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1.
Kaplan  SLMason  EO Mechanisms of pneumococcal antibiotic resistance and treatment of pneumococcal infections in 2002. Pediatr Ann 2002;31250- 260
PubMedArticle
2.
Salgado  CDFarr  BMCalfee  DP Community-acquired methicillin-resistant Staphylococcus aureus: a meta-analysis of prevalence and risk factors. Clin Infect Dis 2003;36131- 139
PubMedArticle
3.
Cosgrove  SESakoulas  GPerencevich  EN  et al.  Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003;3653- 59
PubMedArticle
4.
Centers for Disease Control and Prevention, Staphylococcus aureus resistant to vancomycin: United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51565- 567
PubMed
5.
National Committee for Clinical Laboratory Standards Performance Standards for Antimicrobial Susceptiblity Testing, Tenth Informational Supplement (Aerobic Dilution).  Wayne, Pa: National Committee for Clinical Laboratory Standards; 2000
6.
Jacobs  MR Drug-resistant Streptococcus pneumoniae: rational antibiotic choices. Am J Med 1999;10619S- 25S
PubMedArticle
7.
Bonafede  MRice  LB Emerging antibiotic resistance. J Lab Clin Med 1997;130558- 566
PubMedArticle
8.
McCullers  JAEnglish  BKNovack  R Isolation and characterization of vancomycin-tolerant Streptococcus pneumoniae from the cerebrospinal fluid of a patient who developed recrudescent meningitis. J Infect Dis 2000;181369- 373
PubMedArticle
9.
Novack  RHenriques  BCharpentier  ENormark  SToumanen  E Emergence of vancomycin tolerance in Streptococcus pneumoniae. Nature 1999;399590- 593
PubMedArticle
10.
Liu  HHTomasz  A Penicillin tolerance in multiply drug-resistant natural isolates of Streptococcus pneumoniae. J Infect Dis 1985;152365- 372
PubMedArticle
11.
Paterson  DLRice  LB Empirical antibiotic choice for the seriously ill patient: are minimization of selection of resistant organisms and maximization of individual outcome mutually exclusive? Clin Infect Dis 2003;361006- 1012Article
12.
Greenlee  JECarroll  KC Cerebrospinal fluid in CNS infections.  In: Scheld  WM, Whitley  RJ, Durack  DT, eds. Infections of the Central Nervous System. 2nd ed. Philadelphia, Pa: Lippincott-Raven; 1997:899-922
13.
Gray  LDFedorko  DP Laboratory diagnosis of bacterial meningitis. Clin Microbiol Rev 1992;5130- 145
PubMed
14.
Nathan  BRScheld  WM The potential roles of C-reactive protein and procalcitonin concentrations in the serum and cerebrospinal fluid in the diagnosis of bacterial meningitis.  In: Remington  JS, Schwartz  MN, eds. Current Clinical Topics in Infectious Diseases. Vol 22. Oxford, England: Blackwell Science Ltd; 2002:155-165
15.
Bartlett  JGBradley  SFHerwaldt  LAJacobs  MRPerl  TMPoole  MD A roundtable discussion of antibiotic resistance: putting lessons to work. Am J Med 1999;10649S- 52SArticle
16.
Chang  SSievert  DMHageman  JCBoulton  ML Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N Engl J Med 2003;3481342- 1347
PubMedArticle
17.
Wen  DYBottini  AGHall  WAHaines  SJ The intraventricular use of antibiotics. Neurosurg Clin N Am 1992;3343
PubMed
18.
Golledge  CLMcKenzie  T Monitoring vancomycin concentrations in CSF after intraventricular administration. J Antimicrob Chemother 1988;21262
PubMedArticle
19.
Centers for Disease Control and Prevention, National Nosocomial Infections Surveillance (NNIS) System report, data summary from January 1990-May 1999, issued June 1999. Am J Infect Control 1999;27520- 532
PubMedArticle
20.
Zeana  CKubin  CJDella-Latta  PHammer  SM Vancomycin-resistant Enterococcus faecium meningitis successfully managed with linezolid: case report and review of the literature. Clin Infect Dis 2001;33477- 482
PubMedArticle
21.
Steinmetz  MPVogelbaum  MADe Georgia  MAAndrefsky  JCIsada  C Successful treatment of vancomycin-resistant enterococcus meningitis with linezolid: case report and review of the literature. Crit Care Med 2001;292383- 2385
PubMedArticle
22.
Zurenko  JETodd  WMHafkin  B  et al Development of linezolid-resistant Enterococcus faecium in two compassionate use program patients treated with linezolid.  In: Program and Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, Calif. Washington, DC: American Society for Microbiology; 1999:117. Abstract 848
23.
Williamson  JCGlazier  FSPeacock  JE Successful treatment of ventriculostomy-related meningitis caused by vancomycin-resistant enterococcus with intravenous and intraventricular quinupristin/dalfopristin. Clin Neurol Neurosurg 2002;10454- 56
PubMedArticle
Neurological Review
October 2004

Emerging Antimicrobial-Resistant Infections

Author Affiliations

Author Affiliation: Department of Neurology, Indiana University School of Medicine, Indianapolis.

 

DAVID E.PLEASUREMD

Arch Neurol. 2004;61(10):1512-1514. doi:10.1001/archneur.61.10.1512

Humanity has but three great enemies: fever, famine and war; of these by far the greatest, by far the most terrible, is fever.—William Osler

The emergence of antimicrobial-resistant bacterial infections has changed the recommendations for the empirical therapy of community- and hospital-acquired meningitis. In the United States, approximately 34% of pneumococcal isolates are penicillin nonsusceptible, and approximately 14% are resistant to ceftriaxone.1 More than 50% of nosocomial infections in patients in the intensive care unit are due to methicillin-resistant Staphylococcus aureus.2,3 The first documented case of vancomycin-resistant S aureus was reported in the United States in 2002.4

The National Committee for Clinical Laboratory Standards establishes the standards for determining the susceptibility of bacteria to antibiotics based on the minimum inhibitory concentration (MIC). For pneumococcal meningitis, isolates with an MIC of 0.06 μ g/mL or less are considered susceptible to penicillin, those with an MIC of 0.12 to 1.0 μg/mL to be intermediate, and those with an MIC of 2.0 μg/mL or greater to be resistant. A pneumococcal isolate with an MIC for cefotaxime or ceftriaxone of less than 0.5 μg/mL is considered susceptible, 1.0 μg/mL intermediate, and greater than 2.0 μg/mL resistant.5 A strain of pneumococci is considered nonsusceptible to an antibiotic when the MIC is in the intermediate or resistant range.1

Streptococcus pneumoniae develops resistance to penicillins and cephalosporins through alterations of one or more penicillin-binding proteins.6 Alterations in the penicillin-binding proteins lead to a decrease in the bacteria’s affinity for the antibiotic and thus a decreased susceptibility to the antibiotic.1 The mechanism of resistance is acquired through a process in which a particular genome encoding the alteration is acquired from other bacteria by pneumococci and incorporated into their own DNA.6,7

Vancomycin-resistant strains of pneumococci have not been seen, but strains of S pneumoniae tolerant to vancomycin have been reported. Tolerance is the ability of a bacterium to survive in the presence of an antibiotic, neither growing nor being eradicated by the antibiotic. Tolerance may be the precursor for the development of antimicrobial resistance because it creates survivors of antibiotic therapy.810

To successfully treat an infection, an antibiotic must be selected that will provide a concentration greater than the MIC at the site of infection in the central nervous system for a period adequate to eradicate the organism.1 Central nervous system infection with an organism that is resistant to an antibiotic can often be successfully treated by using higher doses of the antibiotic for a prolonged period, by using a combination of intravenous and intraventricular therapy, or by using a combination of antibiotics.

Empirical therapy of community-acquired bacterial meningitis is based on the possibility that penicillin- and cephalosporin-resistant pneumococci are the causative organisms of the meningitis. A combination of ceftriaxone (pediatric dose, 100 mg/kg per day in a 12-hour dosing interval; adult dose, 2 g every 12 hours), cefotaxime (pediatric dose, 300 mg/kg per day in a 4- to 6-hour dosing interval; adult dose, 3 g every 4 hours), or cefepime (adult dose, 2 g every 12 hours) plus vancomycin (pediatric dose, 40-60 mg/kg/d in a 6- or 12-hour dosing interval; adult dose, 500 mg every 6 hours or 1 g every 12 hours) is recommended.

Inadequate empirical therapy is associated with increased mortality, but excessive antibiotic use promotes the emergence and spread of antibiotic-resistant bacterial pathogens.11 To minimize the use of antibiotics for empirical therapy, specific diagnostic tests that differentiate bacterial meningitis from other central nervous system infections need to be readily available. The possibility of bacterial meningitis is considered when the classic triad of fever, headache, and meningismus is present. The classic cerebrospinal fluid (CSF) abnormalities of bacterial meningitis are as follows: (1) elevated opening pressure; (2) 100 to 5000 white blood cells/mm3 with a predominance of polymorphonuclear leukocytes; (3) glucose concentration of 40 mg/dL or less, a CSF:serum glucose ratio of less than 0.31; and (4) gram stain is positive in 70% to 85% of patients and is dependent on the CSF concentration of bacteria. The likelihood of having a positive gram stain also depends on the specific meningeal pathogen. Ninety percent of cases due to S pneumoniae, 75% of cases due to Neisseria meningitidis, and 50% of cases due to gram-negative bacilli have a positive gram stain. Culture is positive in 80% of patients with bacterial meningitis who have not received antibiotic therapy; 48 hours are usually required for accurate identification.12,13 The CSF will appear cloudy or turbid if there are more than 200 white blood cells/mm3, more than 400 red blood cells/mm3, more than 105 bacterial colony forming units/mL, and/or an elevated protein concentration.

A broad-range polymerase chain reaction can detect small numbers of viable and nonviable organisms in the CSF. When the broad-range polymerase chain reaction is positive, a polymerase chain reaction that uses specific bacterial primers to detect the nucleic acid of S pneumoniae, N meningitidis, Escherichia coli, Listeria monocytogenes, Haemophilus influenzae, and Streptococcus agalactiae should then be done. The CSF lactate concentration is nonspecific and therefore not useful in the diagnosis of bacterial meningitis. The serum procalcitonin has a high sensitivity and specificity for bacterial meningitis. Procalcitonin is a polypeptide that increases in patients with severe bacterial infections.14 It is recommended that lumbar puncture be repeated 36 to 48 hours after the initiation of therapy (unless contraindicated by the neurological examination) to document eradication of the pathogen. This recommendation has become increasingly important to follow with the emergence of antimicrobial-resistant organisms.

Methicillin-resistant S aureus infections have emerged as an increasing threat owing to the easy transmissibility of this pathogen. One of the most significant risk factors associated with nosocomial-acquired methicillin-resistant S aureus is the close proximity of physicians and nurses who are colonized with methicillin-resistant S aureus, spreading it to patients who are sick and who then subsequently become colonized and infected. Similar to how antimicrobial-resistant isolates of S pneumoniae develop, S aureus acquires one particular gene from another bacterium that alters one particular penicillin-binding protein, resulting in absolute resistance to methicillin.15 The enterococci are part of the normal flora of the gastrointestinal tract. Some isolates of vancomycin-resistant S aureus contain the vanA vancomycin-resistant gene. This gene is acquired from vancomycin-resistant enterococci by conjugative transfer.16

Staphylococci are the most common causative organisms of craniotomy bone flap infections, osteomyelitis as a complication of craniotomy, postoperative epidural abscess, and CSF shunt infections. The majority of cases of postoperative meningitis are caused by S aureus, coagulase-negative staphylococci, aerobic gram-negative bacilli, and streptococci. Empirical therapy for postoperative meningitis should include a combination of vancomycin and either ceftazidime or cefepime, based on the possibility that methicillin-resistant S aureus is the causative organism. Effective therapy of methicillin-resistant staphylococcal meningitis may require intraventricular vancomycin, especially in those patients who are unable to mount an inflammatory response in the subarachnoid space. Vancomycin penetrates inflamed meninges more readily than it penetrates noninflamed meninges. The toxicity of intraventricular vancomycin is fairly minimal and primarily based on anecdotal reports that include fever, headache, tinnitus, and mental status changes.17,18 The intraventricular dose of vancomycin is 20 mg per day in adults and 10 mg per day in children.

To prevent the iatrogenic transmission of methicillin- or vancomycin-resistant S aureus, (1) infected patients should be in a private room, (2) gloves must be worn whenever there is direct contact with the patient, (3) masks should be worn when there will be contact with oropharyngeal secretions, (4) gowns should be worn if any soiling of clothes is anticipated, (5) strict hand-washing procedures should be followed before leaving the patient’s room, and (6) stethoscopes and reflex hammers should be cleaned. To examine the fundi when looking for brainstem reflexes in a ventilator-dependent patient in the intensive care unit, a mask, gloves, and a gown should be worn.

Enterococci are part of the normal flora in the gastrointestinal tract and the second most common pathogenic cause of bloodstream infections in patients in the intensive care unit but a relatively uncommon cause of central nervous system infections.19,20 The most common conditions associated with enterococcal meningitis are external ventricular drains, epidural catheters, neurosurgical procedures, immunosuppression therapy, and gastrointestinal disease and Strongyloides species hyperinfection. Most cases of enterococcal meningitis are caused by Enterococcus faecalis.20 Vancomycin-resistant enterococcal infections are a major problem. Enterococci are naturally resistant to several antibiotics and have the ability to acquire resistance through the exchange of genetic material.20 Optimal therapy for vancomycin-resistant enterococcal central nervous system infections has not been established, and recommendations are based on case reports and small series. Vancomycin-resistant Enterococcus faecium meningitis has been successfully treated with linezolid.20,21 Linezolid has good CSF penetration and is generally well tolerated. Unfortunately, there are already case reports of patients with linezolid-resistant E faecium infections.22 Chloramphenicol can be used to treat vancomycin-resistant enterococcal meningitis; however, an increasing number of vancomycin-resistant enterococci are either intermediately susceptible or resistant to chloramphenicol in vitro.21 Quinupristin/dalfopristin are 2 semisynthetic streptogramin antibiotics that are bacteriostatic against enterococcus.21,23 Intravenous quinupristin/dalfopristin penetrates poorly into the subarachnoid space. The administration of quinupristin/dalfopristin by both the intravenous route (7.5 mg/kg every 8 hours) and the intraventricular route (2 mg daily) was successful in eradicating vancomycin-resistant E faecium ventriculostomy-related meningitis.23

In summary, recommendations for empirical therapy of community- and hospital-acquired meningitis are constantly changing because of increasing antimicrobial-resistant bacterial infections. Empirical therapy of community-acquired bacterial meningitis is based on the possibility that penicillin- and cephalosporin-resistant pneumococci are the causative organisms of the meningitis. Empirical therapy for postoperative meningitis should include a combination of vancomycin and ceftazidime or cefepime, based on the possibility that methicillin-resistant S aureus is the causative organism. Inadequate empirical therapy is associated with increased mortality, but excessive antibiotic use promotes the emergence and spread of antibiotic-resistant pathogens. Empirical therapy should be modified when culture results are available. The need for broad-spectrum antimicrobial therapy should be reevaluated on a daily basis. Physicians should take the necessary precautions to limit the iatrogenic spread of antimicrobial organisms.

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Article Information

Correspondence: Karen L. Roos, MD, Department of Neurology, Indiana University School of Medicine, 550 N University Blvd, Suite 4411, Indianapolis, IN 46202-5124.

Accepted for Publication: April 26, 2004.

Previous Presentation: This review was presented at the 128th annual meeting of the American Neurological Association, San Francisco, Calif, October 20, 2003.

References
1.
Kaplan  SLMason  EO Mechanisms of pneumococcal antibiotic resistance and treatment of pneumococcal infections in 2002. Pediatr Ann 2002;31250- 260
PubMedArticle
2.
Salgado  CDFarr  BMCalfee  DP Community-acquired methicillin-resistant Staphylococcus aureus: a meta-analysis of prevalence and risk factors. Clin Infect Dis 2003;36131- 139
PubMedArticle
3.
Cosgrove  SESakoulas  GPerencevich  EN  et al.  Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003;3653- 59
PubMedArticle
4.
Centers for Disease Control and Prevention, Staphylococcus aureus resistant to vancomycin: United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51565- 567
PubMed
5.
National Committee for Clinical Laboratory Standards Performance Standards for Antimicrobial Susceptiblity Testing, Tenth Informational Supplement (Aerobic Dilution).  Wayne, Pa: National Committee for Clinical Laboratory Standards; 2000
6.
Jacobs  MR Drug-resistant Streptococcus pneumoniae: rational antibiotic choices. Am J Med 1999;10619S- 25S
PubMedArticle
7.
Bonafede  MRice  LB Emerging antibiotic resistance. J Lab Clin Med 1997;130558- 566
PubMedArticle
8.
McCullers  JAEnglish  BKNovack  R Isolation and characterization of vancomycin-tolerant Streptococcus pneumoniae from the cerebrospinal fluid of a patient who developed recrudescent meningitis. J Infect Dis 2000;181369- 373
PubMedArticle
9.
Novack  RHenriques  BCharpentier  ENormark  SToumanen  E Emergence of vancomycin tolerance in Streptococcus pneumoniae. Nature 1999;399590- 593
PubMedArticle
10.
Liu  HHTomasz  A Penicillin tolerance in multiply drug-resistant natural isolates of Streptococcus pneumoniae. J Infect Dis 1985;152365- 372
PubMedArticle
11.
Paterson  DLRice  LB Empirical antibiotic choice for the seriously ill patient: are minimization of selection of resistant organisms and maximization of individual outcome mutually exclusive? Clin Infect Dis 2003;361006- 1012Article
12.
Greenlee  JECarroll  KC Cerebrospinal fluid in CNS infections.  In: Scheld  WM, Whitley  RJ, Durack  DT, eds. Infections of the Central Nervous System. 2nd ed. Philadelphia, Pa: Lippincott-Raven; 1997:899-922
13.
Gray  LDFedorko  DP Laboratory diagnosis of bacterial meningitis. Clin Microbiol Rev 1992;5130- 145
PubMed
14.
Nathan  BRScheld  WM The potential roles of C-reactive protein and procalcitonin concentrations in the serum and cerebrospinal fluid in the diagnosis of bacterial meningitis.  In: Remington  JS, Schwartz  MN, eds. Current Clinical Topics in Infectious Diseases. Vol 22. Oxford, England: Blackwell Science Ltd; 2002:155-165
15.
Bartlett  JGBradley  SFHerwaldt  LAJacobs  MRPerl  TMPoole  MD A roundtable discussion of antibiotic resistance: putting lessons to work. Am J Med 1999;10649S- 52SArticle
16.
Chang  SSievert  DMHageman  JCBoulton  ML Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N Engl J Med 2003;3481342- 1347
PubMedArticle
17.
Wen  DYBottini  AGHall  WAHaines  SJ The intraventricular use of antibiotics. Neurosurg Clin N Am 1992;3343
PubMed
18.
Golledge  CLMcKenzie  T Monitoring vancomycin concentrations in CSF after intraventricular administration. J Antimicrob Chemother 1988;21262
PubMedArticle
19.
Centers for Disease Control and Prevention, National Nosocomial Infections Surveillance (NNIS) System report, data summary from January 1990-May 1999, issued June 1999. Am J Infect Control 1999;27520- 532
PubMedArticle
20.
Zeana  CKubin  CJDella-Latta  PHammer  SM Vancomycin-resistant Enterococcus faecium meningitis successfully managed with linezolid: case report and review of the literature. Clin Infect Dis 2001;33477- 482
PubMedArticle
21.
Steinmetz  MPVogelbaum  MADe Georgia  MAAndrefsky  JCIsada  C Successful treatment of vancomycin-resistant enterococcus meningitis with linezolid: case report and review of the literature. Crit Care Med 2001;292383- 2385
PubMedArticle
22.
Zurenko  JETodd  WMHafkin  B  et al Development of linezolid-resistant Enterococcus faecium in two compassionate use program patients treated with linezolid.  In: Program and Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, Calif. Washington, DC: American Society for Microbiology; 1999:117. Abstract 848
23.
Williamson  JCGlazier  FSPeacock  JE Successful treatment of ventriculostomy-related meningitis caused by vancomycin-resistant enterococcus with intravenous and intraventricular quinupristin/dalfopristin. Clin Neurol Neurosurg 2002;10454- 56
PubMedArticle
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