Prophylactic Antibiotics for Cellulitis of the Leg
Prophylactic Antibiotics for Cellulitis of the Leg
This trial suggests that it is highly probable that a substantial reduction in the number of repeat episodes of cellulitis of the leg could be achieved by giving patients prophylactic antibiotics for a period of 6 months after treatment of the acute episode. The result was of borderline statistical significance (meaning that there is an 8% chance that the observed benefits could have occurred by chance), but has to be interpreted in the context of a virtual absence of similar data elsewhere, the large potential magnitude of effect, and the consistency of possible benefit for a range of outcomes. The study indicates that a possible treatment effect deserves further investigation, especially as the intervention is low cost, safe and well tolerated by patients.
Although the PATCH II trial suggested a large treatment effect (a 47% reduction in the risk of a repeat episode), prophylactic penicillin did not prevent all subsequent cases of cellulitis of the leg. This would suggest that other factors are also important in determining whether or not a patient will experience further episodes. This is consistent with other studies, which report that penicillin treatment may not achieve microbial clearance and that even when prophylaxis is ongoing, some patients continue to experience further attacks.
The findings are particularly important as they challenge two commonly held beliefs about the management of cellulitis: (i) that prophylactic penicillin V is warranted only in people with recurrent cellulitis and/or those who have known risk factors for repeat attacks, such as lymphoedema; and (ii) that prophylactic antibiotics are required long-term (or indefinitely) for benefits to be sustained. If the findings of the PATCH II trial are replicated in other studies then it is possible that all patients could be routinely offered a 6-month course of low-dose penicillin V after an attack of cellulitis of the leg. The rationale for such a treatment option is sound. Previous researchers have demonstrated that lymph drainage is compromised following an attack of cellulitis. It is therefore possible that a typical 7–10-day course of antibiotics during the acute phase of the infection may not be sufficient to achieve complete microbial clearance from the lymph system. The traditional model of giving antibiotic prophylaxis only to patients with recurrent cellulitis, or to those who already have chronic lymphoedema may in fact be too late to prevent the permanent impairment to lymph drainage in the leg that ensues following repeated episodes of cellulitis.
Penicillin has been used as long-term medication for many years in other conditions such as rheumatic fever, and group A streptococcus has remained susceptible to penicillin for over 60 years without signs of developing resistance. It therefore represents a very cheap intervention (£18 per 6-month course) that has potential for substantial health savings. Assuming a NNT of 8, this equates to a treatment cost of £144 per episode of cellulitis prevented.
It is disappointing that the trial failed to achieve its recruitment target of 400 participants and thus failed to provide sufficient evidence on which to base firm conclusions. Nevertheless, the trial does suggest a potentially large protective effect that was consistent throughout the follow-up period, and robust in sensitivity analysis.
Future cellulitis trials can benefit from the experiences of the PATCH II trial in designing trials that might recruit patients with cellulitis more successfully. Indeed, the PATCH I trial, which is due to report in early 2012, introduced modifications to the trial design and conduct as a result of our experiences with PATCH II. This trial successfully recruited 274 participants (105% of the original sample size requirement). Changes to the protocol included (i) amending the eligibility criteria so that patients who had had an episode of cellulitis within the last 6 months (rather than 3 months) were able to take part; (ii) amending the case report forms so that recruiting clinicians were able to concentrate on essential medical information, with more routine clinical trial data being collected during telephone contact between the coordinating centre and the participants prior to randomization; (iii) advertising for participants in local media (radio, websites and newspaper advertorials). Setting up dermatology department based cellulitis services treating lower limb cellulitis with once-daily intravenous antibiotics (usually at home or as outpatients) may improve diagnostic accuracy and provide a source of recruitment for future studies.
Notwithstanding under-recruitment, this was a well-conducted trial, with blinded outcome assessment and rigorous allocation concealment. The follow-up period of up to 3 years was sufficient to capture the treatment effect and loss to follow-up was low. Self-reported adherence and safety monitoring would suggest that the treatment was well tolerated and that patients adhered to the treatment schedule successfully.
The PATCH II trial was designed as a pragmatic trial that aimed to reflect current practice as far as possible. Eligibility criteria were broad and contact with health professionals was kept to a minimum as would be the case in normal practice. Recruitment into the trial was conducted in 20 hospitals throughout the U.K. and southern Ireland and should therefore be representative of the type of patients seen in secondary care. However, it is likely that recruited patients had more severe disease than those typically seen in a primary care setting.
This is the first trial to have explored the use of medium-term (6-months) antibiotic prophylaxis in patients who have had cellulitis of the leg. Current clinical guidelines are based on very limited trial evidence and so this trial represents a potentially valuable addition to clinical knowledge. The results of the PATCH I trial (available early 2012, and based on 274 participants) will hopefully shed further light on the use of prophylactic antibiotics for the prevention of cellulitis in patients with recurrent disease.
Discussion
This trial suggests that it is highly probable that a substantial reduction in the number of repeat episodes of cellulitis of the leg could be achieved by giving patients prophylactic antibiotics for a period of 6 months after treatment of the acute episode. The result was of borderline statistical significance (meaning that there is an 8% chance that the observed benefits could have occurred by chance), but has to be interpreted in the context of a virtual absence of similar data elsewhere, the large potential magnitude of effect, and the consistency of possible benefit for a range of outcomes. The study indicates that a possible treatment effect deserves further investigation, especially as the intervention is low cost, safe and well tolerated by patients.
Although the PATCH II trial suggested a large treatment effect (a 47% reduction in the risk of a repeat episode), prophylactic penicillin did not prevent all subsequent cases of cellulitis of the leg. This would suggest that other factors are also important in determining whether or not a patient will experience further episodes. This is consistent with other studies, which report that penicillin treatment may not achieve microbial clearance and that even when prophylaxis is ongoing, some patients continue to experience further attacks.
The findings are particularly important as they challenge two commonly held beliefs about the management of cellulitis: (i) that prophylactic penicillin V is warranted only in people with recurrent cellulitis and/or those who have known risk factors for repeat attacks, such as lymphoedema; and (ii) that prophylactic antibiotics are required long-term (or indefinitely) for benefits to be sustained. If the findings of the PATCH II trial are replicated in other studies then it is possible that all patients could be routinely offered a 6-month course of low-dose penicillin V after an attack of cellulitis of the leg. The rationale for such a treatment option is sound. Previous researchers have demonstrated that lymph drainage is compromised following an attack of cellulitis. It is therefore possible that a typical 7–10-day course of antibiotics during the acute phase of the infection may not be sufficient to achieve complete microbial clearance from the lymph system. The traditional model of giving antibiotic prophylaxis only to patients with recurrent cellulitis, or to those who already have chronic lymphoedema may in fact be too late to prevent the permanent impairment to lymph drainage in the leg that ensues following repeated episodes of cellulitis.
Penicillin has been used as long-term medication for many years in other conditions such as rheumatic fever, and group A streptococcus has remained susceptible to penicillin for over 60 years without signs of developing resistance. It therefore represents a very cheap intervention (£18 per 6-month course) that has potential for substantial health savings. Assuming a NNT of 8, this equates to a treatment cost of £144 per episode of cellulitis prevented.
It is disappointing that the trial failed to achieve its recruitment target of 400 participants and thus failed to provide sufficient evidence on which to base firm conclusions. Nevertheless, the trial does suggest a potentially large protective effect that was consistent throughout the follow-up period, and robust in sensitivity analysis.
Future cellulitis trials can benefit from the experiences of the PATCH II trial in designing trials that might recruit patients with cellulitis more successfully. Indeed, the PATCH I trial, which is due to report in early 2012, introduced modifications to the trial design and conduct as a result of our experiences with PATCH II. This trial successfully recruited 274 participants (105% of the original sample size requirement). Changes to the protocol included (i) amending the eligibility criteria so that patients who had had an episode of cellulitis within the last 6 months (rather than 3 months) were able to take part; (ii) amending the case report forms so that recruiting clinicians were able to concentrate on essential medical information, with more routine clinical trial data being collected during telephone contact between the coordinating centre and the participants prior to randomization; (iii) advertising for participants in local media (radio, websites and newspaper advertorials). Setting up dermatology department based cellulitis services treating lower limb cellulitis with once-daily intravenous antibiotics (usually at home or as outpatients) may improve diagnostic accuracy and provide a source of recruitment for future studies.
Notwithstanding under-recruitment, this was a well-conducted trial, with blinded outcome assessment and rigorous allocation concealment. The follow-up period of up to 3 years was sufficient to capture the treatment effect and loss to follow-up was low. Self-reported adherence and safety monitoring would suggest that the treatment was well tolerated and that patients adhered to the treatment schedule successfully.
The PATCH II trial was designed as a pragmatic trial that aimed to reflect current practice as far as possible. Eligibility criteria were broad and contact with health professionals was kept to a minimum as would be the case in normal practice. Recruitment into the trial was conducted in 20 hospitals throughout the U.K. and southern Ireland and should therefore be representative of the type of patients seen in secondary care. However, it is likely that recruited patients had more severe disease than those typically seen in a primary care setting.
This is the first trial to have explored the use of medium-term (6-months) antibiotic prophylaxis in patients who have had cellulitis of the leg. Current clinical guidelines are based on very limited trial evidence and so this trial represents a potentially valuable addition to clinical knowledge. The results of the PATCH I trial (available early 2012, and based on 274 participants) will hopefully shed further light on the use of prophylactic antibiotics for the prevention of cellulitis in patients with recurrent disease.
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