Dispatch
Increasing Quinolone
Resistance in Salmonella enterica serotype Enteritidis
Kåre Mølbak,* Peter Gerner-Smidt,* and Henrik C. Wegener†
*Statens Serum Institut, Copenhagen, Denmark; and †Danish Zoonosis
Centre, Copenhagen, Denmark
Until recently,
Salmonella enterica serotype Enteritidis has remained sensitive
to most antibiotics. However, national surveillance data from
Denmark show that quinolone resistance in S. Enteritidis
has increased from 0.8% in 1995 to 8.5% in 2000. These data support
concerns that the current use of quinolone in food animals leads
to increasing resistance in S. Enteritidis and that action
should be taken to limit such use.
Salmonella enterica serotype Enteritidis is the most common
cause of foodborne salmonellosis worldwide. Historically, this serotype
has remained sensitive to most antibiotics, unlike other common
serotypes such as Typhimurium, Hadar, Virchow, and Infantis, in
which resistance to a wide range of antimicrobial agents is common
(1). Recently in Denmark, we have recorded increasing
resistance to quinolones in S. Enteritidis from human infections.
This finding is cause for concern because fluoroquinolones are first-line
drugs for treatment of human salmonellosis.
The
Study
From 1995 to 2000, 13,334 S. Enteritidis infections were
recorded in Denmark, accounting for 62% of all zoonotic salmonella
infections. To monitor drug resistance (2), we
examined a random sample of 2,546 isolates, of which 82 (3.2%) were
resistant to the quinolone nalidixic acid. These data showed that
quinolone resistance increased from 0.8% (3 of 384 isolates) in
1995 to 8.5% (31 of 366) in 2000 (Figure).
Resistance to other antimicrobial agents was infrequent, and quinolone
resistance was mainly present as a single resistance.
Quinolone resistance was related to foreign travel as well as S.
Enteritidis phage type (PT). In isolates from patients with a known
history of foreign travel, 8.9% were resistant, compared with 2.4%
in domestically acquired infections (p<0.0001; Table).
In 157 patients who had returned from a European destination (excluding
Scandinavia), 18 (11.5%) had resistant isolates. Resistance was
highest in patients returning from Spain: 12 (19.7%) of 61 isolates
were resistant. Five (7.5%) resistant strains were found in 67 isolates
from Asia (mainly Turkey and Thailand), but no resistant strains
were recovered from 25 persons who had traveled to Africa. Five
patients had visited other countries (1 resistant strain), and we
had no information about the destination for the remaining 48 patients
(3 resistant strains).
The major sources of domestically acquired S. Enteritidis
infections are raw or undercooked eggs produced in Denmark (3,
unpub. data). The most common phage types in Danish layer hens are
PT 6 and PT 8, which accounted for 65.1% of the domestically acquired
infections in our study. Resistance in these two phage types remained
low (Table), as were the rates of resistance
in PT 13A, PT 25, and PT 34. These types also originate from layer
hens. In contrast, the proportion of resistant isolates was highest
in phage types PT 1, PT 4, PT 6A, PT 14B, and PT 21, which are often
associated with infections from imported poultry products, including
imported broiler chickens.
From 1994 to 1997 in England and Wales, quinolone resistance in
S. Enteritidis increased from 0.4 % to 1.3%. As in our study,
resistance was highest in PT 1 (19%) and PT 6A (14%) (4).
These types were mainly associated with foreign travel. In a recent
study from Spain, 31% of 385 S. Enteritidis isolates overall
but 80% of PT 1 isolates were reported to be quinolone resistant
(5).
Conclusions
The emergence of quinolone resistance in the most common salmonella
serotype worldwide is a serious public health concern. Resistance
to nalidixic acid has been associated with reduced efficacy of fluoroquinolones
such as ciprofloxacin (6,7). The use of nalidixic
acid or fluoroquinolones in humans is unlikely to contribute substantially
to the increase in resistance, for the following reasons: An antibiotic
prescribed in connection with a physician’s request for a fecal
specimen is unlikely to have affected the resistance pattern because
treatment is usually initiated after the specimen is collected.
Fluoroquinolones are potent bactericidal drugs and are not likely
to select for resistance when therapeutic concentrations are obtained
(8). Nalidixic acid is used in some developing
countries for the treatment of dysentery, but the this practice
is unlikely to select for quinolone-resistant S. Enteritidis
in the zoonotic reservoir. The prevalence of resistance in S.
Enteritidis was, in our study, highest in patients returning from
developed countries. Furthermore, fluoroquinolones are not used
to treat children. In children <15 years of age, the prevalence
of quinolone-resistant strains was 9.5% (4/42) among patients with
a history of foreign travel and 1.4% (7/499) in domestically acquired
cases. The corresponding figures for adults were 8.9% (23/260) and
2.7% (47/1,744). Finally, the use of quinolones in humans could
not conceivably be responsible for the large variation in the prevalence
of resistance by phage type. If the use of quinolones in human medicine
contributed to the emergence of quinolone resistance in S.
Enteritidis, resistance would be found independently of phage type.
Increasing quinolone resistance is not confined to foodborne salmonella
but also includes campylobacters; resistance is primarily driven
by the use of fluoroquinolones in the livestock production (8,9).
Limited quantities of fluoroquinolones are currently used in food
production in Scandinavia. During 19971998, the annual use
of the liquid formulation of fluoroquinolones for 130 million to
140 million poultry was <150 kg; during 1999–2000, usage decreased
to <100 kg (2). Unfortunately, quantitative
data on the use of fluoroquinolones are not available from most
areas. Several fluoroquinolones are licensed and used in other countries
of Europe, Southeast Asia, and the Americas for treatment of food
animals, particularly for mass medication in the poultry industry,
mainly for broiler chickens (2,8–10). Our data
support concerns that the current pattern of quinolone use in food
animals leads to increasing quinolone resistance in S. Enteritidis
and that action should be taken to limit this use.
Dr. Mølbak is a medical epidemiologist at Statens Serum Institut
in Copenhagen, Denmark. Professional interests include zoonotic
foodborne bacterial infections, diarrheal diseases epidemiology,
and methods in epidemiology.
References
- Threlfall EJ, Ward LR, Skinner JA, Graham A.
Antimicrobial
drug resistance in non-typhoidal Salmonellas from humans in England
and Wales in 1999: decrease in multiple resistance in Salmonella
enterica serotypes Typhimurium, Virchow, and Hadar. Microb
Drug Resist 2000;6:319–25.
- Danish Integrated Antimicrobial Resistance Monitoring and Research
Programme (DANMAP 2000). Consumption of antimicrobial agents and
occurrence of antimicrobial resistance in bacteria from food animals,
foods and humans in Denmark. Copenhagen, Denmark: Danish Zoonoses
Centre; 2001. (www.vetinst.dk)
- Annual report on zoonoses in Denmark, 2000. Copenhagen, Denmark:
Ministry of Food, Agriculture and Fisheries; 2001. (www.vetinst.dk)
- Threlfall EJ, Ward LR, Rowe B. Resistance
to ciprofloxacin in non-typhoidal salmonellas from humans in England
and Wales–the current situation. Clin Microbiol Infect 1999;5:130–4.
- Cruchaga S, Echeita A, Aladuena A, Garcia-Pena J, Frias N, Usera
MA. Antimicrobial
resistance in salmonellae from humans, food and animals in Spain
in 1998. J Antimicrob Chemother 2001;47:315–21.
- Wain J, Hoa NT, Chinh NT, Vinh H, Everett MJ, Diep TS, et al.
Quinolone-resistant
Salmonella typhi in Viet Nam: molecular basis of resistance
and clinical response to treatment. Clin Infect Dis 1997;25:1404–10.
- Mølbak K, Baggesen DL, Aarestrup FM, Ebbesen JM, Engberg J,
Frydendahl K, et al. An
outbreak of multidrug-resistant, quinolone-resistant Salmonella
enterica serotype Typhimurium DT 104. N Engl J Med 1999;341:1420–5.
- Bager F, Helmuth R. Epidemiology
of resistance to quinolones in Salmonella. Vet Res
2001;32:285–90.
- Angulo FJ, Johnson KR, Tauxe TV, Cohen ML. Origins
and consequences of antimicrobial-resistant nontyphoidal Salmonella:
Implications for the use of fluoroquinolones in food animals.
Microb Drug Resist 2000;6:77–83.
- Division of Emerging and Other Communicable Disease Surveillance
and Control. Use of quinolones in food animals and potential impact
on human health: report of a WHO meeting: Geneva, Switzerland;
1998 Jun 2–5. Geneva: World Health Organization; 1998. (Document
no. WHO/EMC/ZDI/98.10.) (www.who.int/emc-documents/zoonoses/docs/whoemczdi9810.html#2)
Table.
Prevalence of quinolone resistance in human isolates of
Salmonella enterica serotype Enteritidis, by phage type
and history of foreign travel. Denmark, 1995–2000. |
|
Phage type |
No history of foreign travel
|
Foreign travel
|
|
|
No. resistant (%)
|
Total
|
No. resistant (%)
|
Total
|
|
1
|
22 (23.4)
|
94
|
11 (29.7)
|
37
|
4
|
7 (2.4)
|
292
|
5 (3.8)
|
131
|
6
|
4 (0.5)
|
765
|
0 (-)
|
28
|
6A
|
1 (5.9)
|
17
|
4 (22.2)
|
18
|
8
|
8 (1.3)
|
627
|
0
|
31
|
13A
|
0 (-)
|
9
|
0
|
4
|
14B
|
1 (20.0)
|
5
|
1 (14.3)
|
7
|
21
|
3 (4.9)
|
61
|
0
|
4
|
21B
|
0 (-)
|
16
|
0
|
0
|
25
|
0 (-)
|
19
|
0
|
0
|
34
|
0 (-)
|
81
|
0
|
2
|
Others and nontypeable
|
6 (3.9)
|
152
|
4 (13.8)
|
29
|
Not typed
|
2 (1.9)
|
105
|
2 (18.2)
|
11
|
Total
|
54 (2.4)
|
2,243
|
27 (8.9)
|
302
|
|
|
|