Pharmacology Consult

Nasal decolonization: potential mupirocin alternatives for SSI prevention

Staphylococcus aureus nasal carriage is a proven risk factor for the development of staphylococcal surgical site infections, or SSIs. S. aureus infections are associated with increased length of hospital stays, increased mortality and higher costs of medical care. Nasal colonization rates with S. aureus have been reported to reach up to 30%, with 1% to 3% having methicillin-resistant organisms.

Nasal decolonization strategies have proven beneficial in reducing not only S. aureus colonization but also S. aureus SSIs. The most common nasal decolonization strategy is to administer mupirocin to the nares starting a few days before surgery. A consequence of mupirocin use, however, has been the development of mupirocin-resistant staphylococci. Because of concerns about resistance and whether patients can be relied upon to apply mupirocin before surgery, alternative approaches to nasal decolonization are being investigated.

Mupirocin

Topical mupirocin is the gold standard topical antibacterial agent for nasal decolonization. It is active against staphylococci, and many gram-negative organisms.

Jeff Brock

Mupirocin is generally well-tolerated, with most reported adverse effects relating to local irritation of the nasal mucosa such as burning, stinging and congestion.

To date, mupirocin is the most widely studied antimicrobial for nasal decolonization, with multiple studies showing its effectiveness in nasal decolonization and SSI prevention. The studies vary in their trial designs, patient populations and primary outcome measures. Meta-analyses of published studies have found that mupirocin decolonization decreases SSI rates among patients undergoing orthopedic surgery, cardiac surgery and neurosurgery. Additionally, a Cochrane Review meta-analysis concluded that, compared with placebo, intranasal mupirocin use was associated with a significant reduction in the rate of S. aureus SSIs (RR = 0.55, 95% CI, 0.43-0.7).

Povidone-iodine

Povidone-iodine is a complex of iodine with polyvinylpyrrolidone and has a long history of use as an antiseptic on skin, wounds and mucous membranes. It has a broad spectrum of activity against many gram-positive organisms, including methicillin-susceptible S. aureus and MRSA, as well as many gram-negative organisms. The use of iodine-based products may have some advantages over mupirocin, such as rapid bactericidal activity (within 10-20 seconds), and there is no evidence that bacteria can develop resistance to iodine. When used for nasal decolonization, povidone-iodine is administered in the nares just before surgery because of its rapid bactericidal activity, unlike mupirocin, which must be used twice a day for 5 days. Intranasal preparations of povidone-iodine are available from various manufacturers in concentrations of 5% or 10%.

A single-center, quasi-experimental study evaluated a preoperative decontamination protocol that included intranasal povidone-iodine to reduce SSIs in orthopedic patients undergoing elective surgery with hardware implantation. Patients used 2% chlorhexidine gluconate washcloths and oral rinse the night before and the morning of surgery, along with intranasal povidone-iodine solution administered to nares the morning of surgery only. The main outcome measure was 30-day infection rates. There were 709 patients — including 365 patients who underwent the decolonization protocol and 344 controls. The SSI rate was significantly lower in the decolonization group (1.1%) than in the control group (3.8%). Multivariate logistic regression analysis determined that MRSA decontamination was an independent predictor of not developing an infection. Although the outcomes were favorable, the study was limited by its single-center study design, as well as the fact that patient MRSA carrier status was not determined before and after decolonization, and that patients were followed for only 30 days.

In another trial, mupirocin nasal formulation was administered twice daily for 5 days, compared with a 5% povidone- iodine solution administered within 2 hours of surgery for joint arthroplasty or spine fusion. The povidone-iodine product used in the study was specially formulated with a film-forming polymer that increases its adherence to the nasal mucosa, providing a more persistent bactericidal effect. Patients also used 2% chlorhexidine cloths to clean the body the night before and the day of surgery. In the intent-to-treat analysis, there was no significant difference in deep SSIs caused by any pathogen (14 vs. 6) or SSIs caused by S. aureus (5 vs. 1) during the 3-month follow up period. However, in the per-protocol analysis, S. aureus SSIs occurred after five of 763 procedures in the mupirocin group, whereas no infections developed after the 776 procedures in the povidone-iodine group (P = .03). Both agents were well-tolerated, but those in the mupirocin group were more likely to report headache, nasal symptoms and sore throat. A higher proportion of patients reported that mupirocin treatment applications were unpleasant compared with those who received povidone-iodine.

Alcohol

Alcohol’s antimicrobial activity is due to its ability to denature proteins. It has activity against a wide range of gram- positive and gram-negative bacteria, including multidrug-resistant pathogens like MRSA. Alcohol is rapidly bactericidal but has virtually no residual antibacterial effects after application. Compared with both mupirocin and povidone-iodine, there are fewer clinical data available using alcohol for nasal decolonization to reduce SSIs.

In a single-center, quasi-experimental intervention, intranasal alcohol was used in a nasal decolonization protocol to reduce staphylococcal SSIs in patients undergoing spine operations. The investigators combined the use of the alcohol-based nasal antiseptic with use of chlorhexidine bath or wipes in a pre- and post-surgical decolonization protocol. The nasal alcohol antiseptic was administered before entering the operating room. After surgery, the nasal decolonization was administered three times daily by staff in the post-surgical units until discharge, at which time the patient and family were instructed to continue applications for an additional 5 to 7 days. Records from 1,073 patients were reviewed, including 400 in the baseline pre-implementation group and 673 in the protocol group. During the 15-month trial, mean infection rates decreased by 81% ) from 1.76 to 0.33 per 100 surgeries. Self-reported compliance with the nasal alcohol application by patients was consistent, averaging 95% over the trial period; however, this was likely overstated because of self-reporting bias.

Retapamulin

Retapamulin is a pleuromutilin antimicrobial agent that is available in a 1% topical ointment that has been FDA approved since 2007 for the treatment of impetigo due to S. aureus or Streptococcus pyogenes. Although it is not approved by the FDA for nasal administration, trials have investigated topical retapamulin for S. aureus decolonization. A phase 1/2 study evaluated the safety and efficacy of retapamulin 1% ointment vs. placebo applied twice daily for 3 to 5 days to the nares in 57 healthy patients colonized with S. aureus. Eradication of S. aureus was achieved in 94% of those who received 3 days of treatment, compared with 92% of those in the 5-day treatment group. In contrast, only 15% of those in the placebo group tested negative for S. aureus. Rates of adverse events were similar between the groups. Most were not serious and included headache, sneezing and nose bleeding.

Retapamulin was compared with placebo for the eradication of MRSA nasal carriage among adult carriers with low-level and high-level mupirocin-resistant strains. Patients were randomly assigned to 1% retapamulin or placebo ointment intranasally twice daily for 5 days, and MRSA clearance was confirmed by follow-up nasal cultures a week after the completion of therapy. Patients who had positive follow-up cultures were given a second course of the same agent (retapamulin or placebo). All participants had a final nasal culture 6 weeks from completion of the initial treatment. Because of the low yield of mupirocin-resistant MRSA strains, recruitment was challenging in the trial. There were only 25 patients in each arm of the study. Retapamulin successfully decolonized 32%, whereas 15% of the placebo group were cleared of MRSA — not a statistically significant difference. Although it is encouraging that retapamulin may successfully clear mupirocin-resistant MRSA, more data are needed to determine its place in a decolonization strategy.

There are many other investigational agents that are being studied, such as tea tree oil, honey, lysostaphin, squalamine and phage therapy, to mention a few. Photodynamic therapy is another method that is being investigated, which involves the use of laser light in combination with light- activated chemicals, such as methylene blue. Although there are promising agents, mupirocin is still the leader in the field because of its ability to eradicate S. aureus in addition to the breadth of clinical data available for reducing SSIs. However, the rapid bactericidal activity of antiseptics such as alcohol and povidone-iodine are attractive options because of their reported tolerability and lack of resistance development. We need additional clinical data to further define their success in reducing SSIs. Because mupirocin resistance continues to increase worldwide, we will likely see additional trials with these agents, as well as studies of other novel agents in the future.

Disclosure: Brock reports no relevant financial disclosures.

Staphylococcus aureus nasal carriage is a proven risk factor for the development of staphylococcal surgical site infections, or SSIs. S. aureus infections are associated with increased length of hospital stays, increased mortality and higher costs of medical care. Nasal colonization rates with S. aureus have been reported to reach up to 30%, with 1% to 3% having methicillin-resistant organisms.

Nasal decolonization strategies have proven beneficial in reducing not only S. aureus colonization but also S. aureus SSIs. The most common nasal decolonization strategy is to administer mupirocin to the nares starting a few days before surgery. A consequence of mupirocin use, however, has been the development of mupirocin-resistant staphylococci. Because of concerns about resistance and whether patients can be relied upon to apply mupirocin before surgery, alternative approaches to nasal decolonization are being investigated.

Mupirocin

Topical mupirocin is the gold standard topical antibacterial agent for nasal decolonization. It is active against staphylococci, and many gram-negative organisms.

Jeff Brock

Mupirocin is generally well-tolerated, with most reported adverse effects relating to local irritation of the nasal mucosa such as burning, stinging and congestion.

To date, mupirocin is the most widely studied antimicrobial for nasal decolonization, with multiple studies showing its effectiveness in nasal decolonization and SSI prevention. The studies vary in their trial designs, patient populations and primary outcome measures. Meta-analyses of published studies have found that mupirocin decolonization decreases SSI rates among patients undergoing orthopedic surgery, cardiac surgery and neurosurgery. Additionally, a Cochrane Review meta-analysis concluded that, compared with placebo, intranasal mupirocin use was associated with a significant reduction in the rate of S. aureus SSIs (RR = 0.55, 95% CI, 0.43-0.7).

Povidone-iodine

Povidone-iodine is a complex of iodine with polyvinylpyrrolidone and has a long history of use as an antiseptic on skin, wounds and mucous membranes. It has a broad spectrum of activity against many gram-positive organisms, including methicillin-susceptible S. aureus and MRSA, as well as many gram-negative organisms. The use of iodine-based products may have some advantages over mupirocin, such as rapid bactericidal activity (within 10-20 seconds), and there is no evidence that bacteria can develop resistance to iodine. When used for nasal decolonization, povidone-iodine is administered in the nares just before surgery because of its rapid bactericidal activity, unlike mupirocin, which must be used twice a day for 5 days. Intranasal preparations of povidone-iodine are available from various manufacturers in concentrations of 5% or 10%.

A single-center, quasi-experimental study evaluated a preoperative decontamination protocol that included intranasal povidone-iodine to reduce SSIs in orthopedic patients undergoing elective surgery with hardware implantation. Patients used 2% chlorhexidine gluconate washcloths and oral rinse the night before and the morning of surgery, along with intranasal povidone-iodine solution administered to nares the morning of surgery only. The main outcome measure was 30-day infection rates. There were 709 patients — including 365 patients who underwent the decolonization protocol and 344 controls. The SSI rate was significantly lower in the decolonization group (1.1%) than in the control group (3.8%). Multivariate logistic regression analysis determined that MRSA decontamination was an independent predictor of not developing an infection. Although the outcomes were favorable, the study was limited by its single-center study design, as well as the fact that patient MRSA carrier status was not determined before and after decolonization, and that patients were followed for only 30 days.

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In another trial, mupirocin nasal formulation was administered twice daily for 5 days, compared with a 5% povidone- iodine solution administered within 2 hours of surgery for joint arthroplasty or spine fusion. The povidone-iodine product used in the study was specially formulated with a film-forming polymer that increases its adherence to the nasal mucosa, providing a more persistent bactericidal effect. Patients also used 2% chlorhexidine cloths to clean the body the night before and the day of surgery. In the intent-to-treat analysis, there was no significant difference in deep SSIs caused by any pathogen (14 vs. 6) or SSIs caused by S. aureus (5 vs. 1) during the 3-month follow up period. However, in the per-protocol analysis, S. aureus SSIs occurred after five of 763 procedures in the mupirocin group, whereas no infections developed after the 776 procedures in the povidone-iodine group (P = .03). Both agents were well-tolerated, but those in the mupirocin group were more likely to report headache, nasal symptoms and sore throat. A higher proportion of patients reported that mupirocin treatment applications were unpleasant compared with those who received povidone-iodine.

Alcohol

Alcohol’s antimicrobial activity is due to its ability to denature proteins. It has activity against a wide range of gram- positive and gram-negative bacteria, including multidrug-resistant pathogens like MRSA. Alcohol is rapidly bactericidal but has virtually no residual antibacterial effects after application. Compared with both mupirocin and povidone-iodine, there are fewer clinical data available using alcohol for nasal decolonization to reduce SSIs.

In a single-center, quasi-experimental intervention, intranasal alcohol was used in a nasal decolonization protocol to reduce staphylococcal SSIs in patients undergoing spine operations. The investigators combined the use of the alcohol-based nasal antiseptic with use of chlorhexidine bath or wipes in a pre- and post-surgical decolonization protocol. The nasal alcohol antiseptic was administered before entering the operating room. After surgery, the nasal decolonization was administered three times daily by staff in the post-surgical units until discharge, at which time the patient and family were instructed to continue applications for an additional 5 to 7 days. Records from 1,073 patients were reviewed, including 400 in the baseline pre-implementation group and 673 in the protocol group. During the 15-month trial, mean infection rates decreased by 81% ) from 1.76 to 0.33 per 100 surgeries. Self-reported compliance with the nasal alcohol application by patients was consistent, averaging 95% over the trial period; however, this was likely overstated because of self-reporting bias.

PAGE BREAK

Retapamulin

Retapamulin is a pleuromutilin antimicrobial agent that is available in a 1% topical ointment that has been FDA approved since 2007 for the treatment of impetigo due to S. aureus or Streptococcus pyogenes. Although it is not approved by the FDA for nasal administration, trials have investigated topical retapamulin for S. aureus decolonization. A phase 1/2 study evaluated the safety and efficacy of retapamulin 1% ointment vs. placebo applied twice daily for 3 to 5 days to the nares in 57 healthy patients colonized with S. aureus. Eradication of S. aureus was achieved in 94% of those who received 3 days of treatment, compared with 92% of those in the 5-day treatment group. In contrast, only 15% of those in the placebo group tested negative for S. aureus. Rates of adverse events were similar between the groups. Most were not serious and included headache, sneezing and nose bleeding.

Retapamulin was compared with placebo for the eradication of MRSA nasal carriage among adult carriers with low-level and high-level mupirocin-resistant strains. Patients were randomly assigned to 1% retapamulin or placebo ointment intranasally twice daily for 5 days, and MRSA clearance was confirmed by follow-up nasal cultures a week after the completion of therapy. Patients who had positive follow-up cultures were given a second course of the same agent (retapamulin or placebo). All participants had a final nasal culture 6 weeks from completion of the initial treatment. Because of the low yield of mupirocin-resistant MRSA strains, recruitment was challenging in the trial. There were only 25 patients in each arm of the study. Retapamulin successfully decolonized 32%, whereas 15% of the placebo group were cleared of MRSA — not a statistically significant difference. Although it is encouraging that retapamulin may successfully clear mupirocin-resistant MRSA, more data are needed to determine its place in a decolonization strategy.

There are many other investigational agents that are being studied, such as tea tree oil, honey, lysostaphin, squalamine and phage therapy, to mention a few. Photodynamic therapy is another method that is being investigated, which involves the use of laser light in combination with light- activated chemicals, such as methylene blue. Although there are promising agents, mupirocin is still the leader in the field because of its ability to eradicate S. aureus in addition to the breadth of clinical data available for reducing SSIs. However, the rapid bactericidal activity of antiseptics such as alcohol and povidone-iodine are attractive options because of their reported tolerability and lack of resistance development. We need additional clinical data to further define their success in reducing SSIs. Because mupirocin resistance continues to increase worldwide, we will likely see additional trials with these agents, as well as studies of other novel agents in the future.

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Disclosure: Brock reports no relevant financial disclosures.