Interventions for the prevention of recurrent erysipelas and cellulitis

Adam Dalal; Marina Eskin‐Schwartz; Daniel Mimouni; Sujoy Ray; Walford Days; Emmilia Hodak; Leonard Leibovici; Mical Paul

doi:10.1002/14651858.CD009758.pub2

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Figure 1

Study selection flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Antibiotic prophylaxis versus no treatment/placebo, on prophylaxis, Outcome 1 Recurrence of cellulitis.

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Analysis 1.2

Comparison 1 Antibiotic prophylaxis versus no treatment/placebo, on prophylaxis, Outcome 2 Incidence rate of recurrence of cellulitis.

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Analysis 1.3

Comparison 1 Antibiotic prophylaxis versus no treatment/placebo, on prophylaxis, Outcome 3 Time to next episode of cellulitis.

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Analysis 1.4

Comparison 1 Antibiotic prophylaxis versus no treatment/placebo, on prophylaxis, Outcome 4 Hospitalisation.

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Analysis 1.5

Comparison 1 Antibiotic prophylaxis versus no treatment/placebo, on prophylaxis, Outcome 5 Any adverse reactions.

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Analysis 1.6

Comparison 1 Antibiotic prophylaxis versus no treatment/placebo, on prophylaxis, Outcome 6 Mortality.

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Analysis 2.1

Comparison 2 Antibiotic prophylaxis versus no treatment/placebo, post‐prophylaxis, Outcome 1 Recurrence of cellulitis.

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Analysis 2.2

Comparison 2 Antibiotic prophylaxis versus no treatment/placebo, post‐prophylaxis, Outcome 2 Incidence rate of recurrence of cellulitis.

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Analysis 2.3

Comparison 2 Antibiotic prophylaxis versus no treatment/placebo, post‐prophylaxis, Outcome 3 Time to next episode of cellulitis.

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Analysis 3.1

Comparison 3 Antibiotic prophylaxis versus no treatment/placebo, overall, Outcome 1 Recurrence of cellulitis.

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Analysis 3.2

Comparison 3 Antibiotic prophylaxis versus no treatment/placebo, overall, Outcome 2 Incidence rate of recurrence of cellulitis.

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Summary of findings for the main comparison. Antibiotic prophylaxis compared to no treatment/placebo for the prevention of recurrent erysipelas and cellulitis

Antibiotic prophylaxis compared to no treatment/placebo for the prevention of recurrent erysipelas and cellulitis ‐ on prophylaxis
Patient or population: People with recurrent erysipelas or cellulitis Intervention: Antibiotic prophylaxis Comparison: No treatment/Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	no treatment/placebo	Antibiotic prophylaxis
Recurrence of cellulitis	Study population		RR 0.31 (0.13 to 0.72)	513 (5 RCTs)	⊕⊕⊕⊝ MODERATE ¹	Number needed to treat for 1 additional beneficial outcome (NNTB) is 6
	316 per 1000	98 per 1000 (41 to 227)
Incidence rate of cellulitis	Study population		RR 0.44 (0.22 to 0.89)	473 (4 RCTs)	⊕⊕⊕⊝ MODERATE ¹	‐
	43 fewer episodes of cellulitis per 1000 person‐months in treatment group (from 8 fewer to 60 fewer)
Time to next episode of cellulitis	Not estimable		HR 0.51 (0.34 to 0.78)	437 (3 RCTs)	⊕⊕⊕⊝ MODERATE ¹	‐
Hospitalisation	Study population		RR 0.77 (0.37 to 1.57)	429 (3 RCTs)	⊕⊕⊝⊝ LOW ²	‐
	74 per 1000	57 per 1000 (27 to 116)
Any adverse reactions	Study population		RR 0.87 (0.58 to 1.30)	469 (4 RCTs)	⊕⊕⊝⊝ LOW ³	‐
	287 per 1000	250 per 1000 (166 to 373)
Quality of life	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: risk ratio; HR: hazard ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹We downgraded by one level because of imprecision due to the low number of events and the small sample size (optimal information size ‐ OIS). ² We downgraded by two levels because of imprecision due to the low number of events and the small sample size (OIS) and the 95% confidence interval overlapping the line of no effect and ranging from benefit to harm. ³We downgraded by two levels because of imprecision due to the considerable low number of events and the small sample size (OIS). We decided not to downgrade any of the outcomes for risk of bias as we decided it was not serious enough to affect the overall quality of the outcome.

Summary of findings for the main comparison. Antibiotic prophylaxis compared to no treatment/placebo for the prevention of recurrent erysipelas and cellulitis

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Table 1. Glossary of terms

Medical term	Explanation
Ambulatory	Ambulatory is when the patient can walk and is not bedridden. When referring to medical care it means that it is being provided to patients that are not hospitalised (outpatients)
Block randomisation	A method of randomisation that ensures allocation of participants into roughly equal sizes of comparison groups
Clostridium difficile	A bacterium that causes inflammation of the colon (colitis), typically resulting in diarrhoea, and is strongly associated with the use of antibiotics
Comorbidity	The presence of one or more diseases or conditions other than those of primary interest
Contralateral	On the opposite side of the body (e.g. a repeat episode of leg cellulitis can recur in the same leg [see 'ipsilateral'] or the other, contralateral leg
Control event rate (CER)	The rate at which events of interest (i.e. episodes of cellulitis in our review) occur in the control group of the study
Diuretics	Commonly known as "water pills" these are drugs that help the body to eliminate unneeded water and salt through the urine
Epidemiology	The study of the health of populations and communities, not just particular individuals
Erythema	Redness of the skin caused by increased blood flow. Often a sign of inflammation or infection
Filariasis	A disease caused by infection with worms, usually in tropical and subtropical areas of the world. The worms reside in the lymphatic system of the affected person and interfere with the drainage of the lymph, subsequently causing a significant swelling of the involved limb
Filarial lymphoedema	see Filiariasis
Folliculitis	Inflammation of hair follicles
Furunculosis	Deep form of inflammation of the hair follicles resulting in lumps caused by the accumulation of pus (boils)
Gastrointestinal	Relating to the stomach and the intestines
Incidence rate/Incidence rate ratio	The number of new occurrences of events in a population divided by its time period at risk; Incidence rate ratio is the ratio of two incidence rates
Ipsilateral	On the same side of the body; as opposed to 'contralateral'
Mastectomy	Surgical removal of one or both breasts
Outpatient/Inpatient	Outpatient is a person that is being treated without being hospitalised overnight and visits the physician in the clinic, hospital or other facility; compared with an inpatient who requires an overnight stay in hospital for medical treatment
Person‐months	The sum of the number of months each participant in the trial has been under observation (treated/followed)
'Per protocol'/Intention‐to‐treat (ITT) analyses	'Per protocol' analysis compares participants in a study based on the treatment they actually took and includes only those patients who completed the treatment originally allocated, as opposed to intention‐to‐treat analysis that compares participants on the basis of their random assignment to groups (treatment or placebo), regardless of adherence to treatment
Prophylaxis	Preventive treatment for disease
Retrospective cohort study	An observational study in which a defined group of people (the cohort) is followed over time. A retrospective cohort study identifies persons from past medical records and follows them from the time of those records to the present
Sensitivity analysis	An analysis used to determine how sensitive the results of a study or systematic review are to changes in how it was done
Tinea pedis	Fungal infection of the foot (athlete's foot)
Tonsillectomy	Surgical removal of tonsils

Table 1. Glossary of terms

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Table 2. Contact with investigators of included studies

Study	Way of communication	Date	Information provided	Notes
Chakroun 1994	email	12/2013	‐ Allocation concealment ‐ Participants follow‐up ‐ Criteria for diagnosis ‐ Adherence ‐ Adverse reactions ‐ Informed consent ‐ Ethical committee approval ‐ Source of funding	Full information was not available for all queries, but investigators responded to all of them
Kasseroller 1998	airmail, email, website	2013 ‐ 2014	‐	Investigator did not reply to our queries We also contacted a potential sponsor, not reported by the author, who confirmed their financial support for the conduct of this study (email correspondence with the head of medical‐scientific department of 'biosyn Arzneimittel GmbH' from January 2015)
Kremer 1991	email and telephone	12/2013 and 1/2014	‐	Data were not available and the investigator did not remember any details
Sjöblom 1993	email	12/2013	‐ Allocation concealment ‐ Participants follow‐up ‐ By whom cellulitis was diagnosed ‐ Adherence ‐ Source of funding	Full information was not available for all queries, but investigators responded to all of them
Thomas 2012	email	1/2014	‐ Episodes of recurrent cellulitis per person‐months (incidence rate) ‐Time to next episode ‐ Adverse events by study arm ‐ Duration of hospitalisation ‐ Quality of life	‐
Thomas 2013	email	1/2014	‐ Episodes of recurrent cellulitis per person‐months (incidence rate) ‐ Quality of life	Hospitalisation and quality of life were not evaluated directly in this trial but were reported by indirect evaluation in Mason 2014

Table 2. Contact with investigators of included studies

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Table 3. Clinical guidelines on antibiotic prophylaxis for the prevention of recurrent cellulitis

Guideline	Organisation	Recommended antibiotic	Duration of Px	No of episodes to initiate Px	Adjunctive Tx	Quality of evidence †
BLS 2016	BLS	penicillin by mouth; alternatives: cephalexin, erythromycin, clarithromycin, clindamycin, doxycycline	2 y; life‐long Px if recurrence after Px stopped	2 ≥/y	skin care, decongestive Tx, antifungal Tx, alcohol wipes; SIT	NS
ALA 2015	ALA	penicillin by mouth; alternatives: cephalexin, erythromycin, clindamycin	2 y; life‐long Px if recurrence after Px stopped	2 ≥/y	skin care, decongestive Tx, bacterial decolonisation Tx; SIT	NS
Stevens 2014	IDSA	penicillin by mouth/IM; alternatives:erythromycin	as long as RF persist	3 – 4 /y	skin care, Tx of oedema, weight reduction	antibiotic Px ‐weak, moderate ‡ duration of Px ‐ strong, moderate ‡ skin care ‐ strong, moderate ‡
Stevens 2005	IDSA	penicillin by mouth/IM; alternatives:erythromycin	NS	frequent	skin care, Tx of oedema compression stockings, diuretics; SIT	grade IIB §
ISL 2013	ISL	penicillin; alternatives: broad spectrum antibiotic	NS	repeat despite physical Tx	skin care, antifungal Tx	NS
Esposito 2011	SIMIT and ISC	penicillin or macrolide	NS	recurrent	skin hygiene and compression stockings	NS
Draijer 2008	NHG	penicillin by mouth/IM	1 ‐ 2 y	2 ≥/y	skin care, compression stockings; SIT	NS
ILF 2006	ILF	penicillin by mouth; alternatives:erythromycin, clindamycin, clarithromycin	2 y; life‐long Px if recurrence after Px stopped	2 ≥/y	skin care, decongestive Tx, antifungal Tx; SIT	NS
CREST 2005	CREST	penicillin or erythromycin by mouth	2 y	2 ≥/y	SIT may be preferable	weak and inconclusive
NICE 2005	NICE	a trial should be considered	NS	> 2/y	skin care, Tx of oedema, compression stockings, weight reduction	weak and inconclusive
Eron 2003	Other^*	antibiotic may be needed; type of antibiotic NS	long term	NS	skin care, Tx of oedema, antifungal Tx; SIT	NS
SFD 2000	SFD	penicillin by mouth/IM; alternatives: macrolide	prolonged, probably indefinitely	several/poorly controlled RF	skin care, Tx of oedema	NS
Duodecim 1999	FMSD	antibiotic should be considered; type of antibiotic NS	long term	frequent	skin care	NS
† Assessement of quality of evidence as defined and graded by the authors of the document. ‡ Strong recommendation, moderate quality ‐ desirable effects clearly outweigh undesirable effects; evidence from RCTs with important limitations or exceptionally strong evidence from unbiased observational studies; recommendation can apply to most patients in most circumstances and further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate. Weak recommendation, moderate quality ‐ desirable effects closely balanced with undesirable effects; evidence from RCTs with important limitations;recommendation may change when higher‐quality evidence becomes available; and further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate. § Moderate evidence ‐ should generally be offered; II ‐ evidence from one well‐designed clinical trial. Abbreviations IM ‐ injections into the muscle (intramuscular) No ‐ number NS ‐ not specified Px ‐ preventive treatment (prophylaxis) RF‐ risk factors SIT ‐ self‐initiated treatment Tx ‐ treatment y ‐ year/s Medical organisations BLS ‐ British Lymphology Society ALA ‐ Australasian Lymphology Association IDSA ‐ Infectious Diseases Society of America ISL ‐ International Society of Lymphology SIMIT ‐ Società Italiana di Malattie Infettive e Tropicali ‐ Italian Society of Infectious Diseases ISC ‐ International Society of Chemotherapy NHG ‐ Nederlands Huisartsen Genootschap ‐ The Dutch College of General Practitioners ILF ‐ International Lymphoedema Framework CREST ‐ Clinical Resources Efficiency Support Team (UK) NICE ‐ National Institute for Health and Clinical Excellence (England) SFD ‐ La Société Française de Dermatologie ‐ The French Society of Dermatology MSD ‐ The Finnish Medical Society Duodecim ^* 5 of 6 experts in this consensus paper were from North America; published in the Journal of the British Society for Antimicrobial Chemotherapy

Table 3. Clinical guidelines on antibiotic prophylaxis for the prevention of recurrent cellulitis

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Comparison 1. Antibiotic prophylaxis versus no treatment/placebo, on prophylaxis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrence of cellulitis Show forest plot	5	513	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.13, 0.72]

2 Incidence rate of recurrence of cellulitis Show forest plot	4	4375	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.22, 0.89]

3 Time to next episode of cellulitis Show forest plot	3		Hazard Ratio (Random, 95% CI)	0.51 [0.34, 0.78]

4 Hospitalisation Show forest plot	3	429	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.37, 1.57]

5 Any adverse reactions Show forest plot	4	469	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.58, 1.30]

5.1 Penicillin	3	437	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.60, 1.10]
5.2 Erythromycin	1	32	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.39, 125.44]
6 Mortality Show forest plot	3	437	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.32, 3.91]

Comparison 1. Antibiotic prophylaxis versus no treatment/placebo, on prophylaxis

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Comparison 2. Antibiotic prophylaxis versus no treatment/placebo, post‐prophylaxis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrence of cellulitis Show forest plot	2	287	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.59, 1.31]

2 Incidence rate of recurrence of cellulitis Show forest plot	2	4566	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.65, 1.36]

3 Time to next episode of cellulitis Show forest plot	2		Hazard Ratio (Random, 95% CI)	0.78 [0.39, 1.56]

Comparison 2. Antibiotic prophylaxis versus no treatment/placebo, post‐prophylaxis

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Comparison 3. Antibiotic prophylaxis versus no treatment/placebo, overall

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrence of cellulitis Show forest plot	2	397	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.59, 0.95]

2 Incidence rate of recurrence of cellulitis Show forest plot	2	7854	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.56, 0.85]

Comparison 3. Antibiotic prophylaxis versus no treatment/placebo, overall

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