173
Journal of Neonatal-Perinatal Medicine 6 (2013) 173–177 DOI 10.3233/NPM-1365512 IOS Press
Case Report
Gentamicin resistance among Escherichia coli strains isolated in neonatal sepsis J. Hasvold∗ , L. Bradford, C. Nelson, C. Harrison, M. Attar and T. Stillwell University of Michigan, Ann Arbor, MI, USA
Received 26 September 2012 Revised 12 January 2013 Accepted 28 January 2013
Abstract. Neonatal sepsis is a significant cause of morbidity and mortality among term and preterm infants. Ampicillin and gentamicin are standard empiric therapy for early onset sepsis. Four cases of neonatal sepsis secondary to Escherichia coli (E. coli) found to be gentamicin resistant occurred within a five week period in one neonatal intensive care unit (NICU). To determine whether these cases could be tied to a single vector of transmission, and to more broadly evaluate the incidence of gentamicin resistant strains of E. coli in the neonatal population at our institution compared to other centers, we reviewed the charts of the four neonates (Infants A through D) and their mothers. The E. coli isolates were sent for Pulse Field Gel Electrophoresis (PFGE) to evaluate for genetic similarity between strains. We also reviewed all positive E. coli cultures from one NICU over a two year period. Infants A and B had genetically indistinguishable strains which matched that of urine and placental cultures of Infant B’s mother. Infant C had a genetically distinct organism. Infant D, the identical twin of Infant C, did not have typing performed. Review of all cultures positive for E. coli at our institution showed a 12.9 percent incidence of gentamicin-resistance. A review of other studies showed that rates of resistance vary considerably by institution. We conclude that gentamicin-resistant E. coli is a relatively uncommon cause of neonatal sepsis, but should remain a consideration in patients who deteriorate despite initiation of empiric antibiotics. Keywords: Neonatal sepsis, antibiotic resistance
1. Introduction Neonatal sepsis is associated with significant morbidity and mortality, particularly in preterm and very low birthweight (VLBW) neonates [1]. Escherichia coli (E. coli) is the most frequent early onset sepsis (EOS) pathogen among preterm infants in the United States and a significant cause of morbidity and mortality in this population. The incidence of E. coli sepsis is inversely proportional to neonatal birth weight, which ∗ Corresponding author: Dr. Jennifer Hasvold, Department of Pediatrics, Mott Children’s Hospital, Ann Arbor MI, 48103, USA. E-mail: [email protected].
means the most vulnerable neonates are also the most likely to develop sepsis secondary to E. coli [2]. Gentamicin is commonly used for empiric treatment of EOS and late onset neonatal sepsis (LOS) [3]. There is a growing concern that empiric sepsis regimens are less sensitive and inclusive than they were in previous eras; this concern also holds true for gentamicin as an agent for empiric coverage of gram negative rods in the neonatal population [4, 5]. We report four cases of gentamicin-resistant E. coli sepsis which occurred over a five week period in our neonatal intensive care unit (NICU), as well as the prevalence of gentamicin resistance at our institution and the infection control epidemiologic investigation that followed. We also
1934-5798/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
174
J. Hasvold et al. / Gentamicin resistant Escherichia coli in neonatal sepsis
summarize the current literature regarding gentamicinresistant E. coli in neonatal populations. We obtained approval for this review from our Institutional Review Board.
2. Case reports Infant A was a 770 gram male born via vaginal delivery at 24 weeks gestation. The mother received seven days of ampicillin/amoxicillin and erythromycin for prolonged premature rupture of membranes (PPROM) and received ampicillin and gentamicin on the day of delivery for presumed chorioamnionitis. She received two doses of betamethasone prior to delivery. Infant A was started on ampicillin and gentamicin for suspected EOS. The initial blood culture was negative; antibiotics were discontinued. On day of life (DOL) 3 he became hypotensive and acidotic. Vancomycin and gentamicin were started for suspected sepsis and necrotizing enterocolitis (NEC). Care was withdrawn that day; subsequently, blood and peritoneal fluid cultures grew gentamicin-resistant E. coli. Infant B is a 680 gram male born via vaginal delivery at 23 weeks gestation. Pregnancy was complicated by gonorrheal infection treated with ceftriaxone, PPROM, advanced cervical dilation, and bulging membranes. The mother received seven days of ampicillin/amoxicillin and erythromycin for PPROM and two doses of betamethasone. The infant was treated with ampicillin and gentamicin for suspected EOS. His clinical course was complicated by NEC and postnatal cytomegalic virus infection. The blood culture on DOL one grew gentamicin-resistant E. coli, as did a urine culture on DOL 52 and a tracheal aspirate culture on DOL 77. The mother’s urine culture from the day prior to delivery and placental culture also grew gentamicin-resistant E. coli. This patient survived to be discharged home from his initial hospitalization. Infant C is a 1210 gram male born via cesarean section at 28 weeks gestation. Pregnancy was complicated by dichorionic-diamniotic twin gestation and premature labor. The mother was admitted on the day of delivery and received single doses of clindamycin and gentamicin prior to the cesarean section. She received two doses of betamethasone one month before and one dose just prior to delivery. Infant C was started on ampicillin and gentamicin for suspected EOS. The initial blood culture remained negative; antibiotics were discontinued. On DOL eight, Infant C experienced per-
sistent desaturations, bilious residuals, hypotension, and hyperglycemia. He was treated with empiric vancomycin and gentamicin. Blood and cerebral spinal fluid (CSF) cultures grew gentamicin-resistant E. coli. Blood and urine cultures grew gentamicin-resistant E. coli again on DOL 109 when he was evaluated and treated for sepsis. The mother had a urine culture obtained eight days following giving birth which grew gentamicin-resistant E. coli. This infant survived to be discharged home from the initial hospitalization. Infant D, twin of infant C, is a 1130 gram male born via cesarean section at 28 weeks gestation. Infant D was prenatally diagnosed with myelomeningocele. He was started on ampicillin and gentamicin for suspected EOS but was then transitioned to cefazolin on DOL five for empiric coverage for indwelling surgical drains after myelomeningocele repair. On DOL ten, he developed leukocytosis and hyperglycemia; cefazolin was changed to vancomycin, and piperacillin/tazobactam was added. He was ultimately treated with a 21-day course of vancomycin, meropenem, and fluconazole for culture-negative sepsis. On DOL 38, he developed NEC and was started on vancomycin, gentamicin, piperacillin/tazobactam, and fluconazole. The blood culture on DOL 38 grew gentamicin-resistant E. coli. A tracheal aspirate culture on DOL 54 and a urine culture at five months of age also grew gentamicin-resistant E. coli. This infant survived to be discharged home from the initial hospitalization.
3. Infection control evaluation These four cases occurred over the course of five weeks. Infants A, B and C had their initial positive blood cultures drawn on the same day, prompting an investigation by Infection Control. Genetic typing of the gentamicin-resistant organisms was performed using Pulse Field Gel Electrophoresis (PFGE) (Mayo Medical Laboratories, Rochester, MN) [6]. Infants A and B had genetically indistinguishable organisms. These matched the organism grown from the urine and placenta from the mother of Infant B. Infant C had a different typing, which matched the isolate from the urine of his mother. PFGE typing was not performed on Infant D, though we presume that it is identical to that of his twin sibling and their mother. Infection Control compared hospital room assignments of both infants and mothers. They also outlined contact with healthcare workers, including delivery
J. Hasvold et al. / Gentamicin resistant Escherichia coli in neonatal sepsis
attendants and staff inserting central lines. The only commonality identified was that the mother of Infant B occupied a pre-partum room the day after the mother of Infants C and D, though these mothers and infants grew genetically different organisms, so that room cannot be considered a site of transmission. We identified 31 NICU patients that had cultures positive for E. coli on at least one occasion between January 2010 and May 2012 from any source (blood, urine, CSF, peritoneal, sputum). Of these, only the aforementioned patients grew E. coli resistant to gentamicin, an incidence of 12.9 percent over the two year period.
4. Discussion Risk factors associated with neonatal sepsis secondary to E. coli include prematurity, PPROM and maternal fever [7]. EOS is more likely than LOS to be secondary to E. coli that is drug resistant [4]. Maternal hospitalization for duration greater than two days has also been implicated with an increased risk of infection by resistant organisms [5]. Other risk factors for antibiotic resistant organisms include low birth weight, prematurity, chorioamnionitis, and antenatal antibiotic exposure in the setting of prolonged rupture of membranes [4, 8, 9]. Compared to gram positive bacteremia, gram negative bacteremia carries a higher morbidity and mortality rate, although this could be partly due to the increased likelihood of those infants being premature [2]. In a large French study of 164 neonates with positive blood cultures, 71 percent of unfavorable outcomes were in neonates with blood cultures positive for E. coli, despite the fact that E. coli accounted for only 22 percent of positive cultures [8]. A number have studies have looked at mortality associated with E. coli sepsis, with reports of mortality ranging from 17 to 35 percent (Table 1). It is important to
175
note that ampicillin sensitive E. coli carries a lower risk of mortality than ampicillin resistant E. coli and gentamicin resistant E. coli. Three studies looked at neonatal mortality associated with ampicillin or gentamicin resistant E. coli when compared to ampicillin sensitive E. coli. All found that antibiotic resistant strains resulted in significantly greater mortality [4, 5, 10]. There is an abundance of literature regarding the increasing rates of resistance of E. coli to ampicillin. Many experts associate this increase with the popularization of intrapartum antibiotics for prevention of vertical GBS transmission [8]. Because rates of ampicillin resistance among E. coli are as high as 85 percent, ampicillin is used in combination with another agent for gram negative coverage [1, 11]. In a retrospective analysis done in the UK, 94 percent of organisms isolated from neonates with positive cultures at less than 48 hours of life were susceptible to the typical regimen of a penicillin combined with gentamicin [12]. While much attention has been paid to the emergence of ampicillin-resistant E. coli, there has been considerably less analysis of trends of gentamicin resistance, despite the fact that gentamicin remains first-line therapy at most institutions [3]. Gentamicin resistance, however, is of growing concern. One recent single center study in Spain saw a rise in gentamicin resistance among E. coli strains isolated in neonatal sepsis, increasing from an incidence of zero to 21 percent over the past two decades [13]. There are several reports on the incidence of Gentamicin resistance among E. coli species in neonatal sepsis, and in aggregate these analyses suggest that the incidence of gentamicin resistance in the neonatal population ranges widely (Table 2). Anectodally, rotation of aminoglycosides may be an effective means of reducing gentamicin resistance. One center, after noting a rise in gentamicin resistance among Enterobacter species, switched from empiric EOS coverage with gentamicin to amikacin for six
Table 1 Mortality in neonates with E. coli EOS or LOS, with and without drug resistance Author Stoll Metzger Bizarro Friedman Hyde
Study population
N
Mortality (%)
Mortality – ampicillin sensitive
Mortality – ampicillin or gentamicin resistant
EOS EOS EOS EOS and LOS EOS and LOS
107 19 24 23 36
33 21 33 35 17
NA 0 NA 20% 5%
NA 33% NA 46% 19%
176
J. Hasvold et al. / Gentamicin resistant Escherichia coli in neonatal sepsis Table 2 Incidence of Gentamicin resistance among E. coli species in neonatal sepsis
Author Friedman Bizarro Alarcon Maayan-Metzger Muller-Pebody Guiral Stoll ∗ Number
Country
Study Population
No. institutions
Dates
E. coli cultures N
Gentamicin resistance N (%)
US US Spain Israel UK Spain US
All neonatal sepsis All neonatal sepsis All neonatal sepsis Preterm, near term neonatal sepsis All neonatal sepsis All neonatal sepsis Neonatal EOS
One One One One Multiple One Multiple
1994–1998 1992–2006 1997–2002 2007 2006–2008 1998–2008 2006–2009
19 182 40 19 345 61 103
5 (26%) 0 (0%) 5 (13%) 4 (21%) 16 (13%) 8 (13%) 4*(4%)
of cultures extrapolated from percentage.
months and noted a dramatic reduction in the incidence of resistant gram negative rods [14]. Additionally, given the rise in aminoglycoside resistance, cefotaxime seems an appealing alternative. However, its use has been tempered by concerns over inducible extended-spectrum betalactamase (ESBL) production. Although a concern, the relationship between ESBL-producing E. coli and previous cephalosporin exposure remains unclear. In a report from a single institution, switching from ampicillin plus gentamicin to ampicillin plus cefotaxime for suspected neonatal sepsis was not associated with increased incidence of cephalosporin-resistant E. coli. There was, however, an increased incidence of drug resistant Enterobacter [15]. Another epidemiologic investigation linked an outbreak of ESBL-producing E. coli to vertical transmission with subsequent nosocomial spread rather than a direct result of increased use of cephalosporin antibiotics within the institution [16]. There are also concerns raised in the literature regarding increased risk of mortality associated with use of cefotaxime in neonatal sepsis, as demonstrated by Clark and colleagues. However, the study had limitations, chiefly in that physicians’ use of cephalosporin antibiotics was driven by individual patient history or prolonged asphyxia in utero, suggesting this population may have been sicker at initiation of therapy. The cefotaxime cohort also had a slightly lower average birthweight and gestational age [17].
Neonates undergoing empiric treatment for clinical sepsis must be closely monitored. Clinicians should maintain a low threshold for modifying antimicrobial coverage in at risk neonates who are not responding to empiric therapy, taking gentamicin resistance into consideration. Local resistance patterns should also be referenced when determining appropriate empiric therapy. Finally, infection control is a key component of preventing the emergence of multidrug resistant organisms in this population.
Financial disclosure statement The authors have no financial relationships relevant to this article to disclose.
References [1]
[2]
[3]
[4]
5. Summary We identified multiple risk factors for antibiotic resistance that were consistent with those highlighted in the literature: prolonged maternal hospitalization, antenatal antibiotic exposure, PPROM, prematurity, and VLBW.
[5]
[6]
Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med 2002;347(4):240-7. Stoll BJ, Hansen N, Sanchez PJ, et al. Early onset neonatal sepsis: The burden of group B streptococcal and E. coli disease continues. Pediatrics 2011;127(5):817-26. Sivanandan S, Soraisham AS, Swarnam K. Choice and duration of antimicrobial therapy for neonatal sepsis and meningitis. Int J Pediatr 2011;2011:712150. doi: 10.1155/ 2011/712150 Friedman S, Shah V, Ohlsson A, Matlow AG. Neonatal Escherichia coli infections: Concerns regarding resistance to current therapy. Acta Paediatr 2000;89:686-9. Maayan-Metzger A, Barzialai A, Keller N, Kuint J. Are the ‘Good Old’ Antibiotics Still Appropriate for EarlyOnset Neonatal Sepsis? A 10 Year Survey. Isr Med Assoc J 2009;11:138-42. Tenover FC, Arbeit RD, Goering RV, et al. Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: Criteria for bacterial strain typing. J Clin Microbiol 1995;33:2233-9.
J. Hasvold et al. / Gentamicin resistant Escherichia coli in neonatal sepsis
[7]
[8]
[9]
[10]
[11]
[12]
Shraag SJ, Hadler JL, Arnold KE, et al. Risk Factors for Invasive, Early-Onset Escherichia coli Infections in the Era of Widespread Intrapartum Antibiotic Use. Pediatrics 2006;118(2):570-6. Kuhn P, et al. Incidence and distribution of pathogens in early-onset neonatal sepsis in the era of antenatal antibiotics. Paediatr Perinat Epidemiol 2010;24:479-87. Alarcon A, Pilar P, Sofia S, et al. Neonatal early onset Escherichia coli sepsis: Trends in incidence and antimicrobial resistance in the era of intrapartum antimicrobial prophylaxis. Pediatric Infect Dis J 2004;23:295-9. Hyde T, Hilger T, Reingold A, et al. Trends in incidence and antimicrobial resistance of early-onset sepsis: Populationbased surveillance in San Francisco and Atlanta. Pediatrics 2002;110(4):690-5. Joseph TA, Pyati SP, Jacobs N. Neonatal early-onset Eschericia coli disease. The effect of intrapartum ampicillin. Arch Pediatr Adolesc Med 1998;152(1):35-40. Muller-Pebody B, Johnson AP, Heath PT, et al. Empirical treatment of neonatal sepsis: Are the current guidelines
[13]
[14]
[15]
[16]
[17]
177
adequate? Arch Dis Child Fetal Neonatal Ed 2011;96: F4-8. Guiral E, Bosch J, Vila J, Soto S. Antimicrobial resistance of Escherichia coli strains causing neonatal sepsis between 1998 and 2008. Chemotherapy 2012;58:123-8. Raz R, Sharir R, Shmilowitz L, Kenes I, Ephros M. The elimination of gentamicin-resistant gram-negative bacteria in a newborn intensive care unit. Infection 1987;15(1):32-4. Spritzer R, Kamp, HJ, Dzoljic G, Sauer PJ. Five years of cefotaxime use in a neonatal intensive care unit. Pediatr Infect Dis J 1990;9:92-6. Tschutter-suddin S, Frei R, Battegay M, Hoesli I, Widmer AF. Extended-Spectrum Beta-Lactamase-Producing Escherichia coli in Neonatal Care Unit. Emerg Infect Dis 2010;16(11):1758-60. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Empiric use of ampicillin and cefotaxime, compared with ampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonatal death. Pediatrics 2006;117(1):67-74.
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Journal of Neonatal-Perinatal Medicine 6 (2013) 173–177 DOI 10.3233/NPM-1365512 IOS Press
Case Report
Gentamicin resistance among Escherichia coli strains isolated in neonatal sepsis J. Hasvold∗ , L. Bradford, C. Nelson, C. Harrison, M. Attar and T. Stillwell University of Michigan, Ann Arbor, MI, USA
Received 26 September 2012 Revised 12 January 2013 Accepted 28 January 2013
Abstract. Neonatal sepsis is a significant cause of morbidity and mortality among term and preterm infants. Ampicillin and gentamicin are standard empiric therapy for early onset sepsis. Four cases of neonatal sepsis secondary to Escherichia coli (E. coli) found to be gentamicin resistant occurred within a five week period in one neonatal intensive care unit (NICU). To determine whether these cases could be tied to a single vector of transmission, and to more broadly evaluate the incidence of gentamicin resistant strains of E. coli in the neonatal population at our institution compared to other centers, we reviewed the charts of the four neonates (Infants A through D) and their mothers. The E. coli isolates were sent for Pulse Field Gel Electrophoresis (PFGE) to evaluate for genetic similarity between strains. We also reviewed all positive E. coli cultures from one NICU over a two year period. Infants A and B had genetically indistinguishable strains which matched that of urine and placental cultures of Infant B’s mother. Infant C had a genetically distinct organism. Infant D, the identical twin of Infant C, did not have typing performed. Review of all cultures positive for E. coli at our institution showed a 12.9 percent incidence of gentamicin-resistance. A review of other studies showed that rates of resistance vary considerably by institution. We conclude that gentamicin-resistant E. coli is a relatively uncommon cause of neonatal sepsis, but should remain a consideration in patients who deteriorate despite initiation of empiric antibiotics. Keywords: Neonatal sepsis, antibiotic resistance
1. Introduction Neonatal sepsis is associated with significant morbidity and mortality, particularly in preterm and very low birthweight (VLBW) neonates [1]. Escherichia coli (E. coli) is the most frequent early onset sepsis (EOS) pathogen among preterm infants in the United States and a significant cause of morbidity and mortality in this population. The incidence of E. coli sepsis is inversely proportional to neonatal birth weight, which ∗ Corresponding author: Dr. Jennifer Hasvold, Department of Pediatrics, Mott Children’s Hospital, Ann Arbor MI, 48103, USA. E-mail: [email protected].
means the most vulnerable neonates are also the most likely to develop sepsis secondary to E. coli [2]. Gentamicin is commonly used for empiric treatment of EOS and late onset neonatal sepsis (LOS) [3]. There is a growing concern that empiric sepsis regimens are less sensitive and inclusive than they were in previous eras; this concern also holds true for gentamicin as an agent for empiric coverage of gram negative rods in the neonatal population [4, 5]. We report four cases of gentamicin-resistant E. coli sepsis which occurred over a five week period in our neonatal intensive care unit (NICU), as well as the prevalence of gentamicin resistance at our institution and the infection control epidemiologic investigation that followed. We also
1934-5798/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
174
J. Hasvold et al. / Gentamicin resistant Escherichia coli in neonatal sepsis
summarize the current literature regarding gentamicinresistant E. coli in neonatal populations. We obtained approval for this review from our Institutional Review Board.
2. Case reports Infant A was a 770 gram male born via vaginal delivery at 24 weeks gestation. The mother received seven days of ampicillin/amoxicillin and erythromycin for prolonged premature rupture of membranes (PPROM) and received ampicillin and gentamicin on the day of delivery for presumed chorioamnionitis. She received two doses of betamethasone prior to delivery. Infant A was started on ampicillin and gentamicin for suspected EOS. The initial blood culture was negative; antibiotics were discontinued. On day of life (DOL) 3 he became hypotensive and acidotic. Vancomycin and gentamicin were started for suspected sepsis and necrotizing enterocolitis (NEC). Care was withdrawn that day; subsequently, blood and peritoneal fluid cultures grew gentamicin-resistant E. coli. Infant B is a 680 gram male born via vaginal delivery at 23 weeks gestation. Pregnancy was complicated by gonorrheal infection treated with ceftriaxone, PPROM, advanced cervical dilation, and bulging membranes. The mother received seven days of ampicillin/amoxicillin and erythromycin for PPROM and two doses of betamethasone. The infant was treated with ampicillin and gentamicin for suspected EOS. His clinical course was complicated by NEC and postnatal cytomegalic virus infection. The blood culture on DOL one grew gentamicin-resistant E. coli, as did a urine culture on DOL 52 and a tracheal aspirate culture on DOL 77. The mother’s urine culture from the day prior to delivery and placental culture also grew gentamicin-resistant E. coli. This patient survived to be discharged home from his initial hospitalization. Infant C is a 1210 gram male born via cesarean section at 28 weeks gestation. Pregnancy was complicated by dichorionic-diamniotic twin gestation and premature labor. The mother was admitted on the day of delivery and received single doses of clindamycin and gentamicin prior to the cesarean section. She received two doses of betamethasone one month before and one dose just prior to delivery. Infant C was started on ampicillin and gentamicin for suspected EOS. The initial blood culture remained negative; antibiotics were discontinued. On DOL eight, Infant C experienced per-
sistent desaturations, bilious residuals, hypotension, and hyperglycemia. He was treated with empiric vancomycin and gentamicin. Blood and cerebral spinal fluid (CSF) cultures grew gentamicin-resistant E. coli. Blood and urine cultures grew gentamicin-resistant E. coli again on DOL 109 when he was evaluated and treated for sepsis. The mother had a urine culture obtained eight days following giving birth which grew gentamicin-resistant E. coli. This infant survived to be discharged home from the initial hospitalization. Infant D, twin of infant C, is a 1130 gram male born via cesarean section at 28 weeks gestation. Infant D was prenatally diagnosed with myelomeningocele. He was started on ampicillin and gentamicin for suspected EOS but was then transitioned to cefazolin on DOL five for empiric coverage for indwelling surgical drains after myelomeningocele repair. On DOL ten, he developed leukocytosis and hyperglycemia; cefazolin was changed to vancomycin, and piperacillin/tazobactam was added. He was ultimately treated with a 21-day course of vancomycin, meropenem, and fluconazole for culture-negative sepsis. On DOL 38, he developed NEC and was started on vancomycin, gentamicin, piperacillin/tazobactam, and fluconazole. The blood culture on DOL 38 grew gentamicin-resistant E. coli. A tracheal aspirate culture on DOL 54 and a urine culture at five months of age also grew gentamicin-resistant E. coli. This infant survived to be discharged home from the initial hospitalization.
3. Infection control evaluation These four cases occurred over the course of five weeks. Infants A, B and C had their initial positive blood cultures drawn on the same day, prompting an investigation by Infection Control. Genetic typing of the gentamicin-resistant organisms was performed using Pulse Field Gel Electrophoresis (PFGE) (Mayo Medical Laboratories, Rochester, MN) [6]. Infants A and B had genetically indistinguishable organisms. These matched the organism grown from the urine and placenta from the mother of Infant B. Infant C had a different typing, which matched the isolate from the urine of his mother. PFGE typing was not performed on Infant D, though we presume that it is identical to that of his twin sibling and their mother. Infection Control compared hospital room assignments of both infants and mothers. They also outlined contact with healthcare workers, including delivery
J. Hasvold et al. / Gentamicin resistant Escherichia coli in neonatal sepsis
attendants and staff inserting central lines. The only commonality identified was that the mother of Infant B occupied a pre-partum room the day after the mother of Infants C and D, though these mothers and infants grew genetically different organisms, so that room cannot be considered a site of transmission. We identified 31 NICU patients that had cultures positive for E. coli on at least one occasion between January 2010 and May 2012 from any source (blood, urine, CSF, peritoneal, sputum). Of these, only the aforementioned patients grew E. coli resistant to gentamicin, an incidence of 12.9 percent over the two year period.
4. Discussion Risk factors associated with neonatal sepsis secondary to E. coli include prematurity, PPROM and maternal fever [7]. EOS is more likely than LOS to be secondary to E. coli that is drug resistant [4]. Maternal hospitalization for duration greater than two days has also been implicated with an increased risk of infection by resistant organisms [5]. Other risk factors for antibiotic resistant organisms include low birth weight, prematurity, chorioamnionitis, and antenatal antibiotic exposure in the setting of prolonged rupture of membranes [4, 8, 9]. Compared to gram positive bacteremia, gram negative bacteremia carries a higher morbidity and mortality rate, although this could be partly due to the increased likelihood of those infants being premature [2]. In a large French study of 164 neonates with positive blood cultures, 71 percent of unfavorable outcomes were in neonates with blood cultures positive for E. coli, despite the fact that E. coli accounted for only 22 percent of positive cultures [8]. A number have studies have looked at mortality associated with E. coli sepsis, with reports of mortality ranging from 17 to 35 percent (Table 1). It is important to
175
note that ampicillin sensitive E. coli carries a lower risk of mortality than ampicillin resistant E. coli and gentamicin resistant E. coli. Three studies looked at neonatal mortality associated with ampicillin or gentamicin resistant E. coli when compared to ampicillin sensitive E. coli. All found that antibiotic resistant strains resulted in significantly greater mortality [4, 5, 10]. There is an abundance of literature regarding the increasing rates of resistance of E. coli to ampicillin. Many experts associate this increase with the popularization of intrapartum antibiotics for prevention of vertical GBS transmission [8]. Because rates of ampicillin resistance among E. coli are as high as 85 percent, ampicillin is used in combination with another agent for gram negative coverage [1, 11]. In a retrospective analysis done in the UK, 94 percent of organisms isolated from neonates with positive cultures at less than 48 hours of life were susceptible to the typical regimen of a penicillin combined with gentamicin [12]. While much attention has been paid to the emergence of ampicillin-resistant E. coli, there has been considerably less analysis of trends of gentamicin resistance, despite the fact that gentamicin remains first-line therapy at most institutions [3]. Gentamicin resistance, however, is of growing concern. One recent single center study in Spain saw a rise in gentamicin resistance among E. coli strains isolated in neonatal sepsis, increasing from an incidence of zero to 21 percent over the past two decades [13]. There are several reports on the incidence of Gentamicin resistance among E. coli species in neonatal sepsis, and in aggregate these analyses suggest that the incidence of gentamicin resistance in the neonatal population ranges widely (Table 2). Anectodally, rotation of aminoglycosides may be an effective means of reducing gentamicin resistance. One center, after noting a rise in gentamicin resistance among Enterobacter species, switched from empiric EOS coverage with gentamicin to amikacin for six
Table 1 Mortality in neonates with E. coli EOS or LOS, with and without drug resistance Author Stoll Metzger Bizarro Friedman Hyde
Study population
N
Mortality (%)
Mortality – ampicillin sensitive
Mortality – ampicillin or gentamicin resistant
EOS EOS EOS EOS and LOS EOS and LOS
107 19 24 23 36
33 21 33 35 17
NA 0 NA 20% 5%
NA 33% NA 46% 19%
176
J. Hasvold et al. / Gentamicin resistant Escherichia coli in neonatal sepsis Table 2 Incidence of Gentamicin resistance among E. coli species in neonatal sepsis
Author Friedman Bizarro Alarcon Maayan-Metzger Muller-Pebody Guiral Stoll ∗ Number
Country
Study Population
No. institutions
Dates
E. coli cultures N
Gentamicin resistance N (%)
US US Spain Israel UK Spain US
All neonatal sepsis All neonatal sepsis All neonatal sepsis Preterm, near term neonatal sepsis All neonatal sepsis All neonatal sepsis Neonatal EOS
One One One One Multiple One Multiple
1994–1998 1992–2006 1997–2002 2007 2006–2008 1998–2008 2006–2009
19 182 40 19 345 61 103
5 (26%) 0 (0%) 5 (13%) 4 (21%) 16 (13%) 8 (13%) 4*(4%)
of cultures extrapolated from percentage.
months and noted a dramatic reduction in the incidence of resistant gram negative rods [14]. Additionally, given the rise in aminoglycoside resistance, cefotaxime seems an appealing alternative. However, its use has been tempered by concerns over inducible extended-spectrum betalactamase (ESBL) production. Although a concern, the relationship between ESBL-producing E. coli and previous cephalosporin exposure remains unclear. In a report from a single institution, switching from ampicillin plus gentamicin to ampicillin plus cefotaxime for suspected neonatal sepsis was not associated with increased incidence of cephalosporin-resistant E. coli. There was, however, an increased incidence of drug resistant Enterobacter [15]. Another epidemiologic investigation linked an outbreak of ESBL-producing E. coli to vertical transmission with subsequent nosocomial spread rather than a direct result of increased use of cephalosporin antibiotics within the institution [16]. There are also concerns raised in the literature regarding increased risk of mortality associated with use of cefotaxime in neonatal sepsis, as demonstrated by Clark and colleagues. However, the study had limitations, chiefly in that physicians’ use of cephalosporin antibiotics was driven by individual patient history or prolonged asphyxia in utero, suggesting this population may have been sicker at initiation of therapy. The cefotaxime cohort also had a slightly lower average birthweight and gestational age [17].
Neonates undergoing empiric treatment for clinical sepsis must be closely monitored. Clinicians should maintain a low threshold for modifying antimicrobial coverage in at risk neonates who are not responding to empiric therapy, taking gentamicin resistance into consideration. Local resistance patterns should also be referenced when determining appropriate empiric therapy. Finally, infection control is a key component of preventing the emergence of multidrug resistant organisms in this population.
Financial disclosure statement The authors have no financial relationships relevant to this article to disclose.
References [1]
[2]
[3]
[4]
5. Summary We identified multiple risk factors for antibiotic resistance that were consistent with those highlighted in the literature: prolonged maternal hospitalization, antenatal antibiotic exposure, PPROM, prematurity, and VLBW.
[5]
[6]
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