Cohort Study



Low-dose penicillin for recurrent cellulitis

J Fam Pract. 2014;63:E9-E11

RCT

Potential PURL Review Form

PURLs Surveillance System

Family Physicians Inquiries Network

|SECTION 1: Identifying Information for Nominated Potential PURL |

|[to be completed by PURLs Project Manager] |

|1. Citation |Thomas KS, Crook AM, Nunn AJ, Foster KA, Mason JM, Chalmers JR, Nasr IS, Brindle RJ, English J, Meredith SK, Reynolds NJ, de |

| |Berker D, Mortimer PS, Williams HC; U.K. Dermatology Clinical Trials Network's PATCH I Trial Team. |

| |Penicillin to prevent recurrent leg cellulitis. N Engl J Med. 2013 May 2;368(18):1695-703. doi: 10.1056/NEJMoa1206300. PubMed |

| |PMID: 23635049. |

|2. Hypertext link to | |

|PDF of full article | |

|3. First date published|5/2/13 |

|study available to | |

|readers | |

|4. PubMed ID |23635049 |

|5. Nominated By |Jim Stevermer Other: |

|6. Institutional |University of Missouri Other: |

|Affiliation of Nominator| |

|7. Date Nominated |5/8/13 |

|8. Identified Through |Info POEMs Other: |

|9. PURLS Editor |Kate Rowland Other: |

|Reviewing Nominated | |

|Potential PURL | |

|10. Nomination Decision |5/16/13 |

|Date | |

|11. Potential PURL |RCT |

|Review Form (PPRF) Type | |

|12. Other comments, | |

|materials or discussion | |

|13. Assigned Potential |Liz Nguyen |

|PURL Reviewer | |

|14. Reviewer Affiliation|University of Chicago Other: |

|15. Date Review Due |6/13/13 |

|16. Abstract |BACKGROUND: |

| |Cellulitis of the leg is a common bacterial infection of the skin and underlying tissue. We compared prophylactic low-dose |

| |penicillin with placebo for the prevention of recurrent cellulitis. |

| |METHODS: |

| |We conducted a double-blind, randomized, controlled trial involving patients with two or more episodes of cellulitis of the leg|

| |who were recruited in 28 hospitals in the United Kingdom and Ireland. Randomization was performed according to a |

| |computer-generated code, and study medications (penicillin [250 mg twice a day] or placebo for 12 months) were dispensed by a |

| |central pharmacy. The primary outcome was the time to a first recurrence. Participants were followed for up to 3 years. Because|

| |the risk of recurrence was not constant over the 3-year period, the primary hypothesis was tested during prophylaxis only. |

| |RESULTS: |

| |A total of 274 patients were recruited. Baseline characteristics were similar in the two groups. The median time to a first |

| |recurrence of cellulitis was 626 days in the penicillin group and 532 days in the placebo group. During the prophylaxis phase, |

| |30 of 136 participants in the penicillin group (22%) had a recurrence, as compared with 51 of 138 participants in the placebo |

| |group (37%) (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P=0.01), yielding a number needed to treat to |

| |prevent one recurrent cellulitis episode of 5 (95% CI, 4 to 9). During the no-intervention follow-up period, there was no |

| |difference between groups in the rate of a first recurrence (27% in both groups). Overall, participants in the penicillin group|

| |had fewer repeat episodes than those in the placebo group (119 vs. 164, P=0.02 for trend). There was no significant |

| |between-group difference in the number of participants with adverse events (37 in the penicillin group and 48 in the placebo |

| |group, P=0.50). |

| |CONCLUSIONS: |

| |In patients with recurrent cellulitis of the leg, penicillin was effective in preventing subsequent attacks during prophylaxis,|

| |but the protective effect diminished progressively once drug therapy was stopped. (Funded by Action Medical Research; PATCH I |

| |Controlled- number, ISRCTN34716921.). |

|17. Pending PURL Review | |

|Date | |

|sECTION 2: Critical Appraisal of Validity |

|[to be completed by the Potential PURL Reviewer] |

|[to be revised by the Pending PURL Reviewer if needed] |

|1. Number of patients starting each|136 Penicillin |

|arm of the study? |138 Placebo |

|2. Main characteristics of study |Inclusion: recurrent episode of cellulitis in past 24 weeks |

|patients (inclusions, exclusions, |Exclusion: doubt about diagnosis of cellulitis in past, use of abx for cellulitis prophylaxis in past 6 months, |

|demographics, settings, etc.)? |penicillin allergy, previous leg ulceration, surgery, or penetrating trauma, unwillingness of recruiting physician |

| |to randomly assign patients for medical reasons, age /= 33, >/= 3 previous episodes of cellulitis, presence of edema  |

|8. What are the adverse effects of |Adverse events: 37 patients (PCN), 48 patients (placebo) |

|intervention compared with no |11 died, not due to meds (8 in PCN, 3 in placebo) |

|intervention? |Adverse events: death, nausea, diarrhea, vulvovaginitis, thrush, rash  |

|9. Study addresses an appropriate | Well covered |

|and clearly focused question - |Adequately addressed |

|select one |Poorly addressed |

| |Not applicable |

| | |

| | |

| | |

| |Comments: Does penicillin prophylaxis decreased cellulitis recurrence |

|10. Random allocation to comparison| Well covered |

|groups |Adequately addressed |

| |Poorly addressed |

| |Not applicable |

| |Comments: Used Nottingham Clinical Trials Unit (NCTU) web-based randomization service |

|11. Concealed allocation to | Well covered |

|comparison groups |Adequately addressed |

| |Poorly addressed |

| |Not applicable |

| |Comments: Treatment assignments sent electronically to pharmacy, meds mailed to patients |

|12. Subjects and investigators kept| Well covered |

|“blind” to comparison group |Adequately addressed |

|allocation |Poorly addressed |

| |Not applicable |

| |Comments: |

|12. Comparison groups are similar | Well covered |

|at the start of the trial |Adequately addressed |

| |Poorly addressed |

| |Not applicable |

| |Comments: late 50s, mostly female, obese, Caucasian |

|14. Were there any differences | Well covered |

|between the groups/arms of the |Adequately addressed |

|study other than the intervention |Poorly addressed |

|under investigation? If yes, please|Not applicable |

|indicate whether the differences |Comments: Similar med compliance (78% placebo and 79% PCN reported taking at least 75% if the tablets) |

|are a potential source of bias. | |

|15. Were all relevant outcomes | Well covered |

|measured in a standardized, valid, |Adequately addressed |

|and reliable way? |Poorly addressed |

| |Not applicable |

| |Comments: telephone follow-up every 3 months for 12 months, then every 6 months thereafter to 36 months, assessed |

| |adverse events and use of health services |

|16. Are patient oriented outcomes |yes-time to and frequency of recurrence of cellulitis are patient oriented outcomes |

|included? If yes, what are they? | |

|17. What percent dropped out, and |5% (15 patients) withdrew consent or were lost to follow-up |

|were lost to follow up? Could this |4% (11 patients) died |

|bias the results? How? | |

|18. Was there an intention-to-treat|yes |

|analysis? If not, could this bias | |

|the results? How? | |

|19. If a multi-site study, are |not sure- doesn't breakdown results by site |

|results comparable for all sites? |Recruitment at 28 hospitals in UK and Ireland |

|20. Is the funding for the trial a |Supported by grant from Action Medical Research- not likely source of bias |

|potential source of bias? If yes, | |

|what measures were taken to insure | |

|scientific integrity? | |

|21. To which patients might the |Patients with recurrent cellulitis, tolerant of penicillin, in areas with low resistance to penicillin.  |

|findings apply? Include patients in| |

|the study and other patients to | |

|whom the findings may be | |

|generalized. | |

|22. In what care settings might the|Outpatient and Inpatient, Nursing homes |

|findings apply, or not apply? | |

|23. To which clinicians or policy |Fam. Med, Derm, IM. ID |

|makers might the findings be | |

|relevant? | |

| |

|SECTION 3: Review of Secondary Literature |

|[to be completed by the Potential PURL Reviewer] |

|[to be revised by the Pending PURL Reviewer as needed] |

|Citation Instructions |For UpTo Date citations, use style modified from |

| |& AMA style. Always use Basow DS as editor & current year as publication year. |

| | |

| |EXAMPLE: Auth I. Title of article. {insert author name if given, & search terms or title.} In: Basow DS, ed. |

| |UpToDate [database online]. Waltham, Mass: UpToDate; 2009. Available at: .  {Insert dated |

| |modified if given.} Accessed February 12, 2009. {whatever date PPRF reviewer did their search.} |

| | |

| |For DynaMed, use the following style: |

| |Depression: treatment {insert search terms or title}. In: DynaMed [database online]. Available at: |

| |. Last updated February 4, 2009. {Insert dated modified if given.}  Accessed June 5,|

| |2009.{search date} |

|1. DynaMed excerpts | |

|2. DynaMed citation/access date |Title. Cellulitis Author. In: DynaMed [database online]. Available at: Last updated: |

| |5/15/13. Accessed 6/10/13 |

|3. Bottom line recommendation or summary |1st line prevention of recurrent cellulitis is emollients, compressive stockings. Can use PCN or erythromycin if |

|of evidence from DynaMed |other measures fail.  |

|(1-2 sentences) | |

|4. UpToDate excerpts | |

|5. UpToDate citation/access date |Always use Basow DS as editor & current year as publication year. |

| |Title. Cellulitis and erysipelasAuthor. Larry M Baddour, MD, FIDSA      In: UpToDate [database online]. Available|

| |at: . Last updated: 5/9/2013. Accessed6/10/13 |

|6. Bottom line recommendation or |Unclear efficacy of prophylactic antibiotics. Current options include penicillin (IM or PO), Clindamycin but for |

|summary of evidence from UpToDate |unclear duration.  |

|(1-2 sentences) | |

|7. PEPID PCP excerpts | |

| | |

|username: fpinauthor | |

|pw: pepidpcp | |

|8. PEPID citation/access data |Author. Title. In: PEPID [database online]. Available at: . Last updated:. Accessed |

|9. PEPID content updating |1. Do you recommend that PEPID get updated on this topic? |

| |Yes, there is important evidence or recommendations that are missing |

| |No, this topic is current, accurate and up to date. |

| |If yes, which PEPID Topic, Title(s): |

| |2. Is there an EBM Inquiry (HelpDesk Answers and Clinical Inquiries) as indicated by the EB icon ([pic]) that |

| |should be updated on the basis of the review? |

| |Yes, there is important evidence or recommendations that are missing |

| |No, this topic is current, accurate and up to date. |

| |If yes, which Evidence Based Inquiry(HelpDesk Answer or Clinical Inquiry), Title(s): |

|10. Other excerpts (USPSTF; other | |

|guidelines; etc.) | |

|11. Citations for other excerpts | |

|12. Bottom line recommendation or | |

|summary of evidence from Other Sources| |

|(1-2 sentences) | |

|SECTION 4: Conclusions |

|[to be completed by the Potential PURL Reviewer] |

|[to be revised by the Pending PURL Reviewer as needed] |

|1. Validity: How well does the study |Give one number on a scale of 1 to 7 |

|minimize sources of internal bias and |(1=extremely well; 4=neutral; 7=extremely poorly) |

|maximize internal validity? |1 2 3 4 5 6 7 |

|2. If 4.1 was coded as 4, 5, 6, or 7, |Double-blinded RCT |

|please describe the potential bias and how | |

|it could affect the study results. | |

|Specifically, what is the likely direction | |

|in which potential sources of internal bias| |

|might affect the results? | |

|3. Relevance: Are the results of this study|Give one number on a scale of 1 to 7 |

|generalizable to and relevant to the health|(1=extremely well; 4=neutral; 7=extremely poorly) |

|care needs of patients cared for by “full |1 2 3 4 5 6 7 |

|scope” family physicians? | |

|4. If 4.3 was coded as 4, 5, 6, or 7, lease|Yes generalizable and relevant |

|provide an explanation. | |

|5. Practice changing potential: If the |Give one number on a scale of 1 to 7 |

|findings of the study are both valid and |(1=definitely a change from current practice; 4=uncertain; 7=definitely not a change from current practice) |

|relevant, does the practice that would be |1 2 3 4 5 6 7 |

|based on these findings represent a change | |

|from current practice? | |

|6. If 4.5 was coded as 1, 2, 3, or 4, |IDSA recommends penicillin, erythromycin for prophylaxis already |

|please describe the potential new practice | |

|recommendation. Please be specific about | |

|what should be done, the target patient | |

|population and the expected benefit. | |

|Applicability to a Family Medical Care |Give one number on a scale of 1 to 7 |

|Setting: |(1=definitely could be done in a medical care setting; 4=uncertain; 7=definitely could not be done in a |

|Is the change in practice recommendation |medical care setting) |

|something that could be done in a medical |1 2 3 4 5 6 7 |

|care setting by a family physician (office,| |

|hospital, nursing home, etc), such as a | |

|prescribing a medication, vitamin or herbal| |

|remedy; performing or ordering a diagnostic| |

|test; performing or referring for a | |

|procedure; advising, educating or | |

|counseling a patient; or creating a system | |

|for implementing an intervention? | |

|8. If you coded 4.7 as a 4, 5, 6 or 7, |Penicillin is cheap, accessible.  |

|please explain. | |

|9. Immediacy of Implementation: Are there |Give one number on a scale of 1 to 7 |

|major barriers to immediate implementation?|(1=definitely could be immediately applied; 4=uncertain; 7=definitely could not be immediately applied) |

|Would the cost or the potential for |1 2 3 4 5 6 7 |

|reimbursement prohibit implementation in | |

|most family medicine practices? Are there | |

|regulatory issues that prohibit | |

|implementation? Is the service, device, | |

|drug or other essentials available on the | |

|market? | |

|10. If you coded 4.9 as 4, 5, 6, or 7, | |

|please explain why. | |

|11. Clinical meaningful outcomes or patient|Give one number on a scale of 1 to 7 |

|oriented outcomes: Are the outcomes |(1=definitely clinically meaningful or patient oriented; 4=uncertain; 7=definitely not clinically meaningful |

|measured in the study clinically meaningful|or patient oriented) |

|or patient oriented? |1 2 3 4 5 6 7 |

|12. If you coded 4.11 as a 4, 5, 6, or 7 |Still unclear how long to continue prophylaxis, differences in recurrence rates decreased once prophylaxis |

|please explain why. |was discontinued.  |

|13. In your opinion, is this a Pending |Give one number on a scale of 1 to 7 |

|PURL? |(1=definitely a Pending PURL; 4=uncertain; 7=definitely not a Pending PURL) |

|Criteria for a Pending PURL: |1 2 3 4 5 6 7 |

|Valid: Strong internal scientific validity;| |

|the findings appears to be true. | |

|Relevant: Relevant to the practice of | |

|family medicine | |

|Practice changing: There is a specific | |

|identifiable new practice recommendation | |

|that is applicable to what family | |

|physicians do in medical care settings and | |

|seems different than current practice. | |

|Applicability in medical setting: | |

|Immediacy of implementation | |

|14. Comments on your response in 4.13 |Clinical meaningfulness still unclear, given unclear what's best in terms of duration of prophylactic |

| |medications and unsure if this is a practice change since current recommendations include prophylactic abx.  |

|SECTION 4.1: Diving for PURLs |

|[optional for the potential PURL reviewer -if you wish to be the author on the summary] |

|1. Study Summary- Please summarize the |This double-blind randomized controlled trial of 274 patients compared penicillin to placebo in prevention of|

|study in 5-7 sentences |recurrent leg cellulitis. Patients received either Penicillin 250 mg PO BID or placebo for 12 months |

| |(prophylaxis phase). Adverse events, use of health services, and recurrence of cellulitis were assessed by |

| |telephone calls at 3-month intervals during the prophylaxis phase and every 6 months during the follow-up |

| |phase (13-36 months). |

| |Primary outcome measure was time from randomization to recurrence of cellulitis. Secondary outcome measures |

| |include proportions of participants with recurrent cellulitis and with new edema or ulceration, adverse |

| |events, length of hospital stay for recurrent cellulitis, and cost-effectiveness. |

| |Median time to recurrent cellulitis was 626 days (penicillin) and 532 days (placebo). During the prophylaxis |

| |phase, there was a 45% risk reduction of recurrent cellulitis in patients who received penicillin (hazard |

| |ratio 0.55, CI 0.35-0.86, p=0.01). Significant risk reduction was not sustained in follow-up phase and there |

| |was no significant difference in adverse events between the 2 groups. |

|Criteria- note yes or no for those which |RELEVENT - Yes |

|this study meets |VALID - Yes |

| |CHANGE IN PRACTICE- No |

| |MEDICAL CARE SETTING - Yes |

| |IMMEDIATELY APPLICABLE - Yes |

| |CLINICALLY MEANINGFUL - Yes |

|3. Bottom Line- one –two sentences noting |Low-dose penicillin can be used to lengthen time to recurrence and decrease the frequency of repeat episodes |

|the bottom line recommendation |of cellulitis. However, it is still uncertain what length of time is best for prophlyactic penicillin use.  |

|4. Title Proposal |Penicillin for the prevention of recurrent cellulitis. |

|SECTION 5: Editorial Decisions |

|[to be completed by the FPIN PURLs Editor or Deputy Editor] |

|1. FPIN PURLs editorial decision |1 Pending PURL Review—Schedule for Review |

|(select one) |2 Pending PURL—Forward to JFP Editor |

| |3 Drop |

|Follow up issues for Pending PURL Reviewer | |

|3. FPIN PURLS Editor making decision |1 Bernard Ewigman |

| |2 Sarah-Anne Schumann |

| |3 John Hickner |

| |4 Kate Rowland |

|4. Date of decision | |

|5. Brief summary of decision | |

|SECTION 6: Survey Questions for SERMO, PURLs Instant Polls and Other Surveys |

|[To be completed by the PURLs Survey Coordinator and PURLs Editor] |

|1. Current Practice Question for Surveys | |

|2. Barriers to Implementation Question for| |

|Surveys | |

|3. Likelihood of Change Question for | |

|Surveys | |

|4. Other Questions for Surveys | |

|SECTION 7: Variables for Secondary Database Analyses |

|1. Population: Age, gender, race, ethnicity | |

|2. Diagnoses | |

|3. Drugs or procedures | |

|SECTION 8: Pending PURL Review Assignment |

|[to be completed by PURLs Project Manager |

|1. Person Assigned for | |

|Pending PURL Review | |

|2. Date Pending PURL Review is due | |

|SECTION 9: Pending PURL Review |

|[to be completed by the Pending PURL Reviewer] |

|1. Did you address the follow up issues | Yes |

|identified at the PURL Jam (Section 5.2). |No |

|Add comments as needed. |Not applicable |

| |Comments: |

|2. Did you review the Sermo poll & Instant | Yes |

|Poll results (if available)? Add comments |No |

|as needed. |Not applicable |

| |Comments: |

|3. Did you modify Sections 2, 3, or 4? Add| Yes |

|comments as needed. |No |

| |Not applicable |

| |Comments: |

|SECTION 10: PURL Authoring Template |

|[to be completed by the assigned PURL Author] |

|Author Citation Information (Name, Degrees, Affiliation) | |

|1. Practice Changer | |

|2. Illustrative Case | |

|3. Background/ | |

|Clinical Context/Introduction/Current Practice/ | |

|4. Study Summary | |

|5. What’s New | |

|6. Caveats | |

|7. Challenges to Implementation | |

|8. Acknowledgment Sentence |The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 |

| |from the National Center For Research Resources, a Clinical Translational Science |

| |Award to the University of Chicago. The content is solely the responsibility of |

| |the authors and does not necessarily represent the official views of the National |

| |Center For Research Resources or the National Institutes of Health. |

| | |

| |If using UHC data: |

| |We acknowledge Sofia Medvedev of University HealthSystem Consortium (UHC) in Oak |

| |Brook, IL for analysis of the National Ambulatory Medical Care Survey data. |

|9. References | |

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