Risk of resistance related to antibiotic use before admission in patients with community-acquired bacteraemia

Gitte Pedersena, Henrik Carl Schønheyderb, Flemming Hald Steffensenc and Henrik Toft Sørensonc,d

a Department of Medicine M, Aalborg Hospital, Aalborg; b Department of Clinical Microbiology, Aalborg Hospital, Aalborg; c The Danish Epidemiology Science Centre at the Department of Epidemiology and Social Medicine, University of Aarhus, Aarhus; d Department of Medicine V, Aarhus University Hospital, Aarhus, Denmark


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We analysed the association of antibiotic therapy before admission and antibiotic resistance of blood isolates in a total of 1717 community-acquired bacteraemias in the County of Northern Jutland during 1992–96. Antibiotics had been prescribed to 14% of the patients during the 30 days before admission and to 37% during the 6 months. The most frequently prescribed antibiotics within 30 days were ampicillin (28%), penicillin G (27%), sulphonamides and/or trimethoprim (16%) and macrolides (14%). The most frequent blood isolates were Escherichia coli (33%), other Enterobacteriaceae 8%), Streptococcus pneumoniae (23%) Staphylococcus aureus (10%). Of the 575 isolates of E. coli, 425 (74%), 432 (75%) and 518 (90%) were susceptible to ampicillin, sulphonamides and trimethoprim, respectively. Previous antibiotic prescriptions were strongly associated with resistance to ampicillin, sulphonamides and trimethoprim in E. coli. The association was less pronounced for S. aureus and enteric rods other than E. coli. Antibiotic prescriptions within the last 3 months predicted antibiotic resistance, and this should be taken into account when selecting empirical antibiotic therapy of severe community-acquired infections.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Evolution of antibiotic resistance is of worldwide concern. 1 Several studies have shown an association between antibiotic use and antibiotic resistance in hospital-acquired infections. Conversely, studies addressing community-acquired infections are few and have mainly focused on respiratory tract and urinary tract infections. 2 ,3 ,4 ,5 ,6 ,7

Approximately 90% of the total consumption of antibiotics in Denmark originate in general practice.8 Antibiotic usage in general practice could thus be a major determinant of antibiotic resistance of isolates in hospitalized patients. In order to examine this hypothesis we determined susceptibility patterns of blood isolates in patients with community-acquired bacteraemia and their antibiotic use during a 6 month period before admission. The aims of the study were to identify predictors of antibiotic resistance in bacteria causing community-acquired bacteraemia and thereby to improve, if possible, the basis for selecting empirical antibiotic therapy.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population

The study was conducted from 1 January 1992 to 31 December 1996 in the County of Northern Jutland, Denmark, which has a population of 490,000 inhabitants (approximately 9% of the total Danish population). The Department of Clinical Microbiology at Aalborg Hospital provides services to all general practices and hospitals in the area (one referral hospital and six district hospitals).

Definition

Community-acquired bacteraemia is an episode of bacteraemia present or incubating at admission to hospital.9 In order to preclude the influence of previous hospitalization on the patient's flora we excluded patients who had been hospitalized within the 30 days before an episode of community-acquired bacteraemia. Only the patient's first episode of monomicrobial bacteraemia was included.

Exposure data

The population-based Pharmaco-Epidemiological Prescription Database of the County of Northern Jutland started in January 1991.10 The County is served by 33 pharmacies equipped with a computerized accounting system from which data are sent to the health insurance administration of the Danish National Health Service. The National Health Service provides tax-supported health care for all inhabitants. Apart from guaranteeing free access to general practitioners and hospitals, the insurance programme refunds 50–75% of the costs associated with the purchase of antibiotics and other drugs prescribed by doctors. The information includes the type of antibiotic prescribed according to the Anatomical Therapeutic Chemical System (ATC) commodity number, date of prescription and date of handling by the pharmacy.

All prescription records concerning antibiotics (ATC group J01, excluding J01X) were retrieved for a 6 month period before the episode of community-acquired bacteraemia. Antibiotics were grouped as follows: (i) penicillin G; (ii) ampicillin and amoxycillin; (iii) isoxazolyl penicillins; (iv) pivmecillinam; (v) sulphonamides, trimethoprim or a combination of them; (vi) fluoroquinolones; (vii) tetracyclines; and (viii) macrolides. From January 1996 reimbursement for tetracyclines was abolished, and data for tetracyclines were not available for that year. No data were available for prescriptions of cephalosporins during the study period, because there was no reimbursement for these antibiotics, but information on the consumption of oral cephalosporins, as related to the total antibiotic consumption (ATC group J), was obtained from the Danish Drug Information, Copenhagen, Denmark.

Microbiological and relevant clinical data for patients with bacteraemia were collected from the Regional Bacteraemia Registry at the Department of Clinical Micro biology.11 Data were collected by physicians as part of the clinical service provided by the Department of Clinical Microbiology. Data included species and type of bacterial isolates and their susceptibility patterns, age and sex of the patient, day of admission and presumed focus of infection.

Linkage of the computerized registers was done by the personal registration number (CPR number) given to all Danes at birth.

Blood cultures

Three blood culture systems were used during the study period. During the first months of 1992, blood was sampled for culture into transport tubes, which were sent for secondary bacteriological culture. By August 1992 this traditional system was replaced by a broth culture system (Colorbact; Statens Serum Institut, Copenhagen). In 1996 the BacT/Alert broth culture system (Organon Teknika, Turnhout, Belgium) was introduced.

Bacteriology

Bacterial isolates were identified according to published guidelines.12 A commercial identification system was used for Enterobacteriaceae.13 Coagulase-negative staphylococci, Corynebacterium spp. and Propionibacterium acnes were regarded as contaminants unless isolated from two or more separate blood culture sets.

Antimicrobial susceptibility was tested with a tablet diffusion method (Neo-Sensitabs; Rosco, Taastrup, Denmark) on Danish horse blood agar with penicillins, cephalosporins (first, second and third generation), a monobactam, carbapenems, aminoglycosides, fluoroquinolone, tetracycline, sulphonamide, trimethoprim and macrolide. 14 Zone size interpretative guidelines were as stated by the manufacturer. For the purpose of analysis, isolates with intermediate susceptibility were included in the susceptible group with the exception of isolates with intermediate susceptibility to gentamicin, which were included in the resistant group. The susceptibility pattern was unknown for four isolates of Streptococcus pneumoniae that did not grow on subculture. For a number of isolates of Escherichia coli , data on susceptibility to sulphonamides, trimethoprim and tetracyclines were missing (four, five and two isolates respectively). For the purpose of analysis, isolates with missing data were included as susceptible.

For further analysis, Enterobacteriaceae other than E. coli were defined as one group (for details see Table II, footnote). E. coli isolates were tested for susceptibility to ampicillin, mecillinam, cefuroxim, sulphonamides, trimethoprim and tetracyclines.


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Table II. Antibiotic susceptibility of the main bacterial groups in 1281 episodes of monomicrobial community-acquired bacteraemia in the County of Northern Jutland from 1992 to 1996
 
Clinical speciality

The clinical speciality was determined by the department to which the patients were admitted when blood cultures were obtained.

Focus of infection

Cultures of other body fluids and sites, e.g. pus, urine or respiratory secretions, were performed as deemed relevant by the attending physicians. The probable focus of infection was assessed on the basis of microbiological and clinical findings. For patients with an episode of E. coli bacteraemia during 1996, reports on microbiological specimens other than blood were reviewed regarding previous isolations.

Statistical analysis

We analysed the data by obtaining contingency tables for antibiotic susceptibility and the main study variables: age, sex, focus of infection, bacterial groups and previous antibiotic prescriptions. We thus calculated odds ratios (ORs) as estimates of the prevalence ratio of antibiotic susceptibility. ORs were presented with approximate 95% confidence limits (CL).We then stratified the contingency tables and fitted multiple logistic regression models to the data adjusted for age, sex and focus of infection. 15 The fit of the model was evaluated by the Hosmer–Lemeshow test.

The study was in accordance with guidelines of the regional scientific ethics committee for use of clinical and laboratory data.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients

We identified 1717 episodes of monomicrobial community-acquired bacteraemia during the 5 year study period. Fifty percent of patients were male, and the median age was 71 years. Table I shows the distribution of sex, age, hospitals, clinical specialities and focus of infection.


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Table I. Characteristics of 1717 patients with an episode of monomicrobial community-acquired bacteraemia in the County of Northern Jutland from 1992 to 1996
 
Bacteriology including antibiotic susceptibility

The main bacterial groups (n = 1281) and their antibiotic susceptibility patterns are summarized in Table II. The following less numerous groups are not shown in Table II: haemolytic streptococci (n = 91; 5%), Salmonella spp. ( n= 55; 3%), miscellaneous Gram-negative bacteria ( n=110; 6%), miscellaneous Gram-positive bacteria ( n = 102; 6%), and anaerobic bacteria ( n = 78; 5%).

We ascertained the distribution of antibiotic resistance among 575 isolates of E. coli : 373 (65%) were susceptible to all antibiotics, 56 (10%) were resistant to one, 56 (10%) to two, 57 (10%) to three, 27 (5%) to four, and six (1%) to five antibiotics, respectively. For 156 patients with E. colibacteraemia in 1996, only nine had an isolate of E. coli from a specimen type other than blood during a 6 month period before admission.

Antibiotic prescriptions

During the 6 months before admission, 628 patients (37%; 95% CL 35–39%) had received 1209 prescriptions of antibiotics, and within 30 days 236 of these patients (14%; 95% CL 12–15%) had received 290 prescriptions. Panels a and b of the Figure show the distribution of prescriptions during the 0–30 days and 31–180 days before admission, respectively. Macrolides tended to be used more frequently during the 0–30 days before admission (OR 1.4; 95% CI 0.9–2.0), while sulphonamides/trimethoprim tended to be used more frequently in the 31–180 days before admission (OR 1.4; 95% CI 1.0–2.0), but because of the small sample size this study lacked statistical precision.




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Figure. Antibiotic prescriptions during (a) the 0—30 days before and (b) the 31—180 days before an episode of community-acquired bacteraemia.

 
During the 6 months before admission, 1089 patients (63%) had had no prescription of antibiotics (Table III). The remaining patients had had a median of one prescription (range 1–10). During the 6 months before admission, antibiotics were prescribed more often to patients with isolates of E. coli or other Enterobacteriaceae than to patients with other aetiological agents (for E.coli , the OR was 1.5 and the 95% CL 1.2–1.9, while for other Enterobacteriaceae the OR was 1.5 and the 95% CL 1.1–2.2). The estimates for S. aureus were: OR, 1.1; 95% CL, 0.8–1.5. Of the patients with E. coli , 326 (57%) had had no antibiotic prescription within the 6 months before admission, while 125 (22%), 65 (11%), 32 (6%) and 27 (3%) had had one, two, three and four or more prescriptions, respectively. The distribution of antibiotic prescriptions was as follows: ampicillin or amoxycillin, 148 prescriptions (31%); sulphonamides and/or trimethoprim, 119 (25%); penicillin G, 79 (16%); isoxazolyl penicillins, 26 (5%); pivmecillinam, 35 (7%); macrolides, 50 (10%); tetracyclines, 15 (3%); and fluoroquinolones, 13 (3%).


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Table III. Number of antibiotic prescriptions in 1717 patients related to main antibiotic groups during the 6 months before an episode of community-acquired bacteraemia
 
Prescriptions of oral cephalosporins were not available from the database but total consumption amounted to 0.14–0.23% of all antibiotics used in the county (0.35 – 0.40% in all of Denmark).

Antibiotic resistance

We analysed the association between previous antibiotic treatment and susceptibility patterns for the major bacterial groups. In the group with S. aureus infections, 63 patients (38%) had received a prescription of antibiotics in the previous 6 months. A comparison of isolates from patients with and without previous antibiotic therapy showed that antibiotic therapy was associated with increased resistance to penicillin (OR 2.1; 95% CL 0.9–4.9).

In the group with infections by Enterobacteriaceae other than E. coli , 67 patients (46%) had received a prescription of antibiotics in the 6 months before admission and the relative risk of resistance to ampicillin, sulphonamides and trimethoprim was OR 0.7 (95% CL 0.3–1.7), OR 2.2 (95% CL 0.6–7.7) and OR 1.2 (95% CL 0.4–3.8) respectively.

In the group with infections by E. coli , 101 patients (17%) had received an antibiotic prescription during 30 days, 81 (14%) in the period 31–90 days before admission, and 67 (12%) in the period 91–180 days before admission. For each of the periods, resistance to one or more antibiotics was associated with the use of antibiotics, as confirmed by analysis adjusted for sex, age and focus of infection: <=30 days, OR 2.9 (95% CL 1.8–4.6); 31–90 days, OR 2.1 (95% CL 1.3–3.6); 91–180 days, OR 1.7 (95% CL 1.0–2.9). If the analysis was restricted to resistance to two or more antibiotics the estimates were: <=30 days, OR 3.3 (95% CL 2.0–5.4); 31–90 days, OR 2.5 (95% CL 1.5–4.4); 91–180 days, OR 1.5 (95% CL 0.8–2.8). Patients were also stratified according to the number of antibiotic prescriptions. For the 125 patients who had received two or more prescriptions, there was a strong association with resistance to two or more antibiotics (OR 3.4 (95% CL 2.1–5.4)).

Similarly, an adjusted analysis was undertaken for resistance to each of the antibiotics ampicillin, sulphonamides and trimethoprim. Antibiotic therapy in the 90 days before admission was strongly associated with increased resistance to all three antibiotics ( Table IV). As the numbers of prescriptions were limited, crude analyses were feasible only when assessing ampicillin, sulphonamides and trimethoprim as predictors of homologous resistance (ampicillin: OR 2.8, 95% CL 1.8–4.5; sulphonamides: OR 3.5, 95% CL 2.1–5.9; trimethoprim: OR 14.3, 95% CL 6.3–32.4).


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Table IV. Predictors of antibiotic resistance to ampicillin, sulphonamides and trimethoprim in 575 episodes of community-acquired bacteraemia with E. coli
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We found a strong association between antibiotic use before admission and risk of resistance in patients with community-acquired bacteraemia. The association was particularly strong in patients with isolates of E. coli . The increase in resistance to sulphonamides was restricted to the urinary tract, whereas for ampicillin it involved any defined focus of infection. The increased resistance to ampicillin, sulphonamides and trimethoprim was discernible for up to 3 months, while that for sulphonamides persisted even longer. Previous antibiotic therapy with ampicillin, sulphonamides and especially trimethoprim was a strong risk factor for homologous resistance.

There was only a slight trend for increased antibiotic resistance of S. aureus and Enterobacteriaceae other than E. coli in patients who had received antibiotics previously. Only resistance to penicillin was included in the analysis of increased resistance of S. aureus as all isolates were susceptible to methicillin. Resistance of S. aureus to erythromycin and tetracycline currently occurs at a very low level in Denmark 6,16 and data on susceptibility to these two antibiotics were not included in the database. The numbers were small for Enterobacteriaceae other than E. coli, and prevalence of antibiotic resistance tended to be high even in isolates from patients who had no record of receiving antibiotics previously.

Our use of population-based registries made selection bias an unlikely explanation for the associations. The computerized data used were collected independently of the study, which reduces the risk of information bias.

Denmark has the lowest use of antibiotics in the Nordic countries, and probably one of the lowest in the world. Thus, there have been only limited problems with antibiotic resistance. 11 ,17 ,18 ,19 However, even in this population with low exposure to antibiotics, we have provided strong evidence for a link between choices and use of antibiotics in general practice and the development and spread of antibiotic-resistant microorganisms.

Ampicillin and amoxycillin account for a major part of the consumption of ß-lactam antibiotics, whereas the consumption of oral cephalosporins is currently low in Denmark. Prescriptions of macrolides, which were more frequent during the 30 days before admission, are highly likely to be targeted towards the infectious disorder for which the patient was admitted, in contrast to the sulphonamides and trimethoprim, which tended to be prescribed irrespective of the bacteraemic episode, presumably as therapy for incidental urinary tract infections.

Patients with polymicrobial bacteraemia were excluded from the study. The association between microbial agent and disease is not as straightforward as in monomicrobial bacteraemia, and analysis of susceptibility patterns is more complex. 20

Only a minority of patients with E. coli bacteraemia had an isolate of E. coli in any type of specimen during the previous 6 months. This suggests that the results were not affected to any considerable extent by patients with chronic E. coli infection and multiple courses of antibiotics.

There is a large variation in use of antibiotics in general practice. 21 We have provided evidence for a link between prescription of antibiotics in general practice and antibiotic resistance. The significant variation in prescription of antibiotics is probably a consequence of the general practitioner's indications for treatment, but large variation is a marker of suboptimal quality. This variation seems to have ecological consequences.

To conclude, in an area with restrictive use of antibiotics we have shown that antibiotic therapy in general practice, and in particular use of broad-spectrum antibiotics, is associated with a notable increase in resistance of blood isolates from community-acquired bacteraemia. This ecological effect of antibiotic therapy extends for at least 3 months, and must be taken into account when selecting empirical antibiotic therapy for patients with severe community-acquired infections. Currently, resistance to mecillinam, second-generation cephalosporins and fluoroquinolones does not constitute a clinical problem, but we envisage that their extended use in general practice would affect their usefulness in treatment of septicaemia.


    Acknowledgments
 
The study was supported by a grant from Aalborg Stifttidendes Julelotteri and by grant 940 from the County of Northern Jutland. The activities of the Danish Epidemiology Science Centre are financed by a grant from the Danish National Research Foundation and a grant from the NASTRA Programme, The Danish Medical Research Council (grant no. 9700677). We thank the staff of the Department of Health Insurance and Preventive Medicine in the County of Northern Jutland for preparing prescription data for analysis.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 23 March 1998; returned 7 May 1998; revised 17 June 1998; accepted 13 August 1998