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Journal of Clinical Microbiology, January 2003, p. 483-485, Vol. 41, No. 1
0095-1137/03/$08.00+0     DOI: 10.1128/JCM.41.1.483-485.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Antimicrobial Activities against 84 Listeria monocytogenes Isolates from Patients with Systemic Listeriosis at a Comprehensive Cancer Center (1955-1997)

Amar Safdar^* and Donald Armstrong

Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Received 31 July 2002/ Returned for modification 1 October 2002/ Accepted 24 October 2002

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Listeriosis is a serious complication in patients undergoing treatment for cancer. We present antimicrobial susceptibility profiles of 84 clinical Listeria monocytogenes isolates. During 1955 to 1997, in vitro susceptibility for penicillin (97.6%), ampicillin (90.7%), erythromycin (98.8%), tetracycline (96.9%), and gentamicin (98.0%) remained unchanged. All isolates were susceptible to amikacin, ciprofloxacin, imipenem, rifampin, trimethoprim-sulfamethoxazole (TMP-SMX), and vancomycin. High prevalence of clindamycin resistance (96.2%) was unexpected. Ampicillin plus gentamicin is standard therapy for systemic listerosis, and TMP-SMX may be used for patients with beta-lactam intolerance. In vitro susceptibility profiles for carbapenem and fluoronated quinolone are promising, although clinical validation is critically needed before routine use is advocated, especially for listeric patients with severe cellular immune defects.

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Systemic listerosis is an infrequent opportunistic complication in patients undergoing treatment for hematologic malignancies (11, 20) or allogeneic hematopoietic stem cell transplantation (21). Listeria monocytogenes frequently invades the central nervous system via hematogenous dissemination, leading to meningioencephalitis, cerebritis, and/or brain abscesses (10). Response to antibiotic therapy is often good, even for patients with severe immune dysfunction (20, 21). Several antimicrobial agents exhibit in vitro activity against L. monocytogenes (1, 8, 13), although ampicillin-based regimens are considered the gold standard for the treatment of systemic listeric infections; aminoglycosides are often added for antimicrobial synergy (15).

Antimicrobial resistance has undergone near-exponential increase during the past decades. The use of common broad-spectrum antibiotics to treat most pathogenic bacteria, given either prophylactically or by empiric-preemptive therapy in high-risk settings, has further accentuated this trend, especially in patients with underlying malignancy. This retrospective analysis was performed to evaluate the prevalence of antimicrobial resistance in disease-related L. monocytogenes, isolated from patients receiving care at a comprehensive cancer center during 1955 to 1997.

(Portions of this study were presented at the 12th International Symposium on Infections in the Immunocompromised Host, International Immunocompromised Host Society, Bergen, Norway, June 2002.)

Study design. This retrospective study was performed at three intervals: 1955 to 1966 (reported in reference 11); 1970 to 1979, and 1991 to 1997. Eighty-four L. monocytogenes isolates were obtained from patients' blood and cerebrospinal fluid samples at the Memorial Sloan-Kettering Cancer Center in New York, N.Y. All specimens were initially processed at the Memorial Sloan-Kettering Cancer Center Microbiology Laboratory, and they also identified L. monocytogenes isolates and conducted antimicrobial susceptibility. L. monocytogenes reidentification and serotype analysis (data not shown) were undertaken at the Centers for Disease Control and Prevention, Atlanta, Ga.

Microorganism identification. L. monocytogenes organisms were isolated and identified by standard methods described elsewhere (11, 21).

Antimicrobial susceptibility. The antimicrobial susceptibility for 60 strains from 1955 to 1979 was performed by an agar plate antibiotic disk diffusion method (Kirby-Bauer technique) (11, 16). Fresh beef heart broth was used to supplement broth culture medium (11). The diameter (in millimeters) of each zone around the antibiotic disk was measured and interpreted according to the National Committee for Clinical Laboratory Standards (NCCLS) recommendations (16). Broth microdilution susceptibility studies were performed during 1991 to 1997. The lowest concentration of drug that inhibited the bacterial growth after incubation for 24 h was considered the MIC, and interpretive breakpoints were determined according to NCCLS guidelines (13). All antimicrobial agents were obtained from their respective manufacturers.

Of 84 L. monocytogenes isolates, 43 (51.2%) were isolated from cerebrospinal fluid samples, 39 (46.4%) were from blood culture specimens, and 2 (2.4%) were from patients who had extracranial end-organ infection (listeric empyema and uveitis). The overall antimicrobial in vitro susceptibility is shown in Table 1. Resistance to ampicillin (9.2%), erythromycin (1.9%), gentamicin (2%), penicillin (2.3%), tetracycline (3%), and ticarcillin-calvulanate (3.8%) was low. All isolates were susceptible to amikacin, cefazolin, cephalothin, rifampin, trimethoprim-sulfamethoxazole (TMP-SMX), and vancomycin. Eighty-seven percent showed in vitro susceptibility to chloramphenicol. High-frequency resistance to clindamycin (96.2%) and the broad-spectrum cephalosporins cefuroxime (80.8%), cefotaxime (66.6%), and ceftriaxone (76.1%) was also observed.

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TABLE 1. Susceptibility of L. monocytogenesis isolates collected from 1955 to 1997a

During 01 January 1991 to 31 December 1997, MICs (determined for the MICs at which both 50 and 90% of the isolates tested were inhibited) were determined by broth microdilution technique, and results are given in Table 2. The 90% inhibitory MIC for amikacin (16.0 µg/ml), ampicillin (1.0 µg/ml), erythromycin (0.25 µg/ml), gentamicin (1.0 µg/ml), penicillin (0.5 µg/ml), tetracycline (<0.25 µg/ml), and TMP-SMX (2.0 µg/ml for TMP and 38.0 µg/ml for SMX) remained within susceptible ranges. Ninetieth percentile of L. monocytogenes isolates showed an imipenem and ciprofloxacin MIC of 1.0 µg/ml.

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TABLE 2. L. monocytogenes susceptibility profile during 1991 to 1997a

L. monocytogenes remains susceptible to a wide variety of antimicrobial agents, although as noted in this report, in vitro resistance to broad-spectrum cephalosporin antibiotics has been observed consistently (8, 13). Since the 1980s, multidrug-resistant enterococci have increased significantly both in the hospital and community environment (6, 18). Plasmids carrying genetic determinants of antibiotic resistance can successfully transfer genetic code from Enterococcus faecalis to L. monocytogenes (2, 4, 19); this observation had raised serious concerns regarding emergence of antibiotic resistance and choice of optimal initial therapy for severe listeric infections in compromised individuals. Similar to this report, others have described no significant rise in drug-resistant L. monocytogenes (Table 3) (5, 9, 11, 13, 22, 23). This may in part be due to the fact that most systemic listerosis is acquired from non-nosocomial environment pools, and hospital-acquired de novo invasive listerosis even in patients with severe immune deficiency is rare (10).

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TABLE 3. Interval antimicrobial resistance profile of clinical L. monocytogenes isolatesa

Penicillin and ampicillin are bactericidal against most strains of L. monocytogenes; however, in the preferred intracellular milieu, these microorganisms become more recalcitrant and even highly effective drugs are rendered bacteriostatic at best (7, 9, 15). The lack of in vivo bactericidal antilisteric effect becomes important in the treatment of systemic opportunistic infections in patients with compromised adaptive cellular immunity (10, 20). Therefore, various drug combinations were explored to evaluate in vivo enhancement of antilisteric activity. Animal studies demonstrated 100-fold greater killing of L. monocytogenes following therapy with penicillin or ampicillin plus gentamicin (12, 15). Presently, combination antimicrobials are considered standard for treatment of opportunistic systemic listerosis (10, 11, 15, 21). However, this bactericidal synergism has not been observed for trimethoprim-sulfamethoxazole plus aminoglycoside, amoxicillin, or ciprofloxacin (1). In fact, indiscriminate use of drug combinations, such as ciprofloxacin plus rifampin, may result in antibacterial antagonism and may increase chances of treatment failure (1).

The new fluorinated quinolones, such as levofloxacin, sparfloxacin, gemifloxacin, and moxifloxacin, are bactericidal against L. monocytogenes. These antimicrobials can achieve greater than 99.9% bacterial killing with no evidence of bacterial regrowth (3, 7, 13, 14). However, no measurable antilisteric effect of ciprofloxacin in intracellular cell culture experiments (17) cautions against therapeutic intervention. Clinical validation is critically needed to determine the role of new-generation fluorinated quinolones and carbapenems in the treatment of L. monocytogenes infections in patients at risk.

 
We are in debt to our late friend and colleague Anne Blevins for her keen interest and tremendous support in the study of listeric infections in patients with cancer.

 
* Corresponding author. Present address: Department of Infectious Diseases, Infection Control, and Employee Health, 402 The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 792-0825. Fax: (713) 745-6839. E-mail: asafdar{at}mdanderson.org.

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Journal of Clinical Microbiology, January 2003, p. 483-485, Vol. 41, No. 1
0095-1137/03/$08.00+0     DOI: 10.1128/JCM.41.1.483-485.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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