart Rate Characteristics  A new technology related to heart rate characteristics (HRC) monitoring may be a promising tool in the early diagnosis of LOS.  24 hours before clinical suggestions of sepsis, neonates have reduced heart rate variability and transient decelerations.  Although the mechanism by which sepsis leads to these abnormalities is not known, it is speculated that cytokines play a role.
    35. 35. Treatment   Choice of antibiotic therapy for suspected sepsis should be tailored for the most likely organism with the highest mortality risk with consideration to local resistance patterns There is inadequate evidence from randomized trials in favor of any particular antimicrobial regimen for the empirical treatment especially for suspected LOS
    36. 36. Treatment   Optimal duration of empiric antimicrobial use decreases the development of antimicrobial resistance, prevents unwanted changes in flora found in the NICU, and minimizes unnecessary expenses for infants who have negative blood culture Prolonged duration of initial empirical antibiotic therapy is associated with adverse effects
    37. 37. Treatment   Vancomycin :CDC recommended against empirical vancomycin therapy to prevent the emergence and spread of vancomycin resistant strains and recommends its use in areas where MRSA is prevalent. An acceptable approach would be to start with cloxacillin and gentamicin as initial antibiotics for LOS in a stable neonate
    38. 38. Treatment  Third generation cephalosporin: provides less coverage for the relevant disease causing organism and increase resistance and risk for fungal infections. This rule does not apply for meningitis Muller-Pebody et al,Arch Dis Child Fetal Neonatal Ed 2011
    39. 39.    10 days of therapy for culture-proven sepsis with minimal or absent focal infection Neonates with S. aureus infection may require 14 days of antibiotic therapy This applies to patients who are at least 32 weeks and above and showed good initial response to antibiotics.
    40. 40.    For neonates with late-onset meningitis, a regimen containing an antistaphylococcal antibiotic, such plus cefotaxime or ceftazidime with or without an aminoglycoside is recommended GBS meningitis is usually treated for 14 to 21 days For meningitis caused by Gram-negative bacteria, a minimum of 21 days is recommended
    41. 41.  Avoid treating colonization and prophylactic antibiotic use for invasive devices.
    42. 42. IVIG The rationale for IVIg infusion is that it could provide type-specific antibodies. The main difficulties with IVIg therapy are as follows:  The effect has been transient  Clinically available IVIg solutions do not contain type-specific antibody  The adverse effects associated with the infusion of any blood product can occur 
    43. 43. Complication  Meningitis: hearing and vision impairment, convulsions, neurodevelop mental impairment, behavioral problems. Polin R A et al,Semin Neonatal 2001
    44. 44. Complications  At school age, a majority of preterm children with late-onset sepsis had motor problems. And lower IQ was and memory and attention were specifically impaired..
    45. 45.  Healthcare associated infection  Multidrug resistant bacteria
    46. 46. Multidrug Resistant Bacteria  ESBL's history starts, as many histories do, with a war: The war between us and the bacteria  Penicillin Lactamase  Cephalosporins  Carbapenems ESBL, NDM-1 Beta ESBL ??? Pennington, Hugh (2010-08-11). "Can we stop the Indian superbug?
    47. 47. Selection Pressure “Survival of the Fittest”
    48. 48. Bacterial DNA
    49. 49. Transfer of Bacterial Genetic Material
    50. 50. Mechanisms of Antibiotics Action 1 3 5 2 4
    51. 51. Mechanisms of Resistance 4 5 6 3 1 2
    52. 52. Definition  Nosocomial infection or Hospital acquired infection  An infection occurring in a patient in a hospital or other healthcare facility in whom the infection was not present or incubating at the time of admission.  This includes infections acquired in the hospital but appearing after discharge Benenson AS. Control of communicable diseases manual, 16th edition. Washington, American Public Health Association, 1995
    53. 53. Prevention
    54. 54. Ignaz Semmelweis (1818-186  Hungarian obstetrician  Pioneer of antiseptic procedures  Decreased incidence puerperal fever and maternal mortality by 90%  Hand hygiene Hanninen, O infection Control 4 (5): 367–370
    55. 55. Chain of Infections
    56. 56. Prevention of HCAI  Validated and standardized prevention strategies have been shown to reduce HCAI  At least 50% of HCAI could be prevented  Most solutions are simple and not resourcedemanding and can be implemented in developed, as well as in transitional and developing countries
    57. 57. Prevention of HCAI  Reducing person to person transmission  Controlling environmental risks for infection  Protecting patients with appropriate use of prophylactic antimicrobials, nutrition, and vaccinations  Limiting the risk of endogenous infections by minimizing invasive procedures , and promoting optimal antimicrobial use  Surveillance of infections, identifying and controlling outbreaks  Prevention of infection in staff members  Enhancing staff patient care practices, and continuing staff education.
    58. 58. Clean Hands..Save Lifes
    59. 59. WHO Hand Washing
    60. 60. The 5 Moments of Hand Washing
    61. 61. Compliance with hand hygiene  Compliance with hand hygiene differs across facilities and countries, but is globally <40%1  Main reasons for non-compliance reported by health-care workers2:  Too busy  Skin irritation  Glove use  Don’t think about it 1Pittet 2Pittet and Boyce. Lancet Infectious Diseases 2001; D, et al. Ann Intern Med 1999
    62. 62. Time constraint = major obstacle for hand hygiene  Adequate handwashing with water and soap requires 40–60 seconds  Average time usually adopted by health-care workers: <10 seconds  Alcohol-based handrubbing: 20–30 seconds