INTRODUCTION — Use of antimicrobial prophylaxis for prevention of bacterial endocarditis is based on theoretical advantage rather than data from clinical trials.
The 2007 American Heart Association (AHA) guideline for the prevention of infective endocarditis (IE)  included major revisions to the 1997 AHA guideline, the 2005 update of those guidelines published by the Medical Letter , and the 2006 American College of Cardiology (ACC)/AHA guideline on the management of valvular heart disease . The 2006 ACC/AHA guidelines were updated in 2020 [4-6]. In 2021, the AHA published a statement analyzing the impact of the 2007 guidelines on the incidence and outcome of IE due to viridans group streptococci, with further recommendations on use of antibiotic prophylaxis . The 2015 European Society of Cardiology guidelines are largely in agreement with the preceding American guidelines except as noted below .
The theoretic basis and clinical approach for use of antimicrobial prophylaxis for prevention of bacterial endocarditis will be reviewed here . Issues related to the diagnosis and treatment of endocarditis are discussed separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Antimicrobial therapy of left-sided native valve endocarditis".)
RATIONALE — The pathogenesis of infective endocarditis (IE) is presumed to involve the following sequence of events :
●Formation of a small thrombus on an abnormal endothelial surface
●Secondary infection of this nidus with bacteria that are transiently circulating in the bloodstream
●Proliferation of bacteria resulting in the formation of vegetations on the endothelial surface
Since the occurrence of bacteremia is crucial to the initiation of an episode of IE, in theory it is reasonable to conclude that preventing or promptly treating transient bacteremia can prevent the above events.
Animal studies — Bacterial endocarditis can be induced experimentally when bacteria with a known ability to cause endocarditis (such as streptococci) are injected into laboratory animals following traumatization of the heart valves with vascular catheters . However, endocarditis does not occur if antibiotics with activity against streptococci are given up to 30 minutes after injection of bacteria [9,11]. Endocarditis is not prevented if such administration of antibiotics is delayed for six hours after injection of bacteria.
These data suggest that antimicrobial therapy can prevent endocarditis either by killing bacteria before they establish a nidus of infection on a susceptible heart valve or by killing bacteria after they adhere to a localized area of damaged valvular endothelium .
Summary of limitations of prophylaxis — No human study has definitively demonstrated that prophylactic antibiotics prevent endocarditis after invasive procedures. However, there are several studies that attempted to address the impact of antibiotic prophylaxis on risk for IE. A systematic review and meta-analysis including 21 trials, 10 time-trend studies, and five observational studies (discussed below) concluded that the evidence base for use of antibiotic prophylaxis was limited and heterogeneous, and the methodologic quality of many studies was poor . (See 'Effect of antibiotic prophylaxis' below.)
Even if antibiotic prophylaxis is effective, its utility is limited by the frequency of IE without any identifiable preceding procedure, the low rate of IE following procedures such as dental work without prophylaxis, and the potential for prophylaxis failure. (See 'On risk of endocarditis' below and 'Impact of procedures on risk of endocarditis' below.)
It has been estimated that, even if antimicrobial prophylaxis is fully effective, less than 10 percent of all cases of endocarditis could be prevented by use of antimicrobial therapy prior to procedures . Various epidemiologic studies showed that up to 5 percent of all cases were preceded by a dental procedure [14,15]. However, even in cases in which there is a close temporal relationship between a dental procedure and the occurrence of endocarditis, causality is uncertain as it is possible that endocarditis occurred as a consequence of the dental condition that led to the procedure or from routine tooth brushing. (See 'Impact of procedures on risk of endocarditis' below.)
An epidemiologic study from France estimated that the risk of developing IE following a dental procedure in adults with predisposing cardiac conditions was 1 in 11,000 for patients with prosthetic valves and no prophylaxis, 1 in 54,000 for patients with native valves and no prophylaxis, and 1 in 150,000 for patients who received prophylaxis . Thus, a large number of prophylaxis doses would be necessary to prevent a very small number of IE cases, suggesting that only the highest risk populations should receive prophylaxis.
Impact of procedures on risk of endocarditis — Invasive dental procedures and other procedures may contribute to the risk of IE, although most cases of IE do not occur after a procedure.
The impact of invasive dental procedures on the risk of IE in patients with prosthetic valves was assessed by a French population-based cohort and case crossover study . In the cohort study, there was no significant difference in the risk of oral streptococcal IE in the three-month period after an invasive dental procedure (risk ratio [RR] 1.25, 95% CI 0.82-1.82) or after an invasive dental procedure without antibiotic prophylaxis (RR 1.57, 95% CI 0.90-2.53) compared with nonexposure periods. However, in the case-control analysis, invasive dental procedures were more frequent during case periods, defined as the 3 months preceding oral streptococcal IE, than during control periods, defined as months 9 to 7 before, months 15 to 13 before, and months 21 to 19 before in the same participants (5.1 versus 3.2 percent; odds ratio 1.66, 95% CI 1.05-2.63).
A similar population-based case-crossover and self-controlled case series study was performed in Taiwan . In the study, cases (defined as having an invasive dental treatment 4, 8, 12, and 16 weeks prior to IE onset) were compared with controls (defined as having an invasive dental treatment six months before the onset of IE). In the self-controlled case series, risks for IE were estimated during weeks 1 to 4, 5 to 9, 9 to 12, and 13 to 16 after an invasive dental treatment; the remaining period was defined as the baseline period. In both analyses, there was no association between invasive dental treatment and risk for IE in the short period following invasive dental treatment.
The impact of invasive medical procedures (other than dental procedures) on the risk of IE was assessed in a Swedish population-based case-crossover study . Several invasive procedures (including coronary artery bypass grafting, procedures of the skin and management of wounds, transfusion, dialysis, bone marrow puncture, and some endoscopies including bronchoscopy) were strongly associated with an increased risk of IE in the 12-week interval following the procedure. However, the clinical significance of this study is uncertain, since information on prior antibiotic use and the microbiology of IE were not provided. In addition, the role of confounders related to general risk of IE in hospitalized patients and patients with significant underlying health comorbidities was not examined.
Effect of antibiotic prophylaxis — Antibiotic trials have examined the impact of antibiotic prophylaxis on bacteremia, but only limited observational data are available on the effect of antibiotic prophylaxis on the risk of IE.
On bacteremia — All antibiotic prophylaxis trials (21 included in the meta-analysis) used bacteremia as an endpoint rather than IE . The meta-analysis found that antibiotic prophylaxis was effective in reducing the incidence of bacteremia (RR 0.53, 95% CI 0.49-0.57).
On risk of endocarditis — The efficacy of antibiotic prophylaxis in reducing the risk of IE has not been established. In a meta-analysis of three case-control studies of patients undergoing dental or other invasive procedures, there was no statistically significant difference in exposure to antibiotic prophylaxis between patients with IE and controls, but the studies were underpowered .
In the above-cited French population-based cohort study, among 138,876 adults with prosthetic heart valves, there were 103,463 invasive dental procedures meeting criteria for antibiotic prophylaxis, which was prescribed for 52,280 procedures (50.1 percent) . The incidence of IE in the three months after an invasive dental procedure was nominally but not significantly lower in patients taking antibiotic prophylaxis (78.1 per 100,000 person years, 95% CI 1.6-154.6) compared with those not taking antibiotic prophylaxis (149.5 per 100,000 person years, 95% CI 56.8-242.2).
Even if antibiotic prophylaxis reduces risk of IE, it may fail. One report included 52 cases of IE that occurred despite receipt of antimicrobial therapy prior to invasive procedures . In the 43 cases with antimicrobial susceptibility data, 63 percent of the pathogens were susceptible to the prophylactic antimicrobial agents that were administered. However, only six cases (12 percent) received regimens recommended by the American Heart Association (AHA).
Time-trend studies — Increases in IE incidence observed in some studies have raised concern that reduced IE prophylaxis in response to guideline changes may have contributed to increased IE rates [20-23].
However, a causal connection is uncertain given the absence of controlled data. Factors that may contribute to perceived increasing rates of IE include lower thresholds for diagnosis of IE, increased prevalence of risk factors, increases in procedures predisposing to IE, and inaccurate coding or counting .
The above cited systematic review included 10 time-trend studies examining the effect of antibiotic prophylaxis guideline change on the incidence of IE, including nine studies of relative antibiotic prophylaxis restriction and one study examining the effect of total antibiotic prophylaxis restriction :
●Among the studies of the effect of relative antibiotic prophylaxis restriction (from the United States and Europe), the reported incidence of IE is increasing; however, a significant inflection point (alteration in the rate of change) in the incidence trend of IE was not identified. Even larger studies may be underpowered to detect a significant change in IE incidence, given limited duration of follow-up.
●Conflicting results have been reported regarding the incidence of streptococcal IE, with some studies reporting a significant increase in the incidence of streptococcal IE  and other studies finding no increase in incidence of viridans group streptococcal IE [25,26]. One study reported a decrease in the incidence of streptococcal IE .
The National Institute for Health and Clinical Excellence (NICE) issued 2008 guidelines recommending complete cessation of antibiotic prophylaxis for IE prevention . In a subsequent study examining the effect of this intervention, a significant increase in the incidence of IE was observed by March 2013, 35 more cases of IE per month were reported than expected based upon the historical trend . In contrast, an analysis of IE incidence in Scotland demonstrated no change in incidence of IE after the 2008 guideline change . The NICE guidelines were revised in 2016 to include the word "routinely" in the following statement: "Antibiotic prophylaxis against infective endocarditis is not recommended routinely for people undergoing dental procedures" .
Similarly, complete cessation of antibiotic prophylaxis was recommended in Sweden in October 2012. An analysis of IE incidence in Sweden before and after the recommendation showed no statistically significant increase in the trend line of IE caused by viridans group streptococci .
Subsequent studies compared rates of antibiotic prophylaxis and incidence of endocarditis relative to publication of the 2007 AHA guidelines [23,32]:
●The first study evaluated patients in the United States before (2003 to 2007) and after (2008 to 2015) publication of the 2007 AHA guidelines . Among moderate-risk individuals, there was a 64 percent (95% CI 59-68 percent) reduction in the rate of antimicrobial prescribing, and an increase in IE incidence among moderate-risk individuals (75%, 95% CI 3-200 percent). Among high-risk individuals, there was a 20 percent reduction in the rate of antimicrobial prescribing (95% CI 4-32 percent), and a significant increase in IE incidence (177 percent; 95% CI 66-361 percent).
●The second study evaluated data on patients in Ontario, Canada between 2002 and 2014 :
•Prescription information was reported for adults ≥65 years of age. In the moderate-risk group, there was a decline in antibiotic prophylaxis prescriptions after the guideline revision (mean quarterly prescriptions 30,680 versus 17,954 per 1 million population); in the high-risk group, there was a slight decrease followed by a gradual increase in prophylaxis prescriptions.
•Among adults ≥65 years old, there was an increase in IE-related hospitalizations (with a higher magnitude in the high-risk versus moderate-risk group) starting three years after the AHA guideline revision. A similar pattern of IE-related hospitalizations was observed among adults 18 to 64 years of age in high- or moderate-risk groups. Among adults ≥65 years of age, there was no significant change in the proportion of Staphylococcus aureus and streptococcal IE episodes over time; among adults 18 to 64 years of age, there was a reduction in the proportion of streptococcal IE and an increase in proportion of S. aureus IE.
These studies identify a decrease in antimicrobial prophylaxis and an increase in IE incidence after publication of the 2007 antimicrobial guideline but do not establish causality, particularly given the three-year gap between guideline publication and increase in IE incidence in the latter study. The decrease in proportion of streptococcal IE despite antibiotic prophylaxis restriction in adults 18 to 64 years of age suggests lack of a causal relationship although this finding is difficult to interpret given the presence of other factors including increasing prevalence of history of drug abuse in this group.
Given the available evidence, we continue to recommend the approach to IE prophylaxis described below, consistent with American College of Cardiology/AHA guidelines . (See 'Clinical approach' below.)
CLINICAL APPROACH — Antimicrobial prophylaxis is suggested for patients with cardiac conditions that confer the highest risk of adverse outcome from infective endocarditis (IE) [1,4,5]. Guidelines issued prior to 2007 recommended prophylaxis for patients at moderate to high risk of IE, a much larger population [2,3].
There is no convincing evidence that antimicrobial prophylaxis provides significant benefit in terms of prevention of IE in many cases . IE is much more likely to result from frequent exposure to random bacteremias associated with daily activities such as tooth brushing than from bacteremia caused by a dental, gastrointestinal, or genitourinary procedure. Maintenance of oral hygiene may reduce the incidence of bacteremia is more important than prophylactic antibiotics for a dental procedure to reduce the risk of IE. Furthermore, the risk of antibiotic-associated adverse events may exceed the benefit, if any, from prophylactic antibiotic therapy.
Antibiotic regimens — For patients with relevant cardiac risk factors undergoing dental procedures, the preferred regimen is oral amoxicillin (adults: 2 grams; children: 50 mg/kg); alternative regimens are summarized in the table (table 1) . (See 'Dental work' below and 'Respiratory tract procedures' below.)
Clindamycin is no longer recommended as an alternative antibiotic regimen for patients undergoing dental procedures, given more frequent and severe adverse reactions associated with this drug compared with other antibiotic agents . In one study of adverse reactions to antibiotics used as endocarditis prophylaxis in England between 2004 and 2014, the rate of adverse drug reactions for amoxicillin was 0 fatal and 23 nonfatal reactions per million prescriptions; for clindamycin, the rate was 13 fatal and 149 nonfatal reactions per million prescriptions . Clostridioides difficile infection adverse drug reactions associated with clindamycin.
In general, antibiotics should be administered 30 to 60 minutes prior to the procedure (an exception is intravenous vancomycin, which should be administered 120 minutes prior to the procedure) . The 2013 guidelines for preoperative antimicrobial prophylaxis stipulate the optimal timing is within 60 minutes before surgical incision .
Patients at highest risk — Prophylaxis is suggested only in the setting of conditions associated with the highest risk of an adverse outcome if IE occurs. These include :
●Prosthetic cardiac valve or material
•Presence of cardiac prosthetic valve
•Transcatheter implantation of prosthetic valves
•Cardiac valve repair with devices, including annuloplasty, rings, or clips
•Left ventricular assist devices or implantable heart
●Previous, relapse, or recurrent IE
●Congenital heart disease
•Unrepaired cyanotic congenital coronary heart disease, including palliative shunts and conduits
•Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by transcatheter during the first six months after the procedure
•Repaired congenital heart disease with residual defects at the site of or adjacent to the site of a prosthetic patch or prosthetic device
•Surgical or transcatheter pulmonary artery valve or conduit placement such as Melody valve and Contegra conduit
●Cardiac transplant recipients who develop cardiac valvulopathy
The above approach is supported by a Danish nationwide registry study including more than 25,000 at high risk for IE (due to prior IE, presence of a prosthetic heart valve, or presence of complex congenital heart disease) . Complex congenital heart disease was identified (largely in infants and children) by a diagnosis code for tetralogy of Fallot, transposition of the great arteries, or truncus arteriosus and was not limited to unrepaired cyanotic heart disease. The cumulative risk of IE at 10 years of follow-up among these groups was 8.8, 6.0, and 1.3 percent, respectively.
On the other hand, there are data suggesting that classification of conditions in the high- versus low/moderate-risk groups should be considered carefully. In one cohort study including more than 3000 patients with IE, the rate of intracardiac complications was similar among those with bicuspid aortic valve and mitral valve prolapse (considered moderate risk) as those in the high-risk group (50 and 47 versus 30 percent; p<0.01) . Another study among patients in the United Kingdom demonstrated that the risk of IE or death during hospitalization for IE associated with some conditions in the moderate-risk group (eg, a broad group of congenital valve anomalies) was similar to the risk associated with some conditions in the high-risk group (eg, prosthetic valves) . These studies are limited in methodology and illustrate the complexities in categorizing patients as high versus low/moderate risk.
The 2015 European Society of Cardiology (ESC) guidelines are largely in agreement with the American Heart Association guidelines about who should receive prophylaxis, except that the ESC does not recommend antibiotic prophylaxis in cardiac transplant patients who have valvulopathy .
Relevant procedures — Antimicrobial prophylaxis is suggested for patients with the cardiac lesions cited above in the setting of procedures likely to result in bacteremia with a microorganism that has the potential ability to cause endocarditis . (See 'Patients at highest risk' above.)
Antibiotics may be required
Dental work — The risk of IE is generally considered to be the highest for dental procedures that involve manipulation of gingival tissue or the periapical region of the teeth or perforation of the oral mucosa, such as tooth extractions or drainage of a dental abscess; this includes routine dental cleaning [1,7,38,39].
In contrast, the following procedures and events do not require prophylaxis: anesthetic injections through noninfected tissue, taking dental radiographs, placement or adjustment of removable prosthodontic or orthodontic appliances, placement of orthodontic brackets, shedding of primary teeth, and bleeding from trauma to lips or oral mucosa .
For patients at risk for IE associated with dental work (see 'Patients at highest risk' above), antibiotic regimens for prophylaxis prior to dental procedures are summarized in the table (table 1). All individuals at risk for developing IE should establish and maintain a program of oral health care including regular professional care, the regular use of manual or powered toothbrushes, dental floss, and other plaque-removing devices.
Respiratory tract procedures — There is no direct evidence that bacteremia associated with respiratory tract procedures causes IE. Antimicrobial prophylaxis is suggested only for procedures involving incision or biopsy of the respiratory tract mucosa; examples include tonsillectomy, adenoidectomy, or bronchoscopy with biopsy . (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults", section on 'Head and neck surgery'.)
Patients who undergo an invasive respiratory tract procedure as part of treatment for an established infection should be treated with an antimicrobial agent that is active against viridans group streptococci. For patients with a respiratory tract infection that is known or suspected to be caused by S. aureus, the regimen should include an agent active against S. aureus such as an antistaphylococcal penicillin or cephalosporin; vancomycin should be used for patients unable to tolerate beta-lactams or patients with known or suspected infection due to methicillin-resistant S. aureus [MRSA].
Skin or soft tissue procedures — Patients undergoing a surgical procedure for management of infected skin, skin structure, or musculoskeletal tissue should receive antibiotic therapy with activity against skin flora. If the pathogen is known, the antibiotic should be targeted accordingly; if the pathogen is not known, empiric antibiotic therapy with activity against MRSA and beta-hemolytic streptococci should be administered.
Cardiac surgery with prosthetic material — Patients undergoing surgery to place prosthetic heart valves or prosthetic intravascular or intracardiac materials should receive antimicrobial prophylaxis for prevention of endocarditis and surgical site infection. This is discussed further separately. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults", section on 'Cardiac surgery'.)
Antibiotics generally not required
Genitourinary and gastrointestinal tract procedures — We suggest no routine prophylaxis for gastrointestinal (GI) or genitourinary (GU) procedures, even for patients with high-risk cardiac conditions [1,4]. The risk of bacteremia for invasive GU procedures such as dilation of strictures, insertions of catheters, and prostatectomy is relatively low. The risk of bacteremia for invasive GI procedures such as lower bowel endoscopy with biopsy or endoscopic retrograde cholangiopancreatography is also low.
Data evaluating the risk of IE associated with GI endoscopy are discussed separately. (See "Antibiotic prophylaxis for gastrointestinal endoscopic procedures".)
Antimicrobial therapy with activity against enterococci is suggested in patients with high-risk cardiac conditions and ongoing GI or GU tract infection.
For those patients with enterococcal urinary tract infection or colonization who are scheduled to undergo elective cystoscopy or urinary tract manipulation, eradication of the organism should be attempted prior to the procedure.
Vaginal or cesarean delivery — Antibiotic prophylaxis for endocarditis prior to delivery is discussed separately. (See "Pregnancy and valve disease", section on 'Endocarditis prophylaxis'.)
Patients on concurrent antibiotics — If patients are receiving antibiotics for other indications at the time that dental or invasive procedures are undertaken, an alternate antibiotic of a different class is often chosen. As an example, if a patient receiving penicillin for rheumatic fever prophylaxis undergoes an invasive dental procedure and requires IE prophylaxis, clindamycin, cephalexin, or azithromycin is often chosen.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment and prevention of infective endocarditis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Endocarditis (The Basics)")
●Beyond the Basics topic (see "Patient education: Antibiotics to prevent heart valve infections (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Evidence to support antimicrobial prophylaxis for prevention of endocarditis is weak. We are in agreement with the American Heart Association guideline for the prevention of infective endocarditis (IE), which was updated in 2021. (See 'Human studies' above and 'Clinical approach' above.)
●We suggest administering antimicrobial prophylaxis for patients with cardiac conditions that confer the highest risk of adverse outcome from IE undergoing procedures likely to result in bacteremia with a microorganism that has the potential ability to cause bacterial endocarditis (Grade 2C). (See 'Clinical approach' above.)
●The following are the highest risk conditions (see 'Patients at highest risk' above):
•Prosthetic cardiac valve or material
-Presence of cardiac prosthetic valve
-Transcatheter implantation of prosthetic valves
-Cardiac valve repair with devices, including annuloplasty, rings, or clips
-Left ventricular assist devices or implantable heart
•Previous, relapse, or recurrent IE
•Congenital heart disease
-Unrepaired cyanotic congenital coronary heart disease, including palliative shunts and conduits
-Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by transcatheter during the first six months after the procedure
-Repaired congenital heart disease with residual defects at the site of or adjacent to the site of a prosthetic patch or prosthetic device
-Surgical or transcatheter pulmonary artery valve or conduit placement such as Melody valve and Contegra conduit
•Cardiac transplant recipients who develop cardiac valvulopathy
●The following are the highest risk procedures (see 'Relevant procedures' above):
•Dental procedures that involve manipulation of either gingival tissue or the periapical region of teeth or perforation of the oral mucosa; this includes routine dental cleaning.
•Procedures of the respiratory tract that involve incision or biopsy of the respiratory mucosa
•Gastrointestinal (GI) or genitourinary (GU) procedures in patients with ongoing GI or GU tract infection
•Procedures on infected skin, skin structure, or musculoskeletal tissue
•Surgery to place prosthetic heart valves or prosthetic intravascular or intracardiac materials
●For adult patients with relevant cardiac risk factors undergoing relevant dental or respiratory tract procedures, the preferred regimen is oral amoxicillin 2 grams; alternative regimens and regimens for children are summarized in the table (table 1). (See 'Antibiotic regimens' above.)
●The approach to prevention of IE for patients with relevant cardiac risk factors undergoing non-dental procedures consists of the following:
•Antimicrobial prophylaxis is suggested for respiratory tract procedures involving incision or biopsy of the respiratory tract mucosa; examples include tonsillectomy, adenoidectomy, or bronchoscopy with biopsy (table 1). Among patients who have a respiratory tract infection that is known or suspected to be caused by Staphylococcus aureus, the regimen should include an agent active against S. aureus such as an antistaphylococcal penicillin or cephalosporin (or vancomycin for patients unable to tolerate beta-lactams or who have suspected or known infection with methicillin-resistant S. aureus). (See 'Respiratory tract procedures' above.)
•We suggest no antimicrobial prophylaxis for GI or GU procedures. In patients with GI or GU tract infection, antimicrobial therapy to prevent associated wound infection or sepsis should include an agent active against enterococci. (See 'Genitourinary and gastrointestinal tract procedures' above.)
•We suggest no IE antimicrobial prophylaxis for vaginal or cesarean delivery. (See 'Vaginal or cesarean delivery' above.)
•Patients with skin or musculoskeletal infections undergoing procedures should receive antimicrobial therapy with activity against staphylococci and beta-hemolytic streptococci. (See 'Skin or soft tissue procedures' above.)