Antibiotic Uses in Neonates


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Antibiotic use in neonates. Protocols , Rationale, Antibiotic stewardship and newer agents, NICU microbiological profile. A grand presentation by Dr. Maskey in TUTH.

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Antibiotic Uses in Neonates

  1. 1. Rational antibiotic use in newborn Nischal Maskey Department of Child Health Mahrajgunj Medical Campus, IOM
  2. 2. Contents • Introduction to rational use of medicine • Effect of antibiotics on neonates • Clinical data • Overview on antibiotics • NICE guidelines on sepsis • Choice and duration of antibiotics • Prophylactic antibiotic use
  3. 3. Definition • Rational use of medicines refers to the correct, proper and appropriate use of medicines. Rational use requires that patients receive the appropriate medicine, in the proper dose, for an adequate period of time, and at the lowest cost to them and their community. (WHO)
  4. 4. What are the consequences of incorrect use of medicines? • Antimicrobial resistance. • Adverse drug reactions and medication errors • Lost resources • Eroded patient confidence
  5. 5. What factors contribute to incorrect use of medicines? • Lack of skills and knowledge • Inappropriate unethical promotion of medicines by pharmaceutical companies • Profits from selling medicines • Unrestricted availability of medicines • Overworked health personnel • Unaffordable medicines • Lack of coordinated national pharmaceutical policy
  6. 6. What can be done to improve rational use of medicines? • A national body to coordinate policies on medicine use and monitor their impact • Evidence-based clinical guidelines for training, supervision and supporting decision-making about medicines • Drug (medicines) and therapeutics committees in districts and hospitals to monitor and implement interventions to improve the use of medicines • Problem-based training in pharmacotherapy and prescribing in undergraduate curricula • Continuing medical education as a requirement of licensure
  7. 7. • Publicly available independent and unbiased information about medicines for health personnel and consumers • Public education about medicines • Elimination of financial incentives that lead to improper prescribing, such as prescribers selling medicines for profit to supplement their income • Regulations to ensure that promotional activities meet ethical criteria • Adequate funding to ensure availability of medicines and health personnel.
  8. 8. Introduction • Antibiotics are the commonest drugs used in the NICU. • Virtually all extremely low birth weight infants receive antibiotics and for all other birth weight groups admitted to the NICU the vast majority are treated with antibiotics • Only a small number eventually have culture proven infection. Clark et al : 98% of preterm infants who received empiric antibiotics were culture negative.
  9. 9. Effect of antibiotics on the neonate • Newborn: sterile gut. • Normal flora: early days of life. • Antibiotics : delay in microflora colonisation with most anaerobes, importantly Bifidobacterium and Lactobacillus. • At 30 days of life Bifidobacterium and Lactobacillus sp: 1/15 breastfed preterm infants who had received antibiotics.
  10. 10. • Antibiotics also limit the number of bacterial species in the normal flora. • As few as 3 species in their flora at Day 10 of life • An inverse dose- response between the duration of antibiotics and the number of species in the flora at Day 30 of life. • Bacterial overgrowth of other species • A major role in restricting the diversity and the volume of the normal flora thus reducing protection from invading pathogens.
  11. 11. • Animal studies : normal gut development is dependent on a diverse and high volume flora and the normal flora also plays a significant role in the physiological and immunodevelopment of the gut . • Normal flora create a physical defence, a role in immune responses. • Polysaccharide produced by Bacteroides fragilis : the cellular and physical maturation of the gut. • Bifidobacterium : immunomodulation, balance proinflammatory and anti- inflammatory cytokine production in the gut resulting in a net antiinflammatory response . • Low bacterial counts and lack of diversity of anaerobes caused by antibiotic use : necrotising enterocolitis (NEC).
  12. 12. Resistance and antibiotics • Antibiotics alter the gut flora: colonisation with resistant organisms. • Resistance is usually to multiple drugs with a higher mortality .
  13. 13. • One NICU : an empiric antibiotic regime of tobramycin and penicillin for EOS and tobramycin and flucloxacillin for LOS and the second unit : cefotaxime and ampicillin. • After 6 months the regimes were reversed. Respiratory and rectal cultures were taken weekly.
  14. 14. • Cefotaxime and ampicillin regime: RR=18 for colonisation with resistant strains and this reversed when the regimes were reversed. • Four LOS occurred, 3 in the cefotaxime and ampicillin group and one in the other group . • Beta-lactam antibiotics : colonisation with multiresistant organisms and regimes that restrict the use of beta-lactam antibiotics reduce resistance.
  15. 15. • Use of aminoglycosides : not associated with significant emergence of resistant organisms. • Cefotaxime: association with increased mortality. • A retrospective study of over 100,000 infants given either gentamicin or cefotaxime with ampicillin empirically in the first 3 days of life. • The relative risk of mortality was increase 1.5 times for infants receiving cefotaxime. Cefotaxime use may increase the risk of fungal infection.
  16. 16. NICU TUTH ( 2070 Baisakh to Bhadra) Acinetobactor (12.5%) Staph aureus (40%) CONS (15%) Klebsiella (10%) E Coli (12.5%) Enterobactor (2.5%) 237 admissions: 30 cases of microbial growth (28 in blood/ 2 in ET tube)
  17. 17. A m p i A m I k a O f l o C e f o t a x V a n c o M e r o L e v o G e n t a C i p r o T Z P C l o r a m C l O x C l i n d T i g e C o l i s t i n R S S S S S R R S S S S E Coli
  18. 18. A m p i A m I k a O f l o C e f o t a x V a n c o M e r o L e v o G e n t a C i p r o T Z P C l o r a m C l O x C l i n d T i g e C o l i s t i n S S S S R S S R R S R S S S E Coli
  19. 19. Staph aureus
  20. 20. A m p i A m I k a O f l o C e f o t a x V a n c o M e r o L e v o G e n t a C i p r o T Z P C l o r a m C l O x C l i n d T i g e C o l i s t i n S S S S R S S S R R S S S R S S S S S S R S S S S S S R
  21. 21. A m p i A m I k a O f l o C e f o t a x V a n c o M e r o L e v o G e n t a C i p r o T Z P C l o r a m C l O x C l i n d T i g e C o l i s t i n S R S S S S S S S S S S S S S S S S S S S S S S S S S R S R S R R S S S S S S S
  22. 22. A m p i A m I k a O f l o C e f o t a x V a n c o M e r o L e v o G e n t a C i p r o T Z P C l o r a m C l O x C l i n d T i g e C o l i s t i n R S S R R S S R S R R S S R S S R S S S S S S S S R S S R R R S R S Acinetobactor
  23. 23. A m p i A m I k a O f l o C e f o t a x V a n c o M e r o L e v o G e n t a C i p r o T Z P C l o r a m C l O x C l i n d T i g e C o l i s t i n S R S R S R R S S S R S S Klebsiella
  24. 24. A m p i A m I k a O f l o C e f o t a x V a n c o M e r o L e v o G e n t a C i p r o T Z P C l o r a m C l O x C l i n d T i g e C o l i s t i n R S S S S S R S R S S S S S S S S S S CONS
  25. 25. Floroquino lones Aminoglyco sides Meropenem Ampicillin Cefotaxim EColi + +/- + +/- +/- Staph + +/- + +/- + Acinetobactor + +/- +/- +/- +/- Klebsiella + + + +/- + CONS + + + + + Meropenem and fluoroquinolones: almost 100% coverage
  26. 26. Antimicrobial Stewardship • Antimicrobial Stewardship is an activity that promotes: 1. The appropriate selection of antimicrobials. 2. The appropriate dosing of antimicrobials. 3. The appropriate route and duration of antimicrobial therapy.
  27. 27. • After confirming that the patient has a indication for antimicrobial therapy, antimicrobial stewardship is the 8 R’s: 1. Right drug, 2. Right time 3. Right dose 4. Right route 5. Right resident 6. Right documentation 7. Right reason 8. Right response
  28. 28. • Core Members of the Antimicrobial Stewardship Team • Infectious disease physician (Director or Co-director) • Clinical pharmacist with infectious disease training (Co- director or core member) • Other members of the team  Microbiologist  Information system specialist  Infection control professional  Hospital epidemiologist
  29. 29. Antimicrobial Stewardship Program: The Components • Prospective audit with intervention and feedback • Formulary restriction and preauthorization • Education • Guidelines and clinical pathways • Antimicrobial order forms • Dose optimization • Parenteral to oral conversion
  30. 30. Amikacin Aminoglycoside antibiotic active against gram-negative bacilli, especially Escherichia coli, Klebsiella, Proteus, Enterobacter, Serratia, and Pseudomonas. Ampicillin Penicillinase-susceptible β-lactam: gram-positive pathogens except Staphylococcus; Salmonella, Shigella, Neisseria, E. coli, and Proteus mirabilis Aztreonam β-Lactam (monobactam) antibiotic with activity against gram- negative aerobic bacteria, Enterobacteriaceae, and Pseudomonas aeruginosa. Carbenicillin Extended-spectrum penicillin (remains susceptible to penicillinase destruction) active against Enterobacter, indole-positive Proteus, and Pseudomonas. Cefotaxime 3rd generation cephalosporin active against gram-positive and gram-negative pathogens. No antipseudomonal activity. Ceftazidime 3rd generation cephalosporin active against gram-positive and gram-negative pathogens, including Pseudomonas aeruginosa.
  31. 31. Chloramphenicol Broad-spectrum protein synthesis inhibitor active against many gram-positive and gram-negative bacteria, Salmonella, vancomycin-resistant Enterococcus faecium, Bacteroides, other anaerobes, Mycoplasma, Chlamydia, and Rickettsia; usually inactive against Pseudomonas. Ciprofloxacin Quinolone antibiotic active against P. aeruginosa, Serratia, Enterobacter, Shigella, Salmonella, Campylobacter, N. gonorrhoeae, H. influenzae, M. catarrhalis, some S. aureus, and some Streptococcus. Clindamycin Protein synthesis inhibitor active against most gram-positive aerobic and anaerobic cocci except Enterococcus. Cloxacillin Penicillinase-resistant penicillin active against S. aureus and other gram-positive cocci except Enterococcus and coagulase- negative staphylococci.
  32. 32. Gentamicin Aminoglycoside antibiotic active against gram-negative bacilli, especially E. coli, Klebsiella, Proteus, Enterobacter, Serratia, and Pseudomonas. Imipenem- cilastatin Carbapenem antibiotic with broad-spectrum activity against gram- positive cocci and gram-negative bacilli, including P. aeruginosa and anaerobes. Meropenem Carbapenem antibiotic with broad-spectrum activity against gram- positive cocci and gram-negative bacilli, including P. aeruginosa and anaerobes. Metronidazole Highly effective in the treatment of infections due to anaerobes.
  33. 33. Ofloxacin Quinolone antibiotic for treatment of conjunctivitis or corneal ulcers (ophthalmic solution) and otitis externa or chronic suppurative otitis media (otic solution) caused by susceptible gram-positive, gram-negative, anaerobic bacteria, or Chlamydia trachomatis. Penicillin G Penicillin active against most gram-positive cocci; S. pneumoniae (resistance is increasing), group A streptococcus, and some gram- negative bacteria (e.g., N. gonorrhoeae, N. meningitidis). Piperacillin Extended-spectrum penicillin active against E. coli, Enterobacter, Serratia, P. aeruginosa, and Bacteroides Piperacillin- tazobactam Extended-spectrum penicillin (piperacillin) combined with a β- lactamase inhibitor (tazobactam) active against S. aureus, H. influenzae, E. coli, Enterobacter, Serratia, Acinetobacter, P. aeruginosa, and Bacteroides.
  34. 34. Tigecycline Tetracycline-class antibiotic (glycylcycline) active against Enterobacteriaceae, including ESBL producers; streptococci (including VRE); staphylococci (including MRSA); and anaerobes. Tobramycin Folic acid antagonist effective in the prophylaxis and treatment of E. coli, Klebsiella, P. mirabilis, and Enterobacter urinary tract infections; P. carinii pneumonia Vancomycin Glycopeptide antibiotic active against most gram-positive pathogens including Staphylococcus (including MRSA and coagulase-negative staphylococci), S. pneumoniae including penicillin-resistant strains, Enterococcus (resistance is increasing), and C. difficile–associated colitis.
  35. 35. Gyawali N, Sanjana RK. Indian J Pediatr. 2013 May;80(5):371-4 Bacteriological profile and antibiogram of neonatal septicemia. • 1,572 samples • Blood culture was positive : 238 (15.13 %) samples. • Gram positive and gram negative organisms were 44.1 % and 55.9 % respectively. • Staphylococcus aureus : predominant isolate followed by Klebsiella spp. • Most of the gram positive isolates exhibited higher resistance to penicillin and cephalosporin. • Susceptibility : aminoglycosides and quinolones. • More than two third isolates of gram negative Enterobacteriaceae showed resistance to ampicillin. • Third generation cephalosporin and aminoglycosides were found to be more satisfactory among gram negative organisms as compared to gram positive.
  36. 36. Shrestha S, Adhikari N, Rai BK, Shreepaili A. Antibiotic resistance pattern of bacterial isolates in neonatal care unit. JNMA J Nepal Med Assoc. 2010 Oct-Dec;50(180):277-81. • The positive yield of blood cultures was 19.56%. • Most common: coagulase negative Staphylococcus, Acinetobacter, Enterobacter and non-haemolytic Streptococcus. • A significant percent of the isolates were resistant to the first line antibiotics. • Gram negative: more than 30% are resistant to cefotaxime and more than 50% are resistant to gentamicin.
  37. 37. Shrestha S, Shrestha NC, Dongol Singh S, Shrestha RB, Kayestha S, Shrestha M, Thakur NK Bacterial Isolates and its Antibiotic Susceptibility Pattern in NICU. . Kathmandu Univ Med J (KUMJ). 2013 Jan-Mar;11(41):66-70. • The blood culture yield : 44.13% with nosocomial sepsis - 10.79%. • 84.08% early onset sepsis and 15.95% late onset sepsis. • Klebsiella infection : commonest organism • Gram positive organisms : 39.36% (Staphylococcus aureus then CONS) • Gram negative organisms: 60.64% (Klebsiella followed by Pseudomonas) • Klebsiella was 87.5% and 78.3% resistance to ampicillin and gentamycin respectively. • Gram negative isolates :87.5% and 77.2% were resistance to ampicillin and gentamycin respectively. • Among gram positive isolates 58.5% and 31.5% resistance to ampicillin and gentamycin respectively. • Resistance to cefotaxim to gram negative and gram positive isolates were 87.34% and 59.35% respectively.
  38. 38. Bhat Y R, Lewis LE, K E V. . Bacterial isolates of early-onset neonatal sepsis and their antibiotic susceptibility pattern between 1998 and 2004: an audit from a center in India. Ital J Pediatr. 2011 Jul 11;37:32. doi: 10.1186/1824-7288-37-32 • 2182 neonates screened, 389 (17.8%) positive blood cultures. • Gram negative species 90.8% of culture isolates. • Pseudomonas (33.2%) and Klebsiella (31.4%) • Acinetobacter (14.4%), Staphylococcus aureus (9.2%), E.coli (4.4%), Enterobacter (2.2%), Citrobacter (3.1%) and Enterococci (2.2%). • In Gram negative group, best susceptibility was to Amikacin (74.5%), followed by other aminoglycosides, ciprofloxacin and cefotaxime. The susceptibility was remarkably low to ampicillin (8.4%). • Gram positive group: susceptibility of 42.9% to erythromycin, 47.6% to ciprofloxacin and above 50% to aminoglycosides. • Of all isolates, 83.8% were susceptible to either cefotaxime or amikacin
  39. 39. NICE GUIDELINE ON EARLY NEONATAL INFECTION • Risk factors for infection  Pre-labour rupture of membranes  Preterm birth (<37 weeks), especially with pre-labour rupture of membranes  Confirmed or suspected chorioamnioitis it is (e.g. intrapartum fever)  Invasive GBS infection in a previous baby  Antibiotic treatment given to mother for confirmed or suspected invasive bacterial infection 24 hours before, during, or 24 hours post labour
  40. 40. Clinical Indicators Suggestive of Infection • Altered behaviour or responsiveness • Altered muscle tone • Feeding difficulties (e.g. feed refusal) • Feed intolerance (e.g. abdominal distension, vomiting) • Altered heart rate • Signs of respiratory distress • Oxygen desaturation • Apnoea • Signs of perinatal asphyxia or hypoxic ischaemia • Seizures • Need for mechanical ventilation (especially term baby)
  41. 41. • PPHN • Temperature abnormality not explained by environment • Signs of shock • Unexplained bleeding disorder ( e.g. thrombocytopenia, INR <2) • Oliguria • Hypo/hyperglycaemia • Metabolic acidosis (BE -10 or greater) • Local signs of infection e.g. skin, eyes • Confirmed or suspected sepsis in a co-twin
  42. 42. Red Flag Signs Suggestive of Neonatal Infection • Systemic antibiotics given to mother for suspected bacterial infection within 24 hours of birth • Seizures • Signs of shock • Need for mechanical ventilation in a term baby • Suspected or confirmed infection in a co-twin
  43. 43. Actions • Any red flags or no red flags but 2 or more risk factors or clinical indicators, perform investigations including blood cultures and start antibiotics
  44. 44. • No red flag or clinical indicators but one risk factor or no red flags or risk factors but one clinical indicator 1. Use clinical judgement and consider withholding antibiotics 2. Monitor baby for clinical indicators of possible infection, including the vital signs 3. Monitor for at least 12 hours from birth (at 1 hors, 2 hours and then 2 hourly for 10 hours) 4. If further clinical concerns perform investigations including blood cultures and start antibiotics
  45. 45. • If a decision is made to give antibiotics aim to start within 30 minutes and always within 1 hour of the decision
  46. 46. Choice of Antibiotics • Use benzyl penicillin and gentamicin as first choice for empirical treatment of suspected infection • Benzylpenicillin  25mg/kg 12 hourly  50mg/kg 12 hourly if baby appears very ill • Gentamicin  4.5 mg/kg  If a second does is to be given (see below) give 36 hours after the first dose  The interval may be shorted based on clinical judgement e.g. for gram –ve infection or if the baby appears very ill
  47. 47. Duration of antibiotic treatment • Consider stopping after 36 hours  If initial clinical suspicion of infection was not strong and  CRP < 10mg/l on both tests and  Blood culture is negative and  The baby is well with no clinical indicators of possible infection • Treat for 5 days if  Strong clinical suggestion of infection  Continued clinical concerns about infection at 36 hours  CRP > 10 mg/l on either measurement  Positive blood culture
  48. 48. • Continue antibiotics beyond 5 days if The baby did not fully recovered at 5 days or This is advisable based on the blood culture result and expert microbiological advice if necessary
  49. 49. Meningitis • If meningitis is suspected but gram stain is uninformative use an antibiotic regimen based on local expert microbiological advice • Review treatment decisions taking into account subsequent CSF results • If CSF Gram stain suggest Group B Streptococcus give benzyl penicillin 50mg/kg 12 hourly and gentamicin 4.5 mg/kg every 36 hours • If culture confirms GBS continue benzylpenicillin for at least 14 days and gentamicin for 5 days • If CSF Gram stain or culture suggests any organism other than GBS. use an antibiotic regimen based on local expert microbiological advice
  50. 50. • In a randomized study, Metsvaht et al. • Ampicillin versus penicillin G both combined with gentamicin in the empirical treatment of neonates ( = 2 8 3) • The clinical failure rate was not different between the two groups (14.1% versus 14.2%).
  51. 51. Choice and Duration of Antimicrobial Therapy for Neonatal Sepsis and Meningitis International Journal of Pediatrics Volume 2011 (2011) • Based on current available evidence, the combination of ampicillin and gentamicin is an appropriate choice for empirical therapy of EOS in neonates, where GBS and E. coli continue to be the predominant organisms. • Expansion of antimicrobial spectrum and also offers synergistic bacterial killing. • Low cost and low rates of emergence of bacterial resistance. • In developing countries, empiric antibiotic therapy should be based individualized for each hospital or region.
  52. 52. Late onset sepsis • CoNS : most common pathogen in LOS followed by S. aureus, Enterococcus spp., and GBS; Gram- negative organisms account for 18–20% of LOS. • The empirical antimicrobial therapy : both Gram- positive and Gram-negative organisms. • In the developed countries, where CoNS is the predominant nosocomial pathogen and where resistance of these isolates to penicillin, semisynthetic penicillin, and gentamicin are common, experts recommend the use of vancomycin as empirical therapy.
  53. 53. • Among 18 participating NICUs in Australasian study group for neonatal infection, nine units used vancomycin and an aminoglycoside as the first-line empirical treatment for LOS • Their mortality from CoNS sepsis was comparable to ampicillin or flucloxacillin together with an aminoglycoside.
  54. 54. • In developing nations, higher percentage of Gram- negative bacteria and greater antimicrobial resistance • About 70% of these isolates may not be covered by the empiric regimen of ampicillin and gentamicin.( Zaidi et al) • High proportion of methicillin-resistant S. aureus (MRSA) strains in many areas, especially south Asia (56%)
  55. 55. • The Cochrane review : study by Miall-Allen et al • Timentin (ticarcillin and clavulanic acid) monotherapy with a combination of flucloxacillin and gentamicin in 28 neonates with suspected LOS • No difference in outcome (mortality/treatment failure) between the two groups.
  56. 56. • Inadequate evidence from randomized trials in favor of any particular antimicrobial regimen for the empirical treatment of suspected LOS. • Vancomycin and third-generation cephalosporin (e.g., cefotaxime) : cardiorespiratory instability and in areas where MRSA is prevalent. • Vancomycin as the initial therapy: emergence of vancomycin-resistant enterococci and its overuse in cases where CoNS isolates represent mere contaminants.
  57. 57. Duration of antibiotic therapy • The duration of antimicrobial therapy for culture-proven sepsis depends on the initial response to the appropriate antimicrobial agent. • Paucity of RCTs evaluating the rationale and safety of the appropriate duration of therapy
  58. 58. • Engle et al. randomized cases of neonatal pneumonia to either 4-day or 7-day course of antibiotics. • Randomization was done on day 4 of antibiotic therapy if the infants were completely asymptomatic for at least 48 hours. • The success of therapy was similar in both the groups
  59. 59. • Chowdhary et al. compared the effectiveness of 7-day versus 14-day antibiotic therapy in 69 infants with blood culture-proven bacterial sepsis. • Randomization on day 7 of antibiotics if the infant had clinical remission by day 5. • More treatment failures in 7-day group • Treatment failures occurred in subjects with S. aureus infection receiving 7-day course
  60. 60. • Gathwala et al. • 10-day versus 14-day course culture-proven neonatal sepsis • Sixty infants were included. • Clinical remission with negative C-reactive protein (CRP). • Cefotaxime and amikacin • 10-day antibiotic therapy is as effective as 14-day therapy in blood-culture-proven neonatal sepsis, if the infant has achieved clinical remission by day 7 of therapy.
  61. 61. • There is limited evidence for infants with younger gestational age (<32 weeks), who are at the highest risk for sepsis. • It is reasonable to treat for 10–14 days with appropriate antimicrobial agents in infants with blood- culture-proven sepsis. • However, in selected situations (neonates ≥32 weeks gestation and ≥1500 grams, who become asymptomatic within 5 days of appropriate therapy), consider stopping antibiotics at 7–10 days, provided appropriate followup can be ensured.
  62. 62. Antimicrobial Choice and Duration of Therapy for Neonatal Meningitis • In 2004, Infectious Disease Society of America 1. EOS, ampicillin with either an aminoglycoside or cefotaxime 2. Late-onset meningitis, a regimen containing an antistaphylococcal antibiotic, such as nafcillin or vancomycin, plus cefotaxime or ceftazidime with or without an aminoglycoside is recommended
  63. 63. • The duration of antimicrobial therapy in the patient with bacterial meningitis has often been based more on tradition than on evidence-based data. • GBS meningitis is usually treated for 14 to 21 days • For uncomplicated neonatal meningitis caused by Gram-negative bacteria, a minimum of 21 days is recommended . • However, these guidelines are not standardized and the duration of therapy may need to be individualized on the basis of the patient’s clinical response.
  64. 64. • Combination of ampicillin and cefotaxime or ampicillin and aminoglycoside is appropriate for treatment of suspected early-onset neonatal meningitis. • For suspected late-onset meningitis, a combination of vancomycin plus a third-generation cephalosporin is recommended while awaiting CSF culture and susceptibility results. The duration of antimicrobial therapy for neonatal meningitis should be 14 to 21 days for GBS, ≥21 days for L. monocytogenes meningitis, and minimum of 21 days for Gram-negative meningitis.
  65. 65. Adverse Effects with Prolonged Duration of Antibiotic Therapy • A 19-center study of 5693 ELBW • Infants with sterile cultures who began initial empirical antibiotic treatment within the first 3 postnatal days • Median duration of empirical antibiotic treatment was 5 days. • Prolonged duration of antibiotic therapy defined as >5 days) was associated with NEC or death (OR 1.30) or death alone (OR 1.46) • Each additional day of antibiotic therapy was associated with a 4% increase in the odds of NEC or death, a 7% increase in the odds of NEC alone, and a 16% increase in the odds of death alone.
  66. 66. • A case-control study in single center. • 124 NEC cases vrs 248 controls on the basis of gestational age, birth weight, and year of admission. • Each day of antibiotic exposure was associated with a 20% increase in the risk of NEC.
  67. 67. • Prolonged antibiotic therapy has also been associated with LOS • 5693 subjects, increased risk of the combined outcome of LOS caused by organisms other than coagulase-negative Staphylococcus or death (4 days: OR: 1.32 ) (5 days: OR: 1.24)
  68. 68. Nosocomial sepsis • Klebsiella spp. (39.6%), Pseudomonas aeruginosa (11.3%) and Coagulase-negative staphylococci (9.4%). Baş AY, Demirel N, Zenciroglu A, Göl N, Tanir G. Nosocomial blood stream infections in a neonatal intensive care unit in Ankara, Turkey. Turk J Pediatr. 2010 Sep-Oct;52(5):464-70. • Staphylococcus aureus (18.5%), Acinectobacter baumannii (16.3%), Klebsiella pneumoniae (11.9%), Escherichia coli (9.6%), and Pseudomonas aeruginosa (8.1%). Tseng YC, Chiu YC, Wang JH, Lin HC, Lin HC, Su BH, Chiu HH. Nosocomial bloodstream infection in a neonatal intensive care unit of a medical center: a three-year review. J Microbiol Immunol Infect. 2002 Sep;35(3):168-72.
  69. 69. • Acinetobacter spp. (47.9%), Pseudomonas spp, (23.6%), Klebsiella/Enterobacter spp. (8.3%), Coagulase-negative staphylococci (8.3%) and Staphylococcus aureus (6.3%) Markovid-Denid L, Durisid J, Nikolid T, Ramadani R, Ilid S, Stevanovid S. Causative agents of neonatal nosocomial infections and their resistance to antibioticsMed Pregl. 2006 Mar-Apr;59(3-4):155-9.
  70. 70. Ventillator associated pneumonia • Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter spp predominant. (Witaya Petdachai in 2004)
  71. 71. Catheter-related bloodstream infection • Gram-positive cocci, which are responsible for at least two-thirds of infections • De Brito et al : coagulase- negative Staphylococci (CoNS) the most common and S. aureus the second leading cause
  72. 72. Amino glycosides Ampicillin Meropenem Cefotaxim Ceftazidime Pseudomonas + + + Klebsiella + + + + CONS Staph + E Coli + + + + Acinetobactor +
  73. 73. Fluro Quino lones Cloxa cillin Piperac illin tazobac tam Vancomycin Aztreo nam Linezolid Pseudomo nas + + + Klebsiella + + CONS + + Staph + + + + + E Coli + + + Acinetoba ctor +
  74. 74. • Prophylactic antibiotics • They are given to prevent infection. • Not indicated in almost all situations in neonatology. • High level evidence: not useful for the prevention of infection following umbilical vessel or central venous catheterisation • Antibiotics for all infants receiving mechanical ventilation not supported by evidence from randomised controlled trials.
  75. 75. • The only prophylactic use of antimicrobials: fungal prophylaxis in preterm infants on broad spectrum antibiotics or with central arterial or venous lines. • A Cochrane systematic review: antifungals reduce the incidence of systemic fungal infections. • To date there is no evidence that use of oral prophylactic antifungal agents has changed the susceptibility of infecting organisms.
  76. 76. Prophylactic antifungal agents • The antifungal prophylaxis guideline (Royal Maternity Hospital, Belfast) • VLBW baby should be considered for antifungal prophylaxis if : • under treatment with a third generation cephalosporin • under treatment for more than 10 consecutive days with a systemic broad spectrum antibiotic • fungal colonisation from surface sites and a central venous catheter in situ.
  77. 77. Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants. Austin N, McGuire W. Cochrane Database Syst Rev. 2013 • 11 eligible trials enrolling a total of 1136 infants • Seven trials (involving 880 infants) compared systemic antifungal prophylaxis versus placebo or no drug • Statistically significant reduction in the incidence of invasive fungal infection in infants • Meta-analysis did not find a statistically significant difference in the risk of death prior to hospital discharge • Very limited data on long-term neurodevelopmental outcomes were available.
  78. 78. Prophylactic oral antifungal agents to prevent systemic candida infection in preterm infants. Austin N, McGuire W. Cochrane Database Syst Rev. 2004 • 3 eligible trials • Nystatin with no treatment (67 infants) • Miconazole with placebo (600 infants) • Nystatin with fluconazole (21 infants).
  79. 79. • Nystatin versus no treatment, systemic fungal infection was significantly reduced • Miconazole with placebo: no significant effect • Neither study found a significant effect on mortality, • No significant difference in the mean number of days infants received ventilation or stayed in the neonatal intensive care unit. • Oral fluconazole with nystatin, no significant difference in systemic fungal infection or mortality was reported.
  80. 80. Selective fluconazole prophylaxis in high‐risk babies to reduce invasive fungal infection Brian A McCrossan, Elaine McHenry, Fiona O'Neill, Grace Ong, and David G Sweet Arch Dis Child Fetal Neonatal Ed v.92(6); Nov 2007 • Fluconazole 6 mg/kg for 3 weeks. Dose interval every 72 h during the first 2 weeks of life. Thereafter, dose interval reduced to every 48 h until 3 weeks old when daily fluconazole is given. • 6/33 babies eligible for prophylaxis developed culture proven Candida sepsis before compared with no (0/31) babies after the guideline was implemented (p=0.03). • Selective antifungal prophylaxis has reduced invasive fungal sepsis
  81. 81. References • Choice and Duration of Antimicrobial Therapy for Neonatal Sepsis and Meningitis International Journal of Pediatrics Volume 2011 (2011) • Cochrane Database Syst Rev. 2013 • Prolonged Initial Empirical Antibiotic Treatment is Associated with Adverse Outcomes in Premature Infants J Pediatr. 2011 November ; 159(5): 720–725. • Choosing the right empirical antibiotics for neonates Arch Dis Child Fetal Neonatal Ed. 2011 January ; 96(1): F2–F3. • Rationing antibiotic use in neonatal units Arch Dis Child Fetal Neonatal Ed 2000;82:F1–F2 • Antibiotic Use and Misuse in the Neonatal Intensive Care Unit Clin Perinatol. 2012 March ; 39(1): 61–68.