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New antibiotics useful in primary careSHAWN SKERRETT, MD, Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington and Harborview Medical Center, Seattle.CHARLES STRATTON, MD, Associate Professor of Pathology and Medicine, Director, Microbiology Laboratory, Vanderbilt University Medical Center, Nashville, Tenn.Several antibiotics arrived on the market during the past year. Will you use them, or are they best saved for use in exceptional situations by tertiary care specialists?
Each year, the FDA approves a few new antimicrobial agents. Occasionally, one is quickly recognized as a potential blockbuster. More often, though, the new drugs are either similar to some already on the market, or they may occupy an important but narrow treatment niche. Methicillin-resistant Staphylococcus aureus (MRSA) infections, which were once acquired only in health care settings, are now widespread in communities across the nation. Vancomycin-resistant enterococci (VRE) are present in many tertiary care facilities. Investigators associated with a study of geographic and temporal trends in antibiotic resistance in Streptococcus pneumoniae predicted in 2003 that by July 1, 2004, 41% of the pneumococci at the CDC's Active Bacterial Core surveillance sites would be resistant to both penicillin and erythromycin.1 In contrast, they added, only 5% will be resistant just to penicillin, and another 5% would be resistant to erythromycin only.
The goal of this article is to update primary care clinicians about new antibiotics and their appropriate use. In addition, selected new antifungal and antiretroviral agents are discussed. ANTIBIOTICSSeveral recently approved or soon to be approved antibiotics may have a role in primary care practice, while others will probably find more use in tertiary care facilities. DaptomycinClass Cyclic lipopeptide Indication The treatment of complicated skin and skin-structure infections caused by susceptible strains of the following organisms: • S aureus (including methicillin-resistant strains) • Streptococcus pyogenes • Streptococcus agalactiae • Streptococcus dysgalactiae (subspecies equisimilis) • Enterococcus faecalis (vancomycin-susceptible strains only). Daptomycin can be used in combination regimens when infection with a gram-negative or anaerobic organism is either suspected or confirmed. This drug's action is rapidly bactericidal. Off-label or investigational use Daptomycin is active against VRE. Utility in primary care This parenteral agent is unlikely to be used widely in primary care practice, although it is one possible alternative for the treatment of patients with resistant, aerobic, gram-positive pathogens, including MRSA. It is approved only for skin and soft-tissue infections, and its application in the treatment of respiratory tract infections is very limited. Researchers are considering daptomycin as a possible alternative to vancomycin, linezolid, and the fluoroquinolones for the treatment of MRSA infections. It may also be useful in the treatment of VRE infections, especially if these become more widely disseminated in the community, as recently occurred in Michigan and Pennsylvania. At this time, specialists do not consider it more effective than linezolid or vancomycin. Although daptomycin is available only for administration via the parenteral route, it is administered once daily, making it possible to deliver it in an ambulatory care setting. Daptomycin is well-tolerated, although it has been associated with myopathy and myositis. While uncommon, these adverse reactions can be severe. Potential problems Dosing more than once a day may lead to elevations of creatine phosphokinase levels. Pseudomembranous colitis is a risk, as it is with all antibacterial agents. Creatine phosphokinase levels should be determined weekly in patients being treated with daptomycin. Assess patients for the development of muscle pain or weakness. Be aware that daptomycin has been confused with the similarly named anticancer agent dactinomycin. Further, the trade name of dactinomycin (Cosmegen) resembles the trade name of daptomycin (Cubicin). Dosage Administer 4 mg/kg over a 30-minute period by IV infusion in 0.9% sodium chloride injection once every 24 hours for 7 to 14 days. In adults with renal impairment characterized by a creatinine clearance of less than 30 mL/min (including patients who are undergoing hemodialysis or continuous ambulatory peritoneal dialysis), give 4 mg/kg once every 48 hours. ErtapenemClass Carbapenem Indication The treatment of adults with one of the following: • Complicated intra-abdominal infection due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis • Complicated skin and skin-structure infections caused by S aureus (methicillin-susceptible strains only), S pyogenes, E coli, or Peptococcus species • Community-acquired pneumonia (CAP) caused by S pneumoniae (penicillin-susceptible strains only), including cases with concomitant bacteremia, Haemophilus influenzae (beta-lactamase-negative strains only), or Moraxella catarrhalis • Complicated urinary tract infections, including pyelonephritis due to E coli, including cases with bacteremia, or Klebsiella pneumoniae • Acute pelvic infections, including postpartum endomyometritis, septic abortion, and postsurgical gynecologic infections caused by S agalactiae, E coli, B fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species, or Prevotella bivia. Utility in primary care Ertapenem has a narrower spectrum of activity than other carbapenems, which may be an advantage in some clinical situations. It is not active against Acinetobacter or Pseudomonas species, but it is very effective against other gram-negative, gram-positive, and anaerobic organisms. Some experts think of ertapenem as a combination of ceftriaxone and metronidazole. It has excellent activity against enteric organisms and is administered once a day. Ertapenem is an appropriate choice in a situation in which you might otherwise use ceftriaxone, but would like to include coverage against anaerobes—for example, a patient admitted for treatment of pneumonia but at risk of aspiration because a seizure disorder, drug overdose, or alcohol abuse. Ertapenem is less expensive than meropenem or imipenem. Daily dosing makes it convenient for treating patients with pneumonia who reside in long term care facilities. Ertapenem can be administered parenterally to patients in the emergency department (ED) and then continued at a long term care facility.2 High-dose ampicillin/sulbactam might be an alternative in this setting, but it must be administered several times a day. Very-broad-spectrum antibiotics such as piperacillin/tazobactam, ticarcillin/clavulanate, imipenem, or meropenem are often prescribed for patients with very severe pneumonia. These agents are more expensive than ertapenem. More important, however, the antipseudomonal activity of these drugs is usually unnecessary in this clinical setting and may contribute to resistance among gram-negative organisms. Potential problems It may be prudent to monitor renal function in elderly patients, as ertapenem is excreted largely by the kidney. As with most antibiotics, pseudomembranous colitis has been reported in association with ertapenem use. Dosage 1 g either given once daily for up to 7 days IM or up to 14 days IV. GemifloxacinClass Fluoroquinolone Indication For the treatment of acute bacterial exacerbation of chronic bronchitis (AECB) caused by S pneumoniae, H influenzae, Haemophilus parainfluenzae, or M catarrhalis and mild to moderate CAP caused by S pneumoniae (including multidrug resistant strains of pneumonia [MDRSP]), H influenzae, M catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or K pneumoniae. Note that MDRSP refers to S pneumoniae strains that are resistant to at least 2 of the following drugs or drug classes: penicillin, second-generation cephalosporins, macrolides, tetracyclines, and trimethoprim/sulfamethoxazole (TMP-SMX). Off-label or investigational use Gemifloxacin is active against some Enterobacteriaceae. In addition, it exhibits in vitro minimal inhibitory concentrations (MICs) of 0.25 mcg/mL or less against at least 90% of strains of 2 gram-positive organisms—S aureus and S pyogenes—and several gram-negative ones, including Legionella pneumophila and Proteus vulgaris. The clinical significance of these in vitro data is unclear. Utility in primary care Gemifloxacin has been available in other countries for several years. Its strong activity against gram-positive bacteria, most importantly S pneumoniae and S aureus, distinguishes it from other fluoroquinolones.3,4 Otherwise, its spectrum of activity is quite similar to those of levofloxacin, gatifloxacin, and moxifloxacin. Unlike ofloxacin, levofloxacin, and ciprofloxacin, however, gemifloxacin is not active against mycobacteria. This is not a common use for these drugs, however. Gemifloxacin is not as useful as ciprofloxacin or levofloxacin against Pseudomonas aeruginosa, a factor which may limit its usefulness in patients with cystic fibrosis. The blood levels of gemifloxacin are lower than those achieved by moxifloxacin and levofloxacin, and its half-life is shorter. Nonetheless, its in vitro antipneumococcal activity is excellent and is estimated to be 4 times that of moxifloxacin and 10 to 100 times that of levofloxacin. Whether these in vitro differences are clinically important is unclear, however. Pneumococcal resistance to levofloxacin has been reported in Canada, and some resistance has been seen in the United States, and treatment failures have also been reported with ciprofloxacin. Gemifloxacin could be a treatment option in this situation. Experts in this field recommend considering gemifloxacin if you suspect drug-resistant pneumococcal infection because of a documented resistant isolate, or because the patient is vulnerable as a result of frequent antibiotic use or recent or frequent hospital stays. Overuse of gemifloxacin could render it less useful, however, so specialists caution against prescribing without a good reason. Also consider that levofloxacin is inexpensive and well-tolerated. Gemifloxacin is expected to be an excellent choice for patients with CAP and AECB, but it may not be any more effective than some other fluoroquinolones or antibiotics in other classes. Gemifloxacin may ultimately be extremely useful in patients with MRSA, and a certain percentage of MRSA isolates are sensitive to fluoroquinolones. Until recently, MRSA was not considered a risk in community-acquired infections and nafcillin, for example, could be safely used in a patient with endocarditis and a history of IV drug use. It is no longer safe to make this assumption. Community acquired MRSA infections, especially skin and soft-tissue infections, are increasing in prevalence. In fact, infectious disease specialists often recommend that when a patient is hospitalized with a staphylococcal infection, even if it was acquired in the community, that it be treated with an agent that is active against MRSA. Risk factors for MRSA include frequent contact with EDs, hospitals, and frequent use of antibiotics. While this is true nationwide, there are geographic differences in the prevalence of community-acquired MRSA. The Houston, Tex, area, for example, has very high rates of community-acquired MRSA. Some of the newer fluoroquinolones are active against anaerobes, organisms which are cause for concern among patients with CAP who may have aspirated oropharyngeal secretions. Moxifloxacin has shown good in vitro activity against anaerobes, but no studies have demonstrated its clinical efficacy against anaerobic infections. Gemifloxacin is less likely to be useful in this situation. Potential problems Overuse of gemifloxacin is a possibility. It is considerably more expensive than levofloxacin, however, which should reduce the amount of overprescribing. Side effects may include diarrhea, rash, and nausea. The incidence of rash is 2.8% but ranges from 1% to 32%, so this drug should not be considered for first-line treatment. As with many fluoroquinolones, there can be prolongation of the QTc interval. Dosage AECB, 320 mg/d for 5 days; CAP, 320 mg/d for 7 days LinezolidClass Oxazolidinones Indications Treatment of patients with • Vancomycin-resistant Enterococcus faecium infections, with or without concomitant bacteremia • Nosocomial pneumonia caused by S aureus (methicillin-resistant and -susceptible strains) or S pneumoniae (penicillin-susceptible strains only) • Complicated skin and skin-structure infections, including diabetic foot infections without concomitant osteomyelitis caused by S aureus (methicillin-resistant and methicillin-susceptible strains), S pyogenes, or S agalactiae • Uncomplicated skin and skin-structure infections cause by S pyogenes or methicillin-susceptible strains of S aureus • CAP caused by methicillin-susceptible strains of S aureus or penicillin-susceptible strains of S pneumoniae, including patients with concomitant bacteremia. Combination therapy may be required if infection with a gram-negative organism is suspected. Off-label or investigational use Linezolid has not been tested in patients with decubitus ulcers but could be useful in that situation. Utility in primary care Linezolid is available for oral and parenteral administration, which facilitates the transition from inpatient to outpatient care. This valuable agent is active against gram-positive organisms, as well as VRE and MRSA.5,6 The use of linezolid has been restricted at some institutions because the drug has been prescribed as a first-line agent for the treatment of patients with staphylococcal infections when the presence of MRSA was possible, but not confirmed. Linezolid is also considerably more expensive than alternative agents, including vancomycin. Accumulated evidence from large clinical studies comparing vancomycin and linezolid in patients with MRSA infections have shown little difference in efficacy. Hospital-acquired pneumonia caused by MRSA seems to be an exception, however, with linezolid producing a better outcome and lower mortality than does vancomycin.7 These data were derived from a subgroup analysis, however, so specialists would like to see the findings replicated elsewhere. For other forms of suspected MRSA infection, vancomycin is still used in most institutions as first-line treatment. Once MRSA is confirmed and the patient is ready for discharge, therapy can continue with linezolid, with its predictable activity against MRSA. Note, however, that the newer fluoroquinolones with good activity against gram-positive organisms, such as gemifloxacin, moxifloxacin, and gatifloxacin, as well as TMP-SMX, may also be effective alternates for oral therapy and are less expensive than linezolid. The microbiological data are crucial in MRSA infections, however. Do not use a fluoroquinolone or TMP-SMX to treat MRSA until the antibiotic sensitivities of the organism are confirmed. In most situations, of course, confirmation of MRSA and the sensitivity data become available at the same time. The bottom line: If the infection is life-threatening, use vancomycin or linezolid. For skin or soft-tissue infections that can be treated orally, consider another antibiotic. Potential problems To prevent the development of resistance to linezolid, experts in this field urge clinicians to avoid using it to treat methicillin-sensitive staphylococcal infections or enterococcus infections that are sensitive to other antibiotics. Severe rashes and lactic acidosis have been reported in patients taking linezolid. Thrombocytopenia is a serious concern in patients treated for 10 to 14 days. Dosage 600 mg IV or po, q12h for 10 to 14 days (adult) TelithromycinClass Ketolide Indication The manufacturer is seeking FDA approval for telithromycin for the treatment of CAP, AECB, and acute bacterial sinusitis. Utility in primary care Ketolides are the latest structural derivatives of erythromycin to be added to the macrolide family. This oral agent was developed to help manage the problem of macrolide resistance in the pneumococcus and multidrug-resistant gram-positive bacteria in general, and it may become a first-line agent for that purpose, at least in areas like Tennessee, where pneumococcal resistance to macrolides approaches 30%. Telithromycin is active against S pneumoniae, H influenzae, M catarrhalis, and S pyogenes. In addition, it is active against some atypical respiratory pathogens, including C pneumoniae, L pneumophila, and M pneumoniae.8 Telithromycin can be taken without regard for meals and requires no dosage reduction in elderly patients or those with hepatic impairment. It is well-absorbed after oral administration and achieves rapid penetration into respiratory tissues and fluids. Potential problems The most common adverse effects associated with telithromycin, which has been available in Europe and Latin America for several years, include diarrhea, nausea, headache, and dizziness. Prolongation of the QTc interval is a possibility and the drug interacts with ketoconazole and itraconazole and is a statin inhibitor. Dosage 800 mg once daily for 5 to 10 days ANTIFUNGALSTwo new antifungal agents have been approved during the past 2 years. One adds to the number of drugs already available to treat athlete's foot. The other is considered a significant advance against invasive aspergillosis. SertaconazoleClass Imidazole Indication Topical treatment of interdigital tinea pedis caused by Trichophyton rubrum Trichophyton mentagrophytes, and Epidermophyton floccosum in immunocompetent patients aged 12 and older. Off-label or investigational use Sertaconazole may also be active against most of the yeast species that cause vulvovaginal candidiasis.9 Potential problems Reactions at the application site include burning, dermatitis, dry skin, and skin tenderness. Hyperpigmentation, desquamation, and vesiculation have also been reported. Utility in primary care This agent may be a useful addition to the medications available to treat athlete's foot. Dosage Apply twice daily for 4 weeks. Review the diagnosis if no improvement is evident after 2 weeks of use. VoriconazoleClass Triazole antifungals Indication Voriconazole is indicated for the treatment of invasive aspergillosis, which is usually caused by Aspergillus fumigatus, and serious fungal infections caused by Scedosporium apiospermum, and Fusarium species, including Fusarium solani, in patients who are intolerant of other agents or whose infections are refractory to other treatments. Off-label or investigational use Voriconazole is active in vitro against all yeast species, as well as Cryptococcus and Blastomyces species, among others. Clinical efficacy data are lacking, however. True fungi that are resistant to other therapies may be susceptible to voriconazole. In addition to invasive aspergillosis, voriconazole is also effective in other forms of this infection, including chronic necrotizing aspergillosis, an indolent, uncommon infection that occurs in patients with chronic obstructive pulmonary disease. Voriconazole may also be beneficial in patients with allergic bronchopulmonary aspergillosis, a hypersensitivity disorder that may occur in patients with asthma. Until now, this condition has been treated with corticosteroids only. A recent Cochrane Database System review of 3 prospective studies enrolling 94 patients suggests a benefit from adding itraconazole to the corticosteroid regimen.10 Voriconazole is more active than itraconazole against this pathogen, so specialists hope that a definitive study will be conducted. Utility in primary care Voriconazole is more effective than amphotericin B for invasive aspergillosis.11 In addition, the drug is significantly better tolerated than amphotericin B. Infectious disease specialists consider it a significant advance in the treatment of aspergillosis. This infection remains a considerable challenge however, as response rates still hover around 50%. Voriconazole is available for oral and parenteral administration. Note that voriconazole is not effective in patients with mucormycosis, a severe complication of diabetes sometimes seen in primary care. Potential problems Visual disturbances have occurred in as many as 40% of patients treated with voriconazole in clinical trials.11 Visual acuity, visual field, and color perception should be monitored if therapy continues for more than 28 days. Visual defects that develop during treatment do not require treatment discontinuation, and they resolve when therapy is concluded. Voriconazole should be used with caution in conjunction with rifampin, phenytoin, or other activators of the cytochrome P-450 enzyme system.12 Dosage adjustments, as described in the prescribing information, may be necessary. Rashes, fever, and GI disturbances have been reported in conjunction with voriconazole treatment. Dosage Loading dose of 6 mg/kg, IV, q12h, for 2 doses following by a maintenance dosage of 4 mg/kg, IV, q12h. The oral maintenance dosage for patients weighing more 40 kg or more is 200 mg, q12h. Adults weighing less than 40 kg get 100 mg, q12h. ANTIRETROVIRAL AGENTSFour new antiretroviral agents were approved in 2003: atazanavir, emtricitabine, enfuvirtide, and fosamprenavir. Each one is approved only for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Enfuvirtide is to be used only in treatment-experienced patients who have evidence of HIV-1 replication despite ongoing antiretroviral therapy. Emtricitabine is a reverse transcriptase inhibitor, while atazanavir and fosamprenavir are protease inhibitors. Enfuvirtide works by preventing the fusion of HIV-1 with CD4+ cells. It is a member of a new class of anti-HIV drugs, the first in 7 years. The cost of a year's supply of enfuvirtide is estimated by the American Foundation for AIDS Research (AmFAR) at $20,000. Atazanavir, emtricitabine, and fosamprenavir are noteworthy because they are taken once or, in the case of fosamprenavir, twice daily. According to AmFAR, this is a major advantage for patients with HIV infection, who often must take large numbers of pills daily to combat either HIV itself and/or opportunistic infections. The availability of antiretroviral agents that can be taken once or twice daily, especially drugs that are taken only in conjunction with other antiretrovirals, may make it easier for patients to adhere to these complex regimens. AIDS treatment recommendations are modified frequently. Although treatment of HIV infections is often conducted by specialists in conjunction with primary care practitioners, you may find it convenient to stay current with these developments. The AIDSinfo Web site, which is maintained by the US Department of Health and Human Services, is available at http://aidsinfo.nih.gov . More than 20 antiretroviral agents are now available in the United States, and many possible combination regimens exist.13 REFERENCES 1. McCormick AW, Whitney CG, Farley MM, et al. Geographic diversity and temporal trends of antimicrobial resistance in Streptococcus pneumoniae in the United States. Nat Med. 2003;9:424-430. Epub 2003 March 10. 2. Woods GL, Isaacs RD, McCarroll KA, et al. Ertapenem therapy for community-acquired pneumonia in the elderly. J Am Geriatr Soc. 2003;51:1526-1532. 3. Jorgensen JH, Weigel LM, Swenson JM, et al. Activities of clinafloxacin, gatifloxacin, gemifloxacin, and trovafloxacin against recent clinical isolates of levofloxacin-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother. 2000;44:2962-2968. 4. Blondeau JM, Hansen G, Metzler KL, et al. In vitro susceptibility of 4903 bacterial isolates to gemifloxacin—an advanced fluoroquinolone. Int J Antimicrob Agents. 2003;22:147-154. 5. Stevens DL, Herr D, Lampiris H, et al, and the Linezolid MRSA Study Group. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis. 2002;34:1481-1490. 6. Kaplan SL, Deville JG, Yogev R, et al, and the Linezolid Pediatric Study Group. Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children. Pediatr Infect Dis J. 2003;22:677-685. 7. Wunderink RG, Rello J, Cammarata SK, et al. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest. 2003;124:1789-1797. 8. Yassin HM, Dever LL. Telithromycin: a new ketolide antimicrobial for treatment of respiratory tract infections. Expert Opin Investig Drugs. 2001;10:353-367. 9. Palacin C, Tarrago C, Agut J, et al. In vitro activity of sertaconazole, fluconazole, ketoconazole, fenticonazole, clotrimazole and itraconazole against pathogenic vaginal yeast isolates. Methods Find Exp Clin Pharmacol. 2001;23:61-64. 10. Wark PA, Gibson PG, Wilson AJ. Azoles for allergic bronchopulmonary aspergillosis associated with asthma. Cochrane Database Syst Rev. 2003;(3):CD001108. 11. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408-415. 12. Purkins L, Wood N, Ghahramani P, et al. Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. Br J Clin Pharmacol. 2003;56(suppl 1):37-44. 13. Panel on Clinical Practices for Treatment of HIV Infection, Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. November 10, 2003. Available at http://www.aidsinfo.nih.gov/ guidelines/adult%5CAA_111003.html. Accessed February 21, 2004. 12 steps to prevent antimicrobial resistance in hospitalized patientsProlonging the usefulness of new and older antibiotics should be a goal of every health care provider. Many antibiotic resistance problems originate in hospitals and other health care facilities. The CDC offers the following 12 steps as a means of preventing the development of resistance in hospitalized patients. Most of these points have application in office practice, as well. PREVENT INFECTION Step 1: Vaccinate • Give influenza and pneumococcal vaccines to at-risk patients before discharge. • Get your own influenza vaccine every year. Step 2: Get the catheters out • Use catheters only when essential. • Use the correct catheter. • Use proper insertion and catheter-care protocols. • Remove catheters when they are no longer essential. DIAGNOSE AND TREAT INFECTION EFFECTIVELY Step 3: Target the pathogen • Culture the patient. • Target empiric therapy to likely pathogens and local antibiogram. • Target definitive therapy to known pathogens and antimicrobial susceptibility test results. Step 4: Access the experts • Consult infectious diseases experts for patients with serious infections. USE ANTIMICROBIALS WISELY Step 5: Practice antimicrobial control • Engage in local antimicrobial control efforts. Step 6: Use local data • Know your antibiogram. • Know your patient population. Step 7: Treat infection, not contamination • Use proper antisepsis for blood and other cultures. • Culture the blood, not the skin or catheter hub. • Use proper methods to obtain and process all cultures. Step 8: Treat infection, not colonization • Treat pneumonia, not the tracheal aspirate. • Treat bacteremia, not the catheter tip or hub. • Treat urinary tract infection, not the indwelling catheter. Step 9: Know when to say No • Treat infection, not contaminants or colonization. • Fever in a patient with an intravenous catheter is not a routine indication for vancomycin. Step 10: Stop antimicrobial treatment • When infection is cured • When cultures are negative and infection is unlikely • When infection is not diagnosed. PREVENT TRANSMISSION Step 11: Isolate the pathogen • Use standard infection control precautions. • Contain infectious body fluids. (Follow airborne, droplet, and contact precautions.) • When in doubt, consult infection-control experts. Step 12: Break the chain of contagion • Stay home when you are sick. • Keep your hands clean. • Set an example. Source: CDC. Campaign to prevent antimicrobial resistance in healthcare settings. Available at: http://www.cdc.gov/drugresistance/healthcare/ha/12steps_HA.htm . Accessed February 21, 2004.
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