Addendum
E. Lang, M. F61des, S. Marghescu
Teicoplanin in the Treatment of Skin and Soft Tissue Infections: Results of a Multicentre Study Summary: The clinical efficacy and safety of teicoplanin was studied in hospitalized patients with skin and soft tissue infections. In an open multicentre study 64 patients were treated with teicoplanin i.v. and/or i.m. Predisposing or complicating factors for infection were present in almost 80% of the patients. Teicoplanin was usually given as an initial loading dose of 400 mg (87.1%), or 800 mg (6.5%) or various doses (6.5%). During the course of the study, the mean daily dose of teicoplanin was 261.3 mg. Sixty of the 62 evaluable patients responded to treatment. 58 gram-positive pathogens were isolated, consisting of Staphylococcus aureus (n = 41), coagulase-negative staphylococci (n = 6) and streptococci (n = 11). Elimination of pathogens was seen in 37/47 of all microbiologically evaluable cases. Persistence, recurrence or reinfection occurred in 7/47, 2/47 and 1/47, respectively. Adverse reactions were reported in only three patients with allergic reaction, local reaction and rise in transaminases in one case each. Therapy failed only in two patients. Zusammenfassung: Die Behandlung von Haut- und Weichteilinfektionen mit Teicoplanin - Ergebnisse einer Multizenterstudie. Die klinische Wirksamkeit und Ver-
tr~iglichkeit von Teicoplanin wurde bei hospitalisierten Patienten mit Haut- und Weichteilinfektionen untersucht. In einer offenen Multizenterstudie wurden 64 Patienten mit Teicoplanin i.v. und/oder i.m. behandelt. Pr~idisponierende oder komplizierende Faktoren ffir Infektionen waren bei fast 80% der Patienten vorhanden. Die Anfangsdosis Teicoplanin war bei 87,1% der Patienten 400 mg einmal t~iglich und bei 6,5% der Patienten 800 rag, 6,5% erhielten variierende Dosen. Im Verlauf der Studie wurde eine mittlere Folgedosis yon 261,3 mg/Tag verabreicht. Ein klinischer Erfolg wurde bei 60/62 auswertbaren Patienten erzielt. Therapieversagen wurde bei zwei Patienten beobachtet. 58 grampositive Erreger konnten isoliert werden. Dies waren Staphylococcus aureus-St~mme (n = 41), koagulase-negative Staphylokokken (n = 6) und Streptokokken (n = 11). In 37/47 aller mikrobiologisch auswertbaren F~ille wurde eine Elimination der Erreger erreicht, Persistenz, Wiederauftreten oder Reinfektion kam bei 7/47, 2/47 bzw. 1/47 der Ffille vor. Unerwfinschte Wirkungen wurden lediglich bei drei Patienten berichtet: eine allergische und eine lokale Reaktion sowie ein Anstieg der Transaminasen.
Introduction In general the majority of skin and soft tissue diseases can be cured by adequate local therapy. However, an increasing number of these infections require systemic antibiotic therapy. Since gram-positive bacteria are the most commonly isolated pathogens in skin and soft tissue infections i.e. surgical wound infections and dermatological infections such as erysipelas or cellulitis, it is reasonable to investigate the highly active anti-gram- positive agent teicoplanin for the treatment of skin and soft tissue infections. The spectrum of the new glycopeptide antibiotic teicoplanin is directed against gram-positive bacteria including methicillin resistant staphylococci [1,2]. Unlike [3-1actams that bind the enzymes responsible for peptidoglycan synthesis, teicoplanin interacts with a structural component of the cellular wall (muramyl-pentapeptide's D-alanyl-Dalanine). Therefore cross-resistance between 13-1actams and teicoplanin does not exist. Furthermore, one-step-resistant mutations have not been found, as it is unlikely that the structure of the muramyl-pentapeptide could be easily changed to inhibit teicoplanin binding. This has been demonstrated by in vitro studies [3]. Teicoplanin differs from vancomycin, the other glycopeptide antibiotic, in that it is eliminated much more slowly, is better tolerated after i.v. administration and offers the 70 / 190
possibility of i.m. administration. The favourable pharmacokinetics of teicoplanin permit a once-daily administration [2,4]. Following i.m. or i.v. administration of either 3 or 6 mg/kg doses to normal human volunteers, teicoplanin achieves high plasma and urine concentrations [5], exceeding the MICs for all susceptible gram-positive bacteria [6-9]. The purpose of this study was to evaluate the efficacy and safety of teicoplanin in the treatment of patients with skin and soft tissue infections.
Patients and Methods Eleven centres in the Federal Republic of Germany participated in this open study. Any hospitalized patient of either sex, 12 years or older, with presumed or proven skin and soft tissue infection, judged to require antimicrobial therapy could be entered in the study after giving informed consent. Patients were excluded from the study if they had a history of hypersensitivity to teicoplanin or vancomycin or if they were pregnant or nursing. The protocol of Dr. med. Eva Lang, Merrell Dow Pharma GmbH, Eisenstr. 40, W-6090 Riisselsheim,Germany;Dr. med.MartaF61des,Hautklinik,W-3000Hannover 91, Germany and MedizinischeKlinik der Albert-Szent-Gy6rgyiUniversit~it,DermatologischeKlinik,Szeged,Hungary;Prof. Dr. reed. S. Manghescu, Hautklinik,W-3000 Hannover 91, Germany.
Infection 19 (1991) No. 3 © MMV MedizinVerlag GmbH Mfinchen,Miinchen 1991
E. Lang et al.: Teicoplanin in Skin and Soft Tissue Infections this study was approved by the appropriate ethical committee. Therapy assessment: The efficacy of teicoplanin was assessed by both clinical and bacteriological criteria according to the following definitions. Cured: Clinical signs and symptoms of infection completely eradicated with no evidenceof infection at the end of treatment. Clinical improvement: Clinical findings subsided during the period of treatment but with incomplete resolution of infection. Recurrence: Initial improvement of signs and symptoms of the infection with a subsequent worsening of the clinical condition due to infection after discontinuing treatment. Failure: No apparent response to antimicrobial therapy. If, in the investigators' opinion, the case was considered to be not evaluable for any reason, this was taken into consideration. The patients were assessed daily to evaluate efficacy of treatment and to detect any clinical signs or symptoms of adverse reactions. For the bacteriological assessment appropriate cultures were obtained before and after treatment. Bacteriological efficacy was assessed according to the following criteria. Elimination: Causative organism was absent at or immediately after termination of therapy or the infection had completely disappeared so that follow-up eulture was impossible. Recurrence: Absence of the causative organism(s) at or immediately after termination of therapy, but reapparance of the same organism(s) at the same site. Reinfection: Causative organism(s) absent at or immediately after termination of therapy but reappearance of another infecting organism(s) at the same site at or before the follow-up visit. Persistence: Continued presence of causative organism(s) at the end of therapy. Not evaluable: Evaluation of the bacteriological response to the study was not possible. Results
Patient Data O f 64 patients treated with teicoplanin 26 were female and 38 were male. The mean age was 51.5 years, range 16-88 years. Five of the patients were considered seriously ill. Most infections were moderate (n -- 35; 54.7%) or severe (n = 23; 35.9%). Mild infections were seen in only six patients (9.4%). Duration of the infection ranged from 1 to 365 days (median 10 days). Clinical Diagnosis There were 29 surgical wound infections, 26 dermatological infections, three cases of infected diabetic gangrene, Table 1: Clinical diagnosis with clinical success rates.
iii;iN!~Nir~i(ii~i~i~i~i:~iii:.i:~i~!::ii:E:~iiiN~i~li~:~i : ~i:~:.::i:~ilii ii!:'ii:iii~i:i:i:~i:i~i~i~i:.:~i:iiiii:: ':ii Dermatological infections Infected diabetic gangrene Infections related to peripheral arterial disease Surgical wound infections Catheter related infections Other infections
24 (2) 3
24 3
100.0% 100.0%
3 29 2 1
3 27 2 1
100.0% 93.1% 100.0% 100.0%
Total
62 (2)
60
96.8%
Two patients (in brackets) were treated less than three days and not included in the evulation of efficacy.
Initial dose
Subsequent dose alternating dosage 9.5%
other 6.5%
1800mg 6 5%
400 mg 87.1%
more than 200 mg/day (mainly 400 mg/day) 15.9%
200 mg/day and less 74.6%
Figure 1: Teicoplanin dosage.
three infections related to peripheral arterial disease, two catheter related infections and one other infection (Table 1).
Predisposing and Complicating Factors In 39/64 of the patients predisposing or complicating factors for infection were reported. Surgery was the most common factor with 17/64 of all patients, followed by diabetes mellitus in 14/64, major injuries (7/64) and others. Previous Antibiotic Treatment Twenty-five patients had received antibiotic therapy within the last 30 days. A m o n g these, penicillins and cephalosporins were most common (10/25 and 7/25, respectively), followed by quinolones (4/25) and macrolide antibiotics (3/25). The most common reason for discontinuation of previous antibiotic treatment was therapeutic failure in two thirds of the cases. Teicoplanin Therapy The dosage regimens for teicoplanin are given in Figure 1. Initially, most patients (50/62) received teicoplanin by the intravenous route, 12/62 by the intramuscular route. On the subsequent days the drug was given intravenously (38/62), followed by the intramuscular route (12/62). In 13/62 cases teicoplanin was administered both intravenously and intramuscularly. The m e a n duration of treatment was 10.4 days (range: 2-71 days). Teicoplanin was usually given as an loading dose of 400 mg (54/62), or 800 mg (4/62) or other doses (4/62). During the course of the study, the mean daily dose of teicoplanin was 261.3 mg (range 85.7-600.0 mg).
Concomitant Treatment Teicoplanin was the sole antimicrobial agent in 54/64 patients, 10/64 received additional antibiotics. In five patients teicoplanin was used in combination with aminoglycosides, followed by penicillins (three patients) and cephalosporins (two patients). Concomitant non-antimicrobial therapy was necessary in 42 patients (65.6%), frequently to treat cardiovascular diseases.
Infection 19 (1991) No. 3 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1991
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E. Lang et al.: Teicoplanin in Skin and Soft Tissue Infections
not evaluable 3.2%
clinical cure or improvement 96.8% Figure 2: Clinical results.
Clinical Outcome Sixty-two patients were clinically evaluable. Two patients were not evaluable for clinical efficacy, as they had received teicoplanin for less than three days. One of these patients was transferred to another clinic and the other patient died because of cardiac failure. Figuro 2 shows the clinical results. Overall success rate was 60/62. Of these 48 were clinically cured and 12 improved. In only two patients therapy failed.
Efficacy in Relation to Clinical Diagnosis Efficacy with regard to the clinical diagnosis is shown in Tablo 1. The only failures noted were in the surgical infection group.
ogens were found, i. e. Proteus and Pseudomonas aeruginosa . Susceptibility was determined in the main part by inhibition zone diameters (breakpoints: - 14 mm susceptible, 11-13 intermediate, ~ 10 resistant). 95.6% of the causative gram-positive microorganisms tested were fully susceptible to teicoplanin. Two strains (S. aureus and coagulase-negative Staphylococcus) were of intermediate susceptibility to teicoplanin. However, the two patients infected with these organisms were clinically cured or improved. Inhibition zone diameter was available for 31/58 of the pathogens, mean inhibition zone diameter was 16.2 + 3.2 mm, ranging from 12 to 25 mm. Only one Staphylococcus and two coagulase-negative staphylococci were shown to be resistant to methicillin.
Bacteriological Results The overall bacteriological outcome of 57 gram-positive pathogens, evaluable for bacteriological efficacy, is shown in Table 2. Thirty-seven pathogens (78.7% of all evaluable cases) were eliminated. Persistence occurred in seven cases (14.9%), while recurrence was seen in two cases (4.3%) and reinfection in one case (2.1%). Staphylococci showed bacteriological results similar to the overall results (Tablo 2). 27/35 of S. aureus and all evaluable coagulase negative staphylococci were eliminated. 5/7 streptococci were eliminated.
Safety
Effcacy
Adverse Reactions
Figure 3 shows the success rates with regard to various factors. There were no significant differences in success rates whether patients exhibited predisposing or complicating factors for infection or not. Monotherapy with teicoplanin compared to antibiotic combination therapy also did not reveal significant differences. Patients who were pretreated with antibiotics showed a rate of cure or improvement of 100% and those without antibiotic pretreatment a rate of 94.6%. In patients with previous antibiotic treatment which failed, a success rate of 100% was reached under teicoplanin therapy. Patients receiving teicoplanin initially without the results of an antibiogramm showed a response rate of 93.9%, while patients receiving specific therapy showed a response rate of 100%.
Adverse reactions were suspected in three patients (4.7%) (Table 3). An allergic reaction (erythema) was documented in one patient and a local reaction in another patient. The former patient had to be withdrawn because of this allergic reaction. The third patient exhibited a rise in transaminases. One patient died during the course of the study due to the underlying disease (cardiac failure).
Bacteriological Outcome Organisms Pathogens were isolated in 50 patients (78.1%). Fifty-eight gram-positive pathogens were isolated, consisting of 41 Staphylococcus aureus, six coagulase-negative staphylococci and 11 streptococci, of which three enterococci strains had not been specified. Two strains of gram-negative path-
72 / 192
Overall Assessment of Global and Local Tolerability Global tolerability was judged good for 62 patients (98.4%). Evaluation of global tolerability was not possible in one patient. Local tolerability was found to be good for 49 patients (98.0%) of 50 patients with i.v. administration and satisfactory for one patient (2.0%). Twenty-two out of 23 patients (95.7%) receiving teicoplanin intramuscularly exhibited good local tolerability, one patient showed satisfactory local tolerability.
Laboratory Safety Data No clinically relevant changes were discernible in the serial biochemical and haematological tests. The most com-
Infection 19 (1991) No. 3 © MMV MedizinVerlag GmbH Miinchen, Miinchen 1991
E. Lang et al.: Teicoplanin in Skin and Soft Tissue Infections
Predisposing factors
Monotherapy vs. combination
Pretreatment
Initial therapy/ antibiogram
Subsequent dosage (severe infection)
1O0%
80%
60% clinical cure or improvement
4O%
20%
0% without
with
(n=23) (n=37)
without
with pretreat-
(n=35) (n=25) ment failed
mono- combin.therapy therapy
(n=51)
(n=9)
before after antibiog, antibiog,
(n=31)
(n=22)
(n=17)
less/ equal
more than
alternating 200 rag/200 mg/ dosage day day (n=6)
(n=45)
(n=8)
Figure 3: Success rate in relation to various factors.
mon change in laboratory parameters was a rise in platelet count. In four out of 64 patients a rise in absolute platelet numbers was seen, which can be attributed to the underlying disease, such as chronic inflammatory diseases, acute infections, abundant bleeding and postoperative complications. The mean platelet count rose from 295.1 to 326.0 x 109/1 in men and from 233.8 to 275.6 x 109/1 in women. Discussion Skin and soft tissue infections are often treated with a
combination of antibiotics since they are caused by a variety of aerobic and anaerobic bacteria. Many of the pathogens causing skin and soft tissue infections are resistant even to newer penicillins and cephalosporins. Teicoplanin has been shown to be active against most gram-positive bacteria, including the staphylococci and streptococci that are commonly responsible for skin and soft tissue infections [7, 10]. Clinical trials with teicoplanin throughout Europe and the USA have shown efficacy in a wide range of infections coupled with a low incidence of adverse events [11-13].
Table 2: Elimination rates (gram-positive pathogens).
iiiiiii?iiiiiiiiiiiiiii]iiiliiiiii iiiiiiiiiiiilliiiiiii i!!!! i!iii!iiiii!iiiiiiti?iiiii1i!iiiiiit!ii!ii?iiiiiiiiiiiii;iiii:iiiiiiiiiiiiiiiiiiii:i!ii!iiiiii;i?iiii!iiiiiilliiiiii!i?iiiiii iiiiiiiiiiiiii?iiiiiiii! iliiiiiiiiiiii$ii iiiiiiiiiliiiiiiitiilzi iiii@!iiiiIii iiiiiiiiiiiil?i i iiiiiiiiiiiii:ili+iiiil:N!iliiiii iiiiiiiti i!iiit!iiiii l iiiiiiiiiiiiiiNi!i,ili+: Dermatological infections Infected diabetic gangrene* Infections related to peripheral arterial disease Surgical wound infections Catheter related infections Other infections
14/15
93.3%
3/3 8/14 1/2 1/1
100.0% 57.1% 50.0% 100.0%
Total
27/35
77.1%
2/2
100.0%
4/4
100.0%
20/21
95.2%
3/3
100.0%
1/2 0/1
50.0% 0.0%
3/3 12/19 1/3 1/1
100.0% 63.2% 33.3% 100.0%
5/5
100.0%
5/7
71.4%
37/47
78.7%
The bacteriological results of the group "infected diabetic gangrene" are not evaluable.
Infection 19 (1991) No. 3
© MMV Medizin Verlag GmbH Miinchen, Miinchen 1991
193 / 73
E. Lang et al.: Teicoplanin in Skin and Soft Tissue Infections
The results of the present study have demonstrated the efficacy and safety of teicoplanin in skin and soft tissue infections. Fourty-eight patients out of 62 with presumed or proven skin and soft tissue infections were clinically cured and 12 improved. Overall success rate was 96.8%, therapy failure occurred only in two patients. This is in good agreement with the results of Lewis and coworkers [11] and Turpin et al. [12], reporting an overall success rate of 92.4% and 91.7%, respectively, in patients with skin and soft tissue infections. The most common adverse effects observed in the European multicentre study [11] were allergic reactions [1.3%), transient rises of liver enzymes (1.5%) and pain at the infection site (1.9%). In this study teicoplanin was also very well tolerated. Only in three patients adverse reactions were reported, being similar to those reported by Lewis et al. [11]. No evidence of nephrotoxicity or ototoxicity was found. To sum it up, this trial has demonstrated that teicoplanin is an effective and safe antibiotic in skin and soft tissue infections.
Acknowledgements Cooperating investigators and bacteriologists in this study were: Investigators: Dr. Bojack, Evangelisches Krankenhaus Oberhausen, Chirurgie; Dr. Broens, Kreiskrankenhaus Wetzlar, Inhere Medizin; Dr. Eichom, Krankenhaus St. Joseph, Regensburg,
Table 3: Adverse reaction.
Allergy Pain at injection site Increase of transaminases
1
Total
3
74 / 194
1
1
1
1 1
1
1
1
1
2
1
Nephrologie; Prof. Dr. Eitel, Chirurgische Universit~itsklinik, M0nchen; Prof. Dr. Hess~Dr. Mohr, St. Elisabeth Klinik, Saarlouis, Orthop~idie; Dr. Kauffmann, Kreiskrankenhaus Fiirstenfeldbruck, Chirurgie; Prof. Dr. Kempf, Hessenklinik Rtisselsheim, Chirurgie; Dr. Reefs, Universit~itsklinik M/inster, Chirurgie; Dr. Tram, Kliniken der Stadt Saarbrficken, Winterberg, Chirurgie; Dr. Vagt, Univ.-Kliniken Frankfurt, Orthop~idie. Bacteriologists: Prof. Dr. Bauernfeind, Max-von-Pettenkofer-Institut, Mfinchen; Dr. Jakobs, Dillingen; Prof. Dr. Kindler, Oberhausen, Dr. Koser, Labor Dr. Koser, Mtinchen; Dr. Naumann, Landesuntersuchungsamt, Regensburg; Prof. Dr. Ritzerfeld, Universit~it MOnster; Dr. Rohr, Staatliches Institut for Gesundheit und Umwelt, Saarbrticken; Dr. V. Schafer, Universit~it Frankfurt/Main; Dr. Schmidt-Mantila, Stadtkrankenhaus Rfisselsheim; Dr. Stiibner, Nordstadt-Krankenhaus, Hannover.
References 1. Bauernfeind, A., Petermiiller, C.: In vitro activity of teichomycin A 2 in comparison with penicillin and vancomycin against gram- positive cocci. Eur. J. Clin. Microbiol. 1 (1982) 278-281. 2. Verbist, L, Tjandramaga, B., Hendrickx, B., Van Hecken, A., Van MeUe, P., Verbesselt, It., Verhaegen, J., De Schepper, P. J.: In vitro activity and human pharmacokinetics of teicoplanin. Antimicrob. Agents Chemother. 26 (1984) 881- 886. 3. Thabaut, A., Meyran, M.: Comparative in vitro study of the activityof teichomycin,vancomycin,and N-formimidoyl-thienamycinon Staphylococcus aureus. Chemioterapia 2 (Suppl. 5) (1983) 12-13. 4. Traina, G. L, Bonati, M.: Pharmacokinetics of teicoplanin in man after intravenous administration. J. Pharmacokinet. Biopharm. 12 (1984) 119- 128. 5. McNulty, C. A. M., Garden, G. M. F., Wise, R., Andrews, M.: The pharmacokinetics and tissue penetration of teicoplanin. J. Antimicrob. Chemother. 16 (1985) 743- 749. 6. Neu, H. C., Labthavikul, P.: In vitro activityof teichomycincompared with those of other antibiotics. Antimicrob. Chemother. 24 (1983) 425-428. 7. Pallanza, 1L, Berti, M., Goldstein, B. P., Mapelli, E., Randisi, E., Scotti, 1L, Arioli, V.: Teichomycin, in vitro and in vivo evaluation in
1
1
8.
9.
10.
11.
12.
13.
comparison with other antibiotics. J. Antimicrob. Chemother. 11 (1983) 419-425. Guenthner, S. H., Wenzel, R. P.: In vitro activities of teichomycin,fusidic acid, flucloxacillin,fosfomycin,and vancomycin against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 26 (1984) 268-269. Chandrasekar, P. H., Price, S., Levine, D. P.: In vitro evaluation of cefpirome (HR 810), teicoplanin and four antimicrobials against enterococci. J. Antimicrob. Chemother. 16 (1985) 179-182. Griineberg, R. N., Ridgway, G. L, Cremer, A. W. F., Felmingham, D.: The sensitivity of gram-positive pathogens to teichomycin and vancomycin. Drugs under Experimental and Clinical Research 9 (1983) 139-141. Lewis, P., Garaud, J.-J., Parenti, F.: A multicentre open clinical trial of teicoplanin in infections caused by gram-positivebacteria. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 61-67. Stillle, W., Sietzen, W., Dieterich, H.-A., Fell, J. J.: Clinical efficacyof teicoplanin. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 69-79. Turpin, P. J., Taylor, G. P., Logan, M. N., Wood, M. J.: Teicoplanin in the treatment of skin and soft tissue infections. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 117-122.
Infection 19 (1991) No. 3 © MMV Medizin Verlag GmbH Miinchen, Mfinchen 1991
E. Lang, M. F61des, S. Marghescu
Teicoplanin in the Treatment of Skin and Soft Tissue Infections: Results of a Multicentre Study Summary: The clinical efficacy and safety of teicoplanin was studied in hospitalized patients with skin and soft tissue infections. In an open multicentre study 64 patients were treated with teicoplanin i.v. and/or i.m. Predisposing or complicating factors for infection were present in almost 80% of the patients. Teicoplanin was usually given as an initial loading dose of 400 mg (87.1%), or 800 mg (6.5%) or various doses (6.5%). During the course of the study, the mean daily dose of teicoplanin was 261.3 mg. Sixty of the 62 evaluable patients responded to treatment. 58 gram-positive pathogens were isolated, consisting of Staphylococcus aureus (n = 41), coagulase-negative staphylococci (n = 6) and streptococci (n = 11). Elimination of pathogens was seen in 37/47 of all microbiologically evaluable cases. Persistence, recurrence or reinfection occurred in 7/47, 2/47 and 1/47, respectively. Adverse reactions were reported in only three patients with allergic reaction, local reaction and rise in transaminases in one case each. Therapy failed only in two patients. Zusammenfassung: Die Behandlung von Haut- und Weichteilinfektionen mit Teicoplanin - Ergebnisse einer Multizenterstudie. Die klinische Wirksamkeit und Ver-
tr~iglichkeit von Teicoplanin wurde bei hospitalisierten Patienten mit Haut- und Weichteilinfektionen untersucht. In einer offenen Multizenterstudie wurden 64 Patienten mit Teicoplanin i.v. und/oder i.m. behandelt. Pr~idisponierende oder komplizierende Faktoren ffir Infektionen waren bei fast 80% der Patienten vorhanden. Die Anfangsdosis Teicoplanin war bei 87,1% der Patienten 400 mg einmal t~iglich und bei 6,5% der Patienten 800 rag, 6,5% erhielten variierende Dosen. Im Verlauf der Studie wurde eine mittlere Folgedosis yon 261,3 mg/Tag verabreicht. Ein klinischer Erfolg wurde bei 60/62 auswertbaren Patienten erzielt. Therapieversagen wurde bei zwei Patienten beobachtet. 58 grampositive Erreger konnten isoliert werden. Dies waren Staphylococcus aureus-St~mme (n = 41), koagulase-negative Staphylokokken (n = 6) und Streptokokken (n = 11). In 37/47 aller mikrobiologisch auswertbaren F~ille wurde eine Elimination der Erreger erreicht, Persistenz, Wiederauftreten oder Reinfektion kam bei 7/47, 2/47 bzw. 1/47 der Ffille vor. Unerwfinschte Wirkungen wurden lediglich bei drei Patienten berichtet: eine allergische und eine lokale Reaktion sowie ein Anstieg der Transaminasen.
Introduction In general the majority of skin and soft tissue diseases can be cured by adequate local therapy. However, an increasing number of these infections require systemic antibiotic therapy. Since gram-positive bacteria are the most commonly isolated pathogens in skin and soft tissue infections i.e. surgical wound infections and dermatological infections such as erysipelas or cellulitis, it is reasonable to investigate the highly active anti-gram- positive agent teicoplanin for the treatment of skin and soft tissue infections. The spectrum of the new glycopeptide antibiotic teicoplanin is directed against gram-positive bacteria including methicillin resistant staphylococci [1,2]. Unlike [3-1actams that bind the enzymes responsible for peptidoglycan synthesis, teicoplanin interacts with a structural component of the cellular wall (muramyl-pentapeptide's D-alanyl-Dalanine). Therefore cross-resistance between 13-1actams and teicoplanin does not exist. Furthermore, one-step-resistant mutations have not been found, as it is unlikely that the structure of the muramyl-pentapeptide could be easily changed to inhibit teicoplanin binding. This has been demonstrated by in vitro studies [3]. Teicoplanin differs from vancomycin, the other glycopeptide antibiotic, in that it is eliminated much more slowly, is better tolerated after i.v. administration and offers the 70 / 190
possibility of i.m. administration. The favourable pharmacokinetics of teicoplanin permit a once-daily administration [2,4]. Following i.m. or i.v. administration of either 3 or 6 mg/kg doses to normal human volunteers, teicoplanin achieves high plasma and urine concentrations [5], exceeding the MICs for all susceptible gram-positive bacteria [6-9]. The purpose of this study was to evaluate the efficacy and safety of teicoplanin in the treatment of patients with skin and soft tissue infections.
Patients and Methods Eleven centres in the Federal Republic of Germany participated in this open study. Any hospitalized patient of either sex, 12 years or older, with presumed or proven skin and soft tissue infection, judged to require antimicrobial therapy could be entered in the study after giving informed consent. Patients were excluded from the study if they had a history of hypersensitivity to teicoplanin or vancomycin or if they were pregnant or nursing. The protocol of Dr. med. Eva Lang, Merrell Dow Pharma GmbH, Eisenstr. 40, W-6090 Riisselsheim,Germany;Dr. med.MartaF61des,Hautklinik,W-3000Hannover 91, Germany and MedizinischeKlinik der Albert-Szent-Gy6rgyiUniversit~it,DermatologischeKlinik,Szeged,Hungary;Prof. Dr. reed. S. Manghescu, Hautklinik,W-3000 Hannover 91, Germany.
Infection 19 (1991) No. 3 © MMV MedizinVerlag GmbH Mfinchen,Miinchen 1991
E. Lang et al.: Teicoplanin in Skin and Soft Tissue Infections this study was approved by the appropriate ethical committee. Therapy assessment: The efficacy of teicoplanin was assessed by both clinical and bacteriological criteria according to the following definitions. Cured: Clinical signs and symptoms of infection completely eradicated with no evidenceof infection at the end of treatment. Clinical improvement: Clinical findings subsided during the period of treatment but with incomplete resolution of infection. Recurrence: Initial improvement of signs and symptoms of the infection with a subsequent worsening of the clinical condition due to infection after discontinuing treatment. Failure: No apparent response to antimicrobial therapy. If, in the investigators' opinion, the case was considered to be not evaluable for any reason, this was taken into consideration. The patients were assessed daily to evaluate efficacy of treatment and to detect any clinical signs or symptoms of adverse reactions. For the bacteriological assessment appropriate cultures were obtained before and after treatment. Bacteriological efficacy was assessed according to the following criteria. Elimination: Causative organism was absent at or immediately after termination of therapy or the infection had completely disappeared so that follow-up eulture was impossible. Recurrence: Absence of the causative organism(s) at or immediately after termination of therapy, but reapparance of the same organism(s) at the same site. Reinfection: Causative organism(s) absent at or immediately after termination of therapy but reappearance of another infecting organism(s) at the same site at or before the follow-up visit. Persistence: Continued presence of causative organism(s) at the end of therapy. Not evaluable: Evaluation of the bacteriological response to the study was not possible. Results
Patient Data O f 64 patients treated with teicoplanin 26 were female and 38 were male. The mean age was 51.5 years, range 16-88 years. Five of the patients were considered seriously ill. Most infections were moderate (n -- 35; 54.7%) or severe (n = 23; 35.9%). Mild infections were seen in only six patients (9.4%). Duration of the infection ranged from 1 to 365 days (median 10 days). Clinical Diagnosis There were 29 surgical wound infections, 26 dermatological infections, three cases of infected diabetic gangrene, Table 1: Clinical diagnosis with clinical success rates.
iii;iN!~Nir~i(ii~i~i~i~i:~iii:.i:~i~!::ii:E:~iiiN~i~li~:~i : ~i:~:.::i:~ilii ii!:'ii:iii~i:i:i:~i:i~i~i~i:.:~i:iiiii:: ':ii Dermatological infections Infected diabetic gangrene Infections related to peripheral arterial disease Surgical wound infections Catheter related infections Other infections
24 (2) 3
24 3
100.0% 100.0%
3 29 2 1
3 27 2 1
100.0% 93.1% 100.0% 100.0%
Total
62 (2)
60
96.8%
Two patients (in brackets) were treated less than three days and not included in the evulation of efficacy.
Initial dose
Subsequent dose alternating dosage 9.5%
other 6.5%
1800mg 6 5%
400 mg 87.1%
more than 200 mg/day (mainly 400 mg/day) 15.9%
200 mg/day and less 74.6%
Figure 1: Teicoplanin dosage.
three infections related to peripheral arterial disease, two catheter related infections and one other infection (Table 1).
Predisposing and Complicating Factors In 39/64 of the patients predisposing or complicating factors for infection were reported. Surgery was the most common factor with 17/64 of all patients, followed by diabetes mellitus in 14/64, major injuries (7/64) and others. Previous Antibiotic Treatment Twenty-five patients had received antibiotic therapy within the last 30 days. A m o n g these, penicillins and cephalosporins were most common (10/25 and 7/25, respectively), followed by quinolones (4/25) and macrolide antibiotics (3/25). The most common reason for discontinuation of previous antibiotic treatment was therapeutic failure in two thirds of the cases. Teicoplanin Therapy The dosage regimens for teicoplanin are given in Figure 1. Initially, most patients (50/62) received teicoplanin by the intravenous route, 12/62 by the intramuscular route. On the subsequent days the drug was given intravenously (38/62), followed by the intramuscular route (12/62). In 13/62 cases teicoplanin was administered both intravenously and intramuscularly. The m e a n duration of treatment was 10.4 days (range: 2-71 days). Teicoplanin was usually given as an loading dose of 400 mg (54/62), or 800 mg (4/62) or other doses (4/62). During the course of the study, the mean daily dose of teicoplanin was 261.3 mg (range 85.7-600.0 mg).
Concomitant Treatment Teicoplanin was the sole antimicrobial agent in 54/64 patients, 10/64 received additional antibiotics. In five patients teicoplanin was used in combination with aminoglycosides, followed by penicillins (three patients) and cephalosporins (two patients). Concomitant non-antimicrobial therapy was necessary in 42 patients (65.6%), frequently to treat cardiovascular diseases.
Infection 19 (1991) No. 3 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1991
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E. Lang et al.: Teicoplanin in Skin and Soft Tissue Infections
not evaluable 3.2%
clinical cure or improvement 96.8% Figure 2: Clinical results.
Clinical Outcome Sixty-two patients were clinically evaluable. Two patients were not evaluable for clinical efficacy, as they had received teicoplanin for less than three days. One of these patients was transferred to another clinic and the other patient died because of cardiac failure. Figuro 2 shows the clinical results. Overall success rate was 60/62. Of these 48 were clinically cured and 12 improved. In only two patients therapy failed.
Efficacy in Relation to Clinical Diagnosis Efficacy with regard to the clinical diagnosis is shown in Tablo 1. The only failures noted were in the surgical infection group.
ogens were found, i. e. Proteus and Pseudomonas aeruginosa . Susceptibility was determined in the main part by inhibition zone diameters (breakpoints: - 14 mm susceptible, 11-13 intermediate, ~ 10 resistant). 95.6% of the causative gram-positive microorganisms tested were fully susceptible to teicoplanin. Two strains (S. aureus and coagulase-negative Staphylococcus) were of intermediate susceptibility to teicoplanin. However, the two patients infected with these organisms were clinically cured or improved. Inhibition zone diameter was available for 31/58 of the pathogens, mean inhibition zone diameter was 16.2 + 3.2 mm, ranging from 12 to 25 mm. Only one Staphylococcus and two coagulase-negative staphylococci were shown to be resistant to methicillin.
Bacteriological Results The overall bacteriological outcome of 57 gram-positive pathogens, evaluable for bacteriological efficacy, is shown in Table 2. Thirty-seven pathogens (78.7% of all evaluable cases) were eliminated. Persistence occurred in seven cases (14.9%), while recurrence was seen in two cases (4.3%) and reinfection in one case (2.1%). Staphylococci showed bacteriological results similar to the overall results (Tablo 2). 27/35 of S. aureus and all evaluable coagulase negative staphylococci were eliminated. 5/7 streptococci were eliminated.
Safety
Effcacy
Adverse Reactions
Figure 3 shows the success rates with regard to various factors. There were no significant differences in success rates whether patients exhibited predisposing or complicating factors for infection or not. Monotherapy with teicoplanin compared to antibiotic combination therapy also did not reveal significant differences. Patients who were pretreated with antibiotics showed a rate of cure or improvement of 100% and those without antibiotic pretreatment a rate of 94.6%. In patients with previous antibiotic treatment which failed, a success rate of 100% was reached under teicoplanin therapy. Patients receiving teicoplanin initially without the results of an antibiogramm showed a response rate of 93.9%, while patients receiving specific therapy showed a response rate of 100%.
Adverse reactions were suspected in three patients (4.7%) (Table 3). An allergic reaction (erythema) was documented in one patient and a local reaction in another patient. The former patient had to be withdrawn because of this allergic reaction. The third patient exhibited a rise in transaminases. One patient died during the course of the study due to the underlying disease (cardiac failure).
Bacteriological Outcome Organisms Pathogens were isolated in 50 patients (78.1%). Fifty-eight gram-positive pathogens were isolated, consisting of 41 Staphylococcus aureus, six coagulase-negative staphylococci and 11 streptococci, of which three enterococci strains had not been specified. Two strains of gram-negative path-
72 / 192
Overall Assessment of Global and Local Tolerability Global tolerability was judged good for 62 patients (98.4%). Evaluation of global tolerability was not possible in one patient. Local tolerability was found to be good for 49 patients (98.0%) of 50 patients with i.v. administration and satisfactory for one patient (2.0%). Twenty-two out of 23 patients (95.7%) receiving teicoplanin intramuscularly exhibited good local tolerability, one patient showed satisfactory local tolerability.
Laboratory Safety Data No clinically relevant changes were discernible in the serial biochemical and haematological tests. The most com-
Infection 19 (1991) No. 3 © MMV MedizinVerlag GmbH Miinchen, Miinchen 1991
E. Lang et al.: Teicoplanin in Skin and Soft Tissue Infections
Predisposing factors
Monotherapy vs. combination
Pretreatment
Initial therapy/ antibiogram
Subsequent dosage (severe infection)
1O0%
80%
60% clinical cure or improvement
4O%
20%
0% without
with
(n=23) (n=37)
without
with pretreat-
(n=35) (n=25) ment failed
mono- combin.therapy therapy
(n=51)
(n=9)
before after antibiog, antibiog,
(n=31)
(n=22)
(n=17)
less/ equal
more than
alternating 200 rag/200 mg/ dosage day day (n=6)
(n=45)
(n=8)
Figure 3: Success rate in relation to various factors.
mon change in laboratory parameters was a rise in platelet count. In four out of 64 patients a rise in absolute platelet numbers was seen, which can be attributed to the underlying disease, such as chronic inflammatory diseases, acute infections, abundant bleeding and postoperative complications. The mean platelet count rose from 295.1 to 326.0 x 109/1 in men and from 233.8 to 275.6 x 109/1 in women. Discussion Skin and soft tissue infections are often treated with a
combination of antibiotics since they are caused by a variety of aerobic and anaerobic bacteria. Many of the pathogens causing skin and soft tissue infections are resistant even to newer penicillins and cephalosporins. Teicoplanin has been shown to be active against most gram-positive bacteria, including the staphylococci and streptococci that are commonly responsible for skin and soft tissue infections [7, 10]. Clinical trials with teicoplanin throughout Europe and the USA have shown efficacy in a wide range of infections coupled with a low incidence of adverse events [11-13].
Table 2: Elimination rates (gram-positive pathogens).
iiiiiii?iiiiiiiiiiiiiii]iiiliiiiii iiiiiiiiiiiilliiiiiii i!!!! i!iii!iiiii!iiiiiiti?iiiii1i!iiiiiit!ii!ii?iiiiiiiiiiiii;iiii:iiiiiiiiiiiiiiiiiiii:i!ii!iiiiii;i?iiii!iiiiiilliiiiii!i?iiiiii iiiiiiiiiiiiii?iiiiiiii! iliiiiiiiiiiii$ii iiiiiiiiiliiiiiiitiilzi iiii@!iiiiIii iiiiiiiiiiiil?i i iiiiiiiiiiiii:ili+iiiil:N!iliiiii iiiiiiiti i!iiit!iiiii l iiiiiiiiiiiiiiNi!i,ili+: Dermatological infections Infected diabetic gangrene* Infections related to peripheral arterial disease Surgical wound infections Catheter related infections Other infections
14/15
93.3%
3/3 8/14 1/2 1/1
100.0% 57.1% 50.0% 100.0%
Total
27/35
77.1%
2/2
100.0%
4/4
100.0%
20/21
95.2%
3/3
100.0%
1/2 0/1
50.0% 0.0%
3/3 12/19 1/3 1/1
100.0% 63.2% 33.3% 100.0%
5/5
100.0%
5/7
71.4%
37/47
78.7%
The bacteriological results of the group "infected diabetic gangrene" are not evaluable.
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© MMV Medizin Verlag GmbH Miinchen, Miinchen 1991
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E. Lang et al.: Teicoplanin in Skin and Soft Tissue Infections
The results of the present study have demonstrated the efficacy and safety of teicoplanin in skin and soft tissue infections. Fourty-eight patients out of 62 with presumed or proven skin and soft tissue infections were clinically cured and 12 improved. Overall success rate was 96.8%, therapy failure occurred only in two patients. This is in good agreement with the results of Lewis and coworkers [11] and Turpin et al. [12], reporting an overall success rate of 92.4% and 91.7%, respectively, in patients with skin and soft tissue infections. The most common adverse effects observed in the European multicentre study [11] were allergic reactions [1.3%), transient rises of liver enzymes (1.5%) and pain at the infection site (1.9%). In this study teicoplanin was also very well tolerated. Only in three patients adverse reactions were reported, being similar to those reported by Lewis et al. [11]. No evidence of nephrotoxicity or ototoxicity was found. To sum it up, this trial has demonstrated that teicoplanin is an effective and safe antibiotic in skin and soft tissue infections.
Acknowledgements Cooperating investigators and bacteriologists in this study were: Investigators: Dr. Bojack, Evangelisches Krankenhaus Oberhausen, Chirurgie; Dr. Broens, Kreiskrankenhaus Wetzlar, Inhere Medizin; Dr. Eichom, Krankenhaus St. Joseph, Regensburg,
Table 3: Adverse reaction.
Allergy Pain at injection site Increase of transaminases
1
Total
3
74 / 194
1
1
1
1 1
1
1
1
1
2
1
Nephrologie; Prof. Dr. Eitel, Chirurgische Universit~itsklinik, M0nchen; Prof. Dr. Hess~Dr. Mohr, St. Elisabeth Klinik, Saarlouis, Orthop~idie; Dr. Kauffmann, Kreiskrankenhaus Fiirstenfeldbruck, Chirurgie; Prof. Dr. Kempf, Hessenklinik Rtisselsheim, Chirurgie; Dr. Reefs, Universit~itsklinik M/inster, Chirurgie; Dr. Tram, Kliniken der Stadt Saarbrficken, Winterberg, Chirurgie; Dr. Vagt, Univ.-Kliniken Frankfurt, Orthop~idie. Bacteriologists: Prof. Dr. Bauernfeind, Max-von-Pettenkofer-Institut, Mfinchen; Dr. Jakobs, Dillingen; Prof. Dr. Kindler, Oberhausen, Dr. Koser, Labor Dr. Koser, Mtinchen; Dr. Naumann, Landesuntersuchungsamt, Regensburg; Prof. Dr. Ritzerfeld, Universit~it MOnster; Dr. Rohr, Staatliches Institut for Gesundheit und Umwelt, Saarbrticken; Dr. V. Schafer, Universit~it Frankfurt/Main; Dr. Schmidt-Mantila, Stadtkrankenhaus Rfisselsheim; Dr. Stiibner, Nordstadt-Krankenhaus, Hannover.
References 1. Bauernfeind, A., Petermiiller, C.: In vitro activity of teichomycin A 2 in comparison with penicillin and vancomycin against gram- positive cocci. Eur. J. Clin. Microbiol. 1 (1982) 278-281. 2. Verbist, L, Tjandramaga, B., Hendrickx, B., Van Hecken, A., Van MeUe, P., Verbesselt, It., Verhaegen, J., De Schepper, P. J.: In vitro activity and human pharmacokinetics of teicoplanin. Antimicrob. Agents Chemother. 26 (1984) 881- 886. 3. Thabaut, A., Meyran, M.: Comparative in vitro study of the activityof teichomycin,vancomycin,and N-formimidoyl-thienamycinon Staphylococcus aureus. Chemioterapia 2 (Suppl. 5) (1983) 12-13. 4. Traina, G. L, Bonati, M.: Pharmacokinetics of teicoplanin in man after intravenous administration. J. Pharmacokinet. Biopharm. 12 (1984) 119- 128. 5. McNulty, C. A. M., Garden, G. M. F., Wise, R., Andrews, M.: The pharmacokinetics and tissue penetration of teicoplanin. J. Antimicrob. Chemother. 16 (1985) 743- 749. 6. Neu, H. C., Labthavikul, P.: In vitro activityof teichomycincompared with those of other antibiotics. Antimicrob. Chemother. 24 (1983) 425-428. 7. Pallanza, 1L, Berti, M., Goldstein, B. P., Mapelli, E., Randisi, E., Scotti, 1L, Arioli, V.: Teichomycin, in vitro and in vivo evaluation in
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comparison with other antibiotics. J. Antimicrob. Chemother. 11 (1983) 419-425. Guenthner, S. H., Wenzel, R. P.: In vitro activities of teichomycin,fusidic acid, flucloxacillin,fosfomycin,and vancomycin against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 26 (1984) 268-269. Chandrasekar, P. H., Price, S., Levine, D. P.: In vitro evaluation of cefpirome (HR 810), teicoplanin and four antimicrobials against enterococci. J. Antimicrob. Chemother. 16 (1985) 179-182. Griineberg, R. N., Ridgway, G. L, Cremer, A. W. F., Felmingham, D.: The sensitivity of gram-positive pathogens to teichomycin and vancomycin. Drugs under Experimental and Clinical Research 9 (1983) 139-141. Lewis, P., Garaud, J.-J., Parenti, F.: A multicentre open clinical trial of teicoplanin in infections caused by gram-positivebacteria. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 61-67. Stillle, W., Sietzen, W., Dieterich, H.-A., Fell, J. J.: Clinical efficacyof teicoplanin. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 69-79. Turpin, P. J., Taylor, G. P., Logan, M. N., Wood, M. J.: Teicoplanin in the treatment of skin and soft tissue infections. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 117-122.
Infection 19 (1991) No. 3 © MMV Medizin Verlag GmbH Miinchen, Mfinchen 1991
