Treatment of infections after exposure to ionizing radiation

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Infections caused by exposure to ionizing radiation can be extremely dangerous, and are of public and government concern. [1] [2] Numerous studies have demonstrated that the susceptibility of organisms to systemic infection increased following exposure to ionizing radiation. [1] The risk of systemic infection is higher when the organism has a combined injury, such as a conventional blast, thermal burn, [3] or radiation burn. [2] There is a direct quantitative relationship between the magnitude of the neutropenia that develops after exposure to radiation and the increased risk of developing infection. Because no controlled studies of therapeutic intervention in humans are available, almost all of the current information is based on animal research. [3]

Contents

Cause of infection

Infections caused by ionizing radiation can be endogenous, originating from the oral and gastrointestinal bacterial flora, and exogenous, originating from breached skin following trauma.

The organisms causing endogenous infections are generally gram negative bacilli such as Enterobacteriaceae (i.e. Escherichia coli, Klebsiella pneumoniae, Proteus spp. ), and Pseudomonas aeruginosa.

Exposure to higher doses of radiation is associated with systemic anaerobic infections due to gram negative bacilli and gram positive cocci. Fungal infections can also emerge in those that fail antimicrobial therapy and stay febrile for over 7–10 days.

Exogenous infections can be caused by organisms that colonize the skin such as Staphylococcus aureus or Streptococcus spp. and organisms that are acquired from the environment such as Pseudomonas spp.

Organisms causing sepsis following exposure to ionizing radiation:

-EndogenousExogenous
Low doses Staphylococcus spp. Enterobacteriaceae ( Klebsiella spp., E coli )None currently known
High dosesFungi, Anaerobic bacteria Pseudomonas aeruginosa, Klebsiella pneumoniae

Principles of treatment

The management of established or suspected infection following exposure to radiation (characterized by neutropenia and fever) is similar to that used for other febrile neutropenic patients. [4] However, important differences between the two conditions exist. The patient that develops neutropenia after radiation is susceptible to irradiation damage to other tissues, such as the gastrointestinal tract, lungs and the central nervous system. These patients may require therapeutic interventions not needed in other types of neutropenic infections. The response of irradiated animals to antimicrobial therapy is sometimes unpredictable, as was evident in experimental studies where metronidazole [5] and pefloxacin [6] therapies were detrimental. [ citation needed ]

Antimicrobial agents that decrease the number of the strict anaerobic component of the gut flora (i.e., metronidazole) generally should not be given because they may enhance systemic infection by aerobic or facultative bacteria, thus facilitating mortality after irradiation. [7]

Choice of antimicrobials

An empirical regimen of antibiotics should be selected, based on the pattern of bacterial susceptibility and nosocomial infections in the particular area and institution and the degree of neutropenia. Broad-spectrum empirical therapy (see below for choices) with high doses of one or more antibiotics should be initiated at the onset of fever. These antimicrobials should be directed at the eradication of Gram-negative aerobic organisms (i.e. Enterobacteriaceae, Pseudomonas ) that account for more than three-fourths of the isolates causing sepsis. Because aerobic and facultative Gram-positive bacteria (mostly alpha-hemolytic streptococci) cause sepsis in about a quarter of the victims, coverage for these organisms may be necessary in the rest of the individuals. [8]

A standardized plan for the management of febrile, neutropenic patients must be devised in each institution or agency., [9] [10] Empirical regimens must contain antibiotics broadly active against Gram-negative aerobic bacteria (a quinolones [i.e. ciprofloxacin, levofloxacin ], a fourth-generation cephalosporins [e.g. cefepime, ceftazidime ], or an aminoglycoside [i.e. gentamicin, amikacin]) [1] Antibiotics directed against Gram-positive bacteria need to be included in instances and institutions where infections due to these organisms are prevalent. ( amoxicillin, vancomycin, or linezolid).

These are the antimicrobial agents that can be used for therapy of infection following exposure to irradiation:

a. First choice: ciprofloxacin (a second-generation quinolone) or levofloxacin (a third-generation quinolone) +/- amoxicillin or vancomycin. Ciprofloxacin is effective against Gram-negative organisms (including Pseudomonas species) but has poor coverage for Gram-positive organisms (including Staphylococcus aureus and Streptococcus pneumoniae ) and some atypical pathogens. Levofloxacin has expanded Gram-positive coverage (penicillin-sensitive and penicillin-resistant S. pneumoniae) and expanded activity against atypical pathogens.

b. Second choice: ceftriaxone (a third-generation cephalosporin) or cefepime (a fourth-generation cephalosporin) +/- amoxicillin or vancomycin. Cefepime exhibits an extended spectrum of activity for Gram-positive bacteria (staphylococci) and Gram-negative organisms, including Pseudomonas aeruginosa and certain Enterobacteriaceae that generally are resistant to most third-generation cephalosporins. Cefepime is an injectable and is not available in an oral form.

c. Third choice: gentamicin or amikacin (both aminoglycosides) +/- amoxicillin or vancomycin (all injectable). Aminoglycosides should be avoided whenever feasible due to associated toxicities.

The second and third choices of antimicrobials are suitable for children because quinolones are not approved for use in this age group.

Antimicrobial Therapy for Sepsis after Irradiation (Duration 21–28 days)
• Quinolones, 2nd or 3rd generation

– Ciprofloxacin (2nd) or Levofloxacin (3rd)

• Cephalosporins, 3rd or 4th generation

– Ceftriaxone (3rd) or Cefepime (4th)

• Aminoglycosides

– Gentamicin or Amikacin

• ± Amoxicillin or Vancomycin
• ± Amphotericin B (persistent fever 7 days on Rx)

The use of these agents should be considered in individuals exposed to doses above 1.5 Gy, should be given to those who develop fever and neutropenia and should be administered within 48 hours of exposure. An estimation of the exposure dose should be done by biological dosimetry whenever possible and by detailed history of exposure.

If infection is documented by cultures, the empirical regimen may require adjustment to provide appropriate coverage for the specific isolate(s). When the patient remains afebrile, the initial regimen should be continued for a minimum of 7 days. Therapy may need to be continued for at least 21–28 days or until the risk of infection has declined because of recovery of the immune system. A mass casualty situation may mandate the use of oral antimicrobials.

Modification of therapy

Modifications of this initial antibiotic regimen should be made when microbiological culture shows specific bacteria that are resistant to the initial antimicrobials. The modification, if needed, should be influenced by a thorough evaluation of the history, physical examination findings, laboratory data, chest radiograph, and epidemiological information. Antifungal coverage with amphotericin B may need to be added.

If diarrhea is present, cultures of stool should be examined for enteropathogens (i.e., Salmonella, Shigella, Campylobacter, and Yersinia). Oral and pharyngeal mucositis and esophagitis suggest Herpes simplex infection or candidiasis. Either empirical antiviral or antifungal therapy or both should be considered.

In addition to infections due to neutropenia, a patient with the Acute Radiation Syndrome will also be at risk for viral, fungal and parasitic infections. If these types of infection are suspected, cultures should be performed and appropriate medication started if indicated.

Related Research Articles

Ampicillin Antibiotic

Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis. It may also be used to prevent group B streptococcal infection in newborns. It is used by mouth, by injection into a muscle, or intravenously. Common side effects include rash, nausea, and diarrhea. It should not be used in people who are allergic to penicillin. Serious side effects may include Clostridium difficile colitis or anaphylaxis. While usable in those with kidney problems, the dose may need to be decreased. Its use during pregnancy and breastfeeding appears to be generally safe.

Beta-lactamase

Beta-lactamases are enzymes produced by bacteria that provide multi- resistance to β-lactam antibiotics such as penicillins, cephalosporins, cephamycins, and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a β-lactam. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.

Gram-negative bacteria Group of bacteria that do not retain the crystal violet stain used in the Gram-staining method of bacterial differentiation

Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the gram-staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall sandwiched between an inner cytoplasmic cell membrane and a bacterial outer membrane.

Acute radiation syndrome Health problems caused by exposure to high levels of ionizing radiation

Acute radiation syndrome (ARS), also known as radiation sickness or radiation poisoning, is a collection of health effects that are caused by being exposed to high amounts of ionizing radiation, in a short period of time. The symptoms of ARS can start within the hour of exposure, and can last for several months. Within the first few days the symptoms are usually nausea, vomiting and a loss of appetite. In the following few hours or weeks will be a few symptoms, which later become additional symptoms, after which either recovery or death follow.

This is the timeline of modern antimicrobial (anti-infective) therapy. The years show when a given drug was released onto the pharmaceutical market. This is not a timeline of the development of the antibiotics themselves.

Broad-spectrum antibiotic

A broad-spectrum antibiotic is an antibiotic that acts on the two major bacterial groups, Gram-positive and Gram-negative, or any antibiotic that acts against a wide range of disease-causing bacteria. These medications are used when a bacterial infection is suspected but the group of bacteria is unknown or when infection with multiple groups of bacteria is suspected. This is in contrast to a narrow-spectrum antibiotic, which is effective against only a specific group of bacteria. Although powerful, broad-spectrum antibiotics pose specific risks, particularly the disruption of native, normal bacteria and the development of antimicrobial resistance. An example of a commonly used broad-spectrum antibiotic is ampicillin.

Aminoglycoside

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.

Cephalosporin

The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as "Cephalosporium".

Ceftazidime

Ceftazidime, sold under the brand names Fortaz among others, is an antibiotic useful for the treatment of a number of bacterial infections. Specifically it is used for joint infections, meningitis, pneumonia, sepsis, urinary tract infections, malignant otitis externa, Pseudomonas aeruginosa infection, and vibrio infection. It is given by injection into a vein, muscle, or eye.

Piperacillin Chemical compound

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

Carbapenem

Carbapenems are a class of highly effective antibiotic agents commonly used for the treatment of severe or high-risk bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta lactam class of antibiotics, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

Community-acquired pneumonia (CAP) refers to pneumonia contracted by a person outside of the healthcare system. In contrast, hospital-acquired pneumonia (HAP) is seen in patients who have recently visited a hospital or who live in long-term care facilities. CAP is common, affecting people of all ages, and its symptoms occur as a result of oxygen-absorbing areas of the lung (alveoli) filling with fluid. This inhibits lung function, causing dyspnea, fever, chest pains and cough.

Cefepime

Cefepime is a fourth-generation cephalosporin antibiotic. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both types of organism than third-generation agents. A 2007 meta-analysis suggested when data of trials were combined, mortality was increased in people treated with cefepime compared with other β-lactam antibiotics. In response, the U.S. Food and Drug Administration (FDA) performed their own meta-analysis which found no mortality difference.

Cefditoren Chemical to treat skin infections

Cefditoren also known as cefditoren pivoxil is a broad-spectrum antibiotic, taken by mouth to treat pneumonia and other infections. It is a third-generation oral cephalosporin with a broad spectrum of activity against bacterial pathogens, including both Gram-positive and Gram-negative bacteria, and it is effective against some antibiotic-resistant bacteria because it is not susceptible to hydrolysis by many common beta-lactamases. The United States Food and Drug Administration approved cefditoren pivoxil for adults and adolescents in 2001. In 2018 Zuventus Healthcare received approval for cefditoren pivoxil dry powder for suspension for the treatment of mild to moderate infection in children which are caused by susceptible strains of the designated microorganisms.

Febrile neutropenia is the development of fever, often with other signs of infection, in a patient with neutropenia, an abnormally low number of neutrophil granulocytes in the blood. The term neutropenic sepsis is also applied, although it tends to be reserved for patients who are less well. In 50% of cases, an infection is detectable; bacteremia is present in approximately 20% of all patients with this condition.

Plasmid-mediated resistance

Plasmid-mediated resistance is the transfer of antibiotic resistance genes which are carried on plasmids. The plasmids can be transferred between bacteria within the same species or between different species via conjugation. Plasmids often carry multiple antibiotic resistance genes, contributing to the spread of multidrug-resistance (MDR). Antibiotic resistance mediated by MDR plasmids severely limits the treatment options for the infections caused by Gram-negative bacteria, especially family Enterobacteriaceae. The global spread of MDR plasmids has been enhanced by selective pressure from antibiotic usage in human and veterinary medicine.

Anaerobic infections are caused by anaerobic bacteria. Obligately anaerobic bacteria do not grow on solid media in room air ; facultatively anaerobic bacteria can grow in the presence or absence of air. Microaerophilic bacteria do not grow at all aerobically or grow poorly, but grow better under 10% carbon dioxide or anaerobically. Anaerobic bacteria can be divided into strict anaerobes that can not grow in the presence of more than 0.5% oxygen and moderate anaerobic bacteria that are able of growing between 2 and 8% oxygen. Anaerobic bacteria usually do not possess catalase, but some can generate superoxide dismutase which protects them from oxygen.

<i>Clostridium tertium</i> Species of bacterium

Clostridium tertium is an anaerobic, motile, gram-positive bacterium. Although it can be considered an uncommon pathogen in humans, there has been substantial evidence of septic episodes in human beings. C. tertium is easily decolorized in Gram-stained smears and can be mistaken for a Gram-negative organism. However, C.tertium does not grow on selective media for Gram-negative organisms.

Ceftolozane/tazobactam Antibiotic

Ceftolozane/tazobactam, sold under the brand name Zerbaxa, is a combination antibiotic medication used for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

References

  1. 1 2 3 Brook I, Elliot T B, Ledney GD, Shomaker MO, Knudson GB. Management of postirradiation infection: lessons learned from animal models. Mil Med. 2004;169:194-7
  2. 1 2 Palmer JL, Deburghgraeve CR, Bird MD, Hauer-Jensen M, Kovacs EJ. Development of a combined radiation and burn injury model. J Burn Care Res. 2011; 32:317-23.
  3. 1 2 Borden Institute. Chapter 2 Acute radiation syndrome
  4. ↑ Reeves GI. Medical implications of enhanced radiation weapons. Mil Med. 2010 ;175:964-70.
  5. ↑ Brook I., Ledney G.D. (1994). "Effect of Antimicrobial Therapy on the Gastrointestinal Bacterial Flora, Infection and Mortality in Mice Exposed to Different Doses of irradiation". Journal of Antimicrobial Chemotherapy . 33 (1): 63–74. doi:10.1093/jac/33.1.63. PMID   8157575.
  6. ↑ Patchen ML, Brook I, Elliott TB, Jackson WE (September 1993). "Adverse effects of pefloxacin in irradiated C3H/HeN mice: correction with glucan therapy". Antimicrob. Agents Chemother. 37 (9): 1882–9. doi:10.1128/aac.37.9.1882. PMC   188087 . PMID   8239601.CS1 maint: multiple names: authors list (link)
  7. ↑ Brook I., Walker R.I., MacVittie T.J. (1988). "Effect of Antimicrobial Therapy on the Bowel Flora and Bacterial Infection in Irradiated Mice". International Journal of Radiation Biology. 53 (5): 709–718. doi:10.1080/09553008814551081. PMID   3283066.CS1 maint: multiple names: authors list (link)
  8. ↑ Brook I, Ledney D. Quinolone therapy in the management of infection after irradiation. Crit Rev Microbiol. 1992;18235-46.
  9. ↑ Coleman CN, Hrdina C, Bader JL, Norwood A, Hayhurst R, Forsha J, Yeskey K, Knebel A. Medical response to a radiologic/nuclear event: integrated plan from the Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services. Ann Emerg Med. 2009 ;53:213-22.
  10. ↑ Bader JL, Nemhauser J, Chang F, Mashayekhi B, Sczcur M, Knebel A, Hrdina C, Coleman N.Radiation event medical management (REMM): website guidance for health care providers. Prehosp Emerg Care. 2008 ;12:1-11.
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