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Treatment of bone and joint infection with teicoplanin: a retrospective analysis of 50 cases
I,,,
H\I\lx,V\I
,I,, Hh\l
Ob
Antimicrobial Agents International
Journal
of Antimicrobial
Agents
7 (1996) 49-51
Treatment of bone and joint infection with teicoplanin: a retrospective analysis of 50 cases V. Dacquet Service Septique. Institut Calot, 62600 rue Dr. Calot, Berck SW Mer. France Accepted
27 December
1995
Abstract
The effectiveness and safety of teicoplanin, 400 mg/day, in combination with other antibiotics in the treatment of bone and joint infections was examined in a retrospective review of 50 cases (most commonly sepsis, osteitis and septic arthritis) treated at one hospital between 1988 and 1994. Previous antibiotic treatment had failed in 36 cases. Patients received teicoplanin and l-3 concurrent antibiotics for 4141 days; 35 patients then received further antibiotics. Clinical success was recorded in 46 cases, with two failures and two non-evaluable outcomes. Bacteriological eradication was achieved in 43 cases. There was one recurrence at 8 months, which was successfully treated with teicoplanin. Five patients showed adverse reactions, but discontinuation of teicoplanin treatment was not necessary. Keywords: Teicoplanin;
Gram-positive
organisms; Bone infection; Joint infection
1. Introduction
It is difficult to mount controlled trials of the treatment of bone and joint infections because of their rarity, but open trials have suggested that the glycopeptide antibiotic teicoplanin is of use in such infections [ 1,2]. Teicoplanin is used in the treatment of Gram-positive infections, particularly against staphylococcal infections in patients sensitive or unresponsive to penicillins and cephalosporins. Teicoplanin has certain characteristics that make it potentially very suitable for long-term treatment of serious chronic joint and bone infections, both in the inpatient and outpatient settings. It offers advantages over vancomycin because it is associated with a lower risk of anaphylactic reaction (‘red man’ syndrome) and monitoring of serum levels is not required. It is known to
*Tel.: +33 2189 2033; Fax: +33 2189 2052. 0924-8579/96/$32.00 0 1996 Elsevier SSDI SO924-8579(96)00009-X
Science B.V. All rights
reserved
penetrate bone well [3] and, because of its long half-life, can be given once-daily by either the intravenous or intramuscular route. The study presented here examines the efficacy and safety of teicoplanin in the treatment of bone or joint infections in a retrospective review of 50 cases in which teicoplanin was used as part of the treatment.
2. Methods Records of 50 cases (from 49 patients) of bone or joint infection treated with teicoplanin, 6 mg/kg/day, at the Institut Calot, France, between 1988 and 1994 were reviewed. The standard teicoplanin regimen at this time was a dose of 400 mg every 12 h for 3 days then 400 mg/day in combination with fusidic acid or an aminoglycoside. Pathogens were identified from bone, tissue or exudate samples and antibiotic susceptibility was tested using the disk method. Demographic details, type of infection, presence of prosthetic material, previous treatment, duration of treatment, concomitant and subsequent antibiotics, serum creatinine or creatinine clearance, adverse events, the outcome at the end of therapy
50
Y Ducquetllnternational
Journal of Antimicrobial Agents 7 (1996) 49-51
and the length of follow-up were noted from patient records.
patients had surgery before the teicoplanin course, ten during the course and five after. 3.4. Bacterial isolates
3. Results 3. I. Sample characteristics Twenty-four patients were male and 25 female. Their ages ranged from 17 to 86 years, with a mean of 58.9 years (95% CI for mean 53.7-64.0 years). Weights were between 43 and 101 kg, with a mean of 68.9 kg (95% CI for mean 65.2-72.6 kg).
Table 1 shows the pathogens identified from patients’ samples. Gram-positive bacteria susceptible to teicoplanin were found in 46 of the 50 cases (92%). Where more than one species was isolated (7 cases) a combination of a staphylococcus and a Gram-negative aerobe, such as Klebsiella, Acinetobacter or Pseudomonas, was most usual. No pure cultures of Gram-negative bacteria were isolated. The causative pathogen was not identified in one case.
3.2. Nature and history of the infections 3.5. Clinical outcome The most common infections were associated with foreign material (27 cases): 2 with osteosynthetic material and 25 with prosthetic implants (18 patients who had received total hip replacements and 7 patients with total knee replacements). There were 12 diagnoses of chronic osteitis not associated with foreign material, 7 of septic arthritis, 2 of spondylitis and one each of bursitis and osteomyelitis. Most of the infections were chronic, with a median duration of 13 months (range 1-123 months). In 36 of the 50 episodes reviewed, previous treatment with other antibiotics (most commonly fusidic acid, ciprofloxacin and netilmicin) had been unsuccessful. 3.3. Antibiotic therapy Patients were treated with teicoplanin for 4-141 days, the median treatment duration being 26.5 days, with one (20 episodes), two (28 episodes) or three (2 episodes) concurrent antibiotics, most commonly netilmicin (34 episodes) and fusidic acid (9 episodes). In 47 of the 50 episodes, the standard teicoplanin dosage regimen was followed. The 3-day loading regimen was not used in three of the cases; for two of these the treatment began with a single daily dose of 400 mg, and for one the dosage was not recorded. In 35 cases, further antibiotics were given when the teicoplanin course was completed. Two Table 1 Pathogens
isolated
from 50 episodes
of bone and joint infection”
Species
Number
Staphvlococcus nureus (methicilhn-resistant) 5. aureus (methicillin-sensitive) Coagulase-negative staphylococci (methicillin-resistant) Coagulase-negative staphylococci (methicillin-sensitive) Streptococcus agalactiae Enterococcus spp. Gram-negative bacteria No growth
17 12
“The pathogen
was not known
in one case.
8 6 3 3 5 3
of isolates
Of the 50 episodes, 46 (92%) were regarded as clinical successes and two (4%) as failures; the outcome was not evaluable for the other two cases. Bacteriological eradication was achieved in 43 cases (86%); persistence was recorded in two cases (4%) and five (10%) were nonevaluable. One of the clinical failures was in a male patient who had developed chronic osteitis of the femur, not associated with foreign material, 2 months after an open fracture sustained in a road accident. The infection was caused by a methicillin-resistant Staphylococcus aureus. The patient was given the standard dosage regimen of teicoplanin in combination with amikacin for 19 days, undergoing surgery on the third day of treatment. Bacterial controls were consistently positive for the same staphylococcal strain. Teicoplanin and amikacin were replaced by pristinamycin without success. The infection persisted at 3 months. The other failure was in a woman who had an infection of a total hip replacement which she refused to have removed. The pathogen was identified as a methicillin-resistant, teicoplanin-sensitive, coagulase-negative staphylococcus. The patient received teicoplanin in combination with netilmicin, perfloxacin and/or metronidazole for 44 days, followed by ofloxacin, but the infection persisted. At follow-up, which varied from 1 week to 66 months (median 8 months; four patients not evaluable) one patient initially counted as a success was found at 8 months to have a recurrence. Clinical success was eventually recorded in this patient after further treatment with teicoplanin. The final assessment was that cure or improvement was achieved in 43 of the 50 episodes (86%), or in 94% of the evaluable episodes. 3.6. Adverse events In five patients (10%) adverse events were noted. Two patients developed renal impairment, one had a local
b: Dacqurtl International Journal of Antimicrohiul Agents 7 i 1996i 49.-51
reaction, one a rise in serum y-glutamyl transferase concentration and in a fifth the event was not recorded. Discontinuation of teicoplanin therapy was not necessary in any of these cases. There was no significant difference in serum creatinine concentrations before and after treatment (9.2 mg/l, range 5.4-24 mgfl and 9.3 mg/l. range 5.6-28 mg/l, respectively; 39 patients). Mean creatinine clearance was 91 (range 50-132) ml/min in 11 patients before teicoplanin treatment and 70 (range 32-138) ml/min in 7 patients at the end of treatment.
4. Discussion The rarity of bone and joint infections makes controlled trials of these infections difficult. The retrospective nature of this study, the lack of controls and the fact that patients were given teicoplanin in combination with other antibiotics for different times, with different subsequent antibiotics and different periods of follow-up, mean that it is not possible to draw absolute conclusions about the efficacy of teicoplanin in bone and joint infections. However, given these limitations, the 86% success rate at follow-up in the 50 cases reviewed suggests that teicoplanin, given in combination with other antibiotics, is an effective treatment in the real and varied world of clinical practice. Only two failures were recorded, one in a patient who failed treatment on preceding and subsequent occasions, and the only recurrence was successfully treated with teicoplanin. The fact that the only other failure was in a patient who refused to have an infected prosthesis removed suggests that adequate debridement and removal of infected prosthetic material is necessary if treatment is to be successful. Teicoplanin has been shown to be effective as monoor combination therapy for bone and joint infections in open clinical trials. With combination therapy using teicoplanin, 6 mg/kg/day (as here), success rates of 7295% have been reported [4]; doses of C-1 5 mg/kg/day [2], 3-6 mglkglday [5] and 200 mglday [6] (given as combination therapy in up to 57% of patients) produced cure rates of 86.7%, 83.2% and 78.6%. respectively. With teicoplanin as sole therapy, clinical success rates of 90.2% in acute osteomyelitis, 73.2% in chronic osteomyelitis and 100% (8 patients) in septic arthritis have been achieved [l]; the dosing regimen in this study was three 12-hourly loading doses of 12 mg/kg followed by a daily maintenance dose of 6 mgfkg for 6 weeks for osteomyelitis or 12 mg/kg for 4 weeks for septic arthritis. Adverse events that may be associated with teicoplanin are more common in the prolonged and often high-dose regimens used for bone and joint infections than in the treatment of other infections. In the present study adverse events were recorded for 10% of episodes,
51
but in no case was it felt necessary to discontinue teicoplanin treatment. In the study discussed above in which teicoplanin was used as sole therapy, 40.8% of the patients showed mild adverse events, mostly rash. fever and nausea [l]. In an open study of patients receiving teicoplanin, 6-15 mg/kg/day, in combination with other antibiotics, rates of adverse reactions were 11% for fever, 10% for rash, 5% for chills and 4% for pruritus [2]; teicoplanin treatment was discontinued in 73.7% of patients who developed fever and 52.4% of those who developed rash. Teicoplanin was discontinued in 27.7% of the patients who received doses of lYmg/kg or above because of rash or fever. Such adverse events are more likely to occur when teicoplanin is given at doses over IO mg/kg/day. The results of the present study at 6 mg/kg/ day suggest that higher doses are not required, and that such lower dose combination regimens allow effective treatment of severe infections with reduced risk of adverse events. One advantage of teicoplanin is that it can be administered to patients at home, offering financial benefits and improving patients’ quality of life. Two of the patients in this study were treated in part in an outpatient setting, and in other studies up to 84% of patients have received some treatment at home [l]. The results of this retrospective study indicate. in agreement with those from other studies. that teicoplanin, given in combination with other antibiotics, is an effective and well-tolerated treatment for bone and joint infections. A prospective, randomized trial would be desirable to confirm this impression but would have practical problems.
References [I] LeFrock
[2]
[3]
[4]
[5]
[6]
JL, Ristuccia AM, Ristuccia PA. Quenzer RW. Haggerty PC, Allen JE. Lettau LA, Schwartz R, Appleby D. Teicoplamn in the treatment of bone and joint infections. Acta Chir 1992:S567:9 13. Griineberg RN. Treatment of bone, joint and vascular-access-associated Gram-positive bacterial infections with reicoplanin. Antimicrab Agents Chemother 1990;34:2392-2397. Wilson APR. Taylor B. Treasure T. Griineberg RN, Patton K. Felmingham D, Sturridge MF. Antibiotic prophylaxis in cardiac surgery: serum and tissue levels of teicoplanin. flucloxacillin and tobramycin. J Antimicrob Chemother 1988:21:201-212. Wilson APR. Griineberg RN, Neu H. A critical review of the dosage of teicoplanin in Europe and the USA. Int J Antimicrob Agents 1994;4:Sl--S30. Lewis P. Garaud JJ. Parenti F. A multicentre open clinical trial of teicoplanin in infections caused by Gram-positive bacteria. J Antimicrob Chemother 1988;21(Suppl A):61 67. Glupczynski Y. Lagast H, Van der Auwera P. Thys JP. Crokaert F. Clinical evaluation of teicoplanin for therapy of severe infections caused by Gram-positive bacteria. Antimicrob Agents Chemothcr 1986;29:52-57.
H\I\lx,V\I
,I,, Hh\l
Ob
Antimicrobial Agents International
Journal
of Antimicrobial
Agents
7 (1996) 49-51
Treatment of bone and joint infection with teicoplanin: a retrospective analysis of 50 cases V. Dacquet Service Septique. Institut Calot, 62600 rue Dr. Calot, Berck SW Mer. France Accepted
27 December
1995
Abstract
The effectiveness and safety of teicoplanin, 400 mg/day, in combination with other antibiotics in the treatment of bone and joint infections was examined in a retrospective review of 50 cases (most commonly sepsis, osteitis and septic arthritis) treated at one hospital between 1988 and 1994. Previous antibiotic treatment had failed in 36 cases. Patients received teicoplanin and l-3 concurrent antibiotics for 4141 days; 35 patients then received further antibiotics. Clinical success was recorded in 46 cases, with two failures and two non-evaluable outcomes. Bacteriological eradication was achieved in 43 cases. There was one recurrence at 8 months, which was successfully treated with teicoplanin. Five patients showed adverse reactions, but discontinuation of teicoplanin treatment was not necessary. Keywords: Teicoplanin;
Gram-positive
organisms; Bone infection; Joint infection
1. Introduction
It is difficult to mount controlled trials of the treatment of bone and joint infections because of their rarity, but open trials have suggested that the glycopeptide antibiotic teicoplanin is of use in such infections [ 1,2]. Teicoplanin is used in the treatment of Gram-positive infections, particularly against staphylococcal infections in patients sensitive or unresponsive to penicillins and cephalosporins. Teicoplanin has certain characteristics that make it potentially very suitable for long-term treatment of serious chronic joint and bone infections, both in the inpatient and outpatient settings. It offers advantages over vancomycin because it is associated with a lower risk of anaphylactic reaction (‘red man’ syndrome) and monitoring of serum levels is not required. It is known to
*Tel.: +33 2189 2033; Fax: +33 2189 2052. 0924-8579/96/$32.00 0 1996 Elsevier SSDI SO924-8579(96)00009-X
Science B.V. All rights
reserved
penetrate bone well [3] and, because of its long half-life, can be given once-daily by either the intravenous or intramuscular route. The study presented here examines the efficacy and safety of teicoplanin in the treatment of bone or joint infections in a retrospective review of 50 cases in which teicoplanin was used as part of the treatment.
2. Methods Records of 50 cases (from 49 patients) of bone or joint infection treated with teicoplanin, 6 mg/kg/day, at the Institut Calot, France, between 1988 and 1994 were reviewed. The standard teicoplanin regimen at this time was a dose of 400 mg every 12 h for 3 days then 400 mg/day in combination with fusidic acid or an aminoglycoside. Pathogens were identified from bone, tissue or exudate samples and antibiotic susceptibility was tested using the disk method. Demographic details, type of infection, presence of prosthetic material, previous treatment, duration of treatment, concomitant and subsequent antibiotics, serum creatinine or creatinine clearance, adverse events, the outcome at the end of therapy
50
Y Ducquetllnternational
Journal of Antimicrobial Agents 7 (1996) 49-51
and the length of follow-up were noted from patient records.
patients had surgery before the teicoplanin course, ten during the course and five after. 3.4. Bacterial isolates
3. Results 3. I. Sample characteristics Twenty-four patients were male and 25 female. Their ages ranged from 17 to 86 years, with a mean of 58.9 years (95% CI for mean 53.7-64.0 years). Weights were between 43 and 101 kg, with a mean of 68.9 kg (95% CI for mean 65.2-72.6 kg).
Table 1 shows the pathogens identified from patients’ samples. Gram-positive bacteria susceptible to teicoplanin were found in 46 of the 50 cases (92%). Where more than one species was isolated (7 cases) a combination of a staphylococcus and a Gram-negative aerobe, such as Klebsiella, Acinetobacter or Pseudomonas, was most usual. No pure cultures of Gram-negative bacteria were isolated. The causative pathogen was not identified in one case.
3.2. Nature and history of the infections 3.5. Clinical outcome The most common infections were associated with foreign material (27 cases): 2 with osteosynthetic material and 25 with prosthetic implants (18 patients who had received total hip replacements and 7 patients with total knee replacements). There were 12 diagnoses of chronic osteitis not associated with foreign material, 7 of septic arthritis, 2 of spondylitis and one each of bursitis and osteomyelitis. Most of the infections were chronic, with a median duration of 13 months (range 1-123 months). In 36 of the 50 episodes reviewed, previous treatment with other antibiotics (most commonly fusidic acid, ciprofloxacin and netilmicin) had been unsuccessful. 3.3. Antibiotic therapy Patients were treated with teicoplanin for 4-141 days, the median treatment duration being 26.5 days, with one (20 episodes), two (28 episodes) or three (2 episodes) concurrent antibiotics, most commonly netilmicin (34 episodes) and fusidic acid (9 episodes). In 47 of the 50 episodes, the standard teicoplanin dosage regimen was followed. The 3-day loading regimen was not used in three of the cases; for two of these the treatment began with a single daily dose of 400 mg, and for one the dosage was not recorded. In 35 cases, further antibiotics were given when the teicoplanin course was completed. Two Table 1 Pathogens
isolated
from 50 episodes
of bone and joint infection”
Species
Number
Staphvlococcus nureus (methicilhn-resistant) 5. aureus (methicillin-sensitive) Coagulase-negative staphylococci (methicillin-resistant) Coagulase-negative staphylococci (methicillin-sensitive) Streptococcus agalactiae Enterococcus spp. Gram-negative bacteria No growth
17 12
“The pathogen
was not known
in one case.
8 6 3 3 5 3
of isolates
Of the 50 episodes, 46 (92%) were regarded as clinical successes and two (4%) as failures; the outcome was not evaluable for the other two cases. Bacteriological eradication was achieved in 43 cases (86%); persistence was recorded in two cases (4%) and five (10%) were nonevaluable. One of the clinical failures was in a male patient who had developed chronic osteitis of the femur, not associated with foreign material, 2 months after an open fracture sustained in a road accident. The infection was caused by a methicillin-resistant Staphylococcus aureus. The patient was given the standard dosage regimen of teicoplanin in combination with amikacin for 19 days, undergoing surgery on the third day of treatment. Bacterial controls were consistently positive for the same staphylococcal strain. Teicoplanin and amikacin were replaced by pristinamycin without success. The infection persisted at 3 months. The other failure was in a woman who had an infection of a total hip replacement which she refused to have removed. The pathogen was identified as a methicillin-resistant, teicoplanin-sensitive, coagulase-negative staphylococcus. The patient received teicoplanin in combination with netilmicin, perfloxacin and/or metronidazole for 44 days, followed by ofloxacin, but the infection persisted. At follow-up, which varied from 1 week to 66 months (median 8 months; four patients not evaluable) one patient initially counted as a success was found at 8 months to have a recurrence. Clinical success was eventually recorded in this patient after further treatment with teicoplanin. The final assessment was that cure or improvement was achieved in 43 of the 50 episodes (86%), or in 94% of the evaluable episodes. 3.6. Adverse events In five patients (10%) adverse events were noted. Two patients developed renal impairment, one had a local
b: Dacqurtl International Journal of Antimicrohiul Agents 7 i 1996i 49.-51
reaction, one a rise in serum y-glutamyl transferase concentration and in a fifth the event was not recorded. Discontinuation of teicoplanin therapy was not necessary in any of these cases. There was no significant difference in serum creatinine concentrations before and after treatment (9.2 mg/l, range 5.4-24 mgfl and 9.3 mg/l. range 5.6-28 mg/l, respectively; 39 patients). Mean creatinine clearance was 91 (range 50-132) ml/min in 11 patients before teicoplanin treatment and 70 (range 32-138) ml/min in 7 patients at the end of treatment.
4. Discussion The rarity of bone and joint infections makes controlled trials of these infections difficult. The retrospective nature of this study, the lack of controls and the fact that patients were given teicoplanin in combination with other antibiotics for different times, with different subsequent antibiotics and different periods of follow-up, mean that it is not possible to draw absolute conclusions about the efficacy of teicoplanin in bone and joint infections. However, given these limitations, the 86% success rate at follow-up in the 50 cases reviewed suggests that teicoplanin, given in combination with other antibiotics, is an effective treatment in the real and varied world of clinical practice. Only two failures were recorded, one in a patient who failed treatment on preceding and subsequent occasions, and the only recurrence was successfully treated with teicoplanin. The fact that the only other failure was in a patient who refused to have an infected prosthesis removed suggests that adequate debridement and removal of infected prosthetic material is necessary if treatment is to be successful. Teicoplanin has been shown to be effective as monoor combination therapy for bone and joint infections in open clinical trials. With combination therapy using teicoplanin, 6 mg/kg/day (as here), success rates of 7295% have been reported [4]; doses of C-1 5 mg/kg/day [2], 3-6 mglkglday [5] and 200 mglday [6] (given as combination therapy in up to 57% of patients) produced cure rates of 86.7%, 83.2% and 78.6%. respectively. With teicoplanin as sole therapy, clinical success rates of 90.2% in acute osteomyelitis, 73.2% in chronic osteomyelitis and 100% (8 patients) in septic arthritis have been achieved [l]; the dosing regimen in this study was three 12-hourly loading doses of 12 mg/kg followed by a daily maintenance dose of 6 mgfkg for 6 weeks for osteomyelitis or 12 mg/kg for 4 weeks for septic arthritis. Adverse events that may be associated with teicoplanin are more common in the prolonged and often high-dose regimens used for bone and joint infections than in the treatment of other infections. In the present study adverse events were recorded for 10% of episodes,
51
but in no case was it felt necessary to discontinue teicoplanin treatment. In the study discussed above in which teicoplanin was used as sole therapy, 40.8% of the patients showed mild adverse events, mostly rash. fever and nausea [l]. In an open study of patients receiving teicoplanin, 6-15 mg/kg/day, in combination with other antibiotics, rates of adverse reactions were 11% for fever, 10% for rash, 5% for chills and 4% for pruritus [2]; teicoplanin treatment was discontinued in 73.7% of patients who developed fever and 52.4% of those who developed rash. Teicoplanin was discontinued in 27.7% of the patients who received doses of lYmg/kg or above because of rash or fever. Such adverse events are more likely to occur when teicoplanin is given at doses over IO mg/kg/day. The results of the present study at 6 mg/kg/ day suggest that higher doses are not required, and that such lower dose combination regimens allow effective treatment of severe infections with reduced risk of adverse events. One advantage of teicoplanin is that it can be administered to patients at home, offering financial benefits and improving patients’ quality of life. Two of the patients in this study were treated in part in an outpatient setting, and in other studies up to 84% of patients have received some treatment at home [l]. The results of this retrospective study indicate. in agreement with those from other studies. that teicoplanin, given in combination with other antibiotics, is an effective and well-tolerated treatment for bone and joint infections. A prospective, randomized trial would be desirable to confirm this impression but would have practical problems.
References [I] LeFrock
[2]
[3]
[4]
[5]
[6]
JL, Ristuccia AM, Ristuccia PA. Quenzer RW. Haggerty PC, Allen JE. Lettau LA, Schwartz R, Appleby D. Teicoplamn in the treatment of bone and joint infections. Acta Chir 1992:S567:9 13. Griineberg RN. Treatment of bone, joint and vascular-access-associated Gram-positive bacterial infections with reicoplanin. Antimicrab Agents Chemother 1990;34:2392-2397. Wilson APR. Taylor B. Treasure T. Griineberg RN, Patton K. Felmingham D, Sturridge MF. Antibiotic prophylaxis in cardiac surgery: serum and tissue levels of teicoplanin. flucloxacillin and tobramycin. J Antimicrob Chemother 1988:21:201-212. Wilson APR. Griineberg RN, Neu H. A critical review of the dosage of teicoplanin in Europe and the USA. Int J Antimicrob Agents 1994;4:Sl--S30. Lewis P. Garaud JJ. Parenti F. A multicentre open clinical trial of teicoplanin in infections caused by Gram-positive bacteria. J Antimicrob Chemother 1988;21(Suppl A):61 67. Glupczynski Y. Lagast H, Van der Auwera P. Thys JP. Crokaert F. Clinical evaluation of teicoplanin for therapy of severe infections caused by Gram-positive bacteria. Antimicrob Agents Chemothcr 1986;29:52-57.