Is it possible to guide clinicians to prescribe the optimal antibiotic therapy for S. aureus infections by solely reporting the most effective antibiotics on the antibiogram? A consulting infectious disease specialist (ID)/clinical microbiologist has a huge impact on the optimized therapy of S. aureus infections, but this is costly and often not possible [2, 3, 6, 17, 18]. Guiding the clinician using the antibiogram as an AMS tool could be a very cost-effective alternative, even if it cannot fully replace an ID consultation. Selective antibiotic reporting is recommended by most AMS guidelines [1,2,3, 12, 19, 20], although the evidence is very scant: very few studies have proved a significant effect on antibiotic consumption for urinary tract infections or infections due to gram-negative pathogens [21,22,23,24,25] or for the use of rifampicin . To our knowledge, there are no studies on frequently occurring and often severe S. aureus infections. To date, selective reporting is poorly implemented in Europe (only in about one third of European countries), predominantly for urine cultures; only in Ireland, Turkey, the UK and Sweden is it endorsed as a standard of care by the health care authorities [19, 20, 27,28,29].
Which antibiotics are the most effective in S. aureus infections to be reported on the "selective" antibiogram?
There is broad consensus that narrow-spectrum beta-lactams such as intravenous flucloxacillin or first generation cephalosporins (cefazolin/cefalexin) have better activity against MSSA than broad-spectrum beta-lactams. The treatment of bacteremia caused by S. aureus with high dose intravenous flucloxacillin or cefazolin is associated with lower mortality rates compared to the treatment with broad-spectrum beta-lactams or vancomycin [13,14,15, 30,31,32,33,34,35]. There is a minimum consensus amongst publications to report oxacillin/flucloxacillin, clindamycin and trimethoprim/ trimethoprim-sulfamethoxazole (the latter for oral treatment) on a selective antibiogram for S. aureus, as well as to omit vancomycin, linezolid or broad-spectrum beta-lactams [19, 20, 36].
How can we measure the effect of the intervention?
We monitored the monthly consumption of different antibiotics using RDD/100 BD, a standardised method for measuring antibiotic use, which is not influenced by fluctuating patient numbers. We compared consumption in the year prior to and after implementing selective susceptibility reporting in our clinic to the reference clinic. We used RDD instead of the frequently used defined daily dose (DDD) [2, 37] as the RDD is based on higher daily doses. This represents the doses used in our investigation more closely (Table 2).
Additionally, we analysed antibiotic use on an individual patient level using “Days of therapy” (DOT), favoured by IDSA guideline 2016 , as this is not impacted by individual dose adjustments. As our electronic patient file system does not allow an automatic assessment of DOT, patient records were analysed manually by three independent reviewers. Thus, we focussed on two patient groups: SSTI and SAB. We chose SSTI because—in contrast to other specialties—there had not been any previous AMS interventions in the involved departments.
What was the impact of the intervention on the use of selectively reported antibiotics?
Regarding the overall consumption of the hospital there was a significant increase of antibiotics recommended for S. aureus infections (from 3.38 to 5.34 RDD/100 BD, p = 0.001; Table 3) after selectively reporting commenced. This increase was particularly remarkable when put into proportion to the overall low rate of S. aureus infections (less than 0.5 newly detected S. aureus infections/colonisations/100 BD).
Especially the use of narrow-spectrum beta-lactams (flucloxacillin/cefazolin/cefalexin) rose significantly after selective reporting.
Intravenous flucloxacillin and cefazolin—used in SAB and the initial therapy of severe S. aureus infections—were analysed as an entity because they were assessed to be equally effective and replaced each other depending on side effects [30, 31, 38]. Their consumption rose from 0.9 to 1.5 RDD/100 BD throughout the hospital. Although a slight increase in the overall use of narrow spectrum beta-lactams could be seen in both hospitals over the course of time (probably due to general AMS interventions in Germany), the changing of antibiograms in our clinic had an immediate and sustained effect on the treatment of SAB in contrast to the reference clinic (Fig. 1).
There was also an immediate striking increase in the consumption of oral cefalexin used in milder infections or follow-up therapy (from 0.3 to 1.4 RDD/100 BD, p = 0.001) (Table3, Fig. 2). This increase exceeds a possible regulatory effect due to a restriction of oral cefuroxime, preauthorised by the pharmacy (simultaneously in both clinics; plus 1.01 oral cefalexin versus minus 0.53 RDD/100 BDD total cefuroxime in the interventional clinic).
As the use of narrow-spectrum beta-lactams was restricted to targeted treatment of S.aureus infections in both hospitals, the overall consumption data indicates that the selective antibiogram significantly increased their use for those infections.
This assumption was confirmed by our individual patient level data. Days of therapy (DOT) of all selectively reported antibiotics rose significantly from 20 to 38 DOT/100 BD (p = 0.020) in SSTI (Table 4) and from 58 to 79 DOT/100 BD (p = 0.002) in SAB (Table 5). In SSTI, we recorded a striking rise of oral cefalexin usage (predominantly used for mild infections without bacteremia) from 1.4 to 9.4 DOT/100 BD (p = 0.005; from 3 to 17 patients), whereas in SAB there was a significant increase in the use of intravenous flucloxacillin/cefazolin from 52 to 75 DOT/100 BD (p = 0.001; from 50 to 72 patients). Selective reporting obviously strongly supported clinicians to optimize the treatment of S. aureus infections after receiving the report. In 77% of cases with SAB, the therapy was converted to a flucloxacillin/cefazolin regime on day 2–4. This is in contrast to 42% conversion rate before the introduction of selective reporting. If you include cases where treatment had initially been started on a flucloxacillin/cefazolin regime, 72 of 81 (89%) of the patients with SAB received appropriate treatment (50 of 86 before intervention). This number could hardly be further increased, since amongst the SAB group there were patients requiring broader therapy spectrum due to further infections (7 vs. 16 patients, mainly aspiration pneumonias or urinary tract infections). We did not exclude these patients because they were difficult to determine (proven versus suspected infections).
Tan et al. showed a similar significant increase in the consumption of selectively reported antibiotics such as nitrofurantoin for targeted therapy and even for calculated therapy of urinary tract infections. Also, for urinary tract infections McNulty et al. . demonstrated "that prescribing reverted to pre-intervention levels once the change in antibiotic reporting had stopped". We decided not to revert the antibiograms to the pre-interventional stage due to ethical reasons, and the goal to enhance the use of more effective narrow-spectrum antibiotics, along with lowering side-effects was reached.
What was the impact of selective reporting on the use of omitted antibiotics?
Considering the overall consumption of the hospital (RRD/100 BD, Table 3), there was no decrease in the use of wide-spectrum antibiotics after selectively not-reporting for S. aureus (42.4 vs. 44.5 RDD/100 BD, p = 0.249). Neither was there an impact on the number of C. difficile infections. We didn´t expect this anyways due to the wide use of these broader spectrum antibiotics for other infections, e.g. sepsis, pneumonia or meningitis. There was even a slight (partly significant) rise in the usage of broad-spectrum antibiotics such as carbapenems and vancomycin in our clinic. In effect this led to an aligning with the significantly higher baseline level of piperacillin-tazobactam, carbapenems, fluorochinolons and vancomycin usage reported by the reference clinic for the pre-interventional period (see also limitations of RDD/100 BD).
Due to the overall low proportion of S.aureus infections, the reduction in the use of omitted antibiotics might be concealed due to their higher usage for other infections. We therefore evaluated individual patient records for two specific indications additionally. In the SAB group (Table 5), there was a significant decline in the use of aminopenicillin-beta-lactamase-inhibitors (from 7.3 to 0.4 DOT/100 BD, from 18 to 2 patients), in favour of intravenous flucloxacillin/cefazolin. A trend towards lower prescription rates of all no longer reported antibiotics (from 54 to 41 DOT/100 BD, p = 0.087) did not reach statistical significance however. This was probably due to low case numbers (86 vs. 81) and polymicrobial infections (see above). In the SSTI group (Table 4), clinicians waived third-generation cephalosporins and carbapenems (6 vs. 0 cases). Due to the heterogeneity of this group, containing a mixture of SSTI diagnoses, its statistical power was limited.
Some limitations to this study need to be mentioned. We evaluated main data by overall antibiotic use by RDD/100 BD, because our electronic patient records did not support statistical evaluations by DOT. However, a general trend towards higher RDD/100 BD is seen throughout many German hospitals caused by a progressive reduction of the average amount of time patient spent in hospital. This is due to the German reimbursement system (DRG) and led to a higher consumption per BD (concentrating intravenous antibiotic therapies using maximal doses during the short stay in the hospital). Additionally average age and number of comorbidities increased. More patients with sepsis needed more wide-spectrum antibiotics .
Furthermore, a rise of AMS counselling and interventions within the last decade has already had a significant impact on the treatment of S. aureus infections such as SAB. This is certainly true for our hospital. Therefore, it´s likely that the advantage of implementing selective reporting might have been shown more clearly in clinics without prior AMS activities.