Resistant Gram-negative Bacteria

Introduction Antibiotic-resistant bacteria aren t new. But gram-negative bacteria, like Enterobacteriaceae, are becoming more resistant to our last-line antibiotics. Some people are calling these bacteria superbugs because they have supergenes. One of the more recent resistant strains is referred to as NDM-1, or New Delhi metallo-betalactamase-1. But extended-spectrum betalactamase (ESBL)-producing Enterobacteriaceae and multidrug resistant Pseudomonas are even more common. 1,2 This article reviews gramnegative bacterial resistance and treatment options. It also describes methods to prevent health care-associated infections. Mechanisms for Resistance Bacterial resistance to antibiotics occurred soon after penicillin became widely used. 3 And resistance has increased since then. In 2004, U.S. resistance rates were just over 50% in ICU and about 30% in non-icu isolates for Pseudomonas aeruginosa. 1 Beta-lactam drugs, such as penicillins and cephalosporins, work in different ways to kill gram-negative bacteria. However, these bacteria have adapted and evolved to become resistant. Decreased permeability. Gram-negative bacteria have an outer membrane which is compromised during drug entry. Gram-negative bacteria resist antibiotics by decreasing the permeability of this membrane. This means that less drug crosses the membrane into the bacteria. 4 Gram-negative bacteria will also use a pump to remove any drugs that penetrate the membrane. 4 Enzyme production. Gram-negative Enterobacteriaceae like Klebsiella and Escherichia are evolving to combat antibiotics. They produce enzymes to break down the broadspectrum beta-lactams. They also produce enzymes to break down many antibiotics that have historically been used last-line. PL Detail-Document #270713 This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER July 2011 Resistant Gram-negative Bacteria Extended-spectrum beta-lactamase-producing Enterobacteriaceae have been inactivating the extended spectrum beta-lactams like aztreonam (Azactam) and third-generation cephalosporins since the 1980 s. 4 These bacteria are also frequently resistant to aminoglycosides and quinolones. 4 Resistance rates exceed 10% in some areas. 2 The threat of these bacteria has increased the use of carbapenem drugs since they usually aren t affected by extended-spectrum beta-lactamases. But gram-negative bacteria evolved again. They began producing carbapenemases (carbapenemhydrolyzing beta-lactamase). The carbapenemases inactivate carbapenems (Primaxin, etc). 5 Carbapenemase-producing bacteria also resist extended spectrum betalactams, quinolones, and aminoglycosides. 4 This leaves very few treatment options for diseases frequently treated with carbapenems. These include diseases such as sepsis of unknown origin, hospital-acquired pneumonia, and bacterial meningitis. The most common of these enzymes is Klebsiella pneumoniae carbapenemase, or KPC. 4 These enzymes aren t limited to Klebsiella. They are also in E. coli and P. aeruginosa and are found throughout the U.S. and Canada. 4 NDM-1 (New Delhi metallo-beta-lactamase-1) is one of the latest identified carbapenemase-producing bacteria. NDM-1 infections have only been seen in the past few years. As of June 2011, there s been about 250 cases worldwide from 2008 to 2010. 6 And only seven of these have been reported in the U.S. and Canada. 6,7 Genetic changes. In addition to the production of enzymes, gram-negative bacteria have undergone genetic mutations. 4 Some have developed resistant genes. The resistance genes are often found in plasmids. Plasmids are very easily transferred between bacteria and allow resistance to spread rapidly. 2,3 NDM-1 is an example of a gram-negative bacteria that has

undergone genetic mutation. 4 NDM-1 can also be transmitted by asymptomatic carriers. 4,7 This bacterial evolution and mutation have resulted in multi-drug resistance, which is a growing public health concern. Identifying Susceptible Patients All patients are susceptible to resistant organisms. However, certain patient populations are more likely to harbor resistant bacteria. Suspect resistance to extended-spectrum betalactams in the following groups. Patients with previous antibiotic use, especially long term use of broad-spectrum antibiotics. This is specifically a concern in patients who ve had recent use of third-generation cephalosporins (ceftriaxone, ceftazidime, etc) or quinolones. 2 Institutionalized patients have a higher risk of multi-drug resistance. This is especially seen in intensive care units. Keep in mind that patients in other areas of the hospital are also susceptible. Patients in long term care facilities and those transferring between institutions are also at risk. 2 Patients with indwelling devices, such as catheters and endotracheal tubes, are more likely to be colonized or infected with multi-drug resistant organisms. Suggest removal of these devices as soon as possible. 2 Patients who are immunocompromised or over 60 years should also be suspected of harboring resistant organisms. 2 Patients who ve recently traveled to India or Pakistan may be at higher risk for NDM-1. 5 There are also reports in Great Britain of resistance in patients who haven t traveled. 7 This is likely due to cross-contamination within the hospital. 5 The CDC recommends asking patients with carbapenem-resistant Enterobacteriaceae about travel to India or Pakistan within the past six months. 8 In the U.S., carbapenem-resistant isolates from patients who received medical treatment in India or Pakistan within the past six months should be sent to the state public health lab. These isolates will then be forwarded to the CDC for additional analysis. 8 It s important to be aware of your hospital s antibiogram and the sensitivity and resistance patterns in your area. Klebsiella pneumoniae carbapenemases may indicate susceptibility to imipenem or meropenem, but the minimum inhibitory concentration (MIC) may be higher (PL Detail-Document #270713: Page 2 of 5) than normal. 2 If you suspect this resistant organism in your area, suggest your lab use ertapenem (Invanz) to identify susceptibility. 2 Specifically request sensitivity testing to colistin and tigecycline if you suspect a carbapenemaseresistant gram-negative infection or if there s intermediate resistance or resistance to carbapenems. Treating Resistant Gram-negative Bacteria The beta-lactams work in a time-dependent manner. So it s important for the drug concentration to remain above the MIC. 2,3 You want to aim for a drug concentration two to four times above the MIC. 3 Consider a carbapenem or tigecycline (Tygacil) as empiric therapy for severe infections thought to be due to gram-negative bacteria. 2 These may be given in combination with an antipseudomonal or an agent that covers methicillin-resistant Staph aureus. 2 It s important to identify the appropriate antibiotic as quickly as possible. Culture and sensitivity results, plus local resistance patterns, should be taken into consideration when selecting therapy. Extended-spectrum beta-lactamase-producing bacteria can typically be treated with carbapenems, such as imipenem and meropenem, or piperacillin-tazobactam (Zosyn, Tazocin). 2,4 Reserve fosfomycin (Monurol) for urinary tract infections. Consider quinolones as a second-line option. 2 Carbapenemase-producing bacteria have limited treatment options. Polymyxins may be appropriate for most infections. 1 Aminoglycosides are sometimes used, but resistance rates are as high as 45% to 90%. 4 Quinolone resistance is above 90% and quinolones should be avoided. 4 Colistin (polymyxin E) has the greatest effectiveness against NDM-1 [Evidence level D; in vitro]. 9 Between 90% to 100% of isolates are susceptible. 4,9 The parenteral formulation is referred to as colistin methanesulfonate (Coly- Mycin M, colistimethate sodium, or CMS). 1,7,10 Even though this drug has been around for over 50 years, there isn t much reliable kinetic data or dosing information available. 7 In the U.S. and Canada, Coly-Mycin M is typically dosed at 2.5 to 5 mg/kg/day in two to four divided doses. Many institutions dose two or three times daily to achieve higher drug concentrations. Note that

(PL Detail-Document #270713: Page 3 of 5) some references use international units. To convert, 12,500 international units of colistin is equal to 1 mg. 10 Adjust the colistin dosage in patients with poor baseline renal function. Follow your institutionspecific protocol. Some institutions use the following adjustments to colistin dosing in patients with renal impairment: MDRD of 40 to 70 ml/min/1.73 m 2 or CrCl of 30 to 49 ml/min give 3.5 mg/kg/day in two divided doses; MDRD of 25 to 40 ml/min/1.73 m 2 or CrCl of 10 to 29 ml/min give 2.5 mg/kg/day in two divided doses; MDRD of 10 to 25 ml/min/1.73 m 2 or CrCl <10 ml/min give 1.5 mg/kg/day as one dose. (MDRD=Modification of Diet in Renal Disease; MDRD equation is used to estimate GFR.) Some clinicians use the adjusted body weight if the patient s actual weight is greater than 130% of their ideal body weight. Monitor renal function daily when patients are in the hospital and every three days if they re outpatient. Also monitor electrolytes. You may see reversible renal or neuro toxicity in patients getting colistin. 1,11 Once daily dosing may increase these toxicities, but this isn t conclusive. Therefore, once daily dosing should be used cautiously. 1,11 The other option for treating carbapenemaseproducing bacteria (including NDM-1) is tigecycline [Evidence level D; in vitro]. 9 But only about 55% to 65% of NDM-1 isolates are susceptible. 4,9 Tigecycline doesn t reach adequate concentrations in the bloodstream or urinary tract, so its use is limited. 2 The usual tigecycline dose is a 100 mg loading dose followed by 50 mg every 12 hours. Some experts suggest higher doses may be needed to treat resistant organisms. The standard length of treatment is five to 14 days. However, resistant organisms and severe infections usually require a longer course of treatment. Use a reduced dose in patients with severe hepatic impairment. 1 The optimal tigecycline dose and duration of use for treating resistant bacteria is not clearly defined. Studies are needed before combination therapy can be routinely recommended. 1,3 Preventing Health Care-associated Infections Being proactive is the key to preventing the spread of resistant bacteria and decreasing the number of health care-associated infections. Hand washing is a simple step that can decrease the spread of infection. Wash your hands for at least ten to 20 seconds. An alcoholbased hand rub is appropriate for most organisms except Clostridium difficile. Use soap and water when C. diff is suspected or if hands are visibly soiled. 12,13 Use personal protective equipment when appropriate. This includes gloves, gown, and face mask or respirator. Remove your gloves and gown before leaving a patient s room and immediately wash your hands after leaving and before touching anything. 12,13 Cross-contamination can be prevented by keeping patient care equipment such as thermometers and pulse oximeters dedicated to a specific patient. Items not appropriate for singleuse should be cleaned and disinfected before use by another patient. 12,13 Isolate patients with resistant organisms or highly contagious disease. 12,13 Use antimicrobials effectively and implement an antimicrobial stewardship program in your facillity. 12,13 Optimize dosing and duration of treatment. 4 Follow treatment guidelines when appropriate. The Public Health Agency of Canada has additional guidelines. These guidelines are for patients identified as colonized or infected with NDM-1 or other carbapenem-resistant gramnegative bacilli within 48 hours of hospital admission. These are intended to prevent and control the spread of resistant organisms: 7,12 1. Clinical screening of all roommates. 2. Six to 12 month review of patient s labs. This is to determine in-hospital presence of organism prior to patient s identification of infection. 3. Consult infection control, microbiology, and public health officials if two or more patients in same organization are infected with or carrying the same organism strain. Consider active culture surveillance on other patients who may have been in contact with these patients.

(PL Detail-Document #270713: Page 4 of 5) 4. Environmental sampling should only be done if there is a major outbreak. Routine sampling of family and staff is not indicated. Conclusion Gram-negative bacterial resistance is becoming more common and is difficult to treat. Identify patients at risk and begin appropriate therapy. Reducing health care-associated infections is just as important as appropriately treating patients. Use antimicrobials judiciously and be aware of local antibiogram and resistance data. Wash your hands frequently, place patients in isolation, and prevent cross-contamination. These simple steps will help prevent the spread of infection. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8. Project Leader in preparation of this PL Detail- Document: Tammie Armeni, RPh, Pharm.D., Assistant Editor Special Expert Contributor: Robert E. Bickerton, MD, FACP References 1. Giamarellou H, Poulakou G. Multi-drug resistant gram-negative infections: what are the treatment options? Drugs 2009;69:1879-901. 2. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant gramnegative organisms: extended-spectrum betalactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc 2011;86:250-9. 3. Ambrose PG, Owens RC. New antibiotics in pulmonary and critical care medicine. Semin Respir Crit Care Med 2000;21:19-32. 4. Fraimow HS, Tsigrelis C. Antimicrobial resistance in the intensive care unit: mechanisms, epidemiology, and management of specific resistant pathogens. Crit Care Clin 2011;27:163-205. 5. Struelens MJ, Monnet DL, Magiorakos AP, et al. New Delhi metallo-beta-lactamase 1-producing Enterobacteriaceae: emergence and response in Europe. Euro Surveill 2010;15(46):pii=19716. 6. Nordmann P, Poirel L, Toleman MA, Walsh TR. Does broad spectrum beta-lactamase resistance due to NDM-1herald the end of the antibiotic era for treatment of infections caused by gram-negative bacteria? J Antimicrob Chemother 2011;66:689-92. 7. Pillai DR, McGeer A, Low DE. New Delhi metallobeta-lactamase-1 in Enterobacteriaceae: emerging resistance. CMAJ 2011;183:59-64. 8. CDC. Detection of Enterobacteriaceae isolates carrying metallo-beta-lactamase United States, 2010. MMWR Morb Mortal Wkly Rep 2010;59:750-1. 9. Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010;10:597-602. 10. Michalopoulos A, Falagas ME. Colistin and polymyxin B in critical care. Crit Care Clin 2008;24:377-91. 11. Nation RL, Li J. Colistin in the 21 st century. Curr Opin Infect Dis 2009;22:535-43. 12. Public Health Agency of Canada. Guidance: infection prevention and control measures for healthcare workers in all healthcare settings: carbapenem-resistant gram-negative bacilli. Ottawa (ON): The Agency, 2010. http://www.phacaspc.gc.ca/nois-sinp/guide/ipcm-mpci/ipcm-mpcieng.php. (Accessed May 4, 2011). 13. CDC. Healthcare-associated infections (HAIs). April 29, 2011. http://www.cdc.gov/hai/index.html. (Accessed May 7, 2011).

(PL Detail-Document #270713: Page 5 of 5) Cite this document as follows: PL Detail-Document, Resistant Gram-negative Bacteria. Pharmacist s Letter/Prescriber s Letter. July 2011. Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Subscribers to the Letter can get Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com