187
DIAG. MICROBIOL.INFECT. DIS. 1990;13:187-189
Economic Impact of Oral Ciprofloxacin Following Standard Intravenous Therapy Robert M. Fliegelman, Patricia M. Mattingly, Cindy L. Dempsey, and Stephen J. Sokalski
INTRODUCTION There is increasing pressure on the clinician to shorten the length of hospitalization for each patient admitted to the hospital and thereby hold down spiraling health care costs. Although the efficacy of sequential intravenous (W)/oral therapy is not yet clearly proven, the concept of completing a course of antibiotic therapy for lower respiratory tract infection with oral agents after initial parenteral therapy is very appealing. At our institution, an 824-bed community teaching hospital, we compared standard parenteral therapy with oral ciprofloxacin following 72 hr of parenteral therapy for lower respiratory tract infections to assess safety and efficacy, as well as potential cost savings of conversion to oral ciprofloxacin.
METHODS All enrolled patients were adults hospitalized with signs and symptoms of lower respiratory infections severe enough to require parenteral therapy. All patients were treated initially with 72 hr of parenteral therapy. After giving written informed consent, patients were randomized to receive either oral ciprofloxacin (750 mg, twice daily) or parenteral therapy From the Section of Infectious Disease and Department of Pharmacy, Christ Hospital and Medical Center, Oak Lawn, Illinois. Address reprint requests to: Dr. P. Mattingly, Department of Pharmacy, Christ Hospital and Medical Center, 4440 West 95th Street, Oak Lawn, IL 60453. Received January 10, 1990;revised and accepted January 12, 1990. © 1990Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50
chosen by the attending physician. Drug therapy was continued until signs and symptoms resolved or the treatment arm was judged a failure by the principal investigators. Complete clinical resolution was defined as the disappearance of all signs and symptoms related to the infection. Clinical improvement was defined as marked or moderate reduction in signs and symptoms of infection. Failure was defined as no abatement in clinical signs and symptoms of infection and reinstitution of parenteral therapy. Bacterial eradication was defined as the absence of the causative organism at the end of therapy. Persistence was defined as the causative organism present at the end of therapy. Superinfection was defined as the presence of a n e w organism during or at the end of therapy judged not to be causing respiratory symptoms. If a new organism was present but judged not to be causing respiratory symptoms, this was termed new colonization. Statistical analysis of continuous data included Student's t-test following log transformations, where necessary. Statistical analysis of categorical data included the Mantel-Haenszel adjusted relative risks and Mantel-Haenszel chi-squares. All susceptibility testing was done by the microtiter (minimum MIC system, with reagents provided by Miles, Inc., Pharmaceutical Division (New Haven, CT).
RESULTS A total of 25 patients (14 male, 11 female) were enrolled in the study. One patient was lost to followup. Ages ranged from 19 to 87 years, with a mean age of 65. Causative organisms and dinical and bacterio-
188
R.M. Fliegelman et al.
TABLE 1.
Causative Organisms
Bacteria
Ciprofloxacin (n = 11)
Streptococcus pneumoniae Haemophilus influenzae Pseudomonas aeruginosa Proteus mirabilis Branhamella catarrhalis Klebsiella pneumoniae Serratia marcescens Staphylococcus epidermidis
3 3 2 0 0 0 0 1
DISCUSSION Control (n = 13) Total 3 0 1 2 1 1 1 0
6 3 3 2 1 1 1 1
logic results are detailed in Tables 1 and 2, respectively. Complete clinical resolution of infection was achieved in 16 patients (67%): seven in the ciprofloxacin group and nine in the control group. Clinical improvement occurred in six additional patients: two ciprofloxacin and four control. Two clinical failures were documented in the ciprofloxacin-treated group. One patient with Haemophilus influenzae pneumonia responded initially to parenteral cefuroxime therapy. Following randomization to oral ciprofloxacin, the patient developed fever and episodic chills unabated for 3 days. This resulted in reinstitution of parenteral therapy. Haemophilus influenzae minimum inhibitory concentration (MIC) for ciprofloxacin was 0.125 ~g/ml, and the organism was eradicated on subsequent cultures. The patient had a concomitant, radiologically proven maxillary sinusitis that required surgical drainage for cure. The second patient had pneumonia that originally cultured Pseudomonas aeruginosa. When the patient did not improve with drug therapy, a subsequent culture revealed methicillin-resistant Staphylococcus aureus (MRSA), also resistant to ciprofloxacin. Intravenous vancomycin was instituted, and the patient responded satisfactorily. TABLE 2.
Clinical and Bacteriologic Results
Clinical outcome Resolution Improvement Failure Bacteriologic outcome Eradication Persistence New colonization Superinfection
Ciprofloxacin (n = 11)
Control (n = 13)
Total
7 2 2
9 4 0
16 6 2
7 0 5 1
7 1 7 1
14 1 12 2
Ciprofloxacin is a fluorinated quinolone antibiotic with excellent in vitro activity against most Grampositive and Gram-negative pathogens likely to cause lower respiratory tract infections (Barry and Jones, 1987; Sanders et al., 1987). Because ciprofloxacin attains adequate serum levels following oral administration (Bergan et al., 1987), and excellent concentrations in bronchial tissue (Thys, 1988), it becomes a logical choice for treatment of such infections after an initial period of parenteral therapy. The results of this study suggest that clinical and bacteriologic outcomes were equivalent in those patients treated with a standard course of parenteral therapy versus those randomized to oral ciprofloxacin, providing pathogens were sensitive to ciprofloxacin. Even in the treatment of pathogens where ciprofloxacin efficacy may be in question (i.e., Streptococcus pneumoniae) (Barry and Jones, 1987; Neu, 1987; Thys, 1988), the results of this study demonstrated acceptable clinical outcome. Three patients in the ciprofloxacin group were treated for pneumonococcal pneumonia (one with bacteremia) with clinical and bacteriologic cure. There are documented reports in the literature of increasing in vitro resistance of MRSA to ciprofloxacin (Isaacs, et al., 1988; Shalit et al., 1989). During this study, there was one case that appeared to be a clinically significant MRSA pneumonia. This developed while the patient was on ciprofloxacin for a previously diagnosed Pseudomonas pneumonia. The MRSA MIC for ciprofloxacin was >4 ~g/ml. Although this represents only one case, concern exists that increasing in vitro resistance to MRSA may correlate with clinical failure. Furthermore, if clinical signs and symptoms of infection reemerge after converting to oral ciprofloxacin, a resistant pathogen must be considered, and appropriate action must be taken. Results of this study demonstrate a 20% decrease in the average length of hospital stay (9.91 days for the ciprofloxacin group vs. 12.31 days for the control group) and a 57% decrease in drug acquisition cost ($243.63 for the ciprofloxacin group vs. $427.37 for the control group). The average savings for patients treated with oral ciprofloxacin was $1159.97 (Table 3). Total savings for the 11 patients receiving oral ciprofloxacin was $12,760. If further studies confirm our data, that efficacy is not compromised by early conversion to oral ciprofloxacin, a substantial cost savings can be realized.
E c o n o m i c I m p a c t of Ciprofloxacin
TABLE 3.
189
A v e r a g e C o s t of T h e r a p y p e r Patient
Duration of treatment (days) Hospital stay (days) Drug cost~ Hospital cost a Total cost ~
Ciprofloxacin
Control
p
Cost Savings
16.0 9.91 $243.63 $4033.00 $4276.63
16.7 12.31 $427.37 $5009.23 $5436.60
0.479 ~ 0.427 a 0.228 b 0.415 a 0.195
--$183.74 $976.23 $1159.97
~Log transformation was performed on data for this variable. bKruskal-Wallis test for nonparametric data. CAcquisition cost and intravenous solution cost. ~Room charge of $407/day. eTotal cost = drug cost + hospital cost.
REFERENCES Barry AL, Jones RN (1987) In vitro activity of ciprofloxacin against gram-positive cocci. Am J Med 82(suppl 4A):2732. Bergan T, Thorsteinsson SB, Solberg R, Bjornskau L, Kolstad IM, Johnsen S (1987) Pharmacokinetics of ciprofloxacin: intravenous and increasing oral doses. Am J Med 82(suppl 4A):97-102. Isaacs RD, Kunke PJ, Cohen RL, Smith JW (1988) Ciprofloxacin resistance in epidemic methicillinresistant Staphylococcus aureus [Letter to editor]. Lancet 1:843.
Neu HC (1987) New antibiotics: areas of appropriate use. J Infect Dis 155:403-417. Sanders CC, Sanders WE, Goering RV (1987) Overview of preclinical studies with ciprofloxacin. Am J Med 82(suppl 4A):2-11. Shalit I, Berger SA, Gorea A, Frimerman H (1989) Widespread quinolone resistance among methicillin-resistant Staphylococcus aureus isolates in a general hospital. Antimicrob Agents Chemother 33:593-594. Thys JP (1988) Quinolones in the treatment of bronchopulmonary infections. Rev Infect Dis 10(suppl 1):$212$5217.
DIAG. MICROBIOL.INFECT. DIS. 1990;13:187-189
Economic Impact of Oral Ciprofloxacin Following Standard Intravenous Therapy Robert M. Fliegelman, Patricia M. Mattingly, Cindy L. Dempsey, and Stephen J. Sokalski
INTRODUCTION There is increasing pressure on the clinician to shorten the length of hospitalization for each patient admitted to the hospital and thereby hold down spiraling health care costs. Although the efficacy of sequential intravenous (W)/oral therapy is not yet clearly proven, the concept of completing a course of antibiotic therapy for lower respiratory tract infection with oral agents after initial parenteral therapy is very appealing. At our institution, an 824-bed community teaching hospital, we compared standard parenteral therapy with oral ciprofloxacin following 72 hr of parenteral therapy for lower respiratory tract infections to assess safety and efficacy, as well as potential cost savings of conversion to oral ciprofloxacin.
METHODS All enrolled patients were adults hospitalized with signs and symptoms of lower respiratory infections severe enough to require parenteral therapy. All patients were treated initially with 72 hr of parenteral therapy. After giving written informed consent, patients were randomized to receive either oral ciprofloxacin (750 mg, twice daily) or parenteral therapy From the Section of Infectious Disease and Department of Pharmacy, Christ Hospital and Medical Center, Oak Lawn, Illinois. Address reprint requests to: Dr. P. Mattingly, Department of Pharmacy, Christ Hospital and Medical Center, 4440 West 95th Street, Oak Lawn, IL 60453. Received January 10, 1990;revised and accepted January 12, 1990. © 1990Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50
chosen by the attending physician. Drug therapy was continued until signs and symptoms resolved or the treatment arm was judged a failure by the principal investigators. Complete clinical resolution was defined as the disappearance of all signs and symptoms related to the infection. Clinical improvement was defined as marked or moderate reduction in signs and symptoms of infection. Failure was defined as no abatement in clinical signs and symptoms of infection and reinstitution of parenteral therapy. Bacterial eradication was defined as the absence of the causative organism at the end of therapy. Persistence was defined as the causative organism present at the end of therapy. Superinfection was defined as the presence of a n e w organism during or at the end of therapy judged not to be causing respiratory symptoms. If a new organism was present but judged not to be causing respiratory symptoms, this was termed new colonization. Statistical analysis of continuous data included Student's t-test following log transformations, where necessary. Statistical analysis of categorical data included the Mantel-Haenszel adjusted relative risks and Mantel-Haenszel chi-squares. All susceptibility testing was done by the microtiter (minimum MIC system, with reagents provided by Miles, Inc., Pharmaceutical Division (New Haven, CT).
RESULTS A total of 25 patients (14 male, 11 female) were enrolled in the study. One patient was lost to followup. Ages ranged from 19 to 87 years, with a mean age of 65. Causative organisms and dinical and bacterio-
188
R.M. Fliegelman et al.
TABLE 1.
Causative Organisms
Bacteria
Ciprofloxacin (n = 11)
Streptococcus pneumoniae Haemophilus influenzae Pseudomonas aeruginosa Proteus mirabilis Branhamella catarrhalis Klebsiella pneumoniae Serratia marcescens Staphylococcus epidermidis
3 3 2 0 0 0 0 1
DISCUSSION Control (n = 13) Total 3 0 1 2 1 1 1 0
6 3 3 2 1 1 1 1
logic results are detailed in Tables 1 and 2, respectively. Complete clinical resolution of infection was achieved in 16 patients (67%): seven in the ciprofloxacin group and nine in the control group. Clinical improvement occurred in six additional patients: two ciprofloxacin and four control. Two clinical failures were documented in the ciprofloxacin-treated group. One patient with Haemophilus influenzae pneumonia responded initially to parenteral cefuroxime therapy. Following randomization to oral ciprofloxacin, the patient developed fever and episodic chills unabated for 3 days. This resulted in reinstitution of parenteral therapy. Haemophilus influenzae minimum inhibitory concentration (MIC) for ciprofloxacin was 0.125 ~g/ml, and the organism was eradicated on subsequent cultures. The patient had a concomitant, radiologically proven maxillary sinusitis that required surgical drainage for cure. The second patient had pneumonia that originally cultured Pseudomonas aeruginosa. When the patient did not improve with drug therapy, a subsequent culture revealed methicillin-resistant Staphylococcus aureus (MRSA), also resistant to ciprofloxacin. Intravenous vancomycin was instituted, and the patient responded satisfactorily. TABLE 2.
Clinical and Bacteriologic Results
Clinical outcome Resolution Improvement Failure Bacteriologic outcome Eradication Persistence New colonization Superinfection
Ciprofloxacin (n = 11)
Control (n = 13)
Total
7 2 2
9 4 0
16 6 2
7 0 5 1
7 1 7 1
14 1 12 2
Ciprofloxacin is a fluorinated quinolone antibiotic with excellent in vitro activity against most Grampositive and Gram-negative pathogens likely to cause lower respiratory tract infections (Barry and Jones, 1987; Sanders et al., 1987). Because ciprofloxacin attains adequate serum levels following oral administration (Bergan et al., 1987), and excellent concentrations in bronchial tissue (Thys, 1988), it becomes a logical choice for treatment of such infections after an initial period of parenteral therapy. The results of this study suggest that clinical and bacteriologic outcomes were equivalent in those patients treated with a standard course of parenteral therapy versus those randomized to oral ciprofloxacin, providing pathogens were sensitive to ciprofloxacin. Even in the treatment of pathogens where ciprofloxacin efficacy may be in question (i.e., Streptococcus pneumoniae) (Barry and Jones, 1987; Neu, 1987; Thys, 1988), the results of this study demonstrated acceptable clinical outcome. Three patients in the ciprofloxacin group were treated for pneumonococcal pneumonia (one with bacteremia) with clinical and bacteriologic cure. There are documented reports in the literature of increasing in vitro resistance of MRSA to ciprofloxacin (Isaacs, et al., 1988; Shalit et al., 1989). During this study, there was one case that appeared to be a clinically significant MRSA pneumonia. This developed while the patient was on ciprofloxacin for a previously diagnosed Pseudomonas pneumonia. The MRSA MIC for ciprofloxacin was >4 ~g/ml. Although this represents only one case, concern exists that increasing in vitro resistance to MRSA may correlate with clinical failure. Furthermore, if clinical signs and symptoms of infection reemerge after converting to oral ciprofloxacin, a resistant pathogen must be considered, and appropriate action must be taken. Results of this study demonstrate a 20% decrease in the average length of hospital stay (9.91 days for the ciprofloxacin group vs. 12.31 days for the control group) and a 57% decrease in drug acquisition cost ($243.63 for the ciprofloxacin group vs. $427.37 for the control group). The average savings for patients treated with oral ciprofloxacin was $1159.97 (Table 3). Total savings for the 11 patients receiving oral ciprofloxacin was $12,760. If further studies confirm our data, that efficacy is not compromised by early conversion to oral ciprofloxacin, a substantial cost savings can be realized.
E c o n o m i c I m p a c t of Ciprofloxacin
TABLE 3.
189
A v e r a g e C o s t of T h e r a p y p e r Patient
Duration of treatment (days) Hospital stay (days) Drug cost~ Hospital cost a Total cost ~
Ciprofloxacin
Control
p
Cost Savings
16.0 9.91 $243.63 $4033.00 $4276.63
16.7 12.31 $427.37 $5009.23 $5436.60
0.479 ~ 0.427 a 0.228 b 0.415 a 0.195
--$183.74 $976.23 $1159.97
~Log transformation was performed on data for this variable. bKruskal-Wallis test for nonparametric data. CAcquisition cost and intravenous solution cost. ~Room charge of $407/day. eTotal cost = drug cost + hospital cost.
REFERENCES Barry AL, Jones RN (1987) In vitro activity of ciprofloxacin against gram-positive cocci. Am J Med 82(suppl 4A):2732. Bergan T, Thorsteinsson SB, Solberg R, Bjornskau L, Kolstad IM, Johnsen S (1987) Pharmacokinetics of ciprofloxacin: intravenous and increasing oral doses. Am J Med 82(suppl 4A):97-102. Isaacs RD, Kunke PJ, Cohen RL, Smith JW (1988) Ciprofloxacin resistance in epidemic methicillinresistant Staphylococcus aureus [Letter to editor]. Lancet 1:843.
Neu HC (1987) New antibiotics: areas of appropriate use. J Infect Dis 155:403-417. Sanders CC, Sanders WE, Goering RV (1987) Overview of preclinical studies with ciprofloxacin. Am J Med 82(suppl 4A):2-11. Shalit I, Berger SA, Gorea A, Frimerman H (1989) Widespread quinolone resistance among methicillin-resistant Staphylococcus aureus isolates in a general hospital. Antimicrob Agents Chemother 33:593-594. Thys JP (1988) Quinolones in the treatment of bronchopulmonary infections. Rev Infect Dis 10(suppl 1):$212$5217.
