By Dr. Geoffrey Modest
Another blog on the potential broader issues with antibiotics… in general, the major issues are those related to antibiotic resistance (see https://stg-blogs.bmj.com/bmjebmspotlight/category/antimicrobial-resistance/ for blogs) and ecological changes in the microbiome (see https://stg-blogs.bmj.com/bmjebmspotlight/category/microbiome/ for blogs). Another issue was highlighted in a recent study of those on longer-term antibiotics and eosinophilia/hypersensitivity reactions (see doi:10.1016/j.jaci.2015.04.005).
Details:
- 824 patients (60% male, median age 60) on long-term, initially in-hospital antibiotics (median therapy duration of 41 days), followed prospectively. All received at least 2 weeks of antibiotics after discharge. Study from 2012-2013. 63% were on only one antibiotic.
- Most were treated for orthopedic infections (n=464) or bacteremia (n=161), most had gram positive organisms (n=641) and the most common antibiotics were cephalosporins (46%), vancomycin (40%) and penicillins (27%).
Results:
- 210 (25% had eosinophilia, defined as absolute eos count (AEC)>500 (range: 500-8610).
- Median time to developing eosinophilia was 15 days ([BUT: the labs were supposed to be drawn weekly, so hard to get very specific data on timing)].
- More eosinophilia in those on vancomycin, penicillin, rifampin, and linezolid. No increased risk with fluoroquinolones or cephalosporins. metronidazole was associated with decreased eosinophilia.
- Patients more likely to have eosinophilia were older (64 vs 59), and discharged to skilled nursing facility vs home (51% vs 39%) [i.e., likely sicker].
- 64 of the 210 patients with eosinophilia (30%) had hypersensitivity reactions (HSR) including rash (n=32, 15%), renal injury (n=31, 15%) and liver injury (n=13, 7%). Less commonly in those without eosinophilia: rash occurred in 6%, renal injury in 10% and liver injury in 7%.
- So, those with eosinophilia were significantly more likely to have a rash [HR=4.16 (2.53-6.83), p<0.001] and renal injury[HR=2.13 (1.36-3.33), p<0.001], though liver injury did not reach significance [HR=1.75 (0.92-3.33), p=0.09].
- Those with eosinophilia who developed HSRs had eosinophilia earlier in the course of therapy (11 vs 17 days, with caveat noted above about accuracy of this timing), and had higher peak AEC (median 857 vs 699).
- Possible DRESS syndrome (drug rash with eosinophilia and systemic symptoms) occurred in 7 (0.8%) of the 824 patients (3% of those who developed eosinophilia), of whom 4 (57%) were getting vancomycin, 3 on penicillins, 2 on metronidazole and 1 each on gentamicin, ceftriaxone and cefepime. 2 of the 7 with DRESS syndrome died.
So, a few points:
- 60% of inpatients get antibiotics, and antibiotics are the most common cause of HSRs.
- Though this study looked at sick inpatients with serious infections, there are a few issues of concern for us in primary care:
- They found that the time to develop eosinophilia was about 15 days after starting antibiotics, but they have no consistent daily CBCs to see if that really is true (ie, could be much less time).
- But even if one needs several weeks of antibiotics, this also happens in the outpatient setting (acne, chronic Lyme disease, refractory prostatitis….).
- They looked at patients on high dose antibiotics and mostly parenteral (except for those on linezolid), but I’m not sure there is a significant difference with long-term oral antibiotics.
- They found a lot more DRESS syndrome than previously described (typically 0.01 to 0.1%, as opposed to the 0.8% above). For a review of the DRESS syndrome, see Am J Med(2011) 124, 588. And I had one kid on minocycline for acne who developed DRESS syndrome after 2-3 weeks, leading to a 3 week hospitalization with an ICU stay for his hepatitis, pneumonitis and renal disease, and a pretty prolonged and awful recovery.
- Unclear why metronidazole was associated with less eosinophilia. They suggest it could be from treating c diff infections, but I think that is less likely, since the main culprit for c diff is the fluorquinolones, and these antibiotics were not associated with eosinophilia in this study, so a little hard for me to reconcile this. Perhaps metronidazole has a direct drug effect on eosinophils??
- Also, sometimes it was difficult to disentangle the relationship with antibiotics, since in many cases patients were on multiple antibiotics.
- The significance of asymptomatic eosinophilia is unclear, but an untested hypothesis would be to assess those on more prolonged courses of antibiotics (e.g. >10 days) and in those who develop eosinophilia, to randomly stop/change antibiotics vs continuing, to see if fewer of the serious hypersensitivity reactions occur (which makes intuitive sense, since the more serious HSRs were in those developing more significant eosinophilia and earlier after starting antibiotics. And the presence of eosinophilia was so highly associated with HSRs). Also, some of these patients in the study (and in clinical practice) developed hypereosinophilia (AEC>1500) which itself does induce tissue damage (no data supplied in the study on how often hypereosinophilia occurred or with which antibiotics, though this might be another reason to check AECs).
- Bottom line: this is just another of the many reasons we should limit antibiotics to the clearest indications, the least time possible, and even consider alternative options more readily (e.g. oral retinoic acid for acne might be safer than antibiotics???, or using bleach baths for recurrent skin infections?? – see https://stg-blogs.bmj.com/bmjebmspotlight/2014/04/02/primary-care-corner-with-geoffrey-modest-md-bleach-baths-to-decrease-recurrent-skin-infections/ for the latter).
See https://stg-blogs.bmj.com/bmjebmspotlight/2015/04/16/primary-care-corner-with-geoffrey-modest-md-antibiotics-for-pneumonia/, a Danish study finding that less-broad antibiotics (e.g. b-lactams such as amoxicillin or amox/clavulanate) work as well for community-acquired pneumonia as those plus macrolide, or fluoroquinolone
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