The patient was well on his way to recovery from head trauma after a fall from a motorcycle. But in the hospital, he developed a fever, stiff neck and severe headache. He became confused and nonresponsive. Tests of his cerebral spinal fluid disclosed a low glucose and elevated protein level and an increased neutrophil count. A strain of Acinetobacter baumannii, which is resistant to all antibiotics, was isolated from his CSF. The patient was treated unsuccessfully with meropenem (Merrem) and systemic polymyxin E (colistin). He died two months later, not from his injury but from a preventable hospital-acquired A. baumannii infection, which was untreatable with available antibiotics.
Antibiotics have changed the world, dramatically reducing human mortality from infectious diseases. Between 1936 (the year before sulfonamides were available) to the early 1950s (15 years into the antibiotic era), deaths in the U.S. from infectious diseases fell 75%, from about 280 per 100,000 to 60 per 100,000. Antibiotics brought about such a massive decline in infectious disease deaths that all medical advances since the early 1950s — including critical care medicine — have resulted in only minor reductions in deaths from infections. In the last 50 years, infectious disease deaths have been reduced only an additional 20 per 100,000.1
But deaths from infectious diseases are no longer declining. We are now seeing the emergence of increasing numbers of resistant pathogens threatening the effectiveness of antibiotics, and the death rate from serious infectious diseases is climbing. Untreatable infections that were of concern in the preantibiotic era are once again becoming a pervasive problem for U.S. healthcare facilities. Bacterial resistance has increased to such an extent that there are a growing number of hospital-acquired infections for which there are no adequate therapeutic options.
The emergence of A. baumannii strains resistant to all commercially available antibiotics is an example. A. baumannii, nicknamed “Iraqibacter” because it is the most frequently isolated gram-negative pathogen from war wounds, has become one of the problem pathogens threatening the current antibiotic era.2 It tends to infect previously healthy wounded veterans transported to military hospitals from Iraq and Afghanistan. Research has shown that A. baumannii — once thought to originate in the soil in Iraq and Afghanistan — is a hospital pathogen mainly acquired in the ERs, ORs and ICUs of combat support hospitals. The pathogen has been found in every hospital on the aeromedical evacuation route for combat wounded soldiers in Iraq, Germany and the U.S.3,4
In wounded soldiers, A. baumannii can cause devastating prostheses infections, deep wound infections, serious skin and soft-tissue infections, necrotizing fasciitis, catheter-related sepsis, primary bloodstream infections, urinary tract infections urinary tract infections, meningitis, endocarditis, intra-abdominal abscess and pneumonias. A number of injured soldiers infected with Acinetobacter have carried the pathogen back home to the U.S., where it has spread throughout the healthcare system, putting civilian patients and hospital workers at risk.4
A. baumannii is a gram-negative (or gram-variable), nonspore-forming, nonmotile, aerobic coccobacilli bacteria commonly found in healthcare environments. It is one of the hospital-acquired pathogens whose antibiotic resistance cannot be blamed on the community use of antibiotics or on the use of antibiotics in animals — but rests primarily on failures of hospital hygiene and the overuse of antibiotics in hospitals.5,6
In the 1970s, A. baumanniiinfections were easily treated because the pathogen was susceptible to most antibiotics. But as a result of increased use of broad-spectrum antibiotics in hospitals during the past three decades, the incidence of multidrug-resistant, extensive drug-resistant and pandrug-resistant strains of A. baumannii (strains resistant to all antibiotics) began increasing worldwide. By the late 1990s, carbapenems (imipenem and meropenem) were the only remaining microbial agents that could be used for severe infections. MDR Acinetobacter, or MDR-AB, is an isolate resistant to at least three of the four classes of antimicrobial agents — penicillins, cephalosporins, fluoroquinolones and aminoglycosides. XDR Acinetobacter is resistant to the antimicrobial agents listed above plus carbapenems. PDR Acinetobacter is resistance to all commercially available antimicrobial agents: penicillins, cephalosporins, fluoroquinolones, aminoglycosides, carbapenems and polymyxins and tigecycline.
The Jump in Resistance
In the last 10 years, the percentage of Acinetobacter infections resistant to carbapenems has risen from less than 5% to more than 40% in U.S. hospitals. Without carbapenems, only colistin (a drug abandoned in the 1960s because of kidney damage and neurotoxicity) or tigecycline (Tygacil) are available as last resort antimicrobials for XDR Acinetobacter infections. However, resistance to both coliston and tigecycline is increasing.7,8 For example, in an outbreak involving 15 New York City hospitals, about 400 A. baumannii cultures were collected from patients’ blood, respiratory secretions, urine and wounds over three months. Fifty-three percent of the isolates were resistant to carbapenems, and 12% were resistant to all available antibiotics.9 This sizeable increase in resistance has been occurring for two reasons: Acinetobacters’ remarkable ability to rapidly acquire resistance genes and its ability to survive under a wide range of environmental conditions in hospitals for extended periods of time.4,8
Fending off Antibiotics
A. baumannii has a wide range of intrinsic and acquired resistance mechanisms that are active against antibiotics. Like other gram-negative bacteria, Acinetobacter has a double cell membrane with a unique lipopolysaccaride (composed of a lipid and a carbohydrate) outer membrane, a periplasmic space (space between the inner out outer cell membranes) and an inner cell wall. Resistance features on the outer membrane include porins (protein channels) that block the entry of antibiotics by regulating permeability and efflux pumps, which pump the antibiotics out of the cell, keeping the level from becoming toxic. The organism also has beta-lactamases (enzymes) that neutralize the effectiveness of beta-lactam antibiotics managing to get into the periplasmic space. Together, the efflux pumps, porins and beta-lactamases are powerful intrinsic mechanisms for antibiotic resistance.4,8 Other resistance mechanisms include penicillin-binding protein modifications, antimicrobial-inactivating enzymes and mutations that change targets (binding sites) or cellular functions.
Acinetobacter also able to acquire iron, adhere to epithelial cells and form biofilms on surfaces (equipment and medical devices) and on human epithelial cells. Biofilms are colonies of bacteria encased within a self-produced, sticky matrix of extracellular polysaccharides that form whenever enough moisture exists. These biofilms facilitate exchange of resistance genes and mechanisms and protect the bacteria from the body’s immune defenses, antimicrobial agents and disinfectants.3,10,11 Most of these resistance mechanisms have come from genetic mutations or from other species of bacteria through the acquisition of genetic materials carrying resistance genes.
In 2005, researchers found a strain of multidrug-resistant A. baumannii with the largest cluster of genes coding for antimicrobial drug resistance ever discovered in a single organism. Forty-five of its 52 resistance genes were clustered within a resistance island (a large piece of DNA) in the genome. Nearly all were acquired from Salmonella, Pseudomonas and E. coli.3
Most Acinetobacter infections occur in critically ill hospitalized patients with severe underlying diseases who have an extended exposure to an ICU. Infections usually involve organ systems with a high fluid content (e.g., the respiratory tract, blood, CSF, peritoneal fluid and the urinary tract) and are often due to multidrug-resistant strains.11,12 Risk factors include underlying diseases, such as chronic lung disease or diabetes; prior treatment with broad-spectrum antibiotics, especially carbapenems and third-generation cephalosporins; surgery and surgical drains; mechanical ventilation; indwelling central IV catheters; urinary catheters; monitoring devices; prolonged length of stay and poor infection control practices.4,11,12
From 2009 to 2010, A. baumannii was the 14th most common pathogen isolated in U.S. hospitals and was responsible for 2.1% of hospital-acquired bloodstream infections, 0.9% of urinary tract infections and 6.6% of pneumonias.13 (Level B)
In the ICU, Acinetobacter is a common cause of a hospital-acquired, aggressive and often fatal pneumonia (with a mortality rate of 40% to 60%). It ranks fifth (behind Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella and Enterobacter spp.) as a major cause of ventilator-associated pneumonia. In its most severe form, the pneumonia is characterized by a fulminant clinical course and a secondary bloodstream infection. In the early stages of infection, Acinetobacter can trigger a severe systemic inflammatory response that can include disseminated intravascular coagulation, septic shock and adult respiratory distress syndrome.3,12-14
In U.S. hospitals, Acinetobacter is the 13th most common cause of catheter-related bloodstream infections, with the third highest mortality rate, up to 43% in ICUs. Risk factors include prior antibiotic use, intravascular catheters, mechanical ventilation and colonization at other body sites. Prognosis is determined by the underlying condition of the patient.3,12 In addition to pneumonias and bloodstream infections, Acinetobacter can cause meningitis after head trauma or neurosurgical procedures or urinary tract infections in patients with indwelling catheters and wound infections.3,14