BRIEFCLINICALOBSERVATIONS
mycin and piperacillin. However, cal worsening and bacteremia, recurrence with a new left lower has been reported in a patient lobe infiltrate developed, and he with pneumococcal pneumonia required reintubation. Sputum [3]. Several studies have evalcultures revealed P. aeruginosa uated the efficacy of ciprofloxacin in the treatment of chronic resistant to all antibiotics tested Ciprofloxacin is a newly released except ciprofloxacin, tobramybronchitis. Davies et al [4] refluoroquinolone antibiotic that tin, and amikacin. The patient ported good response rates for patients treated with ciprofloxahas been approved for use in a was treated with ciprofloxacin, variety of community-acquired 200 mg intravenously every 12 tin for exacerbations of chronic infections, including lower respi- hours, and nebulized tobramycin, bronchitis, unless S. pneumoniae ratory tract infections. This ap- 25 mg every 8 hours, for 14 days was the inciting microbe. Hoogproval has met with some skeptiwith complete clinical and roentkamp-Korstanje and Klein [5] cism, in that the ilz vitro activity genographic resolution of the found that the pneumococcus pneumonia. was slowly eradicated from spuof this agent against Streptococcus pneumoniae, the most freOne day after completing this tum in patients with exacerbaquently isolated organism in course of therapy, the patient tions of chronic bronchitis treatcommunity-acquired pneumoagain developed dyspnea, fever, ed with ciprofloxacin; the organnia, is less than ideal [l]. tachycardia, and a new right low- ism was still present as long as 1 We report a patient who devel- er lobe infiltrate. Sputum re- week after therapy had begun. oped nosocomial pneumococcal vealed many neutrophils and Difficulty in eradicating the pneumonia immediately after gram-positive diplococci on pneumococcus from sputum has completing a course of intraveGram’s stain and yielded a pure been attributed to the relatively nous ciprofloxacin and nebulized culture of S. pneumoniae. Blood high minimal inhibitory concentobramycin for pneumonia due to cultures showed no growth. He trations of ciprofloxacin for this Pseudomonas aeruginosa. We was treated with penicillin G, 1 organism, which range from 0.5 million units intravenously every fig/mL to 4 pg/mL [ 11. Serum levsuspect that the administration of ciprofloxacin and tobramycin 4 hours, with resolution of his ill- els of ciprofloxacin during theraallowed colonization and subse- ness. py with both intravenous and quent infection of the respiratory Ciprofloxacin has excellent ac- oral preparations are quite variable. Mean peak serum levels of tract to occur with S. pneumontivity against most gram-negaiae. tive bacteria, making its potenciprofloxacin after 200 mg given A 61-year-old man entered the tial for the treatment of nosoco- intravenously range from 3.2 to Ann Arbor Veterans Administramial pneumonias promising [2]. 6.3 pg/mL; however, 1 hour later, tion Medical Center in May 1989 It also appears to be quite active levels typically drop to 0.9 to 1.5 for treatment of recurrent atria1 against a number of organisms pg/mL. With oral therapy, mean commonly observed in communipeak serum levels are usually no flutter. His past medical history was remarkable for large cell car- ty-acquired pulmonary infecgreater than 3 pg/mL [6]. Davies cinoma of the lung treated with tions, such as Mycoplasma pneuet al [4] reported a mean peak left upper lobectomy in March moniae, Haemophilis influenciprofloxacin level in sputum of 1986 and chronic obstructive pulzae, Branhamella catarrhalis, only 1.57 pg/mL at a dose of 750 monary disease. and Legionella pneumophila [2]. mg twice a day, which was not The patient had a difficult and However, its activity against high enough to inhibit many prolonged hospital course, com- Streptococcus pyogenes (group strains of S. pneumoniae. Howplicated by acute cholecystitis, A streptococcus) and anaerobes ever, others have reported conrenal failure, respiratory failure is poor, and its activity against S. centrations of ciprofloxacin in pulmonary secretions or lung tisrequiring long-term ventilator pneumoniae is only marginal [l]. Studies documenting the effisue several times greater than support, and recurrent episodes cacy of ciprofloxacin in the therathose found in serum [7,8]. of sepsis. Pneumonia due to P. aeruginpy of pneumococcal pneumonia The development of nosocoosa developed and initially re- are lacking; in fact, failure to re- mial pneumonia can be viewed as sponded to treatment with tobraspond to ciprofloxacin, with clinia multistage process, beginning
SUPERINFECTIONWITH STREPTOCOCCUS PNEUMONlAE DURING THERAPYWITH CIPROFLOXACIN
September
1990
The American
Journal
of Medicine
Volume
89
383
with alteration of the host’s natural microbial flora, colonization of the upper respiratory tract with potential pathogens, subsequent aspiration of these organisms, and the development of pneumonia. Gram-negative bacilli most commonly colonize the respiratory tract in patients who are seriously ill, especially those requiring ventilator support in the intensive care unit setting [9]. Hence, these organisms account for the vast majority of pathogens in nosocomial pneumonia, as opposed to the pneumococcus, which accounts for approximately 3% [lo]. We hypothesize that our patient developed pneumococcal pneumonia as a result of eradication of gram-negative colonization by the combined effects of ciprofloxacin and nebulized tobramycin. Both agents have outstanding activity against gramnegative pathogens and poor-tomarginal activity against S. pneumoniae. This experience may also be a valuable lesson for the outpatient setting. Ciprofloxacin is being dispensed with great frequency for the therapy of community-acquired lower respiratory tract infections. Treatment failure may occur when the primary pathogen is the pneumococcus; these failures could be avoided with more conventional therapy. We would like to alert physicians to this possibility and discourage the indiscriminate use of ciprofloxacin for respiratory infections when the pneumococcus is believed to be a likely etiologic agent.
dysplastic syndrome [6], and some researchers have expressed concern that some solid tumors may have receptors for GM-CSF and be susceptible to its action [7]. Despite this concern, prior studies with malignant B cells in vitro failed to demonstrate any malignant growth potentiation [8]. We describe here the successful use of GM-CSF to treat infections in two patients with acute lymphocytic leukemia (ALL) associated with profound neutropenia secondary to chemotherapy. No stimulation of growth of ALL blasts was evident during or after treatment with GM-CSF. Patient 1. A 23-year-old man developed pre-auricular adenopathy that was diagnosed as nodular well-differentiated lymphoma, and he was treated with chlorambucil. After a brief reSubmitted January 12, 1990, and accepted in response, rapid regrowth of lymph vised form April 30. 1990 nodes occurred and therapy was switched to oral cyclophosphamide. One month later he preSUCCESSFULUSEOF sented with fever, chills, splenoGRANULOCYTE-MACROPHAGE megaly, and a white blood cell COLONY-STIMULATING count of 150,000/mm3, and the FACTORIN PATIENTS WITH diagnosis of ALL was made. The ACUTE LYMPHOCYTIC patient began to receive daunorLEUKEMIA ubucin, vincristine, and prednisone, with a rapid decrease in the Granulocyte-macrophage colowhite blood cell count to 800/ ny-stimulating factor (GM-CSF) mm3. He was transferred to the is a recombinant human hematoMedical College of Virginia, poietic factor with the potential where bone marrow biopsy and to stimulate the growth of neu- aspiration confirmed ALL, and trophil precursors, as well as acticytogenetic study revealed posivate those already produced. It tive Philadelphia chromosome, has been used successfully to pre- trisomy 17, monosomy 8, and vent or treat the neutropenia as- monosomy 14. Immunophenosociated with the treatment of typing disclosed that the cells solid tumor [l]; to stimulate the were pre-B cells. The L17-M regiJAMES J. GORDON,M.D. growth of normal precursors in men [9] of cyclophosphamide, CAROLA. KAUFFMAN; M.D. aplastic anemia [2], hairy cell leuvincristine, and prednisone was Veterans Administration Medical kemia [3], and acquired immunobegun, with a rapid lysis of the deficiency syndrome [4]; and to peripheral blood blasts. HowUniversity of Michigan M;fl;~i reverse some cyclic neutrophil ever, bone marrow biopsy showed disorders [5]. However, it has also hypercellularity with 100% Ann Arbor, Michigan shown the potential to stimulate blasts. He was subsequently 1. Kayser FH. Novak J. In vitro activity of ciprofloxathe growth of disordered clones treated with methotrexate, vintin against gram-positive bacteria. Am J Med 1987; of hematopoietic cells found in cristine, asparaginase, and dexa82 (Suppl 4A): 33-9. 2. Koester JA. Ciprofloxacin: a new fluoroquinolone. patients with advanced myelomethasone [lo], with rapid lysis Am J Med Sci 1988; 297: 128-31. 3. Cooper B. Lawlor M. Pneumococcal bacteremia during ciprofloxacin therapy for pneumococcal pneumonia (brief clinical observation). Am J Med 1989; 87: 475. 4. Davies BI. Maesen FPV, Baur C. Ciprofloxacin in the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1986; 5: 22631. 5. Hoogkamp-Korstanje JAA. Klein SJ. Ciprofloxacin in acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1986; 18: 407-13. 6. Lode H, Hoffken G, Borner K, Koeppe P. Ciprofloxacin intravenous dose variance. Am J Med 1989; 87 (Suppl 5A): 40-5. 7. Reid TMS. Gould IM. Golder D. eta/. Brief report: Respiratory tract penetration of ciprofloxacin. Am J Med 1989; 87 (Suppl 5A): 60-l. 8. Schlenkhoff D, Dalhoff A, Knopf J. Opferkuch W. Penetration of ciprofloxacin into human lung tissue following intravenous injection. Infection 1986; 14: 299-300 9. Johanson WG. Pierce AK, Sanford JP, Thomas GD. Nosocomial respiratory infections with gramnegative bacilli: the significance of colonization in the respiratory tract. Ann Intern Med 1972; 77: 701-6. 10. Jay SJ. Nosocomial infections. Med Clin North Am 1983; 67: 1251-77.
ce:fz
384
September
1990
The American
Journal
of Medicine
Volume
89
mycin and piperacillin. However, cal worsening and bacteremia, recurrence with a new left lower has been reported in a patient lobe infiltrate developed, and he with pneumococcal pneumonia required reintubation. Sputum [3]. Several studies have evalcultures revealed P. aeruginosa uated the efficacy of ciprofloxacin in the treatment of chronic resistant to all antibiotics tested Ciprofloxacin is a newly released except ciprofloxacin, tobramybronchitis. Davies et al [4] refluoroquinolone antibiotic that tin, and amikacin. The patient ported good response rates for patients treated with ciprofloxahas been approved for use in a was treated with ciprofloxacin, variety of community-acquired 200 mg intravenously every 12 tin for exacerbations of chronic infections, including lower respi- hours, and nebulized tobramycin, bronchitis, unless S. pneumoniae ratory tract infections. This ap- 25 mg every 8 hours, for 14 days was the inciting microbe. Hoogproval has met with some skeptiwith complete clinical and roentkamp-Korstanje and Klein [5] cism, in that the ilz vitro activity genographic resolution of the found that the pneumococcus pneumonia. was slowly eradicated from spuof this agent against Streptococcus pneumoniae, the most freOne day after completing this tum in patients with exacerbaquently isolated organism in course of therapy, the patient tions of chronic bronchitis treatcommunity-acquired pneumoagain developed dyspnea, fever, ed with ciprofloxacin; the organnia, is less than ideal [l]. tachycardia, and a new right low- ism was still present as long as 1 We report a patient who devel- er lobe infiltrate. Sputum re- week after therapy had begun. oped nosocomial pneumococcal vealed many neutrophils and Difficulty in eradicating the pneumonia immediately after gram-positive diplococci on pneumococcus from sputum has completing a course of intraveGram’s stain and yielded a pure been attributed to the relatively nous ciprofloxacin and nebulized culture of S. pneumoniae. Blood high minimal inhibitory concentobramycin for pneumonia due to cultures showed no growth. He trations of ciprofloxacin for this Pseudomonas aeruginosa. We was treated with penicillin G, 1 organism, which range from 0.5 million units intravenously every fig/mL to 4 pg/mL [ 11. Serum levsuspect that the administration of ciprofloxacin and tobramycin 4 hours, with resolution of his ill- els of ciprofloxacin during theraallowed colonization and subse- ness. py with both intravenous and quent infection of the respiratory Ciprofloxacin has excellent ac- oral preparations are quite variable. Mean peak serum levels of tract to occur with S. pneumontivity against most gram-negaiae. tive bacteria, making its potenciprofloxacin after 200 mg given A 61-year-old man entered the tial for the treatment of nosoco- intravenously range from 3.2 to Ann Arbor Veterans Administramial pneumonias promising [2]. 6.3 pg/mL; however, 1 hour later, tion Medical Center in May 1989 It also appears to be quite active levels typically drop to 0.9 to 1.5 for treatment of recurrent atria1 against a number of organisms pg/mL. With oral therapy, mean commonly observed in communipeak serum levels are usually no flutter. His past medical history was remarkable for large cell car- ty-acquired pulmonary infecgreater than 3 pg/mL [6]. Davies cinoma of the lung treated with tions, such as Mycoplasma pneuet al [4] reported a mean peak left upper lobectomy in March moniae, Haemophilis influenciprofloxacin level in sputum of 1986 and chronic obstructive pulzae, Branhamella catarrhalis, only 1.57 pg/mL at a dose of 750 monary disease. and Legionella pneumophila [2]. mg twice a day, which was not The patient had a difficult and However, its activity against high enough to inhibit many prolonged hospital course, com- Streptococcus pyogenes (group strains of S. pneumoniae. Howplicated by acute cholecystitis, A streptococcus) and anaerobes ever, others have reported conrenal failure, respiratory failure is poor, and its activity against S. centrations of ciprofloxacin in pulmonary secretions or lung tisrequiring long-term ventilator pneumoniae is only marginal [l]. Studies documenting the effisue several times greater than support, and recurrent episodes cacy of ciprofloxacin in the therathose found in serum [7,8]. of sepsis. Pneumonia due to P. aeruginpy of pneumococcal pneumonia The development of nosocoosa developed and initially re- are lacking; in fact, failure to re- mial pneumonia can be viewed as sponded to treatment with tobraspond to ciprofloxacin, with clinia multistage process, beginning
SUPERINFECTIONWITH STREPTOCOCCUS PNEUMONlAE DURING THERAPYWITH CIPROFLOXACIN
September
1990
The American
Journal
of Medicine
Volume
89
383
with alteration of the host’s natural microbial flora, colonization of the upper respiratory tract with potential pathogens, subsequent aspiration of these organisms, and the development of pneumonia. Gram-negative bacilli most commonly colonize the respiratory tract in patients who are seriously ill, especially those requiring ventilator support in the intensive care unit setting [9]. Hence, these organisms account for the vast majority of pathogens in nosocomial pneumonia, as opposed to the pneumococcus, which accounts for approximately 3% [lo]. We hypothesize that our patient developed pneumococcal pneumonia as a result of eradication of gram-negative colonization by the combined effects of ciprofloxacin and nebulized tobramycin. Both agents have outstanding activity against gramnegative pathogens and poor-tomarginal activity against S. pneumoniae. This experience may also be a valuable lesson for the outpatient setting. Ciprofloxacin is being dispensed with great frequency for the therapy of community-acquired lower respiratory tract infections. Treatment failure may occur when the primary pathogen is the pneumococcus; these failures could be avoided with more conventional therapy. We would like to alert physicians to this possibility and discourage the indiscriminate use of ciprofloxacin for respiratory infections when the pneumococcus is believed to be a likely etiologic agent.
dysplastic syndrome [6], and some researchers have expressed concern that some solid tumors may have receptors for GM-CSF and be susceptible to its action [7]. Despite this concern, prior studies with malignant B cells in vitro failed to demonstrate any malignant growth potentiation [8]. We describe here the successful use of GM-CSF to treat infections in two patients with acute lymphocytic leukemia (ALL) associated with profound neutropenia secondary to chemotherapy. No stimulation of growth of ALL blasts was evident during or after treatment with GM-CSF. Patient 1. A 23-year-old man developed pre-auricular adenopathy that was diagnosed as nodular well-differentiated lymphoma, and he was treated with chlorambucil. After a brief reSubmitted January 12, 1990, and accepted in response, rapid regrowth of lymph vised form April 30. 1990 nodes occurred and therapy was switched to oral cyclophosphamide. One month later he preSUCCESSFULUSEOF sented with fever, chills, splenoGRANULOCYTE-MACROPHAGE megaly, and a white blood cell COLONY-STIMULATING count of 150,000/mm3, and the FACTORIN PATIENTS WITH diagnosis of ALL was made. The ACUTE LYMPHOCYTIC patient began to receive daunorLEUKEMIA ubucin, vincristine, and prednisone, with a rapid decrease in the Granulocyte-macrophage colowhite blood cell count to 800/ ny-stimulating factor (GM-CSF) mm3. He was transferred to the is a recombinant human hematoMedical College of Virginia, poietic factor with the potential where bone marrow biopsy and to stimulate the growth of neu- aspiration confirmed ALL, and trophil precursors, as well as acticytogenetic study revealed posivate those already produced. It tive Philadelphia chromosome, has been used successfully to pre- trisomy 17, monosomy 8, and vent or treat the neutropenia as- monosomy 14. Immunophenosociated with the treatment of typing disclosed that the cells solid tumor [l]; to stimulate the were pre-B cells. The L17-M regiJAMES J. GORDON,M.D. growth of normal precursors in men [9] of cyclophosphamide, CAROLA. KAUFFMAN; M.D. aplastic anemia [2], hairy cell leuvincristine, and prednisone was Veterans Administration Medical kemia [3], and acquired immunobegun, with a rapid lysis of the deficiency syndrome [4]; and to peripheral blood blasts. HowUniversity of Michigan M;fl;~i reverse some cyclic neutrophil ever, bone marrow biopsy showed disorders [5]. However, it has also hypercellularity with 100% Ann Arbor, Michigan shown the potential to stimulate blasts. He was subsequently 1. Kayser FH. Novak J. In vitro activity of ciprofloxathe growth of disordered clones treated with methotrexate, vintin against gram-positive bacteria. Am J Med 1987; of hematopoietic cells found in cristine, asparaginase, and dexa82 (Suppl 4A): 33-9. 2. Koester JA. Ciprofloxacin: a new fluoroquinolone. patients with advanced myelomethasone [lo], with rapid lysis Am J Med Sci 1988; 297: 128-31. 3. Cooper B. Lawlor M. Pneumococcal bacteremia during ciprofloxacin therapy for pneumococcal pneumonia (brief clinical observation). Am J Med 1989; 87: 475. 4. Davies BI. Maesen FPV, Baur C. Ciprofloxacin in the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1986; 5: 22631. 5. Hoogkamp-Korstanje JAA. Klein SJ. Ciprofloxacin in acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1986; 18: 407-13. 6. Lode H, Hoffken G, Borner K, Koeppe P. Ciprofloxacin intravenous dose variance. Am J Med 1989; 87 (Suppl 5A): 40-5. 7. Reid TMS. Gould IM. Golder D. eta/. Brief report: Respiratory tract penetration of ciprofloxacin. Am J Med 1989; 87 (Suppl 5A): 60-l. 8. Schlenkhoff D, Dalhoff A, Knopf J. Opferkuch W. Penetration of ciprofloxacin into human lung tissue following intravenous injection. Infection 1986; 14: 299-300 9. Johanson WG. Pierce AK, Sanford JP, Thomas GD. Nosocomial respiratory infections with gramnegative bacilli: the significance of colonization in the respiratory tract. Ann Intern Med 1972; 77: 701-6. 10. Jay SJ. Nosocomial infections. Med Clin North Am 1983; 67: 1251-77.
ce:fz
384
September
1990
The American
Journal
of Medicine
Volume
89
