Clinical Report
Chemotherapy 1992;38:271-274
V. Krimery, Jr P. Fuchsberger J. Trupl J. Sufliarsky S. Spanik I. Koza Z. Kusenda S. Korec J. Svec P. £)urkovic J. Lakota M. Homikova
Ciprofloxacin plus Vancomycin versus Ceftazidime plus Gentamicin in the Treatment of Pneumonia in Granulocytopenic Patients with or without Venous Catheters Short Communication
Key Words
Abstract
Neutropenic patients Venous catheters Pneumonia
58 granulocytopenic patients with confirmed bronchopneumo nia were divided retrospectively into two groups for this pilot study: group 1 included neutropenic patients with venous cath eters who were treated with ciprofloxacin (CIP; 200-300 mg, i.v. b.i.d.) -(-vancomycin (VAN; 0.5-1 g, i.v. b.i.d.), and group 2, which included patients without venous catheters treated with ceftazidime (2 g, i.v. t.i.d.) + gentamicin (1 mg/kg, i.v. t.i.d.). Pneumonia was diagnosed clinically and radiologically in all patients; 92.3% in group 1 and 46.8% in group 2 were also microbially confirmed. Mixed infections were present in most pa tients. 3 of 26 patients (11.5%) ingroup 1 a n d 9 of 32(20.1%) in group 2 did not recover while 88.5% in group 1 and 71.9% in group 2 recovered. C IP+ VAN seems to be more effective in treating pneumonia in neutropenic patients, with only 1 pa tient in the group suffering an adverse effect compared with 5 in group 2.
V .K rim éry .Jr., M D, PhD Limbovâ 12 833 03 Bratislava (CSFR)
© 1992 S. K arger AG, Basel 0009-3157/92/ 0384-0271 $ 2.75/0
Downloaded by: King's College London 137.73.144.138 - 1/12/2019 7:32:54 PM
Department of Clinical Oncology, Postgraduate Medical School and National Cancer Institute, Bratislava, CSFR
Bronchopneumonia, esophagitis and cath eter-associated sepsis are the most frequent infections in granulocytopenic patients [1], The reason may be the indirect pneumotoxic ity of some cytotoxic drugs, such as methotrex ate and bleomycin, and frequent hospitaliza tions due to pneumonia. The mucotoxicity of bleomycin, 5-fluorouracil and methotrexate in esophagitis, and indwelling catheters in cathe ter-associated sepsis, especially in the induc tion therapy of leukemia [2], support the in fection. In treatment, an aminoglycoside + (3-lactam was the standard therapy: gentamicin (GEN) + cefotaxime, or once daily netilmicin + ceftriaxone or ceftazidime (CTAZ; in mono therapy, or in combination with aminoglyco side) [3], Since 1988, quinolones + (3-lactam inhib itors (BLIs), such as amoxicillin-clavulanate, ticarcillin-clavulanate or sulbactam + ampicillin, were investigated. Because of the unproven efficacy of BLIs against Pseudomonas andAcinetabac ter, mono therapy is not recommended. In patients with catheters in some protocols, vancomycin (VAN) +quinolone or CTAZ were investi gated [3],
Patients and Methods 58 patients with granulocytopenia < l,()(X)/mm3 and radiologically and clinically confirmed bronchopneu monia were enrolled into the study and retrospectively divided as those with (groups 1) or without (group 2); central or peripheral catheters. In group 1, 26 patients (median age 54) were treated with ciprofloxacin (CIP; 200-300 mg, i.v. b.i.d.) + VAN (0.5-1 g, i.v. b.i.d.). In group 2, 32 patients (median age 41) were treated with CTAZ (2 g, i.v. t.i.d.) + GEN (1 mg/kg, i.v. t.i.d.). Audiometry was performed after treatment (each patient starting a cytotoxic protocol is audiologically
272
investigated). Renal and hepatic functions before, dur ing (twice weekly) and after treatment were performed to monitor drug-related toxicity (not only of antibiot ics, but also of other cytotoxic drugs). The renal func tion tests included glomerular filtration and resorption (serum creatinine, creatinine clearance) and tubular function (serum K, Na, Cl, Mg, Ca). The hepatic func tion tests included serum bilirubin, SGPT, SGOT, ALP, GMT, LDH. Cultures for microbiology, includ ing mycology and virus serology for CMV, HZV, influ enza and respiratory syncytial virus, were performed before and after treatment in all patient cultures which were without confirmed bacterial or mycotic origin. In about 30% of cases, bronchoscopy was performed to complete the samples for bacteriology and mycology. Chest x-rays were performed before treatment, on days 5,10,15, and after treatment.
Results and Discussion
Both groups were comparable in the depth and duration of neutropenia and in the spec trum of etiology (table 1). In all patients, neu tropenia < 1,000/mm3 was present. Neutrope nia < 500/mm3was present in 42.3% of group 1 and 32% of group 2 patients, and neutropenia < 100/mm3 was present in 23% of group 1 and 25% of group 2. All patients except 2 in group 1 and 5 in group 5 were treated with corticoste roids. In the etiology, mixed infection was prevalent in both groups (57.7% in group 1, 32% in group 2). The isolated pathogens are in table 1. In patients with catheters at other can cer centers, gram-positive organisms, espe cially staphylococci, streptococci and Candida sp., are emerging pathogens [1,4]. At our center, gram-negative pathogens were prevalent in 1988-1990 [6], but since qui nolones have been introduced (amoxicillinclavulanate + ofloxacin in nonneutropenic pa tients and CIP + VAN as an alternative in neu tropenic patients), the spectrum shifted to gram-positive organisms and fungi, although the mortality associated with infection de creased [5,6]. Nephrotoxicity appeared in 1 patient from
Kríméry Jr./Fuchsberger/Trupl/ Sufliarsky/Spanik/Koza/Kusenda/ Korec/Svec/Durkovié/Lakota/ Horníková
CIP + VAN vs. CTAZ + AMI in Neutropenic Patients
Downloaded by: King's College London 137.73.144.138 - 1/12/2019 7:32:54 PM
Introduction
CIP + VAN
CTAZ + G EN
Patients with neutropenia < 1,000/mm3 (all) < 500/mm3 < 100/mm3
26(100) 11(42) 6(23)
32(100) 10 (32) 8(25)
Mean duration of neutropenia, days < 1,000/mm3 < 500/mm3 < 100/mm3
12.3 10.5 6.5
13.1 10.1 5.9
Underlying disease, % Acute leukemia Non-Hodgkin lymphoma Hodgkin’s disease Chronic leukemia Plasmocytoma
53.8 26.9 0 9.5 9.8
45.2 34.5 12.3 3.9 4.1
Etiology, number of patients Undetermined G + (monoinfection) G - (monoinfection) Fungal (monoinfection) Mixed (G + and G -) Mixed (G+ and fungi) Mixed ( G - and fungi) Mixed (G -, G+ and fungi) Total isolated strains
2 (7.7) 6(23) 2 (7.7) 1 (3.9) 1 (3.9) 4(15.3) 3(11.5) 7 (26.9) 52
37 (71.2) Bacteria 15 (28.8) Fungi 5 Staphylococcus aureus (MRSA) Staphylococcus epidermidis (MRSE) 3 7 B group streptococci 5 Streptococcus faecalis 6 Klebsiella pneumoniae 3 Enterobacter aerogenes 1 Escherichia coli 0 Proteus mirabilis 2 Citrobacter freundii 2 Acinetobacter calcoaceticus 3 Pseudomonas aeruginosa 10 Candida albicans 1 Mucor sp. 0 Aspergillus fumigatus 2 Candida crusei 1 Candida tropicalis 1 Candida (Torulopsis) glabrata
6(18.8) 3 (9.4) 8(25) 5 (15.6) 3 (9.4) 2(6.3) 4 (12.6) 1 (3.1) 46 34 (74) 12 (26) 3 0 4 4 4 6 1 4 1 2 5 9 2 1 0 0 0
273
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Table 1. Patient analysis and results of CIP + VAN versus CTAZ + GEN in the treatment of pneumonia in neutropenic pa tients
Table 1 (continued)
CIP + VAN
CTAZ +G EN
Efficacy of treatment Recovery Failure
23/26 (88.5) 3/26(11.5)
23/32 (71.9) 9/32 (28.1)
Toxicity Nephrotoxicity Ototoxicity + nephrotoxicity
1/26 0/26
5/32 2/32
Figures in parentheses are percentages. G + = Gram-positive; G - = gram-negative.
group 1 and in 5 of group 2, while no ototoxic ity was found in group 1 and 2 cases of tran sient ototoxicity were found in group 2. CIP + VAN seems to have the same or even higher efficacy and less toxicity than the con ventional regimen with CTAZ + GEN.
This result is not surprising, since two stud ies in 1990 presented CIP +teicoplanin as a successful combination in comparison with amikacin + CTAZ and even imipenem [7, 8].
References
274
4 Bodey G: Evolution of antibiotic therapy for infection in neutropenic patients. Rev Infect Dis 1989;11 (suppl 7):1582—1591. 5 Krimery V Jr, Mardiak J, Koza I: Ofloxacin plus amoxicillin clavulanate vs. cefotaxime plus amikacin in neutropenic patients. J Chemother 1991;3(suppl 5):91-92. 6 Krimery V Jr, Fuchsberger P: Fun gal infections before and after de partment change - increasing mor bidity and mortality on fungal infec tions (abstracts). Symp Fungal Infect. Nijmegen, Sept 1991, p 15.
Krim6ry Jr./Fuchsberger/Trupl/ Sufliarsky/Spanik/Koza/Kusenda/ Korec/Svec/Durkoviü/Lakota/ Hornikovä
7 Kelsey S, Collins P, Delord C, Weinhard B, Newland A: A randomized study of teicoplanin plus ciprofloxa cin versus gentamicin plus pipera cillin for the empirical treatment of fever in neutropenic patients. Br J Haematol 1990;76(suppl 2):10-14. 8 Lim SH, Smith PM, Goldstone AH, Machin SJ: A randomised prospec tive study of ceftazidime and cipro floxacin with or without teicoplanin as an empiric antibiotic regimen for febrile neutropenic patients. Br J Haematol 1990;76(suppl 2):41— 45.
CIP + VAN vs. CTAZ+ AM I in Neutropenic Patients
Downloaded by: King's College London 137.73.144.138 - 1/12/2019 7:32:54 PM
1 Wade J: Antibiotic therapy for fe brile granulocytopenic cancer pa tients: Combination therapy vs. monotherapy. Rev Infect Dis 1989; 11:1572-1582. 2 Hughes WT: Guidelines for the use of antimicrobial agents in neutro penic patients with unexplained fe ver. J Infect Dis 1990;161:381-396. 3 Meunier F, Van der Auwera P, Aoun M, Ibrahim S, Tulkens M: Em pirical antimicrobial therapy with a single daily dose of ceftriaxone plus amikacin in febrile granulocyto penic patients: A pilot study. Antimicrob Chemother 1991;27(suppl C):129-139.
Chemotherapy 1992;38:271-274
V. Krimery, Jr P. Fuchsberger J. Trupl J. Sufliarsky S. Spanik I. Koza Z. Kusenda S. Korec J. Svec P. £)urkovic J. Lakota M. Homikova
Ciprofloxacin plus Vancomycin versus Ceftazidime plus Gentamicin in the Treatment of Pneumonia in Granulocytopenic Patients with or without Venous Catheters Short Communication
Key Words
Abstract
Neutropenic patients Venous catheters Pneumonia
58 granulocytopenic patients with confirmed bronchopneumo nia were divided retrospectively into two groups for this pilot study: group 1 included neutropenic patients with venous cath eters who were treated with ciprofloxacin (CIP; 200-300 mg, i.v. b.i.d.) -(-vancomycin (VAN; 0.5-1 g, i.v. b.i.d.), and group 2, which included patients without venous catheters treated with ceftazidime (2 g, i.v. t.i.d.) + gentamicin (1 mg/kg, i.v. t.i.d.). Pneumonia was diagnosed clinically and radiologically in all patients; 92.3% in group 1 and 46.8% in group 2 were also microbially confirmed. Mixed infections were present in most pa tients. 3 of 26 patients (11.5%) ingroup 1 a n d 9 of 32(20.1%) in group 2 did not recover while 88.5% in group 1 and 71.9% in group 2 recovered. C IP+ VAN seems to be more effective in treating pneumonia in neutropenic patients, with only 1 pa tient in the group suffering an adverse effect compared with 5 in group 2.
V .K rim éry .Jr., M D, PhD Limbovâ 12 833 03 Bratislava (CSFR)
© 1992 S. K arger AG, Basel 0009-3157/92/ 0384-0271 $ 2.75/0
Downloaded by: King's College London 137.73.144.138 - 1/12/2019 7:32:54 PM
Department of Clinical Oncology, Postgraduate Medical School and National Cancer Institute, Bratislava, CSFR
Bronchopneumonia, esophagitis and cath eter-associated sepsis are the most frequent infections in granulocytopenic patients [1], The reason may be the indirect pneumotoxic ity of some cytotoxic drugs, such as methotrex ate and bleomycin, and frequent hospitaliza tions due to pneumonia. The mucotoxicity of bleomycin, 5-fluorouracil and methotrexate in esophagitis, and indwelling catheters in cathe ter-associated sepsis, especially in the induc tion therapy of leukemia [2], support the in fection. In treatment, an aminoglycoside + (3-lactam was the standard therapy: gentamicin (GEN) + cefotaxime, or once daily netilmicin + ceftriaxone or ceftazidime (CTAZ; in mono therapy, or in combination with aminoglyco side) [3], Since 1988, quinolones + (3-lactam inhib itors (BLIs), such as amoxicillin-clavulanate, ticarcillin-clavulanate or sulbactam + ampicillin, were investigated. Because of the unproven efficacy of BLIs against Pseudomonas andAcinetabac ter, mono therapy is not recommended. In patients with catheters in some protocols, vancomycin (VAN) +quinolone or CTAZ were investi gated [3],
Patients and Methods 58 patients with granulocytopenia < l,()(X)/mm3 and radiologically and clinically confirmed bronchopneu monia were enrolled into the study and retrospectively divided as those with (groups 1) or without (group 2); central or peripheral catheters. In group 1, 26 patients (median age 54) were treated with ciprofloxacin (CIP; 200-300 mg, i.v. b.i.d.) + VAN (0.5-1 g, i.v. b.i.d.). In group 2, 32 patients (median age 41) were treated with CTAZ (2 g, i.v. t.i.d.) + GEN (1 mg/kg, i.v. t.i.d.). Audiometry was performed after treatment (each patient starting a cytotoxic protocol is audiologically
272
investigated). Renal and hepatic functions before, dur ing (twice weekly) and after treatment were performed to monitor drug-related toxicity (not only of antibiot ics, but also of other cytotoxic drugs). The renal func tion tests included glomerular filtration and resorption (serum creatinine, creatinine clearance) and tubular function (serum K, Na, Cl, Mg, Ca). The hepatic func tion tests included serum bilirubin, SGPT, SGOT, ALP, GMT, LDH. Cultures for microbiology, includ ing mycology and virus serology for CMV, HZV, influ enza and respiratory syncytial virus, were performed before and after treatment in all patient cultures which were without confirmed bacterial or mycotic origin. In about 30% of cases, bronchoscopy was performed to complete the samples for bacteriology and mycology. Chest x-rays were performed before treatment, on days 5,10,15, and after treatment.
Results and Discussion
Both groups were comparable in the depth and duration of neutropenia and in the spec trum of etiology (table 1). In all patients, neu tropenia < 1,000/mm3 was present. Neutrope nia < 500/mm3was present in 42.3% of group 1 and 32% of group 2 patients, and neutropenia < 100/mm3 was present in 23% of group 1 and 25% of group 2. All patients except 2 in group 1 and 5 in group 5 were treated with corticoste roids. In the etiology, mixed infection was prevalent in both groups (57.7% in group 1, 32% in group 2). The isolated pathogens are in table 1. In patients with catheters at other can cer centers, gram-positive organisms, espe cially staphylococci, streptococci and Candida sp., are emerging pathogens [1,4]. At our center, gram-negative pathogens were prevalent in 1988-1990 [6], but since qui nolones have been introduced (amoxicillinclavulanate + ofloxacin in nonneutropenic pa tients and CIP + VAN as an alternative in neu tropenic patients), the spectrum shifted to gram-positive organisms and fungi, although the mortality associated with infection de creased [5,6]. Nephrotoxicity appeared in 1 patient from
Kríméry Jr./Fuchsberger/Trupl/ Sufliarsky/Spanik/Koza/Kusenda/ Korec/Svec/Durkovié/Lakota/ Horníková
CIP + VAN vs. CTAZ + AMI in Neutropenic Patients
Downloaded by: King's College London 137.73.144.138 - 1/12/2019 7:32:54 PM
Introduction
CIP + VAN
CTAZ + G EN
Patients with neutropenia < 1,000/mm3 (all) < 500/mm3 < 100/mm3
26(100) 11(42) 6(23)
32(100) 10 (32) 8(25)
Mean duration of neutropenia, days < 1,000/mm3 < 500/mm3 < 100/mm3
12.3 10.5 6.5
13.1 10.1 5.9
Underlying disease, % Acute leukemia Non-Hodgkin lymphoma Hodgkin’s disease Chronic leukemia Plasmocytoma
53.8 26.9 0 9.5 9.8
45.2 34.5 12.3 3.9 4.1
Etiology, number of patients Undetermined G + (monoinfection) G - (monoinfection) Fungal (monoinfection) Mixed (G + and G -) Mixed (G+ and fungi) Mixed ( G - and fungi) Mixed (G -, G+ and fungi) Total isolated strains
2 (7.7) 6(23) 2 (7.7) 1 (3.9) 1 (3.9) 4(15.3) 3(11.5) 7 (26.9) 52
37 (71.2) Bacteria 15 (28.8) Fungi 5 Staphylococcus aureus (MRSA) Staphylococcus epidermidis (MRSE) 3 7 B group streptococci 5 Streptococcus faecalis 6 Klebsiella pneumoniae 3 Enterobacter aerogenes 1 Escherichia coli 0 Proteus mirabilis 2 Citrobacter freundii 2 Acinetobacter calcoaceticus 3 Pseudomonas aeruginosa 10 Candida albicans 1 Mucor sp. 0 Aspergillus fumigatus 2 Candida crusei 1 Candida tropicalis 1 Candida (Torulopsis) glabrata
6(18.8) 3 (9.4) 8(25) 5 (15.6) 3 (9.4) 2(6.3) 4 (12.6) 1 (3.1) 46 34 (74) 12 (26) 3 0 4 4 4 6 1 4 1 2 5 9 2 1 0 0 0
273
Downloaded by: King's College London 137.73.144.138 - 1/12/2019 7:32:54 PM
Table 1. Patient analysis and results of CIP + VAN versus CTAZ + GEN in the treatment of pneumonia in neutropenic pa tients
Table 1 (continued)
CIP + VAN
CTAZ +G EN
Efficacy of treatment Recovery Failure
23/26 (88.5) 3/26(11.5)
23/32 (71.9) 9/32 (28.1)
Toxicity Nephrotoxicity Ototoxicity + nephrotoxicity
1/26 0/26
5/32 2/32
Figures in parentheses are percentages. G + = Gram-positive; G - = gram-negative.
group 1 and in 5 of group 2, while no ototoxic ity was found in group 1 and 2 cases of tran sient ototoxicity were found in group 2. CIP + VAN seems to have the same or even higher efficacy and less toxicity than the con ventional regimen with CTAZ + GEN.
This result is not surprising, since two stud ies in 1990 presented CIP +teicoplanin as a successful combination in comparison with amikacin + CTAZ and even imipenem [7, 8].
References
274
4 Bodey G: Evolution of antibiotic therapy for infection in neutropenic patients. Rev Infect Dis 1989;11 (suppl 7):1582—1591. 5 Krimery V Jr, Mardiak J, Koza I: Ofloxacin plus amoxicillin clavulanate vs. cefotaxime plus amikacin in neutropenic patients. J Chemother 1991;3(suppl 5):91-92. 6 Krimery V Jr, Fuchsberger P: Fun gal infections before and after de partment change - increasing mor bidity and mortality on fungal infec tions (abstracts). Symp Fungal Infect. Nijmegen, Sept 1991, p 15.
Krim6ry Jr./Fuchsberger/Trupl/ Sufliarsky/Spanik/Koza/Kusenda/ Korec/Svec/Durkoviü/Lakota/ Hornikovä
7 Kelsey S, Collins P, Delord C, Weinhard B, Newland A: A randomized study of teicoplanin plus ciprofloxa cin versus gentamicin plus pipera cillin for the empirical treatment of fever in neutropenic patients. Br J Haematol 1990;76(suppl 2):10-14. 8 Lim SH, Smith PM, Goldstone AH, Machin SJ: A randomised prospec tive study of ceftazidime and cipro floxacin with or without teicoplanin as an empiric antibiotic regimen for febrile neutropenic patients. Br J Haematol 1990;76(suppl 2):41— 45.
CIP + VAN vs. CTAZ+ AM I in Neutropenic Patients
Downloaded by: King's College London 137.73.144.138 - 1/12/2019 7:32:54 PM
1 Wade J: Antibiotic therapy for fe brile granulocytopenic cancer pa tients: Combination therapy vs. monotherapy. Rev Infect Dis 1989; 11:1572-1582. 2 Hughes WT: Guidelines for the use of antimicrobial agents in neutro penic patients with unexplained fe ver. J Infect Dis 1990;161:381-396. 3 Meunier F, Van der Auwera P, Aoun M, Ibrahim S, Tulkens M: Em pirical antimicrobial therapy with a single daily dose of ceftriaxone plus amikacin in febrile granulocyto penic patients: A pilot study. Antimicrob Chemother 1991;27(suppl C):129-139.
