The Development of a Superbug

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Attack of the Killer Acinetobacter baumannii-A History

Natasha Resendes

Over the last 30 years, A.baumannii has emerged as a major nosocomial pathogen. No longer can hospital administrators and healthcare professional ignore the threat of infections by this species of bacteria. However, the threat has been less severe than it is presently and will continue to be so, if not countered by new solutions. In fact, A.baumannii had been classified as a low-grade pathogen as recently as- 2005[1]. The major concern caused by A. baumannii is due to its incredible abilities to pick up genes that code for resistance to antibiotics[2]. Also, a cause for concern is the mortality rate induced by A.baumanii infections. Published data suggest that the crude or related mortality rate ranges from 20% to 60%[1] .


Furthermore, A.baumannii is virtually the perfect species of bacteria to infiltrate hopsitals around the world. A.baumannii can survive in environmental reservoirs (e.g. soil) , but more importantly outside and inside the human body (i.e axilla[3], oral cavity, and respiratory tract[4]) as well[5]). It can survive on hospital beds and other dry surfaces. This is a special concern for hospitals looking to prevent inter-transmission. The most important thing needed to infect patients is its propensity to live inside invasive catheters and mechanical ventilation tubing[6] . Explaining its survival capabilities, A. baumannii has minimal nutritional requirements and is able to grow at various temperatures and pH values[5] .


Another important aspect to consider in the rise of A.baumannii as a major nosocomial pathogen is the antibiotic treatments for it. In the 1970s, A. baumannii was susceptible to most antibiotics[2]. Now, there are few antimicrobial treatments to combat A.baumanii. The evolution of antibiotic treatment presents an interesting interplay between the antibiotics themselves and acquired resistance of A.baumannii. With A.baumannii on the verge of pan-resistance, the future of its treatment does not look promising.


The History of Epidemiology of A.baumannii

1960s and 1970s

When A. Baumannii was first isolated from clinical samples in the 1960s, it was primarily ignored as a commensal, opportunistic, relatively low-grade pathogen. There was no inclination to think A.baumannii would spread by cross-transmission through personnel and inanimate objects. Prior to the 1970s, A. baumannii infections were mostly post-surgical urinary tract infections; Acinetobacter spp. were thought to be sequestered primarily in patients hospitalized in surgical or medical wards[1].


Beyond that, the medical community thought that the level of A.baumannii infections were seasonal. In 1979, the Center for Disease Contol (CDC) described a pattern of infections with infection rates twice as high in late summer as in early winter for each year in the study period from 1974 to 1977[6]. This study validated the opinions of some that A.baumannii infections were triggered by high humidity climates.


Moreover, with the limited scope and limited range of A.baumannii supposed in the 1960s, it was doubted that A. baumannii could cause nosocomial infection outbreaks. In fact, A.baumanni was considered to be a low virulence organism[1]. There was no concern about the link between nosocomial infection and environmental incidences of many acinetobacters reported to be found in animals in 1960s and 1970s[7] [8], as well as reports of isolated Acinetobacter spp. on from human skin in up to 25 percent of healthy adults in the 1960s and 1970s [9].


In spite of vague interest in A. baumannii during that time period, there were reported incidences of A.baumannii being responsible for 1.4% of all nosocomial infections throughout the majority of the 1970s[10].

1980s

At the start of the 1980s, significant improvement in resuscitation techniques in hospitals caused a shift in the location of A. baumanni. Patients were spending more time on facilitated ventilation machines. Thus, A. baumannii started to be isolated more and more frequently from wards like intensive care units (ICUs), where there were a large number of ventilation machines. Retrospectively, this is an indication of the rapid spread of A.baumannii amongst patients in ICUs during that time period[11]. Related to these facts, the incidence of A.baumanni-caused nosocomial pneumonia saw a dramatic increase in the 1980s[11]. Along with increased number of invasive devices like mechanical ventilators in ICUs, incidence of epidemic outbreaks of bacteremia, the disease of bacteria in the bloodstreams, began to climb[12].


The 1980s also saw the spread of major A.baumannii infections to Europe as well. There were numerous reported outbreaks of nosocomial A. baumannii infection across Europe[13]. Even the incidence of multi-drug resistant strains of A.baumannii began in the early 1980s[14].


However, the rise in prevalence of A.baumannii did not maintain itself throughout the 1980s. After a steady five year increase, A. baumannii represented the cause for 9-10% of nosocomial infections. After 1985, the prevalence of A.baumannii decreased dramatically[15]. This coincided with changes in chemical treatment agents used for A.baumannii infections (see Antibiotic treatment-1980s).


Tangently related to the spread of noscomial A.baumannii is its changing taxonomy at the same time. Until the late 1980s, the number of infections was underestimated due to the clumping together of the Acinetobacter genus seemingly in one complex species, A. calcoaceticus on occasion[15].

1990s

In the 1990s, the number of epidemic A.baumannii outbreak started to climb after a decline of infection in the late 1980s[16]. During the same time, two new locations were becoming reservoirs of A. baumannii: pillows and wounds[6][17]. Also, the number of nosocomial pneumonia infections caused by A.baumannii climbed to 4% of all nosocomial pneumonia cases by the mid 1990s. However, with ventilator-assisted pneumonia, the problem was even greater. In the 1990s, A.baumannii were reported to be the main pathogen involved in ventilator-associated pneumonia[6]. The incidence of mortality rates among patients with nosocomial pneumonia caused by A.baumannii was reported to be as high as 71%, with mortality mainly attributed to A.baumannii[6]. Interestingly, the profile of A.baumannii respiratory infections increased in the 1990s despite major advances in the management of ventilator-dependent patients and routine use of effective procedures for the disinfection of respiratory equipment[17].


Similar to the situation of A.baumannii-caused nosocomial pneumonia in the early 1990s, A.baumannii-caused bacteremia, incidences of bacteria in the bloodstream, accounted for 2% of all nosocomial bloodstream infections in the early 1990s[18]. However, like nosocomial pneuomonia, the incidence of bacteremia due to A.baumannii increased by the mid-1990s. Along with its infection rate, the mortality rate of patients diagnosed with bacteremia caused by A.baumannii was 52%, of which the infection was the primary cause[19]. Simultaneously, there were incidences of epidemic outbreaks of bacteremia caused by A.baumannii in several ICUs[12]. Bacteremia infections during this time period were said to have been correlated to the colonization of patients as well[20].


Although the main infections caused by A.baumanii were respiratory and bloodstream-related, other infections caused by A. baumannii also rose in incidence as well. By the mid 1990s, A. baumannii was isolated as the cause of 1% of nosocomial urinary tract infections[6]. Also, the mortality rates among A.baumannii-caused secondary meningitis cases increased to about 25-27% during this time[6][17].

2000s

Since the year 2000, a new source or place of contamination has emerged from the hospital environment: cell phones. Since the spread of cell phone use among hospital personnel worldwide, there have been instances of cross-contamination between A.baumannii-covered hands of hospital personnel and cell phones[21].


To continue the trend in the 1990s, the incidence of A. baumannii on common hospital surfaces has increased to as much as 50%[22]. In fact, the incidence of A.baumannii itself has increased. In a study of Spanish hospitals, 39% of the hospitals had samples with isolated A.baumannii[23]. There has also been an upward trend in crude mortality rate due to A. baumannii infections, rising to as much as 58%[22]. The isolates collected from studies have shown no signs of deprived growth in any conditions[24]. The incidence of A.baumannii infections in ICUs increased to be 10% of total ICU-acquired infection[24].


By 2007, surveys from several European countries had established a global incidence of 9% A.baumanii among agents of nosocomial pneumonia, an increase from the mid-1990s. The crude mortality rates due to nosocomial pneumonia among these surveys were as much as 75%[15].


There have been instances in which "A.baumannii" has caused as high as 10% of nosocomial bacteremia caused by A. baumannii in studies conducted after 2000[25]. The mortality rates associated with these infections have been consisetent with those seen in the 1990s.


During the last few years, the incidence of unusual and rare A.baumannii infection sites has increased. These include the following infections: suppurative thyroiditis, decubitus ulcers, necrotizing enterocolitis, and A. baumannii peritonitis. All of these infections were severe, hard-to-treat, and had high mortality rates[15].


Pharyngeal colonization in patients still seems to be an extremely high reservoir for A.baumannii infection, accounting for as much of 77% of patients[14]. In this decade, there has been high incidence of patient-to-patient transmission that have led to outbreaks in A. baumannii infections[26].

Resistance

1970s

In the early 1970s, A.baumannii had very little resistance to most major classes of antibiotics. This quickly changed. The most ancestral mechanism to antibiotic resistance is the b-lactamase that conferred resistance to penicillin[27] as that antimicrobial was never effective as an antibiotic against A. baummanii in hospital settings. Also, remember this time as one with little focus on A.baumannii in ICUs. Thus ICU patients were receiving higher levels of antibitoics than even other hospital wards. Therefore, A. baumannii probably received a Molecular Class A b-lactamase on a plasmid. Such an b-lactamase like PER-1 would catalyze the hydrolysis of the b-lactam ring, present in every b-lactam antibiotic[28].

There were small instances of low levels of aminoglycoside resistance developed by the late 1970s. The mechanisms that rendered the Acinetobacter spp. strains resistant to aminoglycoside were by in large aminoglycoside-modifying enzymes like phosphotransferase and acetyltransferase[29]. However, there was aminoglycoside resistance not rendered by modifying enzymes. This unexplained resistance could have been due to low levels of decreased permeability of the Acinetobacter or alteration of the ribosome. Both were later shown to incur resistance in gram-negative bacteria like A.baumannii[30].

1980s

In the early 1980s, Goldstein and his colleagues [31] found levels of resistance to ampicillin, aminoglycoside, chloramphenicol, sulfonamides, and high levels of trimethoprim in Acinetobacter species. Resistance of ampicillin and other b-lactam were conferred by the presence of the b-lactamase TEM-1. This is not to be unexpected because at around the same TEM-1 was the most prevalent plasmid-mediated b-lactamase in gram—negative bacteria[32]. The aminoglycoside resistance was primarily conferred by the actions of two enzymes—phosphotransferase (APH(3')(5")I) and adenyltransferase (AAD(3,9). These resistance genes were found on a 167 Kb plasmid. The sources of resistance for the remaining antibioics were unexplained[31].


There also was evidence of tranposon-mediated resistance in A.baumannii by the early 1980s. An A.baumannii strain that was the cause of an epidemic outbreak of respiratory infection contained aminoglycoside resistance. Aminoglycoside-modifying enzymes, cephalosporinases, and TEM-2 b-lactamases were all transposed onto a chromosome of A.baumannii strains [33].


By the mid 1980s, a resistance determinant for tetracycline antibiotic had been isolated from A.baumannii and its function had been identified [34][35]. Water et al. (1983) found the resistance protein (tetA) and its regulatory gene (tetR), mediated from a plamid and a transposon. In Unger et al. (1984) the tetA gene was said to act as a repressor in A. baumannii for tetracycline.


By the late 1980s, aminoglycoside-modifying enzymes had become widespread mechanisms of resistance in A.baumannii strains. Aminoglycoside and b-lactam resistance had become a frequent trans-Atlantic occurrence with outbreaks of aminoglycoside and b-lactam resistance both in Europe and North America[36]. At that time, Acinetobacter clinical strains were highly resistant to most major monotherapy antibiotics of the time (Joly-Guillou & Bergogne- Berezin, 1986) with the following rates of resistance: 75-99 % b-lactams, 96% to cefotaxime, 84-99% to aminglycoside,and 86-5% to tetracycline antibiotics[37].

1990s

In the 1990s, the outbreak of Multi-Drug Resistant (MDR) A.baumanii strains increased dramatically. The outbreak usually involved imipenem-resistant A.baumannii. The susceptibility of A.baumannii to imipenem declined from 98% in 1990 to 64% in 2000[38]. This marked a trend in general with antibiotic treatments of A.baumannii in the 1990s. In a six year study, A.baumannii saws it resisannce to multiple antibiotics dramatically increased as follows: ciprofloxacin (fluoroquinolone), 54.4% and 90.4%; tobramycin (aminoglycoside), 33% and 71.8%; amikacin (aminoglycoside), 21% and 83.7%; ampicillin (b-lactam) plus sulbactam (b-lactam), 65.7% and 84.1%; ceftazidime (cephalosporin), 57.4% and 86.8%; ticarcillin (b-lactam), 70% and 89.4%; trimethoprim plus sulfamethoxazole (sulfonamide), 41.1% and 88.9%[39].

In the early 1990s, imipenem-resistance in A.baumannii was isolated in strains in Europe. One mechanism of resistance involved a modified 24-kiloDalton penicillin-binding-protein (PBPs) with increased affinity for b-lactam antibiotics[40]. This PBP couldn’t be saturated by imipenem and therefore cell-wall synthesis was not prevented. Another mechanism was the isolation of a novel b-lactamase AR1 (Acinetobacter Resistant to Imipenem)[41]. By the mid-1990s, the role of outer-membrane proteins and efflux pumps in resistance began to grow. At the end of the 1990s, imipenem resistance was bolstered with the characterization of OXA-b-lactamases and novel metallo-b-lactamases in the A.baumannii[27].


In the mid 1990s, mutations in topoisomerase genes conferred quinolone resistance in A.baumannii. A mutation in the gyrase A gene coded for a modified protein to bind to DNA gyrase so that it was not inhibited by quinolone antibiotic[42] and DNA replication can take place. Also characterized was a mutation in the parC gene that modified the ParC subunit of topoisomerase IV so that DNA replication cannot be inhibited by quinolone as well[43].


At the end of the decade, an important efflux-pump was isolated in an A.baumannii strain. The AdeABC efflux pump conferred resistance to aminoglycosides, b-lactams, chloramphenicol, erythromycin (macrolide), tetracycline, and ethium bromide[44].

2000s

After the year 2000, the ultimate threat of resistant A.baumannii has almost come to pass. In clinical settings, there have been numerous outbreaks of pan-resistant A. baumannii strains[24][45][46]. The morbidity and mortality rates related to infections by these isolates are extremely high. This has made PDR A.baumannii an organism with even more clinical and public health importance than before.


The prevalence of imipenem resistance has begun to grow even more. There were several discovery of oxacillinases that were capable of hydrolysis of imipenem and other carbapenems like meropenem. There was also characterization of genes that code for carbapenemases like blaVIM genes[47].


Since the year 2000, the prevalence of efflux pump in MDR or PDR A.baumannii has grown tremendously. In Damier-Polle et al. (2008), a second RND pump, AdeIJK was discovered in A.baumannii strain. AdeIJK pump confers resistance to the following antibiotic: β-lactams, chloramphenicol, tetracycline, erythromycin, lincosamides, fluoroquinolones, fusidic acid, novobiocin (aminocoumermycin), and rifampin (ansomycins). It also confers reistance to the following compunds: trimethoprim, acridine, safranin, pyronine, and sodium dodecyl sulfate[48]. The ability to efflux so many different compounds makes it an extremely effective broad-spectrum efflux pump.


Recently, the problem of tigecycline resistance in A.baumannii has become more prevalent. In a recent study of 19 hospitals in Taiwan, isolates were determined to have a low level resistance of 6.9%, also 12.2% of isolates were intermediate of resistance as well. It is important to note that intermediate resistance was seen as high as 51.7% by the US FDA criteria. However, researchers used a more accurate method to determine of the susceptibility of the strains[49]. In a yet-to-published study in Argentina, Fernández Canigia et al. (2009) showed Acinetobacter spp was similarly resistant with 8% of isolates showing resistance to tigecycline[50]. It was recently shown that overexpression of the AdeABC pump already present in A.baumannii strains has led to reduced susceptibility to tigecycline[51]. In Damier-Polle et al. (2008), it was shown the AdeABC and AdeIJK efflux systems contributed to tigecycline more than additively as when compared to AdeABC alone[48] .


As of late, incidences of polymyxin and colisitin-resistant A.baumannii have been becoming more frequent as well. In Korea, there were isolates with high rates of resistance to colistin and polymyxin B were reported[52] .


With the increasing presence of the metallo-b-lactamase and other antibiotics requiring metal ions for entrance in A.baumannii, it is no surprise that A.baumannii has developed heavy metal resistance as well. In Fournier et al. (2006), whole genome sequencing of an entire A.baumannii strain revealed the presence of an arsenic resistance operon, a mercury resistance operon, and a couple of heavy detoxification proteins[2]. This is probably beneficial for survival in the habitats of A.baumannii-the soil and metal-based structures in hospitals.

Antibiotic Treatment

1960 and 1970s

Colistin sulfate has been available for use since the 1960s. It was an effective bactericidal antibiotic for gram-negative bacteria like A.baumannii. No resistance probably developed for two reasons. One, colistin killed the bacteria by disrupting the cell membranes and didn’t rely on the metabolic activity to eliminate infection. Two, the use of the antibiotic was limited due to concern over its toxic effects on patients[53]. There were severe incidences of neurotoxicity and nephrotoxicity as a result of colistin treatment in the 1960s and 1970s. Thus, with the advent of safer and still effective drugs against A.baumanii strains, colistin sulfate was phased out almost completely of A.baumannii treatment by the end of the 1970s[54].


Some of these less toxics drugs to replace colistin were moderate (ampicillin) and broad-spectrum (carbenicillins) b-lactams, aminoglycosides (gentamicin), broad-spectrum (minocycline) tetracycline, and first-generation quinolone (nalidixic acid) antibiotics[55]. The main motivation behind the implementation of the aminoglycoside antibiotics was their generic ability to treat multiple gram-negative infections[56]. However, the b-lactam antibiotics like carbenicillin and ampicillin had a greater effect at first on Acinetobacter infections. This was due to two reasons. First, The aminoglycoside antibiotics had a small level of toxicity inherent to them. Second, the b-lactams had a greater clinical efficacy than the aminoglycosides[57].

By the end of 1970s, nalidixic acid and tetracycline antibiotics was sought after as treatment for A.baumannii because the susceptibilities levels were lower than most known b-lactams and it was less toxic than aminoglycoside antibiotic[56][58]. However, their use did not approach that of aminoglycoside and b-lactam antibiotics.

1980s

The development of resistance to major antibiotics such as ampicillins, gentamycin, and first-and-second generation cephalosporins created a need for new antibiotic to treat gram-negative bacteria like A.baumannii. For the early 1980s, the solution lied in releasing newer generation of classes of antibiotics that had been previously used in A.baumannii. The aminoglycoside replacements included tobramycin and amikacin. To replace the older cephalosporin antibiotic, the third generation cephalosporins cefotaxime and ceftazidime[59] began to used in treatment against A.baumannii infections. Motivations to use newer cephalosporins also included its new broad spectrum of activity against gram-negative bacteria. There were also very important for the treatment for the few cases of A.baumannii-caused meningitis in the 1980s[60].


The early 1980s saw the introduction of the b-lactam sulbactam into clinical settings. Sulbactam had some ability to work on its own because it was not capable of being hydrolyzed by b-lactamases. In fact, sulbactam is a b-lactamase inhibitor. This property of sulbactam caused it to be used primarily in combination with other b-lactams that could be hydrolyzed by a b-lactamase[61].


However, the major antibiotic treatment of A.baumannii infections was released in the mid 1980s. Imipenem was the newest of the b-lactam subclass carbapenem. This subclass of antibiotics had become extremely attractive treatments for Acinetobacter infections for two main reasons. One, their broad-spectrum ability allowed imipenem and other carbapenems to efficiently treat A. baumannii-caused pneumonia. Two, their structure rendered them highly resistant to b-lactamases of the time[62]. Imipenem remained the most frequent agent against A.baumannii infections for much of the next decade.

1990s

The use of imipenem antibiotics to treat A. baumannii infections as the premier agents continued well in the 1990s. Despite the growing incidence of resistance, the level of imipenem use remained relatively high. The persistence of its use in clinical settings can be explained by its superior activity against A.baumannii compared to other antimicrobial agents, even with its growing resistance[63]. As the resistance of imipenem continued to grow, another bacteriostatic carbapenem began to be used in greater frequency-meropenem. In addition to be a broad-spectrum agent against gram-negative bacteria, meropenem is also less likely to cause seizures than imipenem[64].

Besides the continued the use of carbapenems, the combination of anti-A.baumannii agents was a major therapeutic strategy employed in the 1990s. The main purpose of these pairings was to put together drugs that would have similar effects as a monotherapy drug of the same class. This usually involved pairing a drug with high resistance and a drug whose use had been limited. For example, sullbactam, which was first produced in the 1980s, seems to be paired with otherwise compromised penicillins, like ticarcillin[62]. However, the most successful pair of agent to emerge was the team of ampicillin/sulbactam. The pair maintained the best bacteriostatic control of any pair of agents in the 1990s. Also, it was regarded as a more cost effective alternative to imipenem treatment[63].

By the late 1990s, combination therapy was not limited to ampicllin/sulbactam. In fact, combination therapy became the preferred manner to treat A.baumannii infection. There were other successful combinations used during this time. Aminoglycosides were paired with b-lactams like ceftazidime or imipenem. Combinations of b-lactams with fluoroquinolones or rifampicin were proscribed as well[62].

2000s

With the advent of ampicillin/sulbactam resistance and carbapenem resistance, A.baumannii has practically returned to its pre-antibiotic era. The only effective treatment of A.baumannii seems to be colistin (polymyxin) antibiotics. The concern voiced about nephrotoxicity and neurotoxicity in the 1960s and 1970s has been pushed aside in favor of the effectiveness of the antibiotic. Colistin has been shown to have efficacy in treating A.baumannii-caused pneumonia. It also has been shown to be a good therapeutic strategy for treating A.baummannii-caused bacteremia. Besides the major nosocomial infections caused by A.baumannii, colistin is also effective against less prevalent infections. Colistin has been shown to penetrate into the cerebrospinal fluid so that it effectively treats cases of meningitis. On top of its therapeutic abilities, polymyxin antibiotics also act as effective cleaning agents. Polymyxin B was shown to important cleaner of wounds, a good reservoir for bacteria[63].

In the early years after the new millennium, tigecycline, a glycylcycline, was shown to be effective in vivo against A.baumannii. Also, it is has been shown to effectively treat a case of septic shock caused by a pan-drug-resistant A.baumannii[24].

However, this is a new hope for antibiotic treatment for A.baumannii. Doripenem is the latest broad-spectrum carbapemen. It is improved to treat A.baumannii-caused urinary tract infections and intra-abdominal infections. Its ability to treat ventilator-associated pneumonia is being approved clinical testing. In a recent study, doripenem was twice as active as imipenem and meropenem against Acinetobacter isolates. Doripenem was the most active carbapenem tested against other gram-negative bacteria regardless of beta-lactam resistance[65].

See also

Nosocomial CVC Infections due to Antibiotic Resistant Acinetobacter baumannii [2] - A contemporary anaylsis of the A.baumannii" problem

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