The Use and Misuse of Antimicrobials in NICU Ban AL-Sayyed, MD, FAAP, FIDSA Pediatric Infectious Diseases Consultant KFSH& RC

A 20 day old male, X- 27 wk, 900 gm. Developed fever of 38.7 C 0 and apnea. He’s been intubated since admission. An axillary central line was inserted 10 days ago. He received several PRBC transfusions and two courses of IV antibiotics. Blood cultures were sent and they are pending. Is he septic? What is your differential? What is your empirical antibiotic coverage?

Sepsis in Neonates Early onset sepsis (EOS) L ess than 48 to 72 hours Incidence of EOS in VLBW is 2% Late onset sepsis; (LOS) Incidence is higher in premature infants 15% for g 20-25% for infants <1500 g 28% for infants g 43% for infants <750 g

Incidence of Early- and Late-onset Sepsis during Neonatology 2009; 97: GBS Screening

Distribution of Gram-positive and Gram- negative Microorganisms causing Early-Onset Sepsis during Neonatology 2009; 97: 22-28

Early Onset Sepsis Annual Cumulative Incidence (NICU 1997 and 2007) Antibiotics GBS

What is a Nosocomial Infection? CDC: Any infection occurring after admission to hospital, not transplacental Risk factors: - Gestational age and birth weight - Maternal infection - Intrinsic Immunologic Factors: Poor chemotaxis, low levels immunoglobulins, low CH50 Decreased number of CD3, CD4, CD8, and NK cells - Poor skin integrity - Immature gastrointestinal development - Extrinsic Factors: Instrumentation, Procedures

PEDIATRICS Vol. 103 No. 4 April 1999

Late Onset Sepsis Annual Cumulative Incidence (NICU 1997 and 2007)

Neonatology 2009; 97: 22-28

Coag neg Staph Neonatology 2009; 97: 22-28

Journal of Perinatology (2004) 24, 382–388 Pathogen Distribution

Pathogen Distribution in Abha EMHJ Vol. 16 No

Summary Pathogen distribution: Gram positive organisms 50-60% Gram negative organisms 20% Fungal pathogens increasing- ~ 10% Clinical signs and symptoms: Non specific Temperature instability (51%), jaundice (35%), respiratory distress (33%), feeding problems (28%), lethargy (25%), pallor and/or cyanosis (24%), apneic attacks and/or bradycardias (22%), and distended abdomen (17%)

Back to the Case The culture from CVC came back as: Gram negative bacilli. You called the Lab, and the technician said,” it ferments lactose.” How will you change your coverage? Would you do a combination therapy? Why?

Antibiotic Use in NICU

Variation in Antibiotic Use in NICU J Antimicrob Chemother doi: /jac/dkq107

CDC 12-Step Guidelines oppematerjalid/children.pdfhttp:// oppematerjalid/children.pdf Multicenter retrospective observational study of antibiotic use targeted 4 tertiary NICUs to assess adherence Antibiotic regimens, clinical and microbiological data, indications for initiation and continuation of antibiotics (after 72 h of use) were recorded PID Journal Volume 28, Number 12, December 2009

Definition of Inappropriate Use PID Journal Volume 28, Number 12, December 2009

Summary 200 neonates received 323 antibiotic courses totaling 3344 antibiotic-days 28% of courses and 24% of days were judged to be nonadherent to a CDC 12-Step Campaign Inappropriate use was more common with continuation of antibiotics (39%) than with initiation (4%) of therapy Vancomycin was the most commonly used drug of which 284 (32%) days were considered inappropriate Carbapenems were used less frequently (n = 310 antibiotic- days), and 132 (43%) of these days were inappropriate

Summary 2 Nonadherence to CDC 12 step was because of : - Failure to narrow the spectrum - Prolonged antibiotic prophylaxis after surgeries and certain procedures - Treatment of colonization rather than real infection - No targeting of the pathogen

Back to Case The patient’s antibiotics were changed from ceftazidime and vancomycin to meropenem + gentamcin + vancomycin pending sensitivity of the CVC blood culture isolate. The identification revealed Klebsiella oxytoca. The tracheal aspirate grew Stenotrophomonas maltophilia and the patient had a positive nasal PCR for MRSA. Do you agree? How can you modify the antibiotics?

Emerging Infections

Courtesy of CDC

J Antimicro Chemother Jul; 58 (1):

Facts about ESBL Gram-negative species These organisms are resistant to all ß-Lactam antibiotics except cephamycins (cefoxitin, cefotetan) and carbapenems They are frequently resistant to many other classes of antibiotics, including aminoglycosides and fluoroquinolones High rates of third-generation cephalosporin use have been implicated as a major cause of this problem. (Ceftazidime) Carbapenems are the most active and reliable treatment options for infections caused by ESBL isolates Overuse of carbapenems may lead to resistance of other gram- negative organisms; Pseudomonas

Antibiotic Stewardship

IDSA Guidelines Prospective audit with intervention and feedback Education Guidelines and clinical pathways Antimicrobial cycling Antimicrobial order forms Combination therapy Streamlining or de-escalation of therapy Dose optimization The application in pediatrics is not commonly used

Antibiotic Restriction Seoul National Children’s University Hospital High rates of ESBL K pneumoniae (64%) in late 1990’s campaign to decrease use of extended-spectrum cephalosporins Encouraged use of piperacillin/tazobactam Reductions in overall rates, did not elaborate on other interventions

Restriction of Cephalosporins and ESBL in a NICU indianpediatrics.net/sep2010/785.pdf

Antibiotic Cycling A recent systematic review found only four studies worthy of inclusion and concluded that antibiotic cycling could not, at present, be promoted as a methodology to control resistance

Journal of Neonatology Vol. 21, No. 1, Jan. - Mar. 2007

Antibiotic cycling: more than it might seem? Good for Gram-negative resistance control Where antibiotic cycling is introduced and no specific susceptibility problem exists, it can still reduce background levels of resistance for Gram-negative pathogens, not for Gram-positive organisms Helps in reduction of ICU ventilator-associated pneumonia, less convincingly for other types of sepsis.

continue Where antibiotic cycling is introduced, there is an improvement in effective antibiotic prescribing in ICU There is a reduction in ICU mortality rates Journal of Antimicrobial Chemotherapy (2005) 55, 1–5

Journal of Neonatology Vol. 21, No. 1, Jan. - Mar. 2007

“The ideal way to get rid of any infectious disease would be to shoot instantly every person who comes down with it." H. L. Mencken