Gram‐negative resistance: can we combat the coming of a new “Red Plague”?

nfectious diseases scourges in history have had devastating effects on unprepared human populations. Bubonic plague, or the “Black Death”, killed more than a third of Europe’s population from 1346 to 1351, and the “White Plague” (tuberculosis) became epidemic in Europe throughout the 19th century. These plagues provide many lessons from which we can learn if we are to contain the spread of gram-negative resistance — the coming of a new “Red Plague”. In 1884, Danish bacteriologist Hans Christian Gram published a stain method for distinguishing bacteria. Gram-negative bacteria do not retain a blue dye (crystal violet) and are stained pink or red by use of a counterstain, hence the term “red”. In clinical use, “gram-negative” largely refers to the common human pathogens such as Escherichia, Klebsiella, Enterobacter, Proteus and Pseudomonas species. These organisms cause infections such as urinary tract infections, peritonitis, biliary tract infection, hospital-acquired pneumonia, and less common but more serious infections such as liver abscess and neonatal meningitis, among others. While antimicrobial agents were initially highly successful in treating these infections, their unfettered use in both humans and animals has seen rates of antimicrobial resistance rise alarmingly, especially in the developing world. In a 2009 study, > 50% of Escherichia coli in China and > 70% in India were extended-spectrum -lactamase-producing strains, indicative of high-level resistance.2 It is now estimated that up to 100–200 million people in India may harbour gram-negative bacteria that carry the New Delhi metallo--lactamase (NDM-1) enzyme that renders the t is not known how many m these organisms. Poor tibiotic overuse in health prits. developed world are not nts. Antibiotic-resistant s were once thought to be ctions”, but people with community-acquired multiresistant gram-negative bacterial infections are now presenting to general practices and emergency departments. Comprehensive Australia-wide surveillance of resistance trends in gram-negative bacilli is lacking, however. Though rates of resistance are lower in Australia than in the United States, southern Europe and much of Asia, resistance (eg, to third-generation cephalosporins and fluoroquinolones) is rising. The Australian Group on Antimicrobial Resistance surveillance of community-acquired gram-negative isolates has shown that multiresistant E. coli isolates rose from 4.5% in 2008 to 7.2% in 2010.4 Moreover, virtually all key mechanisms of multidrug-resistance in gram-negative bacilli found worldwide have now been detected in Australia.5-8 Establishment of gram-negative resistance in Australia is likely to have several consequences, including the need to treat previously simple infections, such as uncomplicated urinary tract infections, with intravenous instead of oral antimicrobial therapy; the need to treat severe community-acquired sepsis with antibiotics of last resort upfront, and a growing ineffectiveness of surgical antibiotic prophylaxis. The impact of increased resistance would be seen across all age groups, leading to significant costs to the community in both human and economic terms. This shift has already become apparent in children and adults with no prior hospital exposure presenting with infections acquired during travel to countries where resistance is endemic.9 The impact on health care-associated sepsis is likely to be substantial. Are new antibiotics waiting in the wings to save the day? Unfortunately, antibiotic development has all but stalled, and candidate antibiotics in development have limited activity against these resistant pathogens. Two basic strategies remain: enhancing traditional infection control, including hand hygiene and isolation of carriers in hospital; and antibiotic stewardship, where “selection pressure” on bacterial flora is mitigated by reduction in the volume of antibiotics used in clinical practice. Infection control and antibiotic stewardship programs are now mandated in all hospitals through accreditation, but their effectiveness in halting the spread of gram-negative resistance is unknown. What must be done? Without a coordinated effort at government level across all human and animal health care sectors, we are likely doomed to failure. We need to implement national surveillance to map and track the true extent and impact of these infections. We need to proactively implement the princiI