Professional Documents
Culture Documents
Center for International Health and Development, Department of International Health, Boston University School of Public Health, 2Infectious
Diseases Section, Department of Internal Medicine, Boston University School of Medicine, and 3Department of Pediatrics, Childrens Hospital
Boston, Boston, Massachusetts; 4College of Medicine, Mayo Clinic, Rochester, Minnesota; and 5Newborn Medicine Section and 6Department of
Medicine, Philippines General Hospital, and 7Department of Neonatology, Jose Fabella Memorial Hospital, Manila, The Philippines
Background. The growing burden of neonatal mortality associated with hospital-acquired neonatal sepsis in
the developing world creates an urgent need for cost-effective infection-control measures in resource-limited
settings.
Methods. Using a before-and-after comparison design, we measured how rates of staff hand-hygiene compliance, colonization with drug-resistant pathogens (defined as ceftazidime- and/or gentamicin-resistant gramnegative bacilli and drug-resistant gram-positive cocci), bacteremia, and overall mortality changed after the introduction of a simplified package of infection-control measures at 2 neonatal intensive care units (NICUs) in Manila,
The Philippines.
Results. Of all 1827 neonates admitted to the NICU, 561 (30.7%) arrived from delivery already colonized with
drug-resistant bacteria. Of the 1266 neonates who were not already colonized, 578 (45.6%) became newly colonized
with drug-resistant bacteria. Of all 1827 neonates, 358 (19.6%) became bacteremic (78.2% were infected with
gram-negative bacilli) and 615 (33.7%) died. Of 2903 identified drug-resistant colonizing bacteria, 85% were drugresistant gram-negative bacilli (predominantly Klebsiella species, Pseudomonas species, and Acinetobacter species)
and 14% were methicillin-resistant Staphylococcus aureus. Contrasting the control period with the intervention
period at each NICU revealed that staff hand-hygiene compliance improved (NICU 1: relative risk, 1.3; 95%
confidence interval 1.11.5; NICU 2: relative risk, 1.6; 95% confidence interval, 1.42.0) and that overall mortality
decreased (NICU 1: relative risk, 0.5; 95% confidence interval, 0.40.6; NICU 2: relative risk, 0.8; 95% confidence
interval, 0.70.9). However, rates of colonization with drug-resistant pathogens and of sepsis did not change
significantly at either NICU.
Discussion. Nosocomial transmission of drug-resistant pathogens was intense at these 2 NICUs in The Philippines; transmission involved mostly drug-resistant gram-negative bacilli. Infection-control interventions are feasible and are possibly effective in resource-limited hospital settings.
Nosocomial infections contribute a growing, yet underappreciated, share of neonatal mortality in the developing world [1]. Poor hand-hygiene practices [2, 3],
reuse of single-use medication vials and devices [4],
and inadequate sterilization of medical equipment [5]
are key proximate events that facilitate transmission of
Table 1. Baseline characteristics of 2 level-III neonatal intensive care units (NICUs) in Manila, The Philippines.
NICU
Characteristic
7000
825
35,000
900
25
Inborn patients only
Combined level II and III
80 (25 level III)
60
Inborn patients only
Combined level II and III
60
No
1:5
Yes
7
Hand-drying system
Yes
2 (with 1 additional sink located
outside the unit)
Inconsistent
Performed in pharmacy
Inconsistent
Performed at bedside
Piperacillin-tazobactam plus
amikacin
Ciprofloxacin plus meropenem
Neonatal feedings
Figure 1. Study schematic and timeline at 2 neonatal intensive care units (NICUs) in Manila, The Philippines
Enhanced Infection Control CID 2009:48 (1 January) 15
Table 3.
Checklist
Are ethanol handwash supplies sufficient?
Are clean hand towels stocked at each sink?
Are intravascular admixture solutions being prepared in a clean
environment or in the central pharmacy?
Are appropriate decontamination procedures and solutions being
applied to all reusable devices, such as ventilator tubing and
instruments?
Is reusable sterilized equipment completely dry before storage?
Are disinfectants being used according to the manufacturers
instructions?
Do neonatal intensive care unit personnel go from patient to
patient without changing their gowns?
mitted), incidence density of bacteremia (number of bloodstream infections per patient-days), cumulative mortality
(number of NICU deaths per number of NICU admissions),
and hand-hygiene compliance before and after implementation
of the infection-control program (number of observed contacts
between a health care provider and a neonate when appropriate
cleansing with soap and water or ethanol handrub was performed per the total number of contacts).
The sample size was determined for our primary outcome.
Assuming 10% baseline colonization, we estimated that 865
neonates per hospital would be needed to detect a 4% difference
in colonization rate.
RESULTS
each blood culture bottle for each neonate with suspected bacteremia. Most clinical specimens were initially submitted to the
respective microbiology laboratories at the 2 hospitals and were
referred to the Philippines General Hospital research microbiology laboratory for confirmation and/or characterization
with use of BACTEC (Becton Dickinson).
Antibiotic susceptibility testing. For all screening of clinical
isolates, we determined sensitivity by using Kirby-Bauer disk
diffusion. Antibiotic susceptibility classifications were determined on the basis of National Committee for Clinical Laboratory Standards breakpoints [12].
Statistical analyses. Analyses were conducted using SAS,
version 9.2 (SAS Institute), and SPSS software, version 11
(SPSS). In our conceptual model of nosocomially acquired neonatal sepsis, we assumed that colonization typically preceeds
invasive disease and that our interventions act primarily by
interrupting transmission and, hence, colonization. In accordance with these assumptions, our primary outcome was the
proportion of neonates who were newly colonized with the
target bacteria (drug-resistant gram-negative bacilli or grampositive cocci). Therefore, we excluded cases of colonization or
bacteremia during NICU days 01, under the assumption that
these reflected pre-NICU exposures. We calculated the incidence density for colonization or confirmed bacteremia (first
event per patient-days at risk) for each NICU separately. To
prevent double counting of identical isolates, we included only
the first new isolate from a given neonate, after which that
neonate was censored for only that isolate. Subsequent colonizations with a different isolate were still included. In addition,
we calculated incidence density for colonization and sepsis independent of each other. For example, if a neonate became
colonized with a given isolate on day 2 and became bacteremic
with that same isolate on day 4, the bacteremia calculation
would not have been adjusted by censoring from the colonization event on day 2.
Secondary outcomes included rate of bacteremia (number
of positive blood culture results per blood culture bottles sub-
NICU 1
Variable
No. of neonates admitted
No. of swab specimens submitted
Rectal
Nasal
Umbilical
All
Positive isolates
All
Phase I
Phase II
328
Phase I
Phase II
597
597
Total
305
1827
638
1667
1096
654
4055
433
429
1500
1076
1076
3819
609
599
2304
355
354
1363
2473
2458
8986
261/1500 (17)
776/3819 (20)
1340/2304 (58)
526/1363 (39)
2903/8986 (32)
42/261 (16)
41
116/776 (15)
111
268/1340 (20)
263
11
219/261 (84)
660/776 (85)
1072/1340 (80)
525/526 (100)
2476/2903 (85)
88/219 (40)
33
8
6
595/660 (90)
216
265
45
555/1072 (52)
280
159
46
298/525 (57)
112
111
28
1536/2476 (62)
641
543
125
5
34
2
5
44
20
7
26
37
2
23
22
19
127
81
Gram-positive cocci
All
MRSA
VRE
Gram-negative bacilli
427/2903 (15)
416
Enteric
All
Klebsiella pneumoniae pneumoniae
K. pneumoniae ozanae
Escherichia coli
Citrobacter freundii
Enterobacter aerogenes
Other Enterobacter species
Nonenteric
All
131/219 (60)
65/660 (10)
517/1072 (48)
227/525 (43)
940/2476 (38)
Pseudomonas aeruginosa
Acinetobacter baumanii
77
16
10
25
189
261
56
117
332
419
Stenotrophomonas maltophilia
Alcaligenes faecalis
16
22
14
16
42
25
28
26
100
89
NOTE. Data are no. or proportion (%) of isolates, unless otherwise indicated. MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycinresistant enterococci.
VRE isolates by culture of rectal specimens. MRSA was commonly isolated, particularly at NICU 2 (table 4).
Colonization rates did not change significantly at either
NICU between phase I and phase II (table 5), with regard to
ceftazidime resistance and/or gentamicin resistance. Of interest,
the types of detected gram-negative bacilli changed dramatically
at both NICUs; there was an increase in enteric gram-negative
bacilli and a decrease in nonenteric gram-negative bacilli (table
4). At NICU 1, the ratio of enteric to nonenteric gram-negative
bacilli was 40%:60% during phase I and 90%:10% during
phase II (P ! .001). At NICU 2, the ratio of enteric to nonenteric
gram-negative bacilli was 52%:48% during phase I and 57%:
43% during phase II (P p .06). MRSA essentially vanished
from NICU 2 during phase II (relative risk [RR], 0.01; 95%
CI, 0.000.05).
Bacteremia. Overall, 358 (19.6%) of 1828 neonates developed at least 1 episode of bacteremia during their NICU stay,
predominantly due to resistant gram-negative bacilli (78.2%
All
1/526 (0.2)
1
Table 5. Changes in incidence density for target pathogen colonization between phase I and phase II.
Incidence density, no. of new colonizations
per 1000 NICU-days at risk
NICU 1
Pathogen category
NICU 2
Phase I
Phase II
Phase I
Phase II
148.2
166.0
158.9
147.1
.59
.35
343.9
472.9
310.8
434.6
.31
.38
129.5
68.3
128.2
79.3
.94
.54
314.3
205.8
296.9
0.0
!.001
.56
NOTE. Vancomycin-resistant enterococci were too infrequently identified to calculate meaningful incidence rates. MRSA, methicillin-resistant
Staphylococcus aureus.
DISCUSSION
This project tested the effectiveness of a package of infectioncontrol interventions at 2 of the largest NICUs in The Philippines. The interventions were associated with an increased
rate of hand-hygiene compliance in general and of alcoholbased handrub use in particular. However, the overall incidences of colonization with resistant bacteria and of bacteremia
were unchanged. Therefore, although mortality rates decreased
substantially, we were unable to conclude that the interventions
were responsible for the decreases.
Our data provide some bleak insights into the epidemiology
of drug-resistant bacteria at these NICUs: colonization pressure
with drug-resistant pathogens was intense, with correspondingly high rates of bacteremia and mortality. Moreover, the
spectrum of pathogens causing sepsis was remarkable for its
dissimilarity to the spectrum at NICUs in the developed world.
Four of the most common pathogens were nonenteric pathogens: A. baumanii, P. aeruginosa, Stenotrophomonas maltophilia, and A. faecalis (an uncommon pathogen that is rarely
reported in the developing world) [1315]. The high frequency
of nonenteric gram-negative bacilli and the high rates of drug
resistance strongly imply that nosocomial transmission, rather
than mother-to-child transmission during delivery, was responsible for colonization. MRSA colonization was common
(although sepsis was rare), and VRE appeared to be an emerging
threat, which is worrisome, given the lack of prior reports of
VRE infection in The Philippines.
The agents that most commonly cause early neonatal sepsis
in the developed world are group B streptococci (GBS) and E.
coli. However, in our study, GBS sepsis was conspicuous for
its absence, echoing results from the International Infections
in Pregnancy study group, which found GBS colonization rates
to be one-half of those found in Dublin, Ireland, and one-third
of those found in Philadelphia [16, 17]. A recent review by
Zaidi et al. [18] of hospital-acquired neonatal sepsis in developing nations also found GBS in only 2.3% of sepsis episodes.
However, after adjustment for patient-time at risk, overall bacteremia rates did not change at either unit between phase I and
phase II (table 7). However, this adjustment concealed a decrease in the number of cases of nonenteric bacteremia, particularly at NICU 1, and there was an absolute and relative
increase in the number of cases of enteric bacteremia at both
NICUs. In addition, NICU 1 experienced a small but statistically significant increase in the incidence of bacteremia due to
coagulase-negative staphylococci and nonC. albicans Candida
species.
NICU mortality. Mortality rates were high at both NICUs
but decreased during phase II. Of 1828 neonates admitted to
the NICU, 615 (33.6%) died. At NICU 1, the risk of death
decreased during phase II (290 deaths per 1000 admissions
during phase I vs. 144 deaths per 1000 admissions during phase
II; RR, 0.50; 95% CI, 0.380.64); the absolute risk reduction
was 15% (95% CI, 9%20%). Mortality also decreased at NICU
2 during phase II (598 deaths per 1000 admission during phase
I vs. 481 deaths per 1000 admissions during phase II; RR, 0.81;
95% CI, 0.710.91); the absolute risk reduction was 12% (95%
CI, 6%18%).
Hand-hygiene compliance. Hand-hygiene compliance improved at both NICUs during phase II (table 8). Compliance
was evaluated for a mean of 18 h per NICU per month; therefore, there were 513 1-h observations and 5423 patient contacts.
In a comparison of phase II with phase I, the likelihood of
precontact hand-hygiene compliance improved at both units
(NICU 1: RR, 1.3; 95% CI 1.151.49; NICU 2: RR, 1.61; 95%
CI, 1.401.86). The phase II interventions had no impact on
the overall likelihood of postcontact hand-hygiene compliance
at NICU 1 (RR, 0.94; 95% CI, 0.791.11), although there was
a preferential shift toward ethanol-based handrub over soap
and water (P ! .001). At NICU 2, the likelihood of postcontact
hand-hygiene compliance increased during phase II (RR, 1.6;
95% CI, 1.311.98), again with preferential use of ethanol-based
handrub (P p .01).
Table 6. Bloodstream isolates, by neonatal intensive care unit (NICU) and study phase.
NICU 2
NICU 1
Variable
Total no. of blood cultures performed
Positive isolates
Phase I
Phase II
Phase I
Phase II
Total
197
504
289
272
1262
32 (16)
99 (20)
216 (75)
163 (60)
536 (42)
0/32 (0)
0
0
0
25/99 (25)
4
1
2
16/216 (7)
5
0
0
19/163 (12)
3
0
0
60/536 (11)
12
1
2
0
0
0
18
0
11
0
16
0
45
All
Enteric
27/32 (84)
32/99 (32)
198/216 (92)
142/163 (87)
417/536 (78)
All
3/27 (11)
24/32 (75)
138/198 (70)
122/142 (86)
287/417 (69)
0
0
0
3
9
0
0
14
76
16
2
44
78
8
2
34
163
24
4
95
25/27 (93)
9/32 (28)
64/198 (32)
32/142 (28)
130/417 (31)
0
0
5
1
52
3
15
4
72
8
0
22
3
0
4
2
4
6
11
30
0
2
1
5/32 (16)
0
0
0
42/99 (42)
3
0
0
2/216 (1)
3
0
0
2/163 (1)
6
2
1
59/536 (11)
All
Gram-positive cocci
All
MSSA
MRSA
VSE
VRE
Coagulase-negative staphylococci
Gram-negative bacilli
Proteus rettgeri
Nonenteric
All
Pseudomonas species
Acinetobacter baumanii
Stenotrophomonas maltophilia
Alcaligenes faecalis
Burkholderia cepacia
Flavobacterium species
Achromobacter species
Other pathogens
NOTE. Data are no. or proportion (%) of isolates, unless otherwise indicated. MRSA, methicillin-resistant Staphylococcus
aureus; MSSA, methicillin-susceptible S. aureus; VRE, vancomycin-resistant enterococci; VSE, vancomycin-susceptible enterococci.
Klebsiella species
Escherichia coli
Citrobacter species
Enterobacter species
NICU 2
Phase I
Phase II
Phase I
Phase II
21.4
16.8
28.1
8.3
.23
.02
163.3
141.5
166.9
143.0
.85
.93
2.1
6.1
.07
90.5
112.6
.12
13.7
0.0
2.5
6.0
!.01
36.6
27.0
.12
!.01
9.0
14.7
.19
3.5
14.6
!.01
0.6
1.7
.40
Table 8. Hand-hygiene compliance rates, by neonatal intensive care unit (NICU) and study period.
NICU 2
NICU 1
Compliance rate, %
Variable
Compliance rate, %
No. of
observations
No
compliance
Ethanol-based
handrub
Soap
and water
No. of
observations
No
compliance
Ethanol-based
handrub
Soap
and water
440
952
67.1
56.8
2.1
24.6
30.9
18.6
852
476
76.5
62.2
16.3
28.4
7.2
9.5
440
946
75.9
74.1
1.4
9.7
22.5
16.0
851
475
86.9
79
8.3
12.6
4.6
7.8
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