Cepacia and TX Article Part 2

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The cluster A genotype

occurred in six patients, five of whom had  previously been seen at CF

centers in Michigan and who were infected prior to care at the UNC

Hospitals. The fifth patient whose isolate was in this cluster was also

infected with B. cepacia prior to referral, but the patient was

originally from Nebraska and it is not known whether there is a link

between this patient and the other patients whose isolates were in this

cluster. Isolates from patients 1 through 3 and 5 shared identical

genotypes, while isolates from patient 4 differed from those from

patients 1 through 3 and 5 by two bands and isolates from patient 6

differed from those from patients 1 through 3 and 5 by three bands. All

were genomovar III isolates.

  TABLE 1. Summary of genotypes and clusters of B. cepacia complex

isolates recovered from January 1995 to March 2001

  FIG. 1. PFGE banding patterns of six clusters (clusters A to F) of B.

cepacia complex isolates recovered from CF patients at the UNC Hospitals

CF center. The cluster C gel contains a B. multivorans strain designated

23 for purposes of comparison. The cluster E gel contains the Toronto

strain, designated ET, and a cblA+ genomovar III strain, designated 21,

for the purposes of comparison. Numbers on the left are molecular

weights.

Likewise, cluster B isolates (Fig. 1) occurred in those referred patients

seen previously at CF centers within the metropolitan New York City-New

Jersey area and infected prior to care at the UNC Hospitals. Again, all

were genomovar III isolates, and there was no evidence of the spread of

this cluster to any of our clinic CF patients.  Interestingly, cluster C

(Fig. 1) began with patient 11 from Florida, who sought care at the UNC

Hospitals for a possible double lung transplantation and who was already

infected with B. multivorans. This patient had a lengthy hospitalization

from 7 June 1998 until 13 August 1998 and again from 21 August 1998 until

13 March 1999 (Fig. 2). Patient 12 was also hospitalized from 5 through

11 August 1998, during the hospitalization of patient 11, and

subsequently became culture positive for B. multivorans on 5 November

1998. On the same date, patient 12 was

also seen in the adult CF clinic. Patient 13 was a pediatric patient

hospitalized from 29 October 1998 until 12 November 1998 and was later

(11 February 1999) culture positive for B. multivorans. Patient 14 was

hospitalized from 13 through 21 December 1999 and had an overlapping

hospitalization with patient 12. Patient 14 was then culture positive for

B. multivorans on 25 May 2000. Although these patients did not share the

same hospital floor, they did share common hospital services (physical

therapy,  pulmonary function laboratory, and radiology). Since the B.

multivorans isolates from all of these patients share the same genotype

and overlapping hospitalizations were evident, we conclude that

nosocomial, patient-to-patient spread occurred among these patients

either directly or indirectly.

  FIG. 2. Time line graph showing the hospitalization course of patients

(Pt.) 11 to 14. Horizontal bars represent inpatient status, with the

admission date given at the beginning of the bars and the discharge date

given at the ends. Vertical bars represent dates of concurrent admission

resulting in possible cross infection. #, +, and *, the dates that

patients 12, 13, and 14, respectively, first became positive for B.

multivorans infection (see text).

Three small clusters (clusters D to F) (Fig. 1) consisting of isolates

from two patients each were also detected by PFGE, and isolates in one of

these clusters (cluster E) were from siblings who were infected with B.

cepacia and who had been referred to the UNC Hospitals (Fig. 1). As with

cluster C isolates, the isolates in cluster D were from two patients who

also had overlapping  hospitalizations on the same hospital unit that

were clearly documented (data not shown). These two patients represent

part of

the UNC Hospitals CF clinic population. The isolates in cluster F

consisted of isolates from patient 19, who became infected while

receiving care at the UNC Hospitals, and patient 20, who was from New

Jersey and who came to the UNC Hospitals already infected with B. cepacia

genomovar III. We could find no evidence of overlapping hospitalizations

or shared hospital services between these two patients. Therefore, we

suspect that patient 19 may have become infected with an isolate of the

same genotype as that from patient 20 in a nonhospitalized setting (23).

Epidemic clone ET 12, isolated from CF centers in both the United Kingdom

and North America, expresses cable pilin on its surface (25). For this

reason, we performed PCR on our isolates to see if the cblA gene was

present, especially in our cluster isolates. Our results show that the

cblA gene was present in only four isolates, two of which were from

cluster E (isolates from a sibling pair). A comparison of the SpeI

restriction patterns between the B. cepacia cblA+ isolates from the

siblings (patients 17 and 18) and patient 21 with that of the highly

transmissible Toronto strain is shown in Fig. 1. The results indicate

that while the SpeI patterns for the isolates from the siblings are an

exact match, the genotypes produced by isolates from the siblings,

patient 21, and the ET 12 clone differ from each other by more than seven

fragments and are therefore unrelated (25). A fourth patient infected

with a cblA+ strain also showed a unique SpeI genotype, as expected,

since this isolate was a genomovar I strain (data not shown), while the

other cblA+ isolates were genomovar III strains

In an earlier study, we analyzed B. cepacia complex isolates from five

transplant patients and 17 clinic patients and found no evidence of

transmission of B. cepacia complex isolates among these patients (24).

However, we did find a strain of B. cepacia complex in a patient referred

for transplantation evaluation that resulted in the recognition of a

large nosocomial outbreak at the institution from which he was referred

(9). This caused us to be concerned that patients referred for

transplantation might transmit B. cepacia complex strains to patients

receiving their routine care for CF at our institution.  Of the six

clones found in clusters in this study, isolates of four previously

uncharacterized clones (clusters B, C, E, and F) were present in our

referred patients, while cluster A has been reported previously (12) and

cluster D isolates were not present in patients referred for

transplantation. Cluster B isolates were present in four referred

patients from the metropolitan New York City-New Jersey area. To our

knowledge, there is no published study of an epidemic clone of the B.

cepacia complex from CF patients from that geographic area. Th erefore,

we cannot comment on the transmissibility of this clone except to say

that it was present in these four referred CF patients and did not spread

to our clinic CF patients.  Cluster C comprised a clone of B.

multivorans. Among the isolates in the B. cepacia complex,

transmissibility is typically thought to be associated with B. cepacia

genomovar III organisms (2, 7, 9, 11, 21, 22, 25). Person-to-person

spread of B. multivorans is not as frequently described, and most

patients infected with B. multivorans are infected

with unique strains (1, 14). Overlapping hospitalizations could be traced

for all four patients infected with cluster C isolates. Cluster E

consisted of only two isolates from referred patients who were siblings,

but the isolates were cblA+. Again, there was no evidence of spread from

these referred patients to our clinic CF patient population. Cluster F

consisted of isolates from two patients and represented the spread of

B.cepacia genomovar III from a referred patient to a clinic CF patient.

However, we were unable to show any link between these two patients

through overlapping hospitalizations, clinic visits, or hospital services

and therefore consider this cluster not to have occurred nosocomially.  A

closer analysis of the isolates in cluster A indicated that four of

five referred patients from Michigan were infected with isolates with

identical genotypes (cluster A) when they arrived at the UNC Hospitals

and that the isolate from the fifth patient (Fig. 1, patient 4) possessed

a genotype that differed from that of the isolates from the first four

patients by only two bands. Digestion with XbaI and PFGE of the isolate

from patient 4 allowed us to confirm by direct comparison with the PFGE

results of Kumar et al. (12) that these isolates were part of the cluster

of genetically related isolates from five CF centers in Michigan (data

not shown). We were initially alarmed at finding this cluster among our

referred patients. However, we found no evidence of the spread of

isolates in this cluster to any of the other CF patients screened in this

study. Cluster A also included an isolate from a single referred patient

from Nebraska. We have not been able to verify whether this patient

attended some of the same CF camps or CF centers as the rest of the

patients whose isolates were in cluster A.

One of the shortcomings of our study design was that we studied only a

single isolate from each patient. We had two instances in which isolates

from sibling pairs had different genotypes. Patient 14 is a sibling of

patient 23, and both patients were infected with the same genomovar (B.

multivorans) but the genotypes of the isolates were not related. In

another instance, we noted that isolates from siblings (patient 10, whose

isolate was in cluster B, and patient 20, whose isolate was in cluster F)

differed in their genotypic patterns. Since we studied only one isolate

from each patient, it is possible that the siblings may have been

infected with isolates with common genotypes that were not detected. We

previously showed that over time patients harbor B. cepacia complex

isolates with the same genotype (24).  Overall, the results of our

genotype analysis indicate that the spread of a previously characterized,

transmissible clone of B. cepacia from referred patients to our clinic CF

patient population has not occurred.

Other studies have indicated that a high percentage of patients at CF

centers often harbor endemic, transmissible clones (2, 12, 15, 17, 23,

25, 29). In contrast, our PFGE results did not indicate the presence of a

common, transmissible clone among our clinic CF patient population. Our

results more closely parallel those of a recent study (20) indicating

that hospitals with a segregation policy tend to have patients infected

with unique strains. Documented nosocomial spread involved 4 of 26 (15%)

of our clinic B. cepacia complex-infected patients (patients 12 to 14,

whose isolates were in cluster C, and patient 16, whose isolate was in

cluster D).

A recent publication indicated that in the United Kingdom the cblA gene

may be used as a marker to identify strains with an enhanced capacity for

spread (3). We found the cblA gene in only 4 of the 56 B. cepacia

isolates that we examined. Two of the four isolates were from referred

siblings from Canada and were in cluster E. However, the genotype for

cluster E isolates differed from that of the epidemic, cblA+ ET 12

strain, also isolated from Canadian patients, by more than seven

fragments, and they are therefore considered genetically unrelated. There

was no evidence of spread of cblA+ clones in our patient population. Our

data are consistent with those of LiPuma and colleagues (18), who found

that only 1 of 606 isolates carried the cblA gene. These data suggest

that other factors are important in the transmissibility of the genomovar

III organisms.  The most frequently recovered B. cepacia complex species

from CF patients are genomovar III (18), and recent data indicate that CF

transplant

patients infected with genomovar III suffer higher rates of mortality

than those infected with another genomovar (1). However, it is apparent

from our study and those of others that B. multivorans can also be

frequently recovered (8, 18, 28). In fact, our results indicate that B.

multivorans was slightly more prevalent than genomovar III among our CF

patient population (26 and 25 patients, respectively). Our results also

revealed that 36 of the 56 CF patients seeking care at the UNC Hospitals

harbor strains with unique genotypes, so their sources of infection are

likely to be diverse.  In conclusion, our study of B. cepacia

complex-infected CF patients indicated that transmission of an isolate

from a referred patient to our clinic CF patient population occurred in

only two instances (with isolates in clusters C and F), but nosocomial

transmission could clearly be documented for only one of these isolates

(a cluster C isolate). Intracenter transmission of isolates in one,

two-patient cluster (cluster D) occurred within our clinic patient

population. Our clinic patients were infected with a variety of different

genotypes of the B. cepacia complex. These data suggest that CF patients

who were infected with B. cepacia complex isolates and who were referred

for lung transplantation

evaluation were not a major source of the B. cepacia complex organisms

that infected our resident CF clinic population.

* Corresponding author. Mailing address: Clinical Microbiology-Immunology

Laboratories, University of North Carolina Hospitals CB 7600, Chapel

Hill, NC 27514. Phone: . Fax: . E-mail:

pgilliga@....

Present address: Department of Pathology and Area Laboratory Services,

Landstuhl Regional Medical Center, Landstuhl, Germany.

Becki

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