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An extension of quinolone resistance in gram-negatives to the Proteae tribe and a theory of antibiotic use, “Pascal's Wager”
IIDNI Volume 11, Number 8, August 1992 Editor
Associate Editors
C h a r l e s W. S t r a t t o n , MD Departmentof Pathology VanderbiltUniversityMedical Center Nashville,Tennessee
Charles E. Cherubin, MD
Richard E Jacobs, MD
VeteransAdministrationMedicalCenter Wilkes-Barre,Pennsylvania
ArkansasChildren'sHospital Little Rock, Arkansas
Roger G. Finch, FRCP, MRC Path
John T. Sinnott IV, lVlD
NottinghamCity Hospital Nottingham. UnitedKingdom
Universityof South Florida Tampa, Florida
~'OlltClit~
An Extension of Quinolone Resistance in Gram-Negatives to the Proteae Tribe and a Theory of Antibiotic Use, "Pascal's Wager" 57 Charles E. Cherubin Sharon M. Smith Robert H.K. Eng Krisna Pudi Granuiocyte-Coiony Stimulating Factor (G-CSF) in the Treatment of Therapy-Induced Neutropenia: Three Hopeful Studies 60 John N. Greene John W. Hiemenz Kenneth P. Pages
CASE REPORT A Case of Trichosporon Beigelii Endocarditis 8 Years After Aortic Valve Replacement 61 Michael G. Sidarous Michael V. O'Rcilly Charles E. Chcrubin COMMENTS ON CURRENT PUBLICATIONS 63
Elsevier 0278-2316/92/$0.00 + 3.00
H. Bradford Hawley, MD
Philippe Van der Auwera, MD, PhD
Wright StateSchoolof Medicine Dayton, Ohio
InstimtJules Bordet Brussels, Belgium
An Extension of Quinolone Resistance in Gram-Negatives to the Proteae Tribe and a Theory of Antibiotic Use, "Pascal's Wager" Charles E. Cherubin, MD, 1 Sharon M. Smith, PhD, 2 Robert H.K. Eng, MD, 2 and Krisna Pudi 1 IVeteransAffairs Medical Center. Wilkes-Barre,Pennsylvania,and 2VeteransAffairs MedicalCenter, East Orange,New Jersey
The quinolones, including the earliest form of nalidixic acid, have been in clinical use for almost three decades. Nalidixic acid has curiously been far more popular in Europe than in the United States. This usage can easily be confirmed by reference to the nalidixic acid resistance in the Enterobacteriaceae in clinical isolates in Europe (very high) and the United States (far less than 1%). The fluoroquinolones have been in clinical use in this country for about four years. Currently, there are four quinolones commercially available: norfloxacin, ciprofloxacin, ofloxacin, and lomefloxacin. As the quinolones are primarily oral agents, they have gained considerable acceptance in a variety of areas including ud.nary tract, skin and soft tissue, and upper and lower respiratory infections. Unfortunately,
resistance to the quinolones has occurred rapidly for at least two major organisms involved in these infections. The major resistances noted clinically have been in Pseudomonas aeruginosa and Staphylococcus aureus, most especially methicillinresistant Staphylococcus aureus, (MRSA). Acinetobacter resistance has also been seen. This would be anticipated since these three species are far less susceptible to quinolones than are the members of the Enterobacteri. aceae. However, occasionally resistant isolates of Enterobacter, Salmonella, Klebsiella, and Serratia have indeed been reported. Further, significant resistance among S. marcescens has been noted in Japan. It was apparent on a recent review of antimicrobial resistance patterns at the Wilkes-Barre, PA, VAMC that Ja0278-2316 IDINDN 11(8) 57--64, 1992
58
Infectious Diseases Newsletter 11(8) August 1992 100.0% 90.0%
79%
80.0%
70.0%
59%
60.0% 48%
50.0%, 40.0%,
32%
30.0%, 20.0%, 10.0% •
8%
•.
,., ~O
~1
" ,-., .
10%
~
,,.,
'~
°,,,
• •
.
,, -, e
., ¢d
,~ ~
I~
o
t,
Figure 1. Quinolone resistance in gram-negative bacilla at the Wilkes Barre, PA, VAMC.
pan was not the only locale where the majority of S. marcescens isolates were quinolone resistant. Figure 1 gives the frequency of such resistance for 1991 at the Wilkes Barre VAMC. The frequency of resistant isolates is low to nonexistent in E. coli and Klebsiella but very high in members of the old Proteae tribe and Serratia. Three years ago (as far back as the records can be assessed), the rates were far lower. The rates of gentamicin resis-
tance are 50% in these isolates, suggesting by this additional marker that they are nosocomial. The commonest sites include skin, soft tissue, decubiti, and urinary tract. The East Orange VAMC confirms high rates of resistance in these species, with the exception of P. mirabilis, and also in Acinetobacter, which is seldom isolated at the WilkesBarre VAMC (Figure 2). Ciprofloxacin was available during
the period 1989 through 1991. It enjoyed increasing inpatient use to a point equivalent to that of third-generation cephalosporins. Neighboring community hospitals have also seen a rapid increase in the use of this agent during this period but do not report more than 1% to 2% resistance for any gram-negative bacillary species (S. marcescens, for example). The major factors in the difference in these di. vergent results are the longer stay and the greater number of concomitant illnesses of the VA patient. Indeed, there is a large in-house extended care unit and a growing skilled nursing facility between which considerable crosscirculation of nosocomial strains probably occurs. Preliminary information for the first three months of 1992 indicates a continuation of the rise in resistance in these gram-negative bacilli. Analysis of case records of patients at the Wilkes-Barre VAMC receiving ciprofloxacin reveals several interesting aspects of physician's use of antimicrobials. Critical review suggested that more than three-quarters of patients received the quinolone for asymptomatic urinary tract infections or respiratory colonization. Nearly 50% did have some evidence of an infectious process, fever, elevated WBC, etc., in a temporal relationship to the quinolone use. In relatively few instances was the culture of a gramnegative bacillus from the urine, and, in almost no instance from the respiratory tract (the role of the quinolones and most especially ciprofloxacin here is still open for debate), relevant to the patient's illness. The relative lack of toxicity of ciprofloxacin seems to have freed the usual restraints for the use of this antimicrobial agent in these patients; in contrast, the nephrotoxic agent gen-
NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or prope~y as a matt~ of products liability, negligelace or otherwise, or from any usa or operation of any methods, products, instructions or ideas contained in the mnt~ial herein. No suggested test or procedure should he carried out unless, in the reader's judgment, its risk is justified. Because of rapid advances in ',he medical sciences, we re.commend that the independent verification of diagnoses and drug dosages should be made. Discussions, views, and recommendations as to medical procedures, choice of drugs and drug dosages are the responsibility of the authors. Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, New York 10010. Printed in USA at Hanover, PA 17331. Subscription price per year: institutions, $158.00, individuals, $92.00. For postage outside the U.S., add $40.00 (Canada and Mexico require no additional postage). Second-class postage paid at New York, NY, and at additional mailing offices. Pos~naster: Send address changes to Infectious Diseases Newsletter. Elsevier Science Publishing Co., Inc., 655 Avenue oflhe Americas, New York, New York 10010.
© 1992 Elsevier Science Publishing Co., Inc. 0278-2316/92/$0,00 + 3.00
59
Infectious Diseases Newsletter 11(8) August 1992 I00.0% 90.0% 80.0% 70.0%, 59%
~0.0% ~0.0%
45%
40.0%
~0.0%
25%
20.0% 10.0% 0.0%
i
Bibliography
Figure 2. East Orange, NJ, VAMC April 1991-September 1991.
tamicin was not utilized in this manner. I postulate (only half facetiously) that a physician's reflex when confronted with a bacteriology report of an isolate from any body site is to eradicate that organism if there is available to him or her an agent perceived to be relatively innocuous, even if the probability of a patient receiving a benefit is remote. The costs to the patient are also perceived to be minimal. This indeed is "Pascal's wager." The "Pascal's wager" theory of antimicrobial use can be illustrated in another area, that of fluconazole therapy for Candida albicans in the urine of
rather C. tropicalis or other species. Only new admissions to the hospital with Foley catheters grew Candida albicans. In conclusion, a shift of resistance into nosocomial isolates of Proteus, Providencia, Morganella, and Serratia has occurred in two VAMCs under the pressure of heavy use of ciprofloxacin, for the most part being employed to eradicate asymptomatic urinary lract infections and respiratory colonization. One would predict that the next event would be the rise in resistance among Klebsiella and Enterobacter, paralleling what has occurred with gentamiein in nosocomial isolates. Such isolates have just begun to be seen. We postulate an attitude of a "Pascal's wager" for the extreme widespread use of the relatively nontoxic antimicrobials in relativ.ely low-risk situations.
patients with Foley catheters, which has resulted in the development of resistance to azoles at our institution. Prior to the advent of this fluconazole, the only effective therapy effective was amphotericin, either intravenously or by bladder infusion. Both modalities had sufficient toxicity to inhibit their use in many cases. Oral fluconazole changed that, and by 1991 all patients with C. albicans in the urine, sputum, etc., were routinely given a course of fluconazole. By the end of 1991, the majority of fungal isolates from any site were no longer C. albicans but instead other Candida species. Long-term stay patients, for example, did not have C. albicans but
©1992 Elsevier Science Publishing Co., Inc. 0278-2316D2/$0.00 + 3.00
Cherubin CE, Eng RHK: Quinolones for the treatment of infections due to salmonella. Rev Infect Dis 13:343-345, 1991. Fujimaki K, Fujii T, Aoyama H, Sato K-I, Inoue Y, Inoue M, Mitsuhashi S: Quinolone resistance in clinical isolates of Serratia marcescens. Antimicrob Agents Chemother 33:785-787, 1989. Neu HC: Bacterial resistance to fluoroquinolones. Rev Infect Dis 10(Suppl 1):5763, 1988. Parry MF, Pazer KB, Yokna ME: Quinolone resistance: Susceptibility data from a 300-bed community hospital. Am J Med 87(Suppl 5A) :12-16, 1989. Shalit I, Berger SA, Gorea A, Frimerman H: Widespread quinolone resistance anaong methicillin-resistant Staphylococcus aureus isolates in a general hospital. Antimierob Agents Chemother 33:543544, 1989. Smith SM, Eng RHK, Lynch A, Cherubin CE: Observed imipenem and ciprofloxacin resistance in clinical isolates. 30th ICAAC Abstract 54. Atlanta 1990.
Associate Editors
C h a r l e s W. S t r a t t o n , MD Departmentof Pathology VanderbiltUniversityMedical Center Nashville,Tennessee
Charles E. Cherubin, MD
Richard E Jacobs, MD
VeteransAdministrationMedicalCenter Wilkes-Barre,Pennsylvania
ArkansasChildren'sHospital Little Rock, Arkansas
Roger G. Finch, FRCP, MRC Path
John T. Sinnott IV, lVlD
NottinghamCity Hospital Nottingham. UnitedKingdom
Universityof South Florida Tampa, Florida
~'OlltClit~
An Extension of Quinolone Resistance in Gram-Negatives to the Proteae Tribe and a Theory of Antibiotic Use, "Pascal's Wager" 57 Charles E. Cherubin Sharon M. Smith Robert H.K. Eng Krisna Pudi Granuiocyte-Coiony Stimulating Factor (G-CSF) in the Treatment of Therapy-Induced Neutropenia: Three Hopeful Studies 60 John N. Greene John W. Hiemenz Kenneth P. Pages
CASE REPORT A Case of Trichosporon Beigelii Endocarditis 8 Years After Aortic Valve Replacement 61 Michael G. Sidarous Michael V. O'Rcilly Charles E. Chcrubin COMMENTS ON CURRENT PUBLICATIONS 63
Elsevier 0278-2316/92/$0.00 + 3.00
H. Bradford Hawley, MD
Philippe Van der Auwera, MD, PhD
Wright StateSchoolof Medicine Dayton, Ohio
InstimtJules Bordet Brussels, Belgium
An Extension of Quinolone Resistance in Gram-Negatives to the Proteae Tribe and a Theory of Antibiotic Use, "Pascal's Wager" Charles E. Cherubin, MD, 1 Sharon M. Smith, PhD, 2 Robert H.K. Eng, MD, 2 and Krisna Pudi 1 IVeteransAffairs Medical Center. Wilkes-Barre,Pennsylvania,and 2VeteransAffairs MedicalCenter, East Orange,New Jersey
The quinolones, including the earliest form of nalidixic acid, have been in clinical use for almost three decades. Nalidixic acid has curiously been far more popular in Europe than in the United States. This usage can easily be confirmed by reference to the nalidixic acid resistance in the Enterobacteriaceae in clinical isolates in Europe (very high) and the United States (far less than 1%). The fluoroquinolones have been in clinical use in this country for about four years. Currently, there are four quinolones commercially available: norfloxacin, ciprofloxacin, ofloxacin, and lomefloxacin. As the quinolones are primarily oral agents, they have gained considerable acceptance in a variety of areas including ud.nary tract, skin and soft tissue, and upper and lower respiratory infections. Unfortunately,
resistance to the quinolones has occurred rapidly for at least two major organisms involved in these infections. The major resistances noted clinically have been in Pseudomonas aeruginosa and Staphylococcus aureus, most especially methicillinresistant Staphylococcus aureus, (MRSA). Acinetobacter resistance has also been seen. This would be anticipated since these three species are far less susceptible to quinolones than are the members of the Enterobacteri. aceae. However, occasionally resistant isolates of Enterobacter, Salmonella, Klebsiella, and Serratia have indeed been reported. Further, significant resistance among S. marcescens has been noted in Japan. It was apparent on a recent review of antimicrobial resistance patterns at the Wilkes-Barre, PA, VAMC that Ja0278-2316 IDINDN 11(8) 57--64, 1992
58
Infectious Diseases Newsletter 11(8) August 1992 100.0% 90.0%
79%
80.0%
70.0%
59%
60.0% 48%
50.0%, 40.0%,
32%
30.0%, 20.0%, 10.0% •
8%
•.
,., ~O
~1
" ,-., .
10%
~
,,.,
'~
°,,,
• •
.
,, -, e
., ¢d
,~ ~
I~
o
t,
Figure 1. Quinolone resistance in gram-negative bacilla at the Wilkes Barre, PA, VAMC.
pan was not the only locale where the majority of S. marcescens isolates were quinolone resistant. Figure 1 gives the frequency of such resistance for 1991 at the Wilkes Barre VAMC. The frequency of resistant isolates is low to nonexistent in E. coli and Klebsiella but very high in members of the old Proteae tribe and Serratia. Three years ago (as far back as the records can be assessed), the rates were far lower. The rates of gentamicin resis-
tance are 50% in these isolates, suggesting by this additional marker that they are nosocomial. The commonest sites include skin, soft tissue, decubiti, and urinary tract. The East Orange VAMC confirms high rates of resistance in these species, with the exception of P. mirabilis, and also in Acinetobacter, which is seldom isolated at the WilkesBarre VAMC (Figure 2). Ciprofloxacin was available during
the period 1989 through 1991. It enjoyed increasing inpatient use to a point equivalent to that of third-generation cephalosporins. Neighboring community hospitals have also seen a rapid increase in the use of this agent during this period but do not report more than 1% to 2% resistance for any gram-negative bacillary species (S. marcescens, for example). The major factors in the difference in these di. vergent results are the longer stay and the greater number of concomitant illnesses of the VA patient. Indeed, there is a large in-house extended care unit and a growing skilled nursing facility between which considerable crosscirculation of nosocomial strains probably occurs. Preliminary information for the first three months of 1992 indicates a continuation of the rise in resistance in these gram-negative bacilli. Analysis of case records of patients at the Wilkes-Barre VAMC receiving ciprofloxacin reveals several interesting aspects of physician's use of antimicrobials. Critical review suggested that more than three-quarters of patients received the quinolone for asymptomatic urinary tract infections or respiratory colonization. Nearly 50% did have some evidence of an infectious process, fever, elevated WBC, etc., in a temporal relationship to the quinolone use. In relatively few instances was the culture of a gramnegative bacillus from the urine, and, in almost no instance from the respiratory tract (the role of the quinolones and most especially ciprofloxacin here is still open for debate), relevant to the patient's illness. The relative lack of toxicity of ciprofloxacin seems to have freed the usual restraints for the use of this antimicrobial agent in these patients; in contrast, the nephrotoxic agent gen-
NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or prope~y as a matt~ of products liability, negligelace or otherwise, or from any usa or operation of any methods, products, instructions or ideas contained in the mnt~ial herein. No suggested test or procedure should he carried out unless, in the reader's judgment, its risk is justified. Because of rapid advances in ',he medical sciences, we re.commend that the independent verification of diagnoses and drug dosages should be made. Discussions, views, and recommendations as to medical procedures, choice of drugs and drug dosages are the responsibility of the authors. Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, New York 10010. Printed in USA at Hanover, PA 17331. Subscription price per year: institutions, $158.00, individuals, $92.00. For postage outside the U.S., add $40.00 (Canada and Mexico require no additional postage). Second-class postage paid at New York, NY, and at additional mailing offices. Pos~naster: Send address changes to Infectious Diseases Newsletter. Elsevier Science Publishing Co., Inc., 655 Avenue oflhe Americas, New York, New York 10010.
© 1992 Elsevier Science Publishing Co., Inc. 0278-2316/92/$0,00 + 3.00
59
Infectious Diseases Newsletter 11(8) August 1992 I00.0% 90.0% 80.0% 70.0%, 59%
~0.0% ~0.0%
45%
40.0%
~0.0%
25%
20.0% 10.0% 0.0%
i
Bibliography
Figure 2. East Orange, NJ, VAMC April 1991-September 1991.
tamicin was not utilized in this manner. I postulate (only half facetiously) that a physician's reflex when confronted with a bacteriology report of an isolate from any body site is to eradicate that organism if there is available to him or her an agent perceived to be relatively innocuous, even if the probability of a patient receiving a benefit is remote. The costs to the patient are also perceived to be minimal. This indeed is "Pascal's wager." The "Pascal's wager" theory of antimicrobial use can be illustrated in another area, that of fluconazole therapy for Candida albicans in the urine of
rather C. tropicalis or other species. Only new admissions to the hospital with Foley catheters grew Candida albicans. In conclusion, a shift of resistance into nosocomial isolates of Proteus, Providencia, Morganella, and Serratia has occurred in two VAMCs under the pressure of heavy use of ciprofloxacin, for the most part being employed to eradicate asymptomatic urinary lract infections and respiratory colonization. One would predict that the next event would be the rise in resistance among Klebsiella and Enterobacter, paralleling what has occurred with gentamiein in nosocomial isolates. Such isolates have just begun to be seen. We postulate an attitude of a "Pascal's wager" for the extreme widespread use of the relatively nontoxic antimicrobials in relativ.ely low-risk situations.
patients with Foley catheters, which has resulted in the development of resistance to azoles at our institution. Prior to the advent of this fluconazole, the only effective therapy effective was amphotericin, either intravenously or by bladder infusion. Both modalities had sufficient toxicity to inhibit their use in many cases. Oral fluconazole changed that, and by 1991 all patients with C. albicans in the urine, sputum, etc., were routinely given a course of fluconazole. By the end of 1991, the majority of fungal isolates from any site were no longer C. albicans but instead other Candida species. Long-term stay patients, for example, did not have C. albicans but
©1992 Elsevier Science Publishing Co., Inc. 0278-2316D2/$0.00 + 3.00
Cherubin CE, Eng RHK: Quinolones for the treatment of infections due to salmonella. Rev Infect Dis 13:343-345, 1991. Fujimaki K, Fujii T, Aoyama H, Sato K-I, Inoue Y, Inoue M, Mitsuhashi S: Quinolone resistance in clinical isolates of Serratia marcescens. Antimicrob Agents Chemother 33:785-787, 1989. Neu HC: Bacterial resistance to fluoroquinolones. Rev Infect Dis 10(Suppl 1):5763, 1988. Parry MF, Pazer KB, Yokna ME: Quinolone resistance: Susceptibility data from a 300-bed community hospital. Am J Med 87(Suppl 5A) :12-16, 1989. Shalit I, Berger SA, Gorea A, Frimerman H: Widespread quinolone resistance anaong methicillin-resistant Staphylococcus aureus isolates in a general hospital. Antimierob Agents Chemother 33:543544, 1989. Smith SM, Eng RHK, Lynch A, Cherubin CE: Observed imipenem and ciprofloxacin resistance in clinical isolates. 30th ICAAC Abstract 54. Atlanta 1990.