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Fluoroquinolone-resistant Moraxella catarrhalis in a patient with pneumonia: report from the SENTRY antimicrobial surveillance program (1998)
Fluoroquinolone-resistant Moraxella catarrhalis in a Patient with Pneumonia: Report from the SENTRY Antimicrobial Surveillance Program (1998) Joseph R. DiPersio, Ronald N. Jones, Timothy Barrett, Gary V. Doern, and Michael A. Pfaller
Fluoroquinolone resistance in Moraxella catarrhalis isolates has been quite rare. This report presents a case history of a 22-year-old man with compromised immune status and severe pneumonia caused by M. catarrhalis. The organism was markedly resistant (MICs, 1.5–.32 mg/mL) to several marketed fluoroquinolones including the agent (levofloxacin) used for concurrent and prior therapy. The emergence of this problematic strain seems related to chronic exposure of the patient to compounds in the class and poor patient compliance to pre-
scribed medications. The strain was not clonally related to other M. catarrhalis strains isolated in the same hospital during early 1998. This second documented case of a fluoroquinolone-resistant M. catarrhalis clinical isolate presents a warning that resistances can emerge in at-risk patients, and that surveillance systems (SENTRY) will be necessary to monitor for unusual organisms and spread of resistance phenotypes among commonly isolated respiratory tract pathogens. © 1998 Elsevier Science Inc.
INTRODUCTION
macrolides or tetracyclines or trimethoprim/sulfamethoxazole have been reported, albeit infrequently, in publications for more than a decade (Barry et al. 1994; Brown et al. 1989; Davies and Maesen 1988; Kallings 1986; Robledano et al. 1987; Slevin et al. 1984; Zheng 1988). These resistances were documented by a variety of susceptibility test methods and in several nations including the United States, Spain, The Netherlands, New Zealand, Sweden, and China. In contrast, well-controlled studies using standardized test methods, referred strains, and a single-investigator processing format have not detected M. catarrhalis isolates with elevated MICs to fluoroquinolones (Brueggemann et al. 1997; Washington et al. 1996). M. catarrhalis strains also possess intrinsic high MIC values for clindamycin, trimethoprim alone, and vancomycin (Wallace et al. 1990). In 1995 Cunliffe et al. (1995) in the United Kingdom described the first occurrence of a fluoroquino-
b-Lactamase–mediated resistance to penicillins appears ubiquitous in Moraxella catarrhalis with .90% occurrence among clinical strains from recent surveillance trials (Doern et al. 1996; Washington et al. 1996). The common BRO-1 and 2 enzymes also have affinity for some orally administered cephalosporins; thus, incomplete spectrums of activity have been reported for cefixime, cefaclor, loracarbef, cefuroxime, and cefprozil (Barry et al. 1994; Wallace et al. 1990). Furthermore, M. catarrhalis isolates resistant to
From the Summa Health Systems (JRD), Akron City Hospital, Akron, Ohio, USA, and the University of Iowa College of Medicine (TB, RNJ, GVD, MAP), Iowa City, Iowa, USA. Address reprint requests to Professor Ronald N. Jones, M.D., Department of Pathology, C606 GH, University of Iowa College of Medicine, Iowa City, Iowa 52242. Received 10 June 1998; revised and accepted 8 July 1998.
DIAGN MICROBIOL INFECT DIS 1998;32:131–135 © 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0732-8893/98/$19.00 PII S0732-8893(98)00083-2
J.R. DiPersio et al.
132 lone (ciprofloxacin)–resistant M. catarrhalis isolate from a lower respiratory tract infection in a 65-yearold man previously exposed to six courses of ciprofloxacin therapy. This event was very significant because no other documented case had previously been reported in well-controlled investigations, but “nonsusceptible” M. catarrhalis strains had been rarely listed (,1% of strains) in passive surveillance studies (Barry et al. 1994; Jones 1992). In this case presentation, we report a fluoroquinolone-resistant M. catarrhalis isolate from a clinical infection in the state of Ohio in the United States.
MATERIALS AND METHODS Case Report The patient is a 22-year-old African-American man with a history of Bruton’s agammaglobulinemia. His history also includes drug abuse and poor compliance for all prescribed medications. Infections, particularly of the respiratory tract, had been frequent and one month before this admission, he had been treated with levofloxacin for suspected pneumonia. On this admission he complained of shortness of breath, produced a yellow-to-cream-colored sputum,
TABLE 1 Biochemical and Selected Antimicrobial Susceptibility Test Results for Three Strains of M. catarrhalisa Isolated from the Same Institution Strain Numbers Parameter
4B
6B
20B
Negative Diplococcal Positive Positive Positive Positive Negative Positive
Negative Diplococcal Positive Positive Positive Positive Negative Positive
Negative Diplococcal Positive Positive Positive Positive Negative Positive
Positive .4 4 #0.25 4 2 1 2 2 0.5 #0.25 4 0.25 #2 #2 #0.25 .16 0.094 0.125 0.064 0.032 0.064 0.023 0.023 0.016
Positive .4 8 #0.25 2 4 4 0.5 0.25 0.25 #0.25 4 0.25 #2 #2 #0.25 .16 0.094 0.125 0.047 0.023 0.064 0.032 0.023 0.023
Positive .4 4 #0.25 4 2 0.5 1 2 0.5 #0.25 4 0.25 #2 #2 #0.25 .16 .32 .32 .32 .32 .32 1.5 32 1.5
a
Biochemical/microbiologic tests Gram’s stain Structure Catalase Oxidase Nitrate DNase Glucose (acid) Butyric acid Antimicrobial testsb b-Lactamase testc Penicillin G Amoxicillin Amoxicillin/clavulanate (2:1) Cefadroxil Cefprozil Loracarbef Cefuroxime Ceftibuten Cefpodoxime Erythromycin Clindamycin Quinupristin/dalfopristin (30:70) Tetracycline Chloramphenicol Trimethoprim/sulfamethoxazole (1:19) Vancomycin Ciprofloxacinc Ofloxacinc Levofloxacinc Sparfloxacinc Gatifloxacinc Grepafloxacinc Trovafloxacinc Clinafloxacinc a
Identification characteristics were confirmed by the University Hygienic Laboratory (Oakdale), Iowa City, Iowa, USA. Colonies were 1 to 3 mm, pink-brown with a “hockey puck” consistency. b-Lactamase tests were performed using a chromogenic cephalosporin and all susceptibility tests used the reference broth microdilution method (NCCLS 1997, 1998). To assess the fluoroquinolone activity in greater detail over 15 log2 dilution steps, the Etest (AB BIODISK) was applied. b c
Fluoroquinolone-resistant M. catarrhalis and described a fever associated with chills. Significant physical findings were a rapid heart rate and respirations. He was very thin and nasal mucoid drainage was noted. Auscultation of the chest revealed decreased breath sounds and coarse rhonchi. His white blood count was elevated (15.4) with a left-shift and the chest X-ray showed diffuse interstitial infiltrates in the right lobe, similar to findings one month before. Therapy included intravenous antimicrobials (levofloxacin, ampicillin/sulbactam, rifampin), fluid support, and ventilation via intubation with tobramycin aerosol. The patient improved and was extubated slowly because of excessive secretions. The patient was initiated on therapy for his dysphagia and was discharged after 6 weeks of hospitalization. Discharge medications included amoxicillin/clavulanic acid (875 mg bid) and rifampin (300 mg bid) p.o. for one week. The microbiology cultures identified many M. catarrhalis and Streptococcus pneumoniae in the tracheal aspirate, Staphylococcus aureus associated with the triple-lumen catheter access site and Giardia in his stool (metronidazole treatment). The M. catarrhalis strain was b-lactamase positive and the pneumococcus were susceptible to penicillin. In addition, the M. catarrhalis strain was resistant to ciprofloxacin and levofloxacin. The patient had many prior visits to emergency care for respiratory tract infections. Previous cultures in the last 3 years had grown several strains of Haemophilus influenzae (b-lactamase positive and negative), M. catarrhalis, and S. pneumoniae (penicillin MIC of 3.0 mg/mL as well as susceptible strains). Since the index admission having a fluoroquinolone-resistant M. catarrhalis strain, the patient was again hospitalized with a pulmonary infection caused by M. catarrhalis and H. influenzae.
133
FIGURE 1 PFGE patterns (Pme I) for the three isolates of M. catarrhalis. Lane A, strain 20B (this case report); lane B, strain 6B; and lane C, strain 4B.
The identification of M. catarrhalis was made using accepted clinical laboratory practices (Doern et al. 1996; Groschel 1994; Wallace et al. 1990). All findings were confirmed by the University of Iowa Hygienic Laboratory, Oakdale Campus (Iowa City, IA, USA). Molecular methods (ribotyping, pulsed field gel electrophoresis (PFGE)) were also used for the index strain (20B) and two other strains isolated at the same medical center during the calendar month (January 1998) of the index case.
Surveillance Methods The antimicrobial susceptibility for 27 agents was routinely tested against M. catarrhalis isolates by the broth microdilution method in the SENTRY Antimicrobial Surveillance Program, 1998 (NCCLS 1997), a 40-medical-center program in the Americas. These tests are supplemented by the use of the chromogenic cephalosporin b-lactamase test and the application of Etests (AB BIODISK, Solna, Sweden) when required (Bolmstrom et al. 1988). Etest strips for ciprofloxacin, clinafloxacin, gatifloxacin, grepafloxacin, levofloxacin, ofloxacin, sparfloxacin, and trovafloxacin are used to expand the number of tested drugs in this class, as well as the range of dilutions monitored. All test results are interpreted for susceptibility by current NCCLS (1998) tables for nonfastidious species.
RESULTS AND DISCUSSION M. catarrhalis has been established as one of the frequent bacterial pathogens causing infections such as acute otitis media, sinusitis, exacerbations of chronic bronchitis, bronchopneumonia, and infrequently serious invasive infections (meningitis, endocarditis) (Berner et al. 1996; Groschel 1994; Marchant 1990; Wallace et al. 1990; Wood et al. 1996). The organism can be present as a single pathogen or associated with S. pneumoniae and/or H. influenzae in mixed infections. The high rate of b-lactamase production (Doern et al. 1996) with a wide substrate affinity presents an opportunity for this organism to be a copathogen by protecting other susceptible species that could be inhibited by a therapeutic enzyme-
134 labile penicillin or cephalosporin (Wallace et al. 1990). Table 1 shows the results of testing three pathogenic clinical strains of M. catarrhalis isolated at a single institution in early 1998. Strain 20B (this case report) was a b-lactamase–producing organism with a typical antimicrobial susceptibility profile except for a markedly elevated MIC to ciprofloxacin and ofloxacin. Compared with the two control strains of M. catarrhalis (4B, 6B), the most active fluoroquinolones (clinafloxacin, grepafloxacin) were 50 to 100fold less active against strain 20B. The requirement of codrugs in addition to the fluoroquinolone used in this case report to effect a cure of an otherwise susceptible strain possibly reflects the clinical significance of this resistance. Molecular studies (ribotyping, PFGE) were used to compare all three strains; no similarity among these isolates was observed (Figure 1). This case represents only the second welldocumented strain of M. catarrhalis with high-level
J.R. DiPersio et al. resistance to fluoroquinolones, including newer and investigational agents (Cunliffe et al. 1995). The patient’s history of multiple previous exposures to therapy by drugs in this class and poor compliance provided an ideal clinical environment for this resistance to emerge. Fluoroquinolone resistance among other commonly isolated pathogens in community-acquired respiratory tract infections (S. pneumoniae, H. influenzae) remains rare, but clearly have been documented (Jones et al. 1997). Fluoroquinolones should be tested with greater regularity against these species and resistance surveillance programs must monitor a variety of fluoroquinolones to assess variations in potency and spectrum. The authors thank the technical staff of the SENTRY Antimicrobial Surveillance Program (Iowa City, IA, USA) and Kay Meyer for her support in manuscript preparation. This investigation was funded in part by education/research grants from Bristol-Myers Squibb and AB BIODISK.
REFERENCES Barry AL, Pfaller MA, Fuchs PC, Packer RR (1994) In vitro activities of 12 orally administered antimicrobial agents against four species of bacterial respiratory pathogens from U.S. medical centers in 1992 and 1993. Antimicrob Agents Chemother 38:2419–2425. Berner R, Schumacher RF, Brandis M, Forster J (1996) Colonization and infection with Moraxella catarrhalis in childhood. Eur J Clin Microbiol Infect Dis 15:506–509. Bolmstrom A, Arvidson S, Ericson M, Karlsson A (1988) A novel technique for direct quantification of antimicrobial susceptibility of microorganisms (abstr 1209). In: 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, CA. Washington, DC: American Society for Microbiology. Brown BA, Wallace RJ Jr, Flanagan CW, Wilson RW, Luman JI, Redditt SD (1989) Tetracycline and erythromycin resistance among clinical isolates of Branhamella catarrhalis. Antimicrob Agents Chemother 33:1631–1633. Brueggemann AB, Kugler KC, Doern GV (1997) In vitro activity of BAY12–8039, a novel 8-methoxyquinolone and six comparator fluoroquinolones against Streptococcus pneumoniae, Haemophilus influenzae and M. catarrhalis. Antimicrob Agents Chemother 41:1594–1597. Cunliffe NA, Emmanuel FXS, Thomson CJ (1995) Lower respiratory tract infection due to ciprofloxacin-resistant Moraxella catarrhalis. J Antimicrob Chemother 36:273–274. Davies BI, Maesen FPV (1988) The epidemiology of respiratory tract pathogens in Southern Netherlands. Eur Respir J 1:415–420. Doern GV, Brueggemann AB, Pierce G, Hogan T, Holley HP Jr, Rauch A (1996) Prevalence of antimicrobial resistance among 723 outpatient clinical isolates of Moraxella catarrhalis in the United States in 1994 and 1995:
results of a 30-center national surveillance study. Antimicrob Agents Chemother 40:2884–2886. Groschel DHM (1994) Moraxella catarrhalis and other Gramnegative cocci. In: Principles and Practice of Infectious Diseases, Vol. 2. 4th ed. Eds, Mandell GL, Bennett JE, Dolin R. New York: Churchill Livingstone, pp. 1926– 1934. Jones RN (1992) Fluoroquinolone (lomefloxacin) international surveillance trial: a report of 30 months of monitoring in vitro activity. Am J Med 92(suppl 4A):S52–S57. Jones RN, Pfaller MA, Doern GV, Verhoef J, Jones ME, Sader HS, SENTRY Study Group (1997) Initial report of longitudinal, international antimicrobial surveillance study (SENTRY): alarming resistance rates in monitored sites (68 medical centers) in the USA, Canada, South America, and Europe (abstr E-109). Proceedings of the 37th ICAAC. Washington, DC: American Society for Microbiology. Kallings I (1986) Sensitivity of Branhamella catarrhalis to oral antibiotics. Drugs 31:17–22. Marchant CD (1990) Spectrum of disease due to Branhamella catarrhalis in children with particular reference to acute otitis media. Am J Med 88(suppl 5A):15S–19S. National Committee for Clinical Laboratory Standards (NCCLS) (1997) Standard Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically: Approved standard M7–A4. 4th edition. Wayne, PA: NCCLS. National Committee for Clinical Laboratory Standards (1998) Performance Standards for Antimicrobial Susceptibility Testing: Approved Standard M100–S8. Wayne, PA: NCCLS. Robledano L, Rivera MJ, Otal I, Gomez-Lus R (1987) Enzymatic modification of aminoglycoside antibiotics by
Fluoroquinolone-resistant M. catarrhalis
Branhamella catarrhalis carrying an R factor. Drugs Exp Clin Res 13:137–143. Slevin NJ, Aitken J, Thornley PE (1984) Clinical and microbiological features of Branhamella catarrhalis bronchopulmonary infections. Lancet 1:782–783. Wallace RJ, Nash DR, Steingrube VA (1990) Antibiotic susceptibilites and drug resistance in Moraxella (Branhamella) catarrhalis. Am J Med 88(suppl 5A):46S–50S. Washington JA, the Alexander Project Group (1996) A
135
multicenter study of the antimicrobial susceptibility of community-acquired lower respiratory tract pathogens in the United States, 1992–1994. The Alexander Project. Diagn Microbiol Infect Dis 25:183–190. Wood GM, Johnson BC, McCormack JG (1996) Moraxella catarrhalis: pathogenic significance in respiratory tract infections treated by community practitioners. Clin Infect Dis 22:632–636. Zheng X (1988) Beta-lactamase producing Branhamella in Beijing China (letter). Pediatr Infect Dis 7:744.
Fluoroquinolone resistance in Moraxella catarrhalis isolates has been quite rare. This report presents a case history of a 22-year-old man with compromised immune status and severe pneumonia caused by M. catarrhalis. The organism was markedly resistant (MICs, 1.5–.32 mg/mL) to several marketed fluoroquinolones including the agent (levofloxacin) used for concurrent and prior therapy. The emergence of this problematic strain seems related to chronic exposure of the patient to compounds in the class and poor patient compliance to pre-
scribed medications. The strain was not clonally related to other M. catarrhalis strains isolated in the same hospital during early 1998. This second documented case of a fluoroquinolone-resistant M. catarrhalis clinical isolate presents a warning that resistances can emerge in at-risk patients, and that surveillance systems (SENTRY) will be necessary to monitor for unusual organisms and spread of resistance phenotypes among commonly isolated respiratory tract pathogens. © 1998 Elsevier Science Inc.
INTRODUCTION
macrolides or tetracyclines or trimethoprim/sulfamethoxazole have been reported, albeit infrequently, in publications for more than a decade (Barry et al. 1994; Brown et al. 1989; Davies and Maesen 1988; Kallings 1986; Robledano et al. 1987; Slevin et al. 1984; Zheng 1988). These resistances were documented by a variety of susceptibility test methods and in several nations including the United States, Spain, The Netherlands, New Zealand, Sweden, and China. In contrast, well-controlled studies using standardized test methods, referred strains, and a single-investigator processing format have not detected M. catarrhalis isolates with elevated MICs to fluoroquinolones (Brueggemann et al. 1997; Washington et al. 1996). M. catarrhalis strains also possess intrinsic high MIC values for clindamycin, trimethoprim alone, and vancomycin (Wallace et al. 1990). In 1995 Cunliffe et al. (1995) in the United Kingdom described the first occurrence of a fluoroquino-
b-Lactamase–mediated resistance to penicillins appears ubiquitous in Moraxella catarrhalis with .90% occurrence among clinical strains from recent surveillance trials (Doern et al. 1996; Washington et al. 1996). The common BRO-1 and 2 enzymes also have affinity for some orally administered cephalosporins; thus, incomplete spectrums of activity have been reported for cefixime, cefaclor, loracarbef, cefuroxime, and cefprozil (Barry et al. 1994; Wallace et al. 1990). Furthermore, M. catarrhalis isolates resistant to
From the Summa Health Systems (JRD), Akron City Hospital, Akron, Ohio, USA, and the University of Iowa College of Medicine (TB, RNJ, GVD, MAP), Iowa City, Iowa, USA. Address reprint requests to Professor Ronald N. Jones, M.D., Department of Pathology, C606 GH, University of Iowa College of Medicine, Iowa City, Iowa 52242. Received 10 June 1998; revised and accepted 8 July 1998.
DIAGN MICROBIOL INFECT DIS 1998;32:131–135 © 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0732-8893/98/$19.00 PII S0732-8893(98)00083-2
J.R. DiPersio et al.
132 lone (ciprofloxacin)–resistant M. catarrhalis isolate from a lower respiratory tract infection in a 65-yearold man previously exposed to six courses of ciprofloxacin therapy. This event was very significant because no other documented case had previously been reported in well-controlled investigations, but “nonsusceptible” M. catarrhalis strains had been rarely listed (,1% of strains) in passive surveillance studies (Barry et al. 1994; Jones 1992). In this case presentation, we report a fluoroquinolone-resistant M. catarrhalis isolate from a clinical infection in the state of Ohio in the United States.
MATERIALS AND METHODS Case Report The patient is a 22-year-old African-American man with a history of Bruton’s agammaglobulinemia. His history also includes drug abuse and poor compliance for all prescribed medications. Infections, particularly of the respiratory tract, had been frequent and one month before this admission, he had been treated with levofloxacin for suspected pneumonia. On this admission he complained of shortness of breath, produced a yellow-to-cream-colored sputum,
TABLE 1 Biochemical and Selected Antimicrobial Susceptibility Test Results for Three Strains of M. catarrhalisa Isolated from the Same Institution Strain Numbers Parameter
4B
6B
20B
Negative Diplococcal Positive Positive Positive Positive Negative Positive
Negative Diplococcal Positive Positive Positive Positive Negative Positive
Negative Diplococcal Positive Positive Positive Positive Negative Positive
Positive .4 4 #0.25 4 2 1 2 2 0.5 #0.25 4 0.25 #2 #2 #0.25 .16 0.094 0.125 0.064 0.032 0.064 0.023 0.023 0.016
Positive .4 8 #0.25 2 4 4 0.5 0.25 0.25 #0.25 4 0.25 #2 #2 #0.25 .16 0.094 0.125 0.047 0.023 0.064 0.032 0.023 0.023
Positive .4 4 #0.25 4 2 0.5 1 2 0.5 #0.25 4 0.25 #2 #2 #0.25 .16 .32 .32 .32 .32 .32 1.5 32 1.5
a
Biochemical/microbiologic tests Gram’s stain Structure Catalase Oxidase Nitrate DNase Glucose (acid) Butyric acid Antimicrobial testsb b-Lactamase testc Penicillin G Amoxicillin Amoxicillin/clavulanate (2:1) Cefadroxil Cefprozil Loracarbef Cefuroxime Ceftibuten Cefpodoxime Erythromycin Clindamycin Quinupristin/dalfopristin (30:70) Tetracycline Chloramphenicol Trimethoprim/sulfamethoxazole (1:19) Vancomycin Ciprofloxacinc Ofloxacinc Levofloxacinc Sparfloxacinc Gatifloxacinc Grepafloxacinc Trovafloxacinc Clinafloxacinc a
Identification characteristics were confirmed by the University Hygienic Laboratory (Oakdale), Iowa City, Iowa, USA. Colonies were 1 to 3 mm, pink-brown with a “hockey puck” consistency. b-Lactamase tests were performed using a chromogenic cephalosporin and all susceptibility tests used the reference broth microdilution method (NCCLS 1997, 1998). To assess the fluoroquinolone activity in greater detail over 15 log2 dilution steps, the Etest (AB BIODISK) was applied. b c
Fluoroquinolone-resistant M. catarrhalis and described a fever associated with chills. Significant physical findings were a rapid heart rate and respirations. He was very thin and nasal mucoid drainage was noted. Auscultation of the chest revealed decreased breath sounds and coarse rhonchi. His white blood count was elevated (15.4) with a left-shift and the chest X-ray showed diffuse interstitial infiltrates in the right lobe, similar to findings one month before. Therapy included intravenous antimicrobials (levofloxacin, ampicillin/sulbactam, rifampin), fluid support, and ventilation via intubation with tobramycin aerosol. The patient improved and was extubated slowly because of excessive secretions. The patient was initiated on therapy for his dysphagia and was discharged after 6 weeks of hospitalization. Discharge medications included amoxicillin/clavulanic acid (875 mg bid) and rifampin (300 mg bid) p.o. for one week. The microbiology cultures identified many M. catarrhalis and Streptococcus pneumoniae in the tracheal aspirate, Staphylococcus aureus associated with the triple-lumen catheter access site and Giardia in his stool (metronidazole treatment). The M. catarrhalis strain was b-lactamase positive and the pneumococcus were susceptible to penicillin. In addition, the M. catarrhalis strain was resistant to ciprofloxacin and levofloxacin. The patient had many prior visits to emergency care for respiratory tract infections. Previous cultures in the last 3 years had grown several strains of Haemophilus influenzae (b-lactamase positive and negative), M. catarrhalis, and S. pneumoniae (penicillin MIC of 3.0 mg/mL as well as susceptible strains). Since the index admission having a fluoroquinolone-resistant M. catarrhalis strain, the patient was again hospitalized with a pulmonary infection caused by M. catarrhalis and H. influenzae.
133
FIGURE 1 PFGE patterns (Pme I) for the three isolates of M. catarrhalis. Lane A, strain 20B (this case report); lane B, strain 6B; and lane C, strain 4B.
The identification of M. catarrhalis was made using accepted clinical laboratory practices (Doern et al. 1996; Groschel 1994; Wallace et al. 1990). All findings were confirmed by the University of Iowa Hygienic Laboratory, Oakdale Campus (Iowa City, IA, USA). Molecular methods (ribotyping, pulsed field gel electrophoresis (PFGE)) were also used for the index strain (20B) and two other strains isolated at the same medical center during the calendar month (January 1998) of the index case.
Surveillance Methods The antimicrobial susceptibility for 27 agents was routinely tested against M. catarrhalis isolates by the broth microdilution method in the SENTRY Antimicrobial Surveillance Program, 1998 (NCCLS 1997), a 40-medical-center program in the Americas. These tests are supplemented by the use of the chromogenic cephalosporin b-lactamase test and the application of Etests (AB BIODISK, Solna, Sweden) when required (Bolmstrom et al. 1988). Etest strips for ciprofloxacin, clinafloxacin, gatifloxacin, grepafloxacin, levofloxacin, ofloxacin, sparfloxacin, and trovafloxacin are used to expand the number of tested drugs in this class, as well as the range of dilutions monitored. All test results are interpreted for susceptibility by current NCCLS (1998) tables for nonfastidious species.
RESULTS AND DISCUSSION M. catarrhalis has been established as one of the frequent bacterial pathogens causing infections such as acute otitis media, sinusitis, exacerbations of chronic bronchitis, bronchopneumonia, and infrequently serious invasive infections (meningitis, endocarditis) (Berner et al. 1996; Groschel 1994; Marchant 1990; Wallace et al. 1990; Wood et al. 1996). The organism can be present as a single pathogen or associated with S. pneumoniae and/or H. influenzae in mixed infections. The high rate of b-lactamase production (Doern et al. 1996) with a wide substrate affinity presents an opportunity for this organism to be a copathogen by protecting other susceptible species that could be inhibited by a therapeutic enzyme-
134 labile penicillin or cephalosporin (Wallace et al. 1990). Table 1 shows the results of testing three pathogenic clinical strains of M. catarrhalis isolated at a single institution in early 1998. Strain 20B (this case report) was a b-lactamase–producing organism with a typical antimicrobial susceptibility profile except for a markedly elevated MIC to ciprofloxacin and ofloxacin. Compared with the two control strains of M. catarrhalis (4B, 6B), the most active fluoroquinolones (clinafloxacin, grepafloxacin) were 50 to 100fold less active against strain 20B. The requirement of codrugs in addition to the fluoroquinolone used in this case report to effect a cure of an otherwise susceptible strain possibly reflects the clinical significance of this resistance. Molecular studies (ribotyping, PFGE) were used to compare all three strains; no similarity among these isolates was observed (Figure 1). This case represents only the second welldocumented strain of M. catarrhalis with high-level
J.R. DiPersio et al. resistance to fluoroquinolones, including newer and investigational agents (Cunliffe et al. 1995). The patient’s history of multiple previous exposures to therapy by drugs in this class and poor compliance provided an ideal clinical environment for this resistance to emerge. Fluoroquinolone resistance among other commonly isolated pathogens in community-acquired respiratory tract infections (S. pneumoniae, H. influenzae) remains rare, but clearly have been documented (Jones et al. 1997). Fluoroquinolones should be tested with greater regularity against these species and resistance surveillance programs must monitor a variety of fluoroquinolones to assess variations in potency and spectrum. The authors thank the technical staff of the SENTRY Antimicrobial Surveillance Program (Iowa City, IA, USA) and Kay Meyer for her support in manuscript preparation. This investigation was funded in part by education/research grants from Bristol-Myers Squibb and AB BIODISK.
REFERENCES Barry AL, Pfaller MA, Fuchs PC, Packer RR (1994) In vitro activities of 12 orally administered antimicrobial agents against four species of bacterial respiratory pathogens from U.S. medical centers in 1992 and 1993. Antimicrob Agents Chemother 38:2419–2425. Berner R, Schumacher RF, Brandis M, Forster J (1996) Colonization and infection with Moraxella catarrhalis in childhood. Eur J Clin Microbiol Infect Dis 15:506–509. Bolmstrom A, Arvidson S, Ericson M, Karlsson A (1988) A novel technique for direct quantification of antimicrobial susceptibility of microorganisms (abstr 1209). In: 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, CA. Washington, DC: American Society for Microbiology. Brown BA, Wallace RJ Jr, Flanagan CW, Wilson RW, Luman JI, Redditt SD (1989) Tetracycline and erythromycin resistance among clinical isolates of Branhamella catarrhalis. Antimicrob Agents Chemother 33:1631–1633. Brueggemann AB, Kugler KC, Doern GV (1997) In vitro activity of BAY12–8039, a novel 8-methoxyquinolone and six comparator fluoroquinolones against Streptococcus pneumoniae, Haemophilus influenzae and M. catarrhalis. Antimicrob Agents Chemother 41:1594–1597. Cunliffe NA, Emmanuel FXS, Thomson CJ (1995) Lower respiratory tract infection due to ciprofloxacin-resistant Moraxella catarrhalis. J Antimicrob Chemother 36:273–274. Davies BI, Maesen FPV (1988) The epidemiology of respiratory tract pathogens in Southern Netherlands. Eur Respir J 1:415–420. Doern GV, Brueggemann AB, Pierce G, Hogan T, Holley HP Jr, Rauch A (1996) Prevalence of antimicrobial resistance among 723 outpatient clinical isolates of Moraxella catarrhalis in the United States in 1994 and 1995:
results of a 30-center national surveillance study. Antimicrob Agents Chemother 40:2884–2886. Groschel DHM (1994) Moraxella catarrhalis and other Gramnegative cocci. In: Principles and Practice of Infectious Diseases, Vol. 2. 4th ed. Eds, Mandell GL, Bennett JE, Dolin R. New York: Churchill Livingstone, pp. 1926– 1934. Jones RN (1992) Fluoroquinolone (lomefloxacin) international surveillance trial: a report of 30 months of monitoring in vitro activity. Am J Med 92(suppl 4A):S52–S57. Jones RN, Pfaller MA, Doern GV, Verhoef J, Jones ME, Sader HS, SENTRY Study Group (1997) Initial report of longitudinal, international antimicrobial surveillance study (SENTRY): alarming resistance rates in monitored sites (68 medical centers) in the USA, Canada, South America, and Europe (abstr E-109). Proceedings of the 37th ICAAC. Washington, DC: American Society for Microbiology. Kallings I (1986) Sensitivity of Branhamella catarrhalis to oral antibiotics. Drugs 31:17–22. Marchant CD (1990) Spectrum of disease due to Branhamella catarrhalis in children with particular reference to acute otitis media. Am J Med 88(suppl 5A):15S–19S. National Committee for Clinical Laboratory Standards (NCCLS) (1997) Standard Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically: Approved standard M7–A4. 4th edition. Wayne, PA: NCCLS. National Committee for Clinical Laboratory Standards (1998) Performance Standards for Antimicrobial Susceptibility Testing: Approved Standard M100–S8. Wayne, PA: NCCLS. Robledano L, Rivera MJ, Otal I, Gomez-Lus R (1987) Enzymatic modification of aminoglycoside antibiotics by
Fluoroquinolone-resistant M. catarrhalis
Branhamella catarrhalis carrying an R factor. Drugs Exp Clin Res 13:137–143. Slevin NJ, Aitken J, Thornley PE (1984) Clinical and microbiological features of Branhamella catarrhalis bronchopulmonary infections. Lancet 1:782–783. Wallace RJ, Nash DR, Steingrube VA (1990) Antibiotic susceptibilites and drug resistance in Moraxella (Branhamella) catarrhalis. Am J Med 88(suppl 5A):46S–50S. Washington JA, the Alexander Project Group (1996) A
135
multicenter study of the antimicrobial susceptibility of community-acquired lower respiratory tract pathogens in the United States, 1992–1994. The Alexander Project. Diagn Microbiol Infect Dis 25:183–190. Wood GM, Johnson BC, McCormack JG (1996) Moraxella catarrhalis: pathogenic significance in respiratory tract infections treated by community practitioners. Clin Infect Dis 22:632–636. Zheng X (1988) Beta-lactamase producing Branhamella in Beijing China (letter). Pediatr Infect Dis 7:744.