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 drug 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 medicine 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 18 EMERGENCY MEDICINE | NOVEMBER 2009 www.emedmag.com MULTIDRUG-RESISTANT BACTERIA 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 Antimicrobial Resistance 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 www.emedmag.com NOVEMBER 2009 | EMERGENCY MEDICINE 19 MULTIDRUG-RESISTANT BACTERIA 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