Gram positives

What is the impact of Gram positives on health care-associated infections?

Studies have shown that many infections due to Gram-positive cocci (GPC) are often preceded by a variable period of colonization or carrier status. Although decolonizing patients with antibiotics or chemical antiseptics could theoretically reduce the incidence of subsequent infections due to GPC, decolonization is not generally or routinely recommended because of several reasons: inconsistent results from efficacy studies, high rate of re-colonization, lack of a standard regimen for decolonization and increasing reports and concerns of selecting resistant mutants. Thus, prophylaxis with antimicrobial agents is restricted to very limited scenarios: (1). as short-term intervention to abate recurrent methicillin-resistant S. aureus (MRSA) infections or to limit transmission of MRSA among close contacts in an outbreak setting, and (2). as non-selective decontamination of skin surfaces, prior to high-risk surgical procedures and procedures involving implants.

Decolonization for vancomycin-resistant enterococci (VRE) and other GPCs with various antimicrobial agents have been studied; however, none has been shown to be and is not recommended. Moreover, once acquired, intestinal colonization by VRE is believed to persist for many years.

Although there are several candidates under study, there are currently no vaccines that can effectively prevent colonization or infection associated with MRSA or other GPCs.

Which are the common antibiotics (or vaccines) used to prevent and control the infections, and what are key distinguishing features?

Many antibiotics and antimicrobial agents have been studied for prevention and control of healthcare-associated infections due to gram-positive organisms. Three common agents have been studied in monotherapy or in combination therapy for decolonization of MRSA and for prevention of nosocomial infections as shown below.

2% mupirocin

This is the only existing drug that is approved by the United States Food and Drug Administration (FDA) as an intra-nasal ointment for short-term decolonization of MRSA in selected patients. Mupirocin is an antibiotic with narrow-spectrum of activity against gram-positive organisms. Resistance is conferred by the MupAgene and is increasingly reported.

Intra-nasal mupirocin has been used alone and in combination with other antimicrobial agents in numerous studies to reduce the rate of staphylococcal colonization and infection. A systematic review of randomized control trials showed that 2% mupirocin could effectively reduce the overall incidence of staphylococcal infections (e.g., bloodstream infections, catheter-exit site infections, dialysis-related peritonitis, pneumonias, and skin and soft-tissue infections) among high-risk patients (relative risk 0.55; 95% CI: 0.43-0.70). Interestingly, a subgroup analysis among surgical patients showed that mupirocin was not associated with a statistically significant reduction of staphylococcal surgical site infections (RR 0.63; 95% CI 0.38-1.04), though this observation was most likely attributed to low statistical power of the subgroup analysis.

Chlorhexidine gluconate

This is an effective disinfectant against gram-positive and gram-negative bacteria. It is available in aqueous solution, and in combination with alcohol, and in different concentrations (0.5%-4%) and formulations. It is has been used as prophylaxis against infections (including those due to GPCs) by topical application as a body wash, as a nasal ointment and in the form of a mouth rinse. For example, a study from the Netherlands showed that prophylactic application of chlorhexidine gluconate to the nose, oropharynx and the body effectively reduced the rate of nosocomial infections among patients admitted to the hospital and intensive care unit.

Second, chlorhexidine has also been shown to reduce the rates of surgical site infections, such as following orthopedic procedures, when used as a body wash in the days leading up to surgery. Finally, chlorhexidine washes have been used in combination with intra-nasal (usually mupirocin) and systemic antibiotic therapy for short-term decolonization of Staphylococcus aureus (especially MRSA).

Rifampin

This is is an oral antibiotic with high bioavailability. Short course rifampin therapy has been effectively used in combination with topical antimicrobial agents for decolonization of MRSA in patients with recurrent disease. Rifampin-based regimens tend to have higher rates of decolonization and longer time to re-colonization.

Other agents

Other agents that are less frequently used for decolonization and prevention of staphylococcal infections include hexachlorophene, triclosan, trimethoprim-sulfamethoxazole (TMP/SMX), clindamycin and minocycline/doxycycline.

A summary of the available agents and the many features that distinguish each, including efficacy and safety.

Labeled indication

Mupirocin:

• An antibiotic against many gram-positive organisms

• Currently, the only FDA approved drug for decolonization of staphylococcus aureus in the nose

• Increasing reports of resistance that is mediated via MupA genes

Off-label use of antibiotics

Rifampin

• Systemic antibiotic that is used for treatment of mycobacterial infections and for decolonization of Staphylococcus aureus and Neisseria meningitidis

• Effective for short-term decolonization of MRSA when used in combination with topical agents such as nasal mupirocin and chlorhexidine body washes

• Decolonization with rifampin-based regimens appears to have higher probability have maintaining negative MRSA culture than other regimens

• Causes orange tinge to body fluids and contact lenses

• Metabolized by and induces the cytochrome P450 hepatic pathway

• Resistance is mediated by a single amino-acid change and emerges readily

Minocycline/doxycycline

• Binds the 30S subunit of bacterial ribosome

• Can be used as an adjunct agent for decolonization for MRSA

• In a study of combination therapy including doxycycline, rifampin, mupirocin, and chlorhexidine, investigators were able to achieve MRSA decolonization for up to 3 months

• Teratogenic and should not be used in children under 8

Trimethoprim-sulfamethoxazole

• Oral anti-folate antibiotic

• Is a highly effective treatment for most staphylococcal infections

• The current prevalence of trimethoprim-sulfamethoxazole resistance among S. aureus isolates is less than 5%

• Has been found to be as effective as mupirocin for decolonization of MRSA when used in combination with fusidic acid

Clindamycin

• Antibiotic with high bioavailability and activity against many gram-positive organisms and anaerobes

• Has been used as second line therapy for decolonization of susceptible MRSA isolates when first line agents or combination therapy failed

Topical antiseptic agents

Chlorhexidine

• General disinfectant that is effective against gram-positive and gram-negative organisms

• Is available in aqueous form and in combination with alcohol

• Has been widely used as hand sanitizer, pre-operative skin scrub, skin antiseptic prior to venepuncture

• Is commonly used as body wash in combination with nasal mupirocin and a systemic antibiotic for transient decolonization of MRSA

• Resistance is increasingly reported; mediated via qac genes

• Not indicated for application on face, genitalia, and in neonates

Hexachlorophene

• Antiseptic agent that is related to triclosan

• Occasionally used for decolonization

• Active residue on skin is removed by alcohol

• Toxicity can cause CNS irritability and seizures

Triclosan

• A bis-phenol antiseptic with broad-spectrum of activity

• Occasionally used for topical decolonization of MRSA

• Has been used in combination with other interventions to contain outbreaks of MRSA infections

• Exposure to triclosan has been shown to induce small colony variants of MRSA which are resistant to triclosan

A summary of the available agents, including PK/PD data, dosing information for prevention versus treatment, drug-drug interactions, and adverse reactions.

See Table I for information about topical agents.

See Table II for information about oral and parenteral agents.

Drugs currently in development, and what is known about them.

Staphylococcus aureus vaccine V710

This is a recombinant and adjuvanted vaccine of highly-conserved surface-exposed proteins expressed on community-associated and hospital-acquired strains isolates of S. aureus. Animal studies showed development of potentially protective immune response. Subsequent Phase I studies showed that the vaccine was well-tolerated among the 124 volunteers and was able to generate positive antibody responses in approximately 80% of subjects within 14 days.

A phase II/III study began in 2007 to evaluate the efficacy, immunogenicity and safety of the V710 vaccine among adult patients scheduled for cardiothoracic surgical procedures. The primary outcome measures were incidence of S. aureus-related bacteremia and deep wound infection. On June 2011, the manufacturer of the vaccine announced a surprise termination of the study following pre-planned data analysis citing concerns over low likelihood of the study demonstrating clinical benefit and the finding of higher rates of mortality and multi-organ dysfunction among vaccine recipients. The fate of the V710 vaccine project is currently unknown.

Retapamulin

Retapamulin belongs to a new class of antibiotics, the pleuromutilins, and it has received FDA-approval as a topical agent for treatment of impetigo at dosing frequency of twice a day for 5 days. It is exerts its bactericidal effect via interactions with the 50S subunit of the bacterial ribosome. Studies are underway to determine its efficacy for decolonization of MRSA. Retapamulin has been associated with headache, sneezing, nosebleed and skin hypersensitivity when used intranasally.

Lysostaphin

Lysostaphin is an endopeptidase produced by Staphylococcus simulans which works by cleavage of the polyglycine interpeptide bridges of staphylococcal cell walls. It has high in vitro activity against MSSA and MRSA. Early studies conducted in animals have shown effective eradication of mupirocin-resistant SA from the nares of animals. The current status of Lysostaphin remains unclear.

Ramoplanin

Ramoplanin is an intestinal antibiotic that has been studied for its ability to treat C. difficile infection and the potential to eradicate VRE colonization. Ramoplanin is not absorbed following ingestion and comes from a new class of antibiotics known as glycolipodepsipeptides which inhibit cell wall synthesis independently of the D-Ala-D-Ala site that is targeted by glycopeptides. A Phase II study that determined the tolerability and efficacy of ramoplanin showed that significantly more patients who took ramoplanin had become VRE-free by day 7 compared to controls. However, three weeks after cessation of therapy, patients who took ramoplanin were found to have the same level of VRE colonization as controls; thus, the duration of VRE decolonization was short-lived.

Ramoplanin is no longer being studied or used for VRE colonization. Instead, studies have shown its efficacy and potential for the treatment of C. difficile infections.

What are the controversies surrounding the key agents, if any, and what are the pros and cons for each drug?

Rifampin

Rifampin alone or in combination with another drug (e.g., trimethoprim/sulfamethoxazole) has been used to eradicate nasal carriage of S. aureus, including methicillin-resistant strains (MRSA). However, acquired resistance to rifampin occurs rapidly when it is used as monotherapy and often develops by mutations in the gene (rpoB) encoding the beta subunit of DNA-dependent RNA polymerase. Additionally, resistance can be mediated by alterations in membrane permeability. Thus, rifampin should never used as monotherapy for treatment or decolonization of MRSA.

Mupirocin resistance

Mupirocin resistance is increasingly reported among isolates of MRSA. Many experts suspect that inappropriate use of mupirocin is causally related to the increase of resistant mutants. A recent study found that low-level mupirocin resistance together with genotypic resistance to chlorhexidine significantly increases the risk of persistent MRSA carriage even after attempts at decolonizing therapy.

Are there specific guidelines for the use of some or all of these agents?

In 2011, the Infectious Diseases Society of America published its latest clinical practice guidelines on the treatment and prevention of MRSA infections. The guidelines suggested that antimicrobial prophylaxis or decolonization should be restricted to patients with recurrent staphylococcal infections despite conservative measures to improve personal and skin hygiene. The relevant excerpt for MRSA decolonization is below.

Decolonization may be considered in selected cases if:

• A patient develops a recurrent SSTI despite optimizing wound care and hygiene measures.

• Ongoing transmission is occurring among household members or other close contacts despite optimizing wound care and hygiene measures.

Decolonization strategies should be offered in conjunction with ongoing reinforcement of hygiene measures and may include the following: 

• Nasal decolonization with mupirocin twice daily for 5–10 days

• Nasal decolonization with mupirocin twice daily for 5–10 days and topical body decolonization regimens with a skin antiseptic solution (eg, chlorhexidine) for 5–14 days or dilute bleach baths. (For dilute bleach baths, 1 teaspoon per gallon of water [or ¼ cup per ¼ tub or 13 gallons of water] given for 15 min twice weekly for approximately 3 months can be considered.)

Oral antimicrobial therapy is recommended for the treatment of active infection only and is not routinely recommended for decolonization. An oral agent in combination with rifampin, if the strain is susceptible, may be considered for decolonization if infections recur despite above measures.

In cases where household or interpersonal transmission is suspected:

• Personal and environmental hygiene measures in the patient and contacts are recommended 

• Contacts should be evaluated for evidence of S. aureus infection:

• Symptomatic contacts should be evaluated and treated; nasal and topical body decolonization strategies may be considered following treatment of active infection.

• Nasal and topical body decolonization of asymptomatic household contacts may be considered.

The role of cultures in the management of patients with recurrent SSTI is limited:

• Screening cultures prior to decolonization are not routinely recommended if at least 1 of the prior infections was documented as due to MRSA.

• Surveillance cultures following a decolonization regimen are not routinely recommended in the absence of an active infection.

Efforts to decolonize and prevent VRE are not effective and are not recommended.

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