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Copy of Antibiotic Choice for NEC
Transcript of Copy of Antibiotic Choice for NEC
is admitted to the ward for sick neonates on the 7th of November (1826). She shows generalized redness of the integuments and edematous extremities. The temperature of her skin is normal, her cry unaltered; her pulse irregular at a rate of 92/min. The infant has copious green-stained diarrhea. An intense perianal redness is noticed; the abdomen is swollen. On the 12th the green stool is mixed with streaks of blood. ... On the 14th the infant yields a large amount of blood with the stool; her face is thin, livid and entirely distorted; she vomits the administered liquids;
her extremities are cold and livid, her belly is tense; the heartbeat
extremely slow; finally she dies in the evening yielding a large
quantity of black liquid blood through the anus. – When opening
the body on the next morning ... the duodenum is in healthy state,
the terminal ileum is intensely red and swollen, its mucosa friable
and the surface covered with blood. When these fluids are removed,
the membrane looks rough and bloody; its surface furrowed
by numerous wrinkles between which there are deep and
black lines with the aspect of being burned by nitric acid. In addition to these blackish furrows, there are a large number of spots or ecchymoses with the same appearance in different regions of the colon. On these spots the mucosa is so soft that it turns to mash when scraped with the fingernail ...’
- Charles Billard, Paris, 1826 Historical Perspective ‘‘Pathoanatomically it is an exceptionally characteristic enterocolitis predominantly in the ileocecum and the physiologic colon curvatures. It is frequently complicated by peritonitis due to transmigration or perforation. A specific pathogen could not be proven.’
- Kurt Schmidt and Karl Quaiser, Graz, 1952 (They coined the name ‘enterocolitis ulcerosa necroticans’) Pathophysiology Immature Mucosal Barrier Increased permeability of mucosa, leading to ease of bacterial translocation Immature local host defenses Circulatory Instability Exposures Subtle reduction in blood flow and subsequent reperfusion may contribute to bowel injury Implicated (but still no evidence!)
hypoxia from severe RDS
congenital heart disease, PDA, heart failure
umbilical artery catheterization
RBC and exchange transfusion
maternal cocaine use
These kids are all sick! Premies! Formula, breastmilk's oligosacchrides protect against NEC
Hyperosmolar medications (theophyline, MVIs, phenobarbital)
pH-altering medications (H-2 blockers)
Early & prolonged antibiotics Microbial Bowel Overgrowth Immature motility and function
delayed transit time = overgrowth
Altered flora from use of anti/probiotics Treatment Surgical Medical I remember hearing my father express his perplexity about how [necrotizing enterocolitis] could occur and how he felt that a surgical approach, although clearly mitigating once the condition had occurred, was not the right solution to the problem.
...I began to appreciate more fully my father's perplexity and his frustration as a surgeon in addressing a problem that, by its nature, was already at end-stage when he confronted it and the possibility of prevention or interruption of the process was already past."
- Dr. David Stevenson about his father, John Stevenson, pediatric surgeon at Seattle Children's in the 1960s (who published much of the early literature about NEC) Prevention
Types, timing, rates of advancement of feeds
Human milk isolates (lactoferrin)
Bowel rest and decompression, antibiotics But which antibiotics?! Choosing the "right" antibiotics They have to cover the right bugs They should be based on evidence
(or expert opinion) They should cause the fewest side-effects We know the normal colonization at birth from rectovaginal flora
Bugs that have been linked to NEC:
Gram + cocci (strep pneumo, enterococci, staph aureus, coag - staph)
Aerobic and anaerobic enterobacters (E.coli, klebsiella pneumoniae, bacteroides fragilis, enterobacter cloacae
Clostridia (gram + anaerobic)
viruses and fungi have been implicated as well Only 3 studies directly compared effectiveness of different ABx regimens Scheifele, et al, 1987
Amp & Gent vs. Vanc & CTX
No differences in BW > 2200g
In BW < 2200g:
Vanc & CTX with lower rates of death (V/C 0/30 vs. A/G 5/38, P=0.048)
Vanc & CTX with lower rates of need for surgery (V/C 4/30 vs. A/G 13/38, P=0.04)
Vanc & CTX with lower rates of culture-positive peritonitis (V/C 1/30 vs. A/G 10/38, P=0.01)
Vanc & CTX with lower rates of major complications (peritonitis, strictures, feeding intolerance, recurrent NEC) (V/C 10/30 vs. A/G 26/38, P=0.004)
Vanc & CTX with lower rates of thrombocytopenia (V/C 2/329 vs. A/G 13/35, P=0.01) Faix, et al, 1988
Amp & Gent vs. Amp/Gent/Clinda
A/G with lower rates of strictures (A-G 1/18 vs. A-G-C 6/15, P<0.05)
No sig differences in rates of death, gangrene/perforation
Stopped early because of strictures in clinda group
BUT 2 pts in A/G group were treated with clinda too because of clinical deterioration after 24 hrs... Hansen, et al, 1980
Amp& Gent vs. Amp, Gent, & Oral Gent
No sig differences in outcomes (days with peritonitis, days with pneumatosis, major complications)
Avg peak serum gent levels were higher in the A/G/oG group, but there were no differences in trough levels
Underpowered study, blinding was no defined, more mature infants (avg 34-35 weeks) Future study:
Sinn, et al, current
Protocol now on Cochrane Database enrolling pts to randomized, double-blinded study comparing efficacy of different antibiotic regimens (including monotherapy) on mortality and need for surgery Known toxicities of antibiotics
Gent and vanco (ototoxicity, nephrotoxicity)
Antibiotic stewardship/propogation of antibiotic resistence
Choose the narrowest spectrum empiric drug possible for adequate and safe coverage, then pull back once you've identified the bug 2012
CONNECTICUT CHILDREN'S MEDICAL CENTER
ANTIMICROBIAL SUSCEPTIBILITY PROFILE
GRAM NEGATIVES # AMP CFZ CIP COT FOX GEN LEV MER PIM TAX TAZ TOB TRI ZOS NIF AZT
Enterobacter cloacae 53 96 89 91 98 100 92 79 83 91 81 87 47 84
Escherichia coli 349 53 91 93 80 99 93 93 100 97 97 97 94 97 97 99 97
Klebsiella pneumoniae 63 89 97 92 95 92 97 100 97 97 97 92 97 97 62 94
Proteus mirabilis 34 82 88 100 91 97 100 100 100 100 97 100 97 100 100 97
Pseudomonasaeruginosa 86 87 78 84 91 86 94 91 91 84
Serratia marcescens 38 84 92 29 79 92 100 100 95 95 66 97 86 95
Stenothrophomonas 30 90 83 27
GRAM POSITIVES # AMP CFZ COT CLI LEV OXA TET VAN ERY NIF
Staph aureus MSSA 261 100 100 79 100 95 100 62 100
Staph aureus MRSA 254 100 91 98 100 13 100
Staph NOT aureus 164 48 77 54 48 90 100 29 100
Streptococcus pneumo 35 69 97 100 66
Enterococcus faecalis 120 100 12 100 100
Enterococcus faecium 12* 67 58 75 33 Summary:
Is clinda the best choice for anaerobic coverage? Is it safest?
Unasyn covers everything A/G/C cover
Neither unasyn or A/G/C cover pseudomonas. To get that, zosyn would do it
Monotherapy may be easier to dose, come with fewer mistakes, have fewer side effects, and propagate less resistance. Head-to-head trials are anticipated at this time. Most commonly used regimens
Most largely based on severity of illness and gram negative resistance patterns
CCMC/UConn: A/G/C x5-7 days
All over the internet (A/G/Flagyl)
UpToDate: Vanco, Gent, Zosyn, until cultures negative, then d/c all but Zosyn References 1. Schanler RJ, Abrams, SA. Pathology and pathogenesis of necrotizing enterocolitis in newborns. In: UpToDate, Kim, MS (Ed), UpToDate, Waltham, MA, 2012.
2. Murdoch EM, Sinha AK, Shanmugalingam ST, et al. Doppler flow velocimetry in the superior mesenteric artery on the first day of life in preterm infants and the risk of neonatal necrotizing enterocolitis. Pediatrics 2006;118:1999.
3. Guillet R, Stoll BJ, Cotten CM, et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006;117:e137.
4. Scheifele DW, Ginter GL, Olsen E, et al. Comparison of two antibiotic regimens for neonatal necrotizing enterocolitis. J Antimicrob Chemother 1987;20:421-429.
5. Faix RG, Polley TZ, Grasela TH. A randomized, controlled trial of parenteral clindamycin in neonatal necrotizing enterocolitis. J Pediatr 1988;112:271-277.
6. Hansen TN, Ritter DA, Speer ME, et al. A randomized, controlled study of oral gentamicin in the treatment of neonatal necrotizing enterocolitis. J Pediatr 1980;97:836-839.
7. Vermeylen D, De Laet MH, Pardou A, et al. Neonatal necrotizing enterocolitis: from reduction of mortality to reduction of morbidity. Acta Anaesthesiol 1985;36:253-159.
8. Sinn JKH, Shah D. [Intervention Protocol] Antibiotic regimens for the empirical treatment of newborn infants with necrotizing enterocolitis. Cochrane Database of Syst Reviews 2008;4:CD007448.
9. Schanler RJ, Abrams, SA. Management of necrotizing enterocolitis in newborns. In: UpToDate, Kim, MS (Ed), UpToDate, Waltham, MA, 2012.
10. Stevenson DK, Blakely ML. Historical Perspectives: Necrotizing Enterocolitis: An Inherited or Acquired Condition? NeoReviews 2006;7:e125.
11. Obladen M. Necrotizing Enterocolitis - 150 Years of Fruitless Search for the Cause. Neonatology 2009;96:203-210.