Nephrology 19 (2014) 157–163
Complications and outcomes of trimethoprim–sulphamethoxazole as chemoprophylaxis for pneumocystis pneumonia in renal transplant recipients NICOS MITSIDES,1 KERRY GREENAN,2 DARREN GREEN,3 RACHEL MIDDLETON,1 ELIZABETH LAMERTON,4 JUDITH ALLEN,4 JANE REDSHAW,1 PAUL R CHADWICK,5 CHINARI PK SUBUDHI5 and GRAHAME WOOD1 1 3
Nephrology Department, 4Pharmacy Department and 5Microbiology Department, Salford Royal NHS Foundation Trust, Salford, and 2School of Medicine and Institute of Population Health, University of Manchester, Manchester, UK
KEY WORDS: adverse events, pneumocystis pneumonia, transplantation, trimethoprim-sulphamethoxazole. Correspondence: Dr Nicos Mitsides, Nephrology Department, Salford Royal NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK. Email: [email protected]
Accepted for publication 23 December 2013. Accepted manuscript online 6 January 2014. doi:10.1111/nep.12201 There are no conﬂicts of interest for any of the author.
SUMMARY AT A GLANCE Mitsides et al. describe their experience with giving universal chemoprophylaxis to 290 established renal transplant recipients, following an outbreak of pneumocystis pneumonia in their unit. Complications of their trimethoprim/sulphamethoxazole therapy are described, in particular 22% of patients had some rise in their serum creatinine and 2% had leukopaenia.
ABSTRACT: Background: Following a pneumocystis pneumonia (PCP) outbreak in our nephrology unit, all transplant patients were offered chemoprophylaxis with trimethoprim–sulphamethoxazole (TMP-SMX) as the first line agent. A high rate of complications was noted. We aimed to quantify TMP-SMX associated adverse events and evaluate its prophylactic benefit in their light. Potential risk factors for complications’ development were also investigated. Method: This was an observational study of outcomes in transplant recipients commenced on TMP-SMX prophylaxis for 1year period. End-points were adverse events due to TMP-SMX, the additional medical burden resulting from these events, and PCP diagnosis. Results: 290 patients commenced on TMP-SMX. 110 (38%) developed complications with most common being rise in serum creatinine (Cr) (n = 63, 22%) followed by gastrointestinal symptoms (n = 15, 5%), and leucopenia (n = 5, 2%). PCP incidence fell from 19 cases in 19 months to 2 cases in 12 months. Baseline renal function (P = 0.019) was an independent predictors for developing rise in Cr with TMP-SMX. Conclusion: Use of chemoprophylaxis is an effective strategy in dealing with a PCP outbreak but can lead to a high number of complications. Rises in serum Cr can cause significant concern and increase in the number of investigations.
Pneumocystis pneumonia (PCP) is a devastating condition affecting immunocompromised populations. Caused by the fungal organism Pneumocystis jirovecii, PCP can reach mortality figures of 35% if treated1 and 90% if untreated2 in HIV negative immunocopromised patients. Renal transplant recipients are such a group of patients and in recent years there has been an increase in reporting of outbreaks of PCP involving this population.3–5 In our renal unit 19 cases of PCP involving immunosuppressed renal patients occurred between December 2009 and June 2011. Of these cases, 13 involved renal transplant recipients. © 2014 Asian Paciﬁc Society of Nephrology
The aetiology of PCP is not entirely understood but there have been links with person-to-person transmission and environmental exposure.3 Most transplant centres use chemoprophylaxis against PCP in the first 3–6 months following transplantation.6 In response to our PCP outbreak, all transplant recipients followed up in our unit were offered 12 months of chemoprophylaxis. Trimethoprim–sulphamethoxazole (TMP-SMX) was used as first line agent7 and dapsone as second line.8 Both of these agents have been associated with significant adverse reactions.9–11 Indeed, we were faced with a high 157
N Mitsides et al.
rate of adverse events, prompting us to investigate these further. The aim of this study was to quantify the adverse events associated with TMP-SMX PCP chemoprophylaxis in renal transplant recipients, and explore whether the benefit of its use outweighed the complications. We also set to investigate potential risk factors that would predispose patients to TMPSMX related complications.
SUBJECTS AND METHODS Following the outbreak of PCP in our unit, chemoprophylaxis was offered to all other transplant recipients. Exceptions were made for women of childbearing age undergoing family planning. All transplant patients receiving follow-up in our unit were more than 6 months post-transplantation. First line chemoprophylaxis was TMP-SMX 400/80 mg once a day.6,11 All patients’ general practitioners were instructed to check biochemical profile and full blood count one week after starting treatment. Patients also received regular follow up at our unit, appointments determined on an individual patient basis. They also had access to the transplant telephone advice line and a drop-in clinic. Data collection was performed prospectively for all cases of TMP-SMX intolerance, either through admission records or following attendance to special drug review clinics set up to deal with adverse events. Data for those who did not experience any adverse events were obtained retrospectively from electronic patient records. All data were anonymised and formed part of our investigation and surveillance into our PCP outbreak with the Health Protection Agency. Therefore, Research Ethics Committee approval was not required. Outcomes were fed back to the Trust’s Infection Control and Transplant Governance Groups. Recording of creatinine and estimated glomerular filtration rate (eGFR) was determined by clinical requirement during follow up, not a pre-specified protocol as part of this study. For this reason, data for this study were taken from three time points: date of start of TMP-SMX (time point A); presentation with adverse event or, in patients who did not present with a complication, a matched sample from the clinic visit closest to six months after starting prophylaxis (B); a sample from the clinic visit closest to 6 months after time point B (C). Measured outcomes were: (i) cessation of TMP-SMX due to any adverse events; (ii) the additional medical burden as a result of these events; and (iii) diagnosis of PCP. An adverse event was defined as any recognized side-effect of TMP-SMX which led to cessation of the drug, acute kidney injury (AKI) deemed to be due to TMP-SMX, or leucopenia of total white cell count (WCC) < 4.0 × 109/L. AKI associated with TMPSMX was defined as a serum creatinine (Cr) rise of ≥20% from baseline within 6 months of starting TMP-SMX and 158
leading to cessation of the agent, and with resolution of AKI within a further 6 months and without evidence of other causes for the AKI. Medical burden was measured by number and duration of hospital admissions directly due to complications of chemoprophylaxis, additional medical reviews (nurse lead consultations, renal drop-in clinic, early clinic follow-up), and additional investigations (blood test, imaging, transplant biopsies). Patients with sulphonamide-related side-effects were offered desensitization12 and those with rise in Cr < 20% were offered TMP-SMX dose reduction. A PCP case was defined as a patient receiving renal follow up at Salford Royal Hospital presenting with clinical or radiological picture consistent with PCP and diagnosis confirmation by polymerase chain reaction (PCR) on sputum samples. The frequency of each adverse event and the patient characteristics of each adverse event group were compared qualitatively between groups and with the control group of patients who suffered no adverse events. Statistical association between patient characteristics, baseline laboratory data, concurrent medication and adverse events were only explored for TMP-SMX associated AKI as the other events were too infrequent. Univariate analysis of association was made by either independent sample T-test for continuous variables or χ2 test for binary variables. Measured variables with established linked with renal function (age of patient, age of transplant, calcineurin inhibitor (CNI) use, renin-angiotensin system (RAS) blockade, diuretic use) or that were statistically significant on univariate analysis (α ≤ 0.05) were entered into a multivariate Cox regression model comparing TMP-SMX associated AKI with all other patients. Changes in dose of RAS blockade and diuretics were not recorded comprehensively and so no adjustment is made in the analysis. This is acknowledged as a short-coming. Patients who had changes in dose of CNI after onset of AKI and in whom AKI resolved were not categorized as TMPSMX associated AKI as the exact cause of AKI could not be determined. Comparison was made between the time-averaged number of cases of PCP prior to the use of chemoprophylaxis versus the combined number of chemoprophylaxis-related hospital admissions, invasive procedures, and new cases of PCP during the period of prophylaxis.
RESULTS Of 303 patients offered pneumocystis prophylaxis, 13 had previous intolerance of TMP-SMX. This left 290 patients in the final cohort for analysis. Mean patient age was 52 ± 13 years at the time of initiation of prophylaxis, with a mean graft age of 7.4 ± 6.7 years. This was the patient’s first graft in 253 cases (87%). The baseline eGFR was 50 ± 19 mL/min per 1.73 m2. Detailed cohort characteristics are shown in Table 1. 81.4% of patients were on CNI therapy (21% cyclosporine, 60.4% tacrolimus). Other medications with © 2014 Asian Paciﬁc Society of Nephrology
Pneumocystis pneumonia chemoprophylaxis
Table 1 Characteristics of the patient cohort, divided by side-effect category No adverse event
190 (66) 51 ± 13 8.8 ± 7.2 1 (1–3) 125 (66) 174 ± 66 209 ± 65
63 (22) 53 ± 12 8.9 ± 7.2 1 (1–3) 34 (54) 89 ± 63 208 ± 50
5 (2) 51 ± 8 4.6 ± 6.7 1 (1–2) 1 (20) 111 ± 75 226 ± 29
15 (5) 58 ± 11 8.2 ± 4.9 1 (1–2) 8 (53) 45 ± 36 232 ± 104
17 (6) 56 ± 10 6.3 ± 4.4 1 (1–2) 11 (65) 21 ± 35 206 ± 28
140 ± 58 14 ± 13 53 ± 21
141 ± 45 33 ± 15 47 ± 14
144 ± 54 23 ± 17 43 ± 17
155 ± 63 23 ± 19 43 ± 26
138 ± 52 14 ± 13 54 ± 26
92 (49) 105 (55) 156 (82) 31 (16) 95 (50) 28 (15)
34 (54) 27 (43) 50 (79) 9 (14) 31 (49) 14 (22)
2 (40) 4 (80) 5 (100) 1 (20) 0 (0) 0 (0)
11 (73) 7 (47) 9 (60) 4 (27) 6 (40) 4 (27)
9 (53) 9 (53) 13 (77) 3 (18) 10 (59) 4 (24)
Cohort characteristics Number of patients (n, % of cohort) Age of patient (years) Age of transplant (years) Median number of transplants (range) Gender (% male) Time to presentation of event (days)† Time from presentation to follow up Laboratory results Baseline creatinine (μmol/L) % change in creatinine at presentation Baseline eGFR (mL/min per 1.73 m2) Medication Prednisolone (%) MMF (%) CNI (%) Azathioprine (%) RAS blockade (%) Diuretic (%)
†Or at clinic visit closest to but before six months after prophylaxis started if no side-effects. AKI, acute kidney injury; CNI, calcineurin inhibitor; eGFR, estimated glomerular ﬁltration rate; MMF, mycophenolate mofetil; RAS, renin-angiotensin system; TMP-SMX, trimethoprim–sulfamethoxazole.
Table 2 Baseline immunosuppressive and nephrotoxic medication being prescribed to patients in the cohort Immunosuppressive therapy at start of prophylaxis Number of immunosuppressants Azathioprine use, n (%) Azathioprine dose (mg per day) Cyclosporine use, n (%) Cyclosporine dose (mg per day) MMF use, n (%) MMF dose (mg per day) Prednisolone use, n (%) Prednisolone dose (mg per day) Sirolimus/everolimus use, n (%) Sirolimus/everolimus dose (mg per day) Tacrolimus use, n (%) Tacrolimus dose (mg per day) Other, nephrotoxic medication RAS blockade Diuretics
2.0 ± 0.6 43 (14.8%) 93.4 ± 37.9 61 (21.0%) 140.4 ± 63.9 154 (53.1%) 1317 ± 469 143 (49.3%) 5.5 ± 3.2 10 (3.4%) 2.2 ± 0.7 175 (60.4%) 4.5 ± 2.5 143 (49.3%) 50 (17.2%)
RAS, renin-angiotensin system; MMF, mycophenolate mofetil. Dose values given are the mean ± standard deviation doses for individuals on the drug only, not the mean dose across the whole cohort.
nephrotoxic potential were common with 49% being on RAS blockade and 17% on diuretics (Table 2). A total of 110 patients (38%) suffered a complication necessitating cessation of TMP-SMX. These were most commonly an AKI that resolved after cessation of the drug (n = 63, 22%), gastrointestinal symptoms (n = 15, 5%) and leucopenia (n = 5, 2%). Details of the characteristics of each patient group, compared with those who suffered no adverse © 2014 Asian Paciﬁc Society of Nephrology
event are shown in Table 1. The change in eGFR from start of prophylaxis to end follow up (time point C) for patients with AKI was −0.2 ± 4.2 mL/min per 1.73 m2 over a mean total follow up of 304 ± 108 days, for patients with other complications was −4.3 ± 9.0 mL/min per 1.73 m2 over 266 ± 99 days, and for patients without complications (who stayed on TMP-SMX) −4.0 ± 11.3 mL/min per 1.73 m2 over 387 ± 90 days. These data are shown in Figure 1 and demonstrate that one can have reasonable confidence in TMP-SMX being the cause of AKI in those cases labelled as such for the regression analysis (shown in Table 3). Factors associated with AKI on univariate analysis were age of the transplant (P = 0.006) but not age of the patient, eGFR at baseline (P = 0.048) and the use of mycophenolate mofetil (MMF) (P = 0.033), cyclosporine (P = 0.034), and sirolimus (P = 0.037). Tacrolimus was not significant, and dose was not significant for any of the drugs listed above. eGFR retained significant on multivariate analysis (P = 0.019, see also Fig. 2). All patients with intolerance required unplanned medical review and a dedicated review clinic was set up. All cases with rise in Cr required extra investigations to rule out other causes of allograft dysfunction, including renal ultrasound imaging (18%) and virology (EBV, CMV and BK) (38%). All cases with leucopenia also had their virology checked. Renal profile, full blood count, urinary protein : creatinine ratio and urinary cultures were performed in all suspected cases of TMP-SMX intolerance. In all but 10 cases with rise in Cr, renal function returned to baseline following discontinuation of TMP-SMX. Of these 10 cases, 8 had renal biopsies; 2 showed acute cellular rejection, 1 antibody-mediated rejection, 1 mesangiocapillary 159
N Mitsides et al.
Serum Creatinine (µmol/L)
0 TMP-SMX AKI
Fig. 1 Comparison of estimated glomerular ﬁltration rate at three different time points start of prophylaxis; presentation of ( 6 months after cessation of complication†; TMP-SMX‡) in patients with trimethoprimsulfamethoxazole associated acute kidney injury, other side-effects, or no complications. AKI, acute kidney injury; eGFR, estimated glomerular ﬁltration rate; TMP-SMX, trimethoprim– sulfamethoxazole. †time point B; ‡time point C.
0.86 (0.77–0.98) 2.28 (0.95–5.56) 1.01 (0.98–1.05) 1.12 (0.95–1.31) 1.51 (0.95–2.40) 1.34 (0.89–2.03) 1.20 (0.81–1.78) 1.04 (0.63–1.72)
0.019 0.067 0.486 0.195 0.084 0.159 0.364 0.486
The hazard ratios for baseline eGFR and age of patient are given for each 10 unit increment rise. Hazard ratio for age of graft is per year, and other hazard ratios are for the presence of the factor compared with its absence. eGFR, estimated glomerular ﬁltration rate; MMF, mycophenolate mofetil; RAS, rennin-angiotensin system; Sig., statistical signiﬁcance on multivariate analysis.
glomerulonephritis, 1 IgA nephropathy and 3 showed chronic interstitial fibrosis and atrophy. All gastrointestinal and skin symptoms resolved after TMPSMX discontinuation or regimen modification. Few patients responded to desensitization (3%) or dose reduction (5%). The remainder had to stop TMP-SMX. All but 2 leucopeniae returned to baseline with discontinuation of TMP-SMX, while the rest showed partial response. 160
Baseline eGFR (mL/min per 1.73 m2) Sirolimus use Age of transplant (years) Age of patient (years) Cyclosporine use MMF use RAS blockade use Diuretic use
Hazard ratio (95% CI)
% of patients with given baseline eGFR 20% 40% 60% 80%
Table 3 Results of forward stepwise Cox regression analysis of time to AKI after starting TMP-SMX prophylaxis
60+ 45-59 30-44 Baseline 15-29 eGFR (mL/ min per 1. 73m 2)