Multidrug-Resistant Gram-Negative Bacteria: Trends, Risk Factors, and Treatments A worldwide public health problem, antibiotic resistance leads to treatment-resistant infections associated with prolonged hospitalizations, increased cost, and greater risk for morbidity.

Lee S. Engel MD, PhD

CASE INTRODUCTION An 80-year-old female nursing home resident with Antibiotics have saved the lives of millions of people a history of dementia, anemia, atrial fibrillation, and have contributed to the major gains in life ex- hypertension, incontinence, and recurrent urinary pectancy over the last century. In US hospitals, 190 tract infections (UTIs), as well as a long-term Foley million doses of antibiotics are administered each catheter, is admitted because she was found to be day.1 Furthermore, more than 133 million courses febrile and less responsive than normal. The patient of antibiotics are prescribed each year for outpatients. has no allergies. Upon admission, she has a However, antibiotic use has also resulted in a major temperature of 38.9ºC, heart rate of 92 beats/min, health care challenge—the development and spread and blood pressure of 106/64 mm Hg. The patient of resistant bacteria. Worldwide, antimicrobial resis- opens her eyes to stimuli but does not speak. Aside tance is most evident in diarrheal diseases, respira- from poor dentition and an irregular heart rate, tory tract infections, meningitis, sexually transmitted findings on physical examination, which includes infections, and hospital and health care–acquired in- a pulmonary and abdominal examination, are nor- fections.2 Vancomycin-resistant enterococci, methi- mal. Serum chemistries demonstrate a white blood cillin-resistant Staphylococcus aureus, multidrug-resis- cell (WBC) count of 11,300 cells/mm3. Her blood tant (MDR) Mycobacterium tuberculosis,2 and MDR urea nitrogen level is 86 mg/dL, and her creatinine gram-negative bacteria (Table 1)3-9 are examples of concentration is 2.1 mg/dL (calculated glomerular this emerging crisis.10 The development of extended- filtration rate of 24 mL/min/1.73m2). Urinalysis spectrum ␤-lactamases (ESBLs) and carbapenemases demonstrates 40 to 50 WBCs per high-powered that target gram-negative bacteria has resulted in in- field (hpf), 20 epithelial cells per hpf, 3+ protein, fections that can be extremely difficult to treat, lead- positive nitrites, and leukocyte esterase. Blood and ing to increased morbidity and mortality.11 urine samples are sent to the microbiology labora- Most studies define multidrug resistance as resis- tory for routine culture. The patient is started on tance to more than two classes of antibiotics.4,11-13 IV fluids for hydration and renally dosed empiric The incidence of infection with MDR gram-nega- antibiotic coverage with piperacillin-tazobactam for tive bacteria is on the rise. Analysis of data from the a probable UTI and possible sepsis. National Nosocomial Infections Surveillance System from 1986 to 2003 demonstrated a significant in- Dr. Engel is an assistant professor of clinical and crease in antibiotic resistance in gram-negative bac- infectious disease and associate program director of the teria isolated from infections in the ICU.14,15 During internal medicine residency program in the department of internal medicine at Louisiana State University Health this period, there was a tenfold increase in resistance Sciences Center in New Orleans. among Klebsiella spp, twofold increase in resistance

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among Escherichia coli, threefold increase in multidrug bacter, have developed fluoroquinolone resistance.18 resistance among Pseudomonas aeruginosa, and 20% Antibiotics select for bacteria with either inherent increase in carbapenem-resistant Acinetobacter spp.4,14 resistance or resistance acquired through gene mu- The Study for Monitoring tation or transfer of genetic material.19 The spread Trends (SMART), which began in 2002, is the only of resistance, mediated through transferable genetic worldwide surveillance program designed to monitor elements such as plasmids and transposons, is as- longitudinally the in vitro antimicrobial susceptibility sociated with epidemics of drug-resistant bacteria.19 of gram-negative bacilli isolated from intra-abdomi- Resistance mechanisms include drug efflux systems, nal infections.16 SMART demonstrated increased antibiotic-modifying enzymes, outer-membrane pro- detection of ESBL-producing bacteria from 2003 to tein changes, and antibiotic-target modification.19,20 2004. In 2004, the percentages of ESBL-producing Resistance to ␤-lactam antibiotics often involves E coli, Klebsiella spp, and Enterobacter spp were 10%, production of ␤-lactamases but can also result from 17%, and 22%, respectively.16 drug efflux pumps or outer-membrane changes that decrease drug permeability.20 Resistance to amino- FACTORS ASSOCIATED WITH ANTIBIOTIC glycosides often involves modifying enzymes, efflux RESISTANCE systems, and ribosomal RNA methylation.20 Re- Global population demographic changes, human sistance to fluoroquinolones occurs through target behavior, environmental changes, improved medi- modification of the DNA gyrase, efflux systems, and cal technology, bacterial evolution, and the break- outer membrane changes.20 down of public health systems have been associ- ated with the development and spread of antibiotic RISK FACTORS FOR MDR GRAM-NEGATIVE resistance.17 With regard to the global population, BACTERIAL INFECTION urban migration, immigration, and increased travel The frequency of antibiotic-resistant health care–as- have all increased the spread of antimicrobial resis- sociated infections has increased every year for the last tance. Liberation of sexual practices, institutional 2 decades. Risk factors for colonization and infection child care, and alcohol and drug abuse are behav- with an MDR gram-negative bacterium include age ioral factors that can result in the emergence and greater than 65 years, antibiotic exposure within the spread of resistance. Improved medical technology preceding 90 days, hospital admission for at least 2 has resulted in a greater proportion of people living days in the preceding 90 days, residence in a nursing with chronic medical conditions, such as end-stage home, having an indwelling catheter (central venous, renal disease and diabetes, that are associated with arterial, or urinary), mechanical ventilation, tube feed- an increased number and chronicity of infections. ing, hepatic failure, and long-term hemodialysis.21-23 Decreased funding for public health initiatives has The population in the United States is aging. resulted in decreased ability to prevent disease and In 1990, 4% of the population was older than 65 to respond to new infectious threats associated with years, and by 2040, this group is projected to ac- immigration, travel, and natural disasters. count for about 25% of the population.17 Compared Antibiotic use is the main driving force for the de- with younger people, older patients are more likely velopment and selection of drug-resistant bacteria.2 to have comorbid condi- Self-medication with antibiotics, patient perception, tions, indwelling medical >>FAST TRACK<< patient compliance, physician prescribing practices, devices, poor nutritional Antibiotic use is the and antibiotic use in hospitals are all associated with status, poor functional sta- main driving force for the emergence and spread of antimicrobial resis- tus, and decreased barrier the development and tance.2 While overuse and misuse of antibiotics by to infection (such as skin selection of drug-resistant doctors and patients have caused most of the rise in breakdown or diminished bacteria. antimicrobial resistance, antibiotics used in the farm- cough reflex); these are all ing of food animals has also had significant effect.18 risk factors for acquisition of resistant organisms.24 Globally, half of all antibiotics produced are used The incidence of bloodstream infections, pneumo- in food animals. As a result of antibiotic use, food- nia, and UTIs increases with age.24 Gram-negative borne pathogens, such as Salmonella and Campylo- bacteria are associated with 70% of bloodstream

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TABLE 1. Common Multidrug-Resistant Gram-Negative Bacteria

Bacteria Common Infections Common Resistance Antibiotics for Mechanisms Multidrug-Resistant Strains

Klebsiella Pneumonia ␤-Lactamases Carbapenems pneumoniae (extended-spectrum Urinary tract infections ␤-lactamases) Amikacin

Wound infections Carbapenemases Tigecycline

Bloodstream infections Antibiotic-target Colistin Peritonitis modification

Meningitis

Escherichia coli Urinary tract infections ␤-Lactamases Carbapenems (extended-spectrum Bloodstream infections ␤-lactamases) Amikacin

Pneumonia Carbapenemases Tigecycline

Wound infections Antibiotic-target Colistin Peritonitis modification

Cholangitis

Meningitis

Enterobacter spp Pneumonia ␤-Lactamases Carbapenems (extended-spectrum Urinary tract infections Amikacin ␤-lactamases) Bloodstream infections Tigecycline Carbapenemases Wound infections Colistin Antibiotic-target modification

Serratia marcescens Urinary tract infections ␤-Lactamases Carbapenems (extended-spectrum Wound infections ␤-lactamases) Amikacin Pneumonia Tigecycline Antibiotic-target Bloodstream infections modification

Acinetobacter Pneumonia (ventilator Multidrug efflux pump Amikacin baumannii associated) Antibiotic-modifying Tigecycline Bloodstream infections enzymes Colistin Wound infections Antibiotic-target modification Urinary tract infections

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TABLE 1. Common Multidrug-Resistant Gram-Negative Bacteria continued

Bacteria Common Infections Common Resistance Antibiotics for Mechanisms Multidrug Resistant Strains

Pseudomonas Pneumonia Intrinsic antibiotic Tigecycline aeruginosa resistance Bloodstream infections Colistin ␤ -lactamases Amikacin Urinary tract infections (extended-spectrum ␤-lactamase) Wound infections

Carbapenemases Burn infections

Osteomyelitis Multidrug efflux pump

Meningitis Antibiotic-modifying enzymes Ocular infections

Reduced outer- membrane permeability

Stenotrophomonas Pneumonia (ventilator Reduced outer- Co-trimoxazole maltophilia associated) membrane permeability Tigecycline Bloodstream infections Multidrug efflux pump Colistin Wound infections Antibiotic-modifying enzymes

Neisseria gonorrhoeae Urethritis/cervicitis ␤-Lactamases Cefixime

Pelvic inflammatory disease Target-site mutation Ceftriaxone (DNA gyrase/ Disseminated gonorrhea topoisomerase) Spectinomycin

Reduced outer- Azithromycin membrane permeability

Data extracted from Volles and Branan3; Shorr4; Cunha5; Michalopoulos and Falagas6; Vergidis and Falagas7; Chemaly et al8; and Jamal et al.9

infections in the elderly. While E coli remains the ED.13 E coli was the most common MDR gram-nega- most common cause of UTI in the elderly, other tive bacteria isolated.8 Risk factors for community- pathogens, including Klebsiella and Pseudomonas, acquired UTIs caused by ESBL-producing E coli in- are more common in this group than in younger clude having more than three UTIs in the preceding patients and also have the potential for multidrug year, use of a ␤-lactam antibiotic in the preceding 3 resistance.13 Furthermore, elderly patients are more months, prostatic disease, age greater than 65 years, likely than younger patients to have a complicated use of a urinary catheter, the presence of a urologic UTI due to comorbid disease and the presence of or neurologic abnormality, and residence in a long- indwelling catheters.13,24 term care facility.25 Retrospective review has suggested that multidrug A prospective study designed to develop a predica- resistance occurs in 37% of isolates from UTIs in the tive model of antimicrobial-resistant gram-negative www.emedmag.com NOVEMBER 2009 | EMERGENCY MEDICINE 21 MULTIDRUG-RESISTANT BACTERIA

bacteremia in the ED revealed that hospitalization in by Enterobacteriaceae have variable resistance to the prior month, prior infection with resistant bac- cephalosporins, penicillins, ␤-lactamase inhibitors, teria, post-transplantation immunosuppressant use, and monobactams. ESBLs have plasmid-encoded leukopenia (absolute neutrophil count <1,000 cells/ genes associated with a great ability to spread be- mm3), leukocytosis (white blood cell count >15,000 tween bacteria.11 The ESBL-producing phenotype is cells/mm3), residence in a nursing home, history of present in approximately 10% to 15% of the Entero- 10 stroke, and poor oxygen saturation (SpO2 <95%) pre- bacteriaceae. ESBL-producing Enterobacteriaceae dicted the isolation of resistant bacteria from infected have traditionally been treated with carbapenems; patients.22 Patients with more than two of the above however, some ESBL-producing Enterobacteriaceae factors had a predicted resistance rate of approxi- now also produce carbapenemases.23 mately 40%, with a sensitivity of 67% and specificity of 75%.22 Specificity of this model increased when Acinetobacter spp patients had more than four of these risk factors. The Acinetobacter calcoaceticus-baumannii complex has emerged as a MDR nosocomial and community-ac- IMPACT OF GRAM-NEGATIVE quired pathogen. Acinetobacter was a common wound BACTERIAL RESISTANCE isolate during Operation Desert Storm and after Most studies have demonstrated that MDR gram- natural disasters such as the 2004 Asian tsunami.10 negative infections convey increased mortality, lon- The incidence of Acinetobacter has increased in venti- ger hospital stays, and higher hospital costs when lator-associated pneumonia, bloodstream infections, compared with infections associated with susceptible surgical site infections, and UTIs.10,27 Furthermore, strains.4,11,12,26 The mortality rate was 15% greater, strains of Acinetobacter that are resistant to all ami- length of stay in the ICU was 6 days longer, and noglycosides, cephalosporins, ␤-lactams, and fluo- an initial inappropriate antibiotic selection was 20% roquinolones are increasing in prevalence.10 These more common for patients with MDR gram-nega- MDR strains are problematic to treat and are asso- tive blood stream infections than for patients with ciated with more frequent relapses. Antibiotics such antibiotic-sensitive gram-negative bacteria.12 The as colistin and tigecycline are being employed more median hospital cost is about $10,000 to $50,000 frequently in the treatment of MDR Acinetobacter.27 greater for infections caused by MDR gram-nega- tive bacteria;4,10,26 this in- Pseudomonas aeruginosa >>FAST TRACK<< creased cost is related to Pseudomonas aeruginosa is associated with a variety of Pseudomonas is the longer duration of hospital infections, including pneumonia, UTIs, wound infec- second most frequent stays and higher cost of an- tions, and bacteremia. Pseudomonas is the second most pathogen isolated from tibiotics used to treat these frequent pathogen isolated from health care–associ- health care–associated infections. Furthermore, ated pneumonia and skin and soft-tissue infections.10 pneumonia and skin and there is a substantial cost Pseudomonas, which has intrinsic antibiotic resistance, soft-tissue infections. for controlling infections. has also acquired other mechanisms of resistance, For instance, the cost of including ␤-lactamases, carbapenemases, and multi- new antimicrobial development is estimated at drug efflux pumps. Rates of resistance to third-gen- $1 billion per drug. There is also a large cost as- eration/antipseudomonal cephalosporins, carbapen- sociated with enforcing isolation procedures used to ems, and quinolones have continued to rise during reduce the spread of resistant pathogens.4 the last 10 years.10 About 30% of MDR P aeruginosa exhibited resistance to four antibiotic drug classes (ie, GRAM-NEGATIVE PATHOGENS OF CONCERN cephalosporins, carbapenems, aminoglycosides, and ESBL-Producing Enterobacteriaceae fluoroquinolones).27 Agents such as colistin are now Enterobacteriaceae are the family of gram-negative being used to treat these MDR strains.27 bacteria that includes Klebsiella spp, E coli, Enterobac- ter spp, Salmonella spp, and Serratia spp. Among this Stenotrophomonas maltophilia family, ␤-lactamase production is the most common An environmental organism, Stenotrophomonas mechanism of resistance.4 The ESBLs produced maltophilia is found in almost all types of aquatic

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or humid environments, including drinking water.27 (after chlamydia).29 In 2007, the US Centers for This bacterium is not inherently virulent, but it can Disease Control and Prevention updated the treat- colonize the surfaces of medical devices and respira- ment guidelines for gonorrhea due to widespread tory tract epithelium. It has been an increasing cause resistance to fluoroquinolones.29 Current guidelines of pneumonia and bloodstream infections in immu- recommend the use of ceftriaxone, cefixime, spec- nocompromised patients. Specific risk factors for in- tinomycin, or a single oral of azithromycin 2 g fection with S maltophilia include an extended stay (for penicillin-allergic patients).29 Treatment failure in a critical care unit, prolonged mechanical ventila- with oral cephalosporins has now been reported in tion, tracheotomy, exposure to broad-spectrum an- Japan, and its spread is imminent.30 Unfortunately, tibiotics, chemotherapy-induced neutropenia, and there are few good existing antibiotics or agents in leukemia.28 S maltophilia has a high-level intrinsic development for the treatment of cephalosporin- resistance to many antibiotics, including ␤-lactams, resistant isolates. quinolones, aminoglycosides, and tetracycline, as well as to some disinfectants and silver used to line TREATMENT OF MULTIDRUG-RESISTANT catheters. Furthermore, it has increasing resistance GRAM-NEGATIVE BACTERIA to co-trimoxazole, the first-line drug used to treat The emergence of MDR gram-negative organ- S maltophilia infections. Antibiotics such as colistin isms presents a significant treatment challenge for and tigecycline are now used more frequently to practicing physicians (see Table 2 for treatment op- treat co-trimoxazole–resistant S maltophilia.28 tions).3 Patients with severe sepsis or septic shock should receive broad-spectrum antibiotics until the Neisseria gonorrhoeae causative bacterium has been isolated and its suscep- Neisseria gonorrhoeae is the second most common tibility has been determined. For patients who are sexually transmitted disease in the United States severely ill, combination therapy is warranted. After

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TABLE 2. Antibiotics For Multidrug-Resistant Gram-Negative Infections

Antibiotic Dosagea Most Frequently Reported Adverse Events

Carbapenem

Meropenem 1 g IV every 8 hours Headache, nausea, vomiting, diarrhea, rash, seizures (imipenem) Imipenem 500 mg IV every 6 hours

Ertapenem 1 g IV or IM every 24 hours

Doripenem 500 mg IV every 8 hours

Tigecycline Start 100 mg IV for first dose, Nausea, vomiting, diarrhea then 50 mg IV every 12 hours

Amikacin 7.5 mg/kg IV or IM every 12 hoursb Neurotoxicity, manifested as vestibular and permanent bilateral auditory ototoxicity; nephrotoxicity

Colistin 2.5 to 5 mg/kg/day IV divided two Neurotoxicity, nephrotoxicity (polymyxin E) to four times per day

IV = intravenous; IM = intramuscular a Renal dosing not listed b Peak and trough levels should be monitored Data extracted from Volles and Branan.3

the susceptibilities are known, antibiotic therapy can the treatment of intra-abdominal infection; pneumo- be de-escalated to narrower-spectrum antibiotics. nia; UTI; meningitis; gynecologic infection; bacte- There are a limited number of older antibiotics rial septicemia; bone, joint, and skin infections; en- that have activity against MDR gram-negative bac- docarditis; and polymicrobic infections. teria; likewise, there are very few new antibiotics in There are differences between individual carba- development for the treatment of infections caused penems. Imipenem is administered with cilastatin, by these bacteria.20,31 The lack of treatment options which inhibits breakdown of the drug by enzymes is due to the cost associated with developing new in the proximal renal tubule cells. Imipenem has antibiotics, the withdrawal of many large pharma- slightly better activity for gram-positive pathogens, ceutical companies from antibacterial research and while meropenem is slightly more active against development, and the difficulty of devising antibiotics gram-negative bacteria. Imipenem commonly lowers with novel mechanisms of action.31 None of the anti- the seizure threshold more than the other carbap- bacterial agents in clinical trials possesses sufficiently enems. Ertapenem can be given once daily but does novel modes of action to circumvent antibiotic-resis- not cover Pseudomonas. Doripenem is the newest car- tance mechanisms of gram-negative bacteria.31 Out bapenem and is more active against Pseudomonas than of necessity, there has been a resurgence in the use are the other .7 Unfortunately, many strains of of older antibiotics (eg, amikacin, colistin).5,6 Pseudomonas, Acinetobacter, and Stenotrophomonas have general resistance to carbapenems.3 Furthermore, Carbapenems there are now ESBL-producing Klebsiella that can The carbapenems (ie, meropenem, imipenem, er- produce carbapenemases.23 tapenem, doripenem) are ␤-lactam antibiotics with the broadest spectrum of activity of all drug classes.3 Tigecycline They are first-line agents for ESBL-producing En- Derived from minocycline, tigecycline is a glycylcy- terobacteriaceae and are approved by the FDA for cline that was licensed for use in the United States

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in 2005.31 Glycylcyclines bind to the ribosome five coli and Klebsiella and has been used to control out- times more strongly than does tetracycline and can breaks of carbapenemase-resistant A baumannii in an overcome common resistance mechanisms described ICU.9 Resistance has been described and is thought for tetracycline.8 Tigecycline has broad coverage that to be related to broad-spectrum efflux pumps.7 includes methicillin-resistant S aureus, ESBL-pro- ducing Klebsiella and E coli, and Acinetobacter.3 Ti- Amikacin gecycline is not active against Pseudomonas, Morgan- Amikacin is the aminoglycoside that has the greatest ella, or Providencia. Tigecycline is FDA approved for degree of antipseudomonal activity.27 Amikacin has complicated skin/skin-structure infections, compli- only one location susceptible cated intra-abdominal infections, and community- to enzymatic inactivation by acquired bacterial pneumonia, including cases with acetylating enzymes; thus, it >>FAST TRACK<< concomitant bacteremia. Tigecycline is bacteriostatic is more resistant to inacti- Tigecycline has proven and comes only in a parenteral form. This agent does vation than are gentamicin to be beneficial in the not require renal dosing, as the liver metabolizes it. and tobramycin, which have treatment of serious Dosing is 50 mg every 12 hours after a 100-mg initial six locations for inactivation. infections in patients with loading dose. The most common adverse effects are Amikacin is FDA approved cancer. nausea, vomiting, and diarrhea. for the short-term treat- Tigecycline has proven to be beneficial in the treat- ment of serious infections due to susceptible strains ment of serious infections in patients with cancer.8 of gram-negative bacteria, including Pseudomonas, E Tigecycline has activity against ESBL-producing E coli, species of indole-positive and indole-negative

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Proteus, Providencia spp, Klebsiella-Enterobacter-Serra- tibacterial peptides designed to disrupt bacterial tia spp, and Acinetobacter spp. Treatment indications membranes are in development.31 Antivirulence include bacterial septicemia (including neonatal sep- agents are also being studied. For example, agents sis); serious infections of the respiratory tract, bones designed to inhibit lipopolysaccharide biosynthesis and joints, central nervous system (including menin- and efflux pump inhibitors are under investigation.31 gitis), skin, and soft tissue; intra-abdominal infections However, despite this research, few novel antibiot- (including peritonitis); burn infections; postoperative ics are entering phase 1 studies at this time.31 For infections (including postvascular surgery); and com- this reason, antibiotic stewardship and good infec- plicated and recurrent UTIs. At present, amikacin is tion control measures are of the utmost importance used as part of combination therapy for an additive or in the battle against the development and spread of synergistic effect against MDR strains of P aeruginosa, MDR gram-negative bacteria. A baumannii, and Enterobacteriaceae. CASE RESOLUTION AND DISCUSSION Colistin The patient’s blood cultures did not grow, but her First discovered in 1947, colistin (polymyxin E) is a urine culture grew greater than 100,000 colony- cationic polypeptide that was used clinically until it forming units of a K pneumoniae that was resistant to fell out of favor in the 1970s.6 Colistin binds phos- ampicillin/sulbactam, aztreonam, cefepime, ceftriax- pholipids in the outer membrane of gram-negative one, imipenem, meropenem, and ciprofloxacin. The bacteria, causing cell wall destabilization and cell isolate was sensitive to piperacillin-tazobactam but death. Colistin is bactericidal against many MDR positive for ESBL. It was also sensitive to tobramycin, gram-negative bacteria, including P aeruginosa, A gentamicin, amikacin, and tigecycline. Based on the baumannii, Klebsiella pneumoniae, and E coli.3,6 Co- results of sensitivity testing and the presence of re- listin is not active against Proteus, Providencia, Burk- nal insufficiency, the patient’s antibiotic coverage was holderia, Neisseria, or Serratia.3,5,6 Colistin is FDA ap- changed from piperacillin-tazobactam to tigecycline, proved for the treatment of starting with an initial dose of 100 mg IV and then >>FAST TRACK<< acute or chronic infections 50 mg IV every 12 hours. Following the change of due to sensitive strains of antibiotics, the patient’s Foley catheter was replaced, Sitafloxacin, currently undergoing trials, is a certain gram-negative ba- her renal function improved with hydration, her fluoroquinolone that has cilli, particularly P aeru- temperature and WBC count normalized, and she improved activity in vitro ginosa in association with returned to her baseline functional capacity. This against several gram- cystic fibrosis. Dosing can patient had several risk factors for an MDR gram- negative pathogens. be confusing because there negative bacterium, including her age, residence in a are differences in units nursing home, and long-term Foley catheterization. between the packaging in Even though the isolate appeared to be sensitive to the United States (mg) and Europe (international piperacillin-tazobactam, the presence of an ESBL units).6 Dosing in the United States ranges from 2.5 would inactivate this antibiotic. Furthermore, this to 5 mg/kg/day divided two to four times a day in isolate was most likely producing a carbapenemase, patients with normal renal function.3 Nephrotoxicity as it was resistant to imipenem and meropenem. The and neurotoxicity have been associated with colistin physician chose tigecycline instead of an aminoglyco- use in the past; however, recent data indicate that side because tigecycline does not require renal dosing may be less prominent than previously re- adjustment, and evidence in the published literature ported.5 Resistance occurs through changes in the suggests that this antibiotic is effective for UTIs. Q outer membrane of the bacteria.3 REFERENCES Future Treatment Options 1. American College of Physicians—American Society of Internal Medicine. Antibiotic resistance. American College of Physi- Sitafloxacin, currently undergoing trials, is a fluoro- cians Web site. http://www.acponline.org/patients_families/ quinolone that has improved activity in vitro against diseases_conditions/antiobiotic_resistance. Published 2000. Accessed October 25, 2009. several gram-negative pathogens, including Acineto- 2. World Health Organization. Antimicrobial resistance. Fact bacter and levofloxacin-resistant Pseudomonas.31 An- sheet 194. World Health Organization Web site. www.who.int/

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