Kim Johnson

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Nosocomial CVC Infections due to Antibiotic Resistant

Acinetobacter baumannii

A Project for BIO351


The Clinical Problem: Hospitals That Kill

Nosocomial (hospital derived) infections can be devastating, even life threatening, to a patient already compromised by an underlying and primary medical condition. An individual seeking treatment at a medical facility for heart disease or respiratory failure may not have the stamina or immune system available to fend off a systemic bacterial infection.

Central venous catheter (CVC) use is common in most wards of the hospital, including the intensive care unit (ICU) where critical patients are treated. Studies show that "approximately 3.5 million CVC's are used in the U.S. annually leading to approximately 250,000 CVC-related infections and an estimated 40,000 deaths."[1] Infection can be derived as a result of several risk factors, including contaminated medical ventilators, intravascular access devices, insufficient sterilization due to health care personnel, or inanimate surfaces in the patients vicinity (bedding, counters, faucets).[2]

Acinetobacter baumannii derived infection is dangerous and often leads to nosocomial bacteremia or pneumonia,[2] which can result in death. Improper use of indwelling medical devices is one of the culprits enabling bacteria to enter the human body, with CVC use being one of the top causes of A. baumannii derived bacteremia. Correct therapeutic applications can often be outdated, as the organism has an exceptional ability in accumulating foreign DNA containing antibiotic resistance into its chromosome. Worse yet, even if this bacterial strain were susceptible to the antibiotic given the patient survivability rates are only about 50%.[3] Mortality rates with inadequate treatment of nosocomial A. baumannii bloodstream infections can be as high as 91%.[3]

Nosocomial bloodstream infections caused by Acinetobacter baumannii merits further study regarding its effects on compromised patients and its rates of eluding antibiotic therapy with increasing resistance. The high prevalence of mortality the organism causes via colonizing CVCs and other medical devices only amplifies this cause, as they are in constant use in patient care.


Suspect Profile

Acinetobacter baumannii is a gram-negative aerobic coccobacillus that is widespread in nature and has been viewed as an opportunistic pathogen since the 1970s.[4] This organism occupies a variety of ecological niches, originating in soil and water but has been found colonizing hospital surfaces and on patient skin. This isolate belongs to the genus Acinetobacter, a group of species known for their frequently changing genetic diversity.[4] It is known for causing a variety of nosocomial infections, making this the only species of Acinetobacter with the most impact in medicine today.[5]

A complete listing of the Acinetobacter species and taxonomy can be located here at GenBank. Further information can also be found at my colleague's page here.

Epidemiology

For the past thirty decades, A. baumannii has risen in the clinical setting, and can account for 2% to 10% of the organisms causing bacteremia in health care facilities.[6] occupying hospital surfaces and residing commensurately on patients until it has a means to colonize internally. It has the ability to survive for long periods of time on common surfaces in the hospital,[7] including counters, sinks, and medical equipment. Some clinical reports allude to its ability to be transmitted via respiration of infectious airborne particles[8] and through individual contact, usually as result of hospital personnel.[7] There has been a correlation between an infection with this organism and patient location or treatment upon admission, with an increased rate of acquiring an A. baumannii infection in the ICU and [following] use of an indwelling medical device.[2]

Transmission

This organism raises concern in the clinical setting as it is usually acquired from the intensive care unit, due to this location being the main source of A. baumannii bloodstream disease.[4] Its ability to cause bacteremia is contributed to the modes of transmission, such as in airborne pathways and contact of contaminated surfaces. Airborne transmission of Acinetobacter species was seen in a study where sterile settle plates were placed near patients with colonized skin and respiratory tract infections; the plates were positive for Acinetobacter species and indicated the species was transmitted there by an airborne pathway.[4]

Coming in contact with contaminated surfaces was a large portion of Acinetobacter baumannii transmission, notably in the hands of health care workers.[4] Studies show that 19% to 29% of hospital personnel hands were colonized by this species.[4] One outbreak was contributed to a health personnel's negligence to remove their contaminated gloves between patients while another was due to a contaminated therapist touching respiratory equipment.[4] Other contamination sources were linked to ventilators only being cleaned between patients (not before), sink traps, floors, and patient skin. The latter contributes to contamination of the hubs and lines of central venous catheters.[9]

Mortality

Mortality is increased when a patient is infected with nosocomial derived Acinetobacter baumannii, and the rates are still high when the proper therapeutic action is taken. Smolyakov, et al. found that by treating patients who had nosocomial BSI from A. baumannii with a therapy that stopped the organism, the mortality rate was only 41%; patients who were treated with an antibiotic the organism was resistant to had a mortality rate of almost 92%.[3] This could be attributed to the underlying conditions of the patient: age, cardiac disease, renal failure, admission to the ICU, and use of a CVC.[3] Side effects with this infection include septic shock, which is a result of A. baumannii bacteremia in about 25% to 30% of cases.[7]

High mortality rates can be attributed to the infection in conjunction with the primary medical condition that the patients were seeking aide for. In a weakened physical state, it seems that the host body cannot sustain warding of bacteremia on top of other complications.

Central Venous Catheter Use and Infection

Medical devices are an integral part of patient care in the hospital. They include, but are not limited to, providing parenteral nutrition, mechanical ventilation, distributing of medicine throughout the body, and facilitating blood draws.[1] Extremely useful as they are in saving lives, incorrect use can instead ensure that they can be a cause of death. Reusable devices have been linked to nosocomial infections, as it is found that "of the two million nosocomial infections diagnosed annually, as many as 50% are associated with implanted devices,"[9] due primarily to improper sterilization techniques.[4]

Currently patients with urinary catheters and intravascular devices are more prone to acquiring nosocomial infections.[2] Colonization of these indwelling medical devices can occur in as little as twenty four hours.[10] Most CVCs are colonized by a bacterial biofilm matrix, which originate from the patient's skin and migrate along the external catheter surface or integrate into the catheter through the hub/port; this allows for direct access into the bloodstream.[9]

The nosocomial infection seen primarily from the use of central venous catheters is a bacteremia, also known as a blood stream infection (or BSI). BSIs can be caused by a multitude of bacterial strains, but notably "gram-negative bacilli were responsible more often than gram-positive cocci for catheter tip colonization (53% vs 46%) and they were responsible for all the bacteremias (5.1%) related to catheters,"[11] indicating that A. baumannii can certainly be a legitimate culprit. A recent study by Wisplinghoff, et al. found that in 24 of 49 hospitals, there were 166 confirmed cases of bacteremia cause by Acinetobacter species. Of those colonized by A. baumannii, 73.9% of patients had central venous catheters that contributed to their nosocomial infection.[2]

Bloodstream infections have been linked to duration of CVC use, line breaks, skin care around the site of insertion, and the placement of the CVC itself.[12] Failure to maintain the catheter while it is in use can make the patient susceptible to contracting an A. baumannii or other bacterial disease.

Treatment and Eradication

The CDC recommends that proper hand washing and decontaminating the areas where infected individuals were contained are the best ways to prevent the spread of the organism. Treatment methods should be based on an individual basis and after correct confirmation that the infection is caused by this organism.[13]

Medicinal Therapy

Acinetobacter baumannii infections have been treated by virtually all classes of antibiotics, and its susceptibility is only induced when a new antibiotic is introduced to an environment where it was not present before. For instance, in Taiwan hospitals are able to treat A. baumannii infections with ciprofloxacin, whereas findings from Germany and Spain indicate that most of the BSI infections with this organism are resistant to that same antibiotic.[2] Susceptibility rates differ amongst countries that have differing standards of treatment for bloodstream infections, seen below in the comparison between Israel and the United States.

Sample of susceptibility rates between Israel (Smolyakov 2003) and the United States (Wisplinghoff 2000). Note that the rates of susceptibility differ for each antibiotic class.

The rise in multi-drug resistant Acintobacter species has lead to a search for more functional and effective antibiotics that it has not developed insusceptibility to. The efficacy of antimicrobials to conquer Acinetobacter baumannii bacteremias has been limited to a few drugs: polymyxin E (colistin), ampicillin-sulbactam (with or without rifampicin), imipenim, and minocyclin-polymyxin B.[3] Imipenim and minocyclin-polymyxin B are not as useful as the other two therapeutic agents, due to overexposure in the environment and A. baumannii's ability to rapidly acquire resistance.[6] Considering the fact that A. baumannii infections are often seen in compromised patients, Colistin use is also limited due to its detrimental side effects, including nephrotoxicicty, neurotoxicity, and neuromucscular blockade.[3]

Monotherapy may not be effective against all A. baumannii infections, as it has been noted that even the highly effective antibiotic polymyxin B can select isolates for resistance when used alone, but its efficacy is increased when given in tandem with rifampin.[14] In 2003, the medical treatment took another route in combating A. baumannii infections by utilizing combination therapy, similar to the antibiotic cocktails given to HIV and Tuberculosis patients. It was seen that by giving ampicillin-sulbactam treatment in tandem, the rate of MDR A. baumannii nosocomial BSI mortality rate decreased by nearly fifty percent.[3] Triple therapy was also effective in counteracting A. baumannii BSI, with patients receiving the combination ampicillin-sulbactam treatment in conjunction with imipenim.[3] However, some trials with this treatment are still in the in vitro phase, although it has been utilized for in vivo use with some MDR A. baumannii patients.

Environmental Prevention

Environmental contamination is an important cause of nosocomial infection, especially in regard to prevention of A. baumannii infections from inanimate objects and surrounding surfaces.[7] Decontamination of the environment is an integral part in maintaining patient health in the clinical setting, however the insistence by A. baumannii to a biofilm lifestyle makes eradication of the organism very difficult. Disinfecting surfaces colonized by such an organism requires penetration of the biofilm matrix and lysis of all cells within the population to ensure a sterile environment. Also, since the organism can reside on skin, correct preventative measures need to be taken in regards to cleanliness.

Some hospital officials have proceeded with extreme overhauls in the ICU departments to eradicate A. baumannii colonies. In conjunction with sterilizing medical ventilators and devices, they have shut down ICUs, removed all patients and decontaminated the area with antimicrobial detergents and a re-painting of all the walls.[15] However, this aseptic ward was found to be re-colonized quickly after the admission of infected patients back into the ICU[15], noting that even a thorough purging and cleaning can limit microbial growth cannot fully extirpate A. baumannii from the environment. It has even been suggested that undertaking a complete structural redesigning of ICU and other hospital wards could be the ultimate way to reduce A. baumannii nosocomial infections[15], but the costs would be a prohibitive alternative rather than the implementation of a stringent cleaning regimen.

Patient Contact Treatments

Hand Washing

A common preventative method that appears to require more attention is the simple act of washing hands between patient contact regardless of visible contamination. It was observed that health care workers in one hospital only washed their hands about 10% of the time before patient contact and only 22% after patient contact,[16] essentially assisting bacterial transmission all over the facility. This is a critical health care issue, especially in regards to decreasing the amount of nosocomial A. baumannii infections in patients. Acinetobacter baumannii is a commensal organism, so touching a contaminated surface or colonized patient and not washing before caring for another patient greatly increases their risk for catching the organism. Hand washing education was implemented in this hospital along with installation of alcohol based antimicrobial hand sanitizer, causing the level of hand hygiene to increase to 23% before patient care and 48% after patient care.[16]

CVC Maintenance

One would assume that the best method for treating an infection from CVC use would be to simply remove the device, but if the source is necessary for patient survival then other techniques must be applied. Decreasing the duration of device use, applying topical antimicrobials to the patient skin prior to insertion, and replacing CVCs linked to prevention[10] are all relatively easy methods for controlling A. baumannii infections. More stringent solutions implementing the use of antibiotics or antimicrobials within central venous catheter lines have also been applied to confront the gram-negative biofilm dilemma, including those caused by Acinetobacter species. In an earlier study (1999) it was found that impregnating central venous catheters with antibiotics had a greater effect than antimicrobials for fighting internal CVC colonizations, while antimicrobials were more effective in preventing external CVC colonization.[17] They found that catheters impregnated with the two antibiotics minocycline and rifampin had "remarkably low rates of catheter-related bloodstream infection (0.3 percent) and [internal] catheter colonization (7.9 percent)."[17] When testing with the antimicrobials chlorhexidine and silver sulfadiazine, they found that the external surface of the catheter had reduced colonization.[17]

Recently, the Angiotech Pharmaceuticals company is undergoing a new trial implementing the use of 5-Fluorouracil (5-FU), a known anti-cancer drug, on coated CVCs in an effort to reduce microbial biofilm production.[1] The product 5-FU has been shown to impede biofilm colonization and to inhibit bacterial proliferation[1], making it a new frontier for the advancement of maintaining sterile CVC use. Plus, using the drug with an "off label" use will limit its exposure in the bacterial environment[1], thus decreasing the rate of resistance that A. baumannii could acquire.

Persistence

Acinetobacter baumannii has the amazing ability to incorporate foreign DNA into its chromosome, expressing the genes necessary for survival and resistance in a ever-changing environment. With this, it is surprising that the organism is not the most prevalent in the clinical setting, unlike the E. coli bacteria. Its lack in prevalence could be associated with a decreased fitness in maintaining a large genome, missing vital mutations to increase MDR, combination antibiotic therapy or inopportune living conditions. Regardless, A. baumannii's increasing abilities for persistence ensures that it will be a constant in the community.

Pathogenicity

Acinetobacter species are extremely nonspecific about the type of foreign DNA they can obtain from a variety of surroundings and organisms. It is this trait that allowed some species to attain resistance genes that enabled them to persist in hostile antimicrobial environments. The flexible genetic diversity in A. baumannii is seen as an important mechanism for pathogenesis, allowing the organism to have selective advantages over others with more fixed genomes.[18]

The pathogenic profile of A. baumannii has not been fully explored, but some mechanisms have been investigated in its role as a nosocomial organism inhabiting a clinical setting. Tomaras found that the use of a unique pilus mechanism allows Acinetobacter to colonize onto catheters and respiratory equipment as a biofilm and eventually migrating its way through the system into the bloodstream.[5] Other mechanisms include inducing cell apoptosis, where the Omp38 outer membrane protein A. baumannii produces is localized to the mitochondria of human epithelial cells, inducing mitochondrial decomposition and releasing apoptytic molecules.[19]

The need for increased knowledge about the potential virulence pattern this organism can display is increasing as A. baumannii becomes more persistent in patient environments. Untreated (unknown infection) or inadequately treated (treating strains with antibiotics it displays resistance to) Acinetobacter infections can usually lead to severe illness and death, with some mortality rates as high as 73% in patients with this infection.[18]

Biofilm Matrix

Biofilms are aggregates of microorganisms and allow for their persistence in hostile environments and sometimes through inoculations of antibiotics. The Center for Disease Control has recently found that about 65% of all infections found in developing countries are caused by biofilms and have caused infections corresponding with use of all known indwelling medical devices.[20] Acinetobacter baumannii commonly colonizes medical devices and common surfaces with a biofilm matrix, aggregating on glass and plastic surfaces with a specialized mechanism of attachment and produce polysaccharide polymers to increase adhesion and provide structure.[10] This gives the organism an edge for resilience, as antibiotics have to be able to penetrate the outer shell of the biofilm before it can pose a threat to the cells dwelling inside.

Electron microscopy detected that A. baumannii's ability to form a biofilm is attributed to a novel pilus assembly system that allows the bacteria to grasp and adhere to an inert surface, as well as stacking on each other to increase the volume of the biofilm.[5] Tomaras, et al. found that genetic analysis of the gene encoding the pilus was from Pseudomonas species, another gram-negative genus with the ability to colonize via biofilm formation.[5] Tomaras also showed that the gene was integral for biofilm formation, as disrupting the gene prevented A. baumannii cells from aggregating together and forming a permanent structure.

The pilus mechanism utilized by A. baumannii allowed a biofilm matrix on catheters because it was able to adhere to the plastic hub and to each other, multiply successfully, and eventually migrate down the catheter into the host. Its close evolutionary proximity to the Pseudomonas and constant exposure to other known pathogenic species in the clinical environment lends some understanding to how A. baumannii came to be a pathogen itself.[6]

Genetic Resistance Profile

There are many strains of Acinetobacter baumannii that harbor different pathogenic abilities. Some carry entire genomic isolates dedicated to mechanisms that eradicate antibiotics from the organism, while others contain mechanisms to tolerate metal exposure in the environment. This organism also can accumulate more of these resistance mechanisms from other bacteria or from naked DNA left in the environment, a trait that allowed A. baumannii to develop multi-drug resistance strains within just three decades.[6]

One particular strain termed AYE carries an 86,190-bp (base pair) genetic region or "resistance island" containing 45 genes known for resistance against antibiotics and heavy metals.[6] AYE is termed an MDR strain, containing resistance against most β-lactams and all aminoglycosides, fluoroquinolones, chloramphenicol, tetracycline and rifampin, and is epidemic in clinics across France.[6] In 2007 the strain A. baumannii ATCC17978 was genetically sequenced, revealing that it contained a 3,976,746-bp genome possessing an additional 74 potential antibiotic resistant genes.[18] The genome of ATCC17978 consists of 28 genetic islands containing 16 genes linked to virulence, with the largest of these genetic islands being 133,740-bp and containing genes encoding virulence that are homologous to other known pathogenic bacteria.[18].

Both strains contain islands that hold genes encoding heavy metal resistance. Heavy metals have been a contaminant in the environment long before commercially made antibiotics made an impact, and may assist in resistance mechanisms.[21] Having heavy metals a constant in the environment exerts a form of pressure on bacteria, where those that persist (through a series of mutations or genetic determinants) will survive to repopulate the area and pass on their survival genes to their offspring. Some genes encoding heavy metal resistance are located on the same integron as antibiotic resistance genes and can be transferred simultaneously; others are a part of the same element and are activated by the same path, like encoding an efflux pump that recognizes both heavy metals and certain antibiotics.[21]

This organism's capability to increase its genetic profile and utilize most of the foreign DNA it accumulates further expedites the need to understand the strains in health care facilities and develop a proper treatment for each case. It is only a matter of time before the strain of Acinetobacter baumannii that is present in the nearest clinical facility accrues enough genetic material to become a full multi-drug resistant organism.

References

Abbreviation chart.jpg
  1. 1.0 1.1 1.2 1.3 1.4 (2007, July 11). Angiotech completes enrollment in its central venous catheter (CVC) pivotal study. Retrieved November 22, 2008, from Medical News Today. Web site: http://www.medicalnewstoday.com/articles/76473.php
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Wisplinghoff H, Edmond MB, Pfaller MA, Jones RN, Wenzel RP, Seifert H. (2000). Nosocomial bloodstream infections caused by Acinetobacter species in United States hospitals: Clinical features, molecular epidemiology, and antimicrobial susceptibility. Clinical Infectious Diseases. 31, 690-697.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Smolyakov R. et al. (2003). Nosocomial multi-drug resistant Acinetobacter baumannii bloodstream infection: Risk factors and outcome with ampicillin-sulbactam treatment. Journal of Hospital Infection. 54, 32-38.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Forster DH, Daschner FD. (1998). Acinetobacter species as nosocomial pathogens. European Journal of Clinical Microbiology & Infectious Diseases. 17, 73-77.
  5. 5.0 5.1 5.2 5.3 Tomaras AP, Dorsey CW, Edelmann RE, Actis LA. (2003). Attachment to and biofilm formation on abiotic surfaces by Acinetobacter baumannii: involvement of a novel chaperone-usher pili assembly system. Microbiology. 149, 3473-3484.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 Fournier P. et al. (2006). Comparative genomics of multidrug resistance in Acinetobacter baumannii. PLoS Genetics. 2, 62-72.
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  13. Centers for Disease Control and Prevention, (2004, Sept 24). Drug-resistant Acinetobacter infections in healthcare settings. Retrieved November 25, 2008, Web site: http://www.cdc.gov/ncidod/dhqp/ar_acinetobacter.html
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  15. 15.0 15.1 15.2 Weinstein RA, & Bonten M. (2002). Infection control in the ICU environment. New York, NY: Springer-Verlag.
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  17. 17.0 17.1 17.2 Darouiche RO, et al. (1999) A comparison of two antimicrobial-impregnated central venous catheters. The New England Journal of Medicine. 340, 1-8.
  18. 18.0 18.1 18.2 18.3 Smith MG, Gianoulis TA, Pukatzki S, Mekalanos JJ, Ornston LN, Gerstein M, Snyder M. (2007). New insights into Acinetobacter baumannii pathogenesis revealed by high-density pyrosequencing and transposon mutagenesis. Genes and Development. 21, 601-614.
  19. Choi CH, et al. (2005). Outer membrane protein 38 of Acinetobacter baumannii localizes to the mitochondria and induces apoptosis of epithelial cells. Cellular Microbiology. 7, 1127-1138.
  20. Lewis K (2007). Persister cells, dormancy and infectious disease. Nature. 5, 48-56.
  21. 21.0 21.1 Baker-Austin C, Wright MS, Stepanauskasc R, and McArthur JV. (2006). Co-selection of antibiotic and metal resistance. TRENDS in Microbiology. 14,176-182.