In this single-center analysis, prophylactic effects for PCP in CTDs patients receiving prolonged high-dose GCs were similar between TMP-SMX and atovaquone. To the best of our knowledge, this is the first article to compare the effects of atovaquone with TMP-SMX in CTDs patients.
Previously, a few studies compared the prophylactic effects of TMP-SMX with atovaquone in patients without CTD [11, 12]. One prospective trial compared TMP-SMX to atovaquone for PCP prophylaxis in 39 patients (double-strength TMP-SMX daily [ n = 19] or 1500 mg of atovaquone daily [n = 20]) following autologous hematopoietic cell transplantation . There were no cases of PCP in either group at 12 months post-transplant. Another trial involving 185 renal transplant recipients (single-strength TMP-SMX daily [ n = 160] or 1500 mg of atovaquone daily [n = 25]) also found no cases of PCP in either group at 12 months post-transplant . The need for dose reduction and/or premature discontinuation of therapy secondary to AEs was more common in TMP-SMX-treated patients in both studies. Among HIV-infected patients who cannot tolerate TMP-SMX, atovaquone and dapsone were similarly effective for the prevention of PCP as compared to dapsone or aerosolized pentamidine . These and the present findings indicate that atovaquone is an alternative prophylactic agent for PCP prophylaxis.
In the present study, 23.9% of patients among the TMP-SMX discontinued the therapy due to AEs. The discontinuation rate is considered to be much higher as compared to previously reported studies among patients without CTD [4, 14]. There have been some studies that reported a higher discontinuation rate among CTD patients due to AEs [7, 15]. In a retrospective study involving Japanese patients with CTDs who started PCP prophylaxis, 43% (41/96) discontinued TMP-SMX due to AEs . In another study investigated Japanese CTDs patients on high-dose GCs, the discontinuation rate of single-strength TMP-SMX was 20.7% (12/58) owing to AEs within the period of 24 weeks . Although the reasons for higher discontinuation rate among certain patient population are not entirely clear, there are several plausible explanations. First, older adults may be at risk of developing AEs from TMP-SMX more frequently due to age-related physiological and pharmacokinetic changes . Second, SLE patients are reported to have higher frequencies of sulfa allergy . Third, reported AEs could be related to flare of CTDs or influence of concomitant drugs for CTDs, such as cyclophosphamide. Half dose of daily single-strength TMP-SMX tablet regimen or dose-escalation regimen may be considered in light of lower frequency of AEs, but their efficacies of those PCP prophylaxis regimens have not been proven yet [15, 18]. In fact, we experienced 2 PCP cases in the TMP-SMX who were administered with less than half dose of daily single-strength TMP-SMX. Therefore, alternative prophylactic agents may be preferred in case patients are intolerant of TMP-SMX.
Atovaquone is an antiprotozoal drug that is used for the prevention of PCP for patients who are intolerant of TMP-SMX. Among non-HIV patients, PCP prophylaxis with atovaquone is reported to be beneficial for patients following transplantation [11, 12]. Although atovaquone is a well-tolerated drug, physicians should pay attention to patients’ medication adherence because the bioavailability of atovaquone is significantly reduced when administered in the fasting state as compared to be taken after a meal . Lower plasma concentration may lead to inadequate prophylaxis. Previously, 2 cases of prophylaxis failure were reported in transplant recipients who were receiving low dose of atovaquone .
The present study had several limitations. First, because it was a single-center study, these results may not be generalizable to a different patient population. Second, the number of PCP cases was relatively small. Third, our study was based on medical record review and some documentation may have been incomplete. Finally, majority of the patients in the atovaquone initially received TMP-SMX for PCP prophylaxis. Although their PCP incident rate may be affected, the impact was probably small over the period of 1 year because all of them stopped TMP-SMX within 4 weeks.
The strengths of this study include the use of data based on relatively large number of CTDs patients receiving high-dose GCs with detailed clinical data including both clinical outcomes and adverse events. We used sophisticated statistical models adjusting for potential confounders using inverse probability of treatment weighting and the Fine-Gray hazard competing risk regression model.
In conclusion, prophylactic effects for PCP in CTDs patients receiving prolonged high-dose GCs were similar between TMP-SMX and atovaquone. Atovaquone could be used for PCP prophylaxis in CTDs patients who are intolerant of TMP-SMX. Further studies should aim to replicate our results in a larger scale.