S733
TIcarcillin-Clavulanate Therapy for Bacterial Skin and Soft TIssue Infections Thomas M. File, Jr., and James
s. Tan
From the Service of Infectious Disease, Akron City Hospital, Akron; and the Section of Infectious Disease, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio
Skin and soft tissue infections are commonly encountered in clinical practice. Bacterial infections of the skin range from mild pyodermas to life-threatening necrotizing infections [1, 2]. In clinical practice, most skin infections are diagnosed and treated clinically without the benefit of microbiologic confirmation. This practice is cost-effective since, with a few exceptions, pyodermas are due to Staphylococcus aureus or t3-hemolytic streptococci and are therefore responsive to t3-lactamase-resistant penicillins, first-generation cephalosporins, clindamycin, and erythromycin. Large skin lesions generally are aspirated or drained by incision. However, in patients with chronic indolent infection, skin ulcers of the extremities or other pressure-induced infections, infections following surgery or trauma, and histotoxic necrotizing infection, the "educated-guess" approach may not be sufficient. A large number of potential pathogens in addition to S. aureus and various species of streptococci may be involved in such infections; these pathogens include Enterobacteriaceae, Pseudomonas species, and anaerobes. These infections are influenced by the local epidemiology (geographic area), previous antimicrobial therapy, previous surgical procedures, type of wound care, and host defense status. Ideally, the provision of optimal antimicrobial therapy requires that an appropriate culture be performed before therapy is initiated. Culture of a specimen from the area of a closed infection such as an abscess is straightforward. Specimens obtained by aspiration or by incision and drainage are acceptable. However, cultures of samples obtained from cutaneous ulcers and open surgical or traumatic wounds, may not represent the true nature of the infection. Sapico et al. [3] and
Reprints and correspondence: Dr. Thomas M. File, Jr., 75 Arch Street, Suite 105, Akron, Ohio 44304. Reviews of Infectious D6eases 1991;13(Suppl 9):S73~ © 1991 by The University of Chicago. AU rights reserved. 0162-Q886/9l/l304-0017$02.00
Lee at al. [4] have shown that the results of cultures of deep tissue specimens obtained by curettage or needle aspiration
achieve a much greater correlation with the true pathogens than do cultures of superficial swab specimens. For patients with diabetic foot infections, Wheat et al. [5] have demonstrated that appropriately obtained specimens often include fewer organisms than do inappropriately obtained specimens and, therefore, permit the use of more specific antimicrobial therapy. This paper presents multicenter experience with ticarcillinclavulanate and summarizes the clinical and microbiologic efficacyof the combination. The data presented are from published clinical trials of ticarcillin-clavulanate as therapy for bacterial skin and soft tissue infections. It must be acknowledged that there are limitations to the comparability of the results of these studies. When an antimicrobial agent is evaluated for its efficacy, the results of treatment are judged by the clinical and microbiologic response. The objective measurement of microbiologic status is difficult for many patients who have an ulcer or open wound because of the poor reliability of the results of initial cultures. Ideally, for open wounds, a deep wound or open wound biopsy specimen should be obtained for culture to avoid contaminated areas. Unfortunately, no standard recommendations of culture have been accepted. In addition, the evaluation of efficacy has to include interventions other than antimicrobial therapy, such as the role of surgery, local wound care, and the status of the host. For most of the studies published, much of this information is lacking.
TIcarcillin-Clavulanate Therapy for Skin and Soft TIssue Infections Ticarcillin-clavulanate is active in vitro against the vast majority of pathogens involved in skin and soft tissue infections [6]. The addition of the {j-lactamase inhibitor clavulanate to ticarcillin expands its activity to include methicillin-sensitive staphylococci and significantly increases its activity against Bacteroidesfragilis and other anaerobes. Studies by Cuchural
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 5, 2015
TIcarcillin-elavulanate is active in vitro against the vast majority of pathogens involved in skin and soft tissue infections. A compilation of six controlled clinical trials of ticarcillin-clavulanate for treatment of skin infections showed a satisfactory clinical response in 175 (93%) of 189cases. The bacteriologic response included eradication of Staphylococcus aureus, Enterococcus species, Enterobacteriaceae, and Pseudomonas aeruginosa in 88%, 75%, 88%, and 77% of cases, respectively. In addition, the records of 17 patients with diabetic foot infections who were treated with ticarcillin-clavulanate as monotherapy in controlled trials are reviewed. Eight of these infections were cured and eight were improved at the end of therapy. The available clinical data suggest that ticarcillin-elavulanate is effective antimicrobial therapy for skin infections.
S734
File and Tan
Table 1. Clinical efficacy of ticarcillin-clavulanate as therapy for skin infections in six clinical trials.
Author [reference]
No. of patients with satisfactory clinical response*/ total no. of patients (%)
Pankey et al. [12]
10/12 (83)
LeFrock et al. [13] Rao et al. [14]
71/76 (93) 30/33 (91)
Tan et al. [15]
17/18 (94)
Timmes [16]
13/14 (93)
Johnson et al. [17] Total
34/36 (94)
Remarks Efficacy of 75 % for eight cefazolin-treated controls Noncomparative Efficacy of 89 % for 36 moxalactam-treated controls Efficacy of 81 % for 16 moxalactam-treated controls Surgical wound infections Efficacy of 80% for 10 moxalactam-treated controls Noncomparative
175/189 (93)
NOTE. Cellulitis, skin abscesses, infected wounds, and ulcer infections of the extremities were treated. The dose was 3.1 g (3 g of ticarcillin and 0.1 g of clavulanate), and the usual dosing interval was every 6 hours (range, 4-8 hours). * Satisfactory clinical response includes cure and improvement.
known if any of these isolates produced the Richmond and Sykes classes I and IV 13 -lactamases that are not inhibited by clavulanic acid [6]. Tan et al. [15] observed one isolate of P. aeruginosa recovered from the site of a diabetic foot infection that persisted despite clinical improvement; the MIC before therapy was 32 ILg/mL, and the MIC at the end oftherapy was >128 ILg/mL. The development of resistance in P. aeruginosa during therapy with other broad-spectrum 13-lactam agents has also been observed [19]. Data are available for 410 pathogens evaluated in 215 infections of skin structures included for evaluation in all clinical trials of ticarcillin-clavulanate preceding its release (data supplied by Beecham Laboratories, Bristol, TN; table 3). Cellulitis, skin abscesses, infected surgical wounds, and other infections were treated. Eradication of 91.5% of all pathogens and of 89 % of ticarcillin-resistant pathogens occurred. Because S. aureus is considered to be the most common pathogen involved in skin infections, it is important to evaluate the efficacy of ticarcillin-clavulanate against this pathogen specifically. Table 4 shows the clinical and bacteriologic results of all cases of monomicrobial skin infections caused by S. aureus that were included in the clinical trials of ticarcillin-clavulanate preceding its release (data supplied by 1.W. Alexander, Beecham Laboratories). A satisfactory clinical response was observed in 95 % of patients and the only clinical failures were due to "failure to surgically drain cutaneous abscesses." Bacteriologic eradication occurred in 36 of
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 5, 2015
et al. [7] have documented in vitro activity of ticarcillinclavulanate against the B. fragilis group of pathogens. The addition of clavulanate to ticarcillin also enhances activity against certain gram-negative pathogens, such as Klebsiella species: Although clavulanate does not inhibit the 13-lactamases found in Pseudomonas aeruginosa, most Enterobacter species, and Citrobacter species, organisms that may be involved in mixed soft tissue infections or postoperative infections, ticarcillin itself is relatively active against these organisms. Ticarcillin has "moderate" (intermediate) activity against most isolates of Enterococcus faecalis (usual MIC, 32-64 ILg/mL) [8]. The addition of clavulanate does not affect the activity ofticarcillin against most isolates of enterococci. However, rare 13-lactamase-producing isolates that would be anticipated to be susceptible to the combination of ticarcillin and clavulanate have been reported. Pharmacokinetic studies evaluating antibiotic levels in thread fluid and blister fluid indicate that they are adequate for the treatment of infections caused by a wide variety of skin pathogens, including S. aureus, Enterobacteriaceae, P. aeruginosa, and other gram-negative aerobic and anaerobic bacteria [9, 10]. Furthermore, experimental animal studies have documented the in vivo bactericidal effectof ticarcillin-clavulanate for soft tissue infections due to staphylococci and Bacteroides species [11]. The efficacy of ticarcillin-clavulanate in the therapy for skin and soft tissue infections has been evaluated in previously published clinical trials. The clinical efficacy of ticarcillinclavulanate in six clinical trials is summarized in table 1 [12-17]. Cellulitis, skin abscesses, infected wounds, and ulcer infections of the extremities were treated. The usual dose ofthe combination used in these studies was 3.1 g (3 g of ticarcillin and 0.1 g of clavulanate), and the usual dosing interval was 6 hours (range, 4-8 hours). The clinical response was satisfactory (cure or significant improvement) in 175 (93 %) of 189 of the cases in a compilation of these clinical trials. Many of these trials were comparative, and in the individual studies, the patients who received ticarcillin-clavulanate responded as well as or slightly better than the treated controls. In most cases the comparative agent was a first-generation cephalosporin (cefazolin) or a third-generation cephalosporin (moxalactam). LeFrock et al. [13] commented that surgical drainage, debridement, and frequent changes of dressing are necessary to achieve good results. In general, ticarcillinclavulanate was well tolerated and exhibited a safety profile similar to that of ticarcillin [18]. The bacteriologic efficacy of ticarcillin-clavulanate in four of these clinical trials for which complete bacteriologic data were available for analysis is included in table 2. The great majority of patients included in these trials had polymicrobial infections. S. aureus, Enterococcus species, Enterobacteriaceae, and P. aeruginosa were eradicated in 88 %, 75 %, 88 %, and 77% of the infections, respectively. LeFrock et al. [13] noted that one isolate each of Enterobacter, Klebsiella, and Citrobacter acquired resistance to the combination. It is not
RID 1991;13 (Suppl 9)
Ticarcillin-Clavulanate for Skin Infections
RID 1991;13 (Suppl 9)
S735
Table 2. Bacteriologic efficacy of ticarcillin-elavulanate as therapy for skin infections in four clinical trials. No. of isolates in indicated study Pankey et al. [12]
Pathogen
7
S. aureus Coagulase-negative staphylococci ~-Hemolytic streptococci Enterococcus species Enterobacteriaceae P. aeruginosa
5 2 1 12 2
LeFrock et al. [13]
Tan et al. [15]
39 7 13 12 52* 6
14 7
5 7 8 5t
* Acquired resistance was noted for one isolate each of Enterobacter species,
Timmes [16] 6 5 5
No. of pathogens eradicated/total no. of pathogens (%) 58/66 21/24 24/25 15/20 64/73 10/13
(88) (88) (96) (75) (88) (77)
Klebsiella species, and Citrobacter species.
t Acquired resistance was noted for one isolate.
Table 3. Bacteriologic efficacy of ticarcillin-clavulanate as therapy for 215 infections of skin structures included for evaluation in all clinical trials preceding release of the combination. No. of indicated strain eradicated/ no. of evaluable strains All strains
Pathogen S. aureus S. epidermidis Enterococcus species Streptococcus pyogenes Streptococcus species Escherichia coli Klebsiella species Proteus species Enterobacter species Citrobacter species Serratia marcescens
Other Enterobacteriaceae P. aeruginosa Other aerobes Anaerobes Total NOTE.
91/104 27/31 27/33 41/41 28/30 20/21 12/12 29/31 19/20 5/6 3/3 10/11 17/20 21/22 25/25 375/410 (91.5%)
Data supplied by Beecham Laboratories.
Ticarcillinresistant strains 69/78 13/16 1/1 2/2 3/3 7/7 2/2 2/3 1/1
1/1 4/4 105/118 (89.0%)
Table 4. Efficacy of ticarcillin-clavulanate therapy for monomicrobial skin infections due to S. aureus in multicenter trials preceding release of the combination. Characteristic
Value
No. of patients Mean age (y) Diagnosis (no. of patients) Cellulitis Abscess Other Underlying condition (no. of patients) Diabetes Drug use Malignancy Surgical wound Mean days of therapy Response (no. of patients [%]) Satisfactory clinical Satisfactory bacteriologic
43 45 22 11 10 9
5 4
5 11 41 (95)* 39 (91)t
NOTE. Data supplied by Beecham Laboratories. * Cure, 36 patients; improvement, five patients. t Eradication, 36 patients; effective (bacteriologic reduction to colonization), three patients.
Table 5. Ticarcillin-clavulanate therapy for diabetic foot infections in multicenter investigations. Results
Characteristic Total no. of evaluable patients Mean age (y) Clinical response (no. of patients) Cure Improvement Failure Bacteriological response (no. of pathogens eradicated/total no. of pathogens) S. aureus ~-Hemolytic streptococci Coagulase-negative staphylococci Enterococcus species Enterobacteriaceae P. aeruginosa Anaerobes Other pathogens Total NOTE.
17 (nine males) 59 (27-83) 8 8 1
6/9 3/3 6/7 2/5
16/17 3/5 6/6 2/2 44/54 (81 %)
Data are from Tan et al. [15] and from Beecham Laboratories.
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43 cases; three additional cases were classified as "effective" because the number of organisms was reduced to a few colonies in clinically cured infections. These organisms were considered by the investigator to represent colonization. No large controlled trials of ticarcillin-clavulanate as monotherapy for mixed necrotizing infections have been done. However, data for 17patients with diabetic foot infections who were treated with ticarcillin-clavulanate as monotherapy in controlled trials are tabulated in table 5. Cases include nine from our own experience and an additional eight that were on file at Beecham Laboratories (data supplied by G. W. Reedy). Thirteen infections were polymicrobial, and an average of 3.8 pathogens were isolated per infection. The mean duration of therapy for all 17 patients was 12 days. Eight of the infections were considered to be cured, and eight were improved (defined as substantial diminution in the severity
S736
File and Thn
References
1. Finch R. Skin and soft-tissue infections. Lancet 1988;1:164-7 2. Swartz MN. Cellulitis andsuperficialinfections. In: Mandell GL, Douglas RG, Bennett IE, eds. Principles and practice of infectious diseases. 2nd ed, New York: John Wiley and Sons, 1985:598-609 3. Sapico FL, Canawati HN, Witte JL, Montogomerie JZ, Wagner FW Jr, Bessman AN. Quantitative aerobic and anaerobic bacteriology of infected diabetic feet. J Clin Microbiol 1980;12:413-20 4. Lee P-C, Turnidge J, McDonald PJ. Fine-needle aspiration biopsy in diagnosis of soft tissue infections. J Clin Microbiol 1985;22:80-3 5. Wheat U, Allen SD, Henry M, Kernek CB, Siders JA, Kuebler T, Fineberg N, Norton J. Diabetic foot infections: bacteriologic analysis. 'Arch Intern Med 1986;146:1935--40 6, Neu HC, ed. Beta-lactamaseinhibition: therapeutic advances, Am J Med 1985;75(Suppl 5B):1-195 7. Cuchural GJ Jr, Thlly FP, Jacobus NV, Aldridge K, Cleary T, Finegold SM, Hill G, Iannini P, O'Keefe JP, Pierson C, Crook D, Russo T, Hecht D. Susceptibility of the Bacteroidesfragilis group in the United States: analysis by site of isolation. Antimicrob Agents Chemother 1988;32:717-22 8. Pulverer G, Peters G, Kunstmann G. In-vitro activity ofticarcillin with and without clavulanic acid against clinical isolates of gram-positive and gram-negative bacteria. J Antimicrob Chemother 1986;17(Suppl C):1-5 9. Bennett S, Wise R, Weston D, Dent 1. Pharmacokinetics and tissue penetration of ticarcillin combined with clavulanic acid. Antimicrob Agents Chemother 1983;23:831-4 10. Walstad RA, HelIum KB, Thurmann-Nielsen E, Dale LG. Pharmacokinetics and tissue penetration of timentin: a simultaneous study of serum, urine, lymph, suction blister and subcutaneous thread fluid. J Antimicrob Chemother 1986;17(Suppl C):71-SO 11. Boon RJ, Beale AS, SutherlandR. Bactericidal effects ticarcillin-davulanic acid against ~-lactamase-producing bacteria in vivo.AntimicrobAgents Chemother 1986;29:838-44 12. Pankey GA, Katner HP, Valainis GT, Clarkson MJ, Cortez LM, Dalovisio JR. Overview of bacterial infections of the skin and soft tissue and clinical experience with ticarcillin plus clavulanate potassium in their treatment. Am J Med 1985;79(Suppl 5B):I06-15 13. LeFrock JL, Johnson ES, Smith LG, Rosenberg E. Noncomparative trial of ticarcillin plus clavulanic acid in skin and soft tissue infections. Am J Med 1985;79(Suppl 5B):122-5 14. Rao B, See RC, Chuah SK, Bansal MB, Lou MA, Thadepalli H. Ticarcillin plus clavulanic acid versus moxalaetam in the treatment of skin and soft tissue infections. Am J Med 1985;79(Suppl 5B):126-9 15. ThoJS, File TM, Salstrom S-1. Timentin versus moxalactam in the treatment of skin and soft tissue infections. Am J Med 1985;79(Suppl 5B):13Q-3 16. Timmes J1. Comparative study of ticarcillin plus clavulanate potassium and moxalactam in the treatment of surgical infections of the soft tissue. Am J Med 1985;79(Suppl 5B):134-5 17. Johnson CC, Reinhardt 1F, \¥cillaceSL, Terpenning MS, Helsel CL, Mulligan ME, Finegold SM, George WL. Safety and efficacy of ticarcillin plus clavulanic acid in the treatment of infections of soft tissue, bone, and joint. Am J Med 1985;79(Suppl 5B):136--40 18. Croydon EAP, Hermoso C. An evaluation of the safety and tolerance of Timentin, J Antimicrob Chemother 1986;17(Suppl C):233--4O 19. Calandra G, Ricci F, Wang C, Brown K. Cross-resistance and imipenem [letter]. Lancet 1986;2:340-1 20. Calandra GB, Gaupp W, Brown KR. Imipenem/cilastatin treatment of lower extremity skin and soft tissue infections in diabetics. Scand J Infect Dis Suppl 1987;52:15-9
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of presenting signsand symptoms) at the end of therapy. The rate of satisfactory clinical response was94 %. Of 54 pretherapy pathogens, 44 (81%) were eradicated. These pathogens included S. aureus, {j-hemolytic streptococci,coagulase-negativestaphylococci, Enterococcus species, Enterobacteriaceae, P. aeruginosa, anaerobes, and other pathogens. The single patient in whom treatment failed had very poor vascularity in the infected foot, which had cutaneous evidence of gangrenous tissue and required amputation. It is difficult to compare various antibioticregimens in the therapy for diabeticfoot infections since the response of such infections is dependent on factors such as the status of vascularity, presenceof gangrene, adequate surgical debridement, control of the levelof blood sugar, and presence of underlying osteomyelitis. Nevertheless, it is of interest to compare the results with ticarcillin-clavulanate with those recently reported for imipenem-eilastatinin the treatment of skin and soft tissue infections of the lower extremities in diabetics. Calandra et al. [20] reviewed 94 cases of evaluable skin and soft tissue infectionsof the lower extremities in diabetic patients treated in the United States with imipenem-cilastatin and for which the data were in the files of Merck Sharp & Dohme's Research Laboratory (West Point, PA) by August 1986. Seventy-two patientshad footinfections. More thanonehalf of these patients failed to respond to previous antibiotic therapy. The mean duration of therapy with imipenem-cilastatin was 14days, and most patientsweretreated with 2 glday. The clinicaland bacteriologicoutcomesof these studies were similar to those for ticarcillin-elavulanate. Calandra et al. reported satisfactory clinical results in 92 % of the patients (47% cure and 45% improvement) and eradication of 79% of the pathogens. All eight clinical failures occurred in patients who either required amputation or for whom amputation was predicted at the time of clinical evaluation. In summary, the results of available clinical trials suggest that ticarcillin-clavulanate is effective antimicrobial therapy for skin infections. The broad-spectrum coverage of the combination, whichincludes Staphylococcus species (methicillinsensitive), gram-negative bacilli(including Enterobacteriaceae and Pseudomonas) and anaerobes, makes this an ideal empiric agent for postoperative wound infections, bite-wound infections, and mixed aerobic/anaerobic necrotizing skin infections. The real utility of a broad-spectrum antimicrobial agentsuchas ticarcillin-elavulanate can be basedon its efficacy in the therapy for difficult-to-treatsevere infections, such as secondarily infected diabetic footulcers and other necrotizing infections.Clinical experience in this area, as well as further controlledstudies, will providebetter information concerning the use of this agent in patients with such infections.
RID 1991;13 (Suppl 9)
TIcarcillin-Clavulanate Therapy for Bacterial Skin and Soft TIssue Infections Thomas M. File, Jr., and James
s. Tan
From the Service of Infectious Disease, Akron City Hospital, Akron; and the Section of Infectious Disease, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio
Skin and soft tissue infections are commonly encountered in clinical practice. Bacterial infections of the skin range from mild pyodermas to life-threatening necrotizing infections [1, 2]. In clinical practice, most skin infections are diagnosed and treated clinically without the benefit of microbiologic confirmation. This practice is cost-effective since, with a few exceptions, pyodermas are due to Staphylococcus aureus or t3-hemolytic streptococci and are therefore responsive to t3-lactamase-resistant penicillins, first-generation cephalosporins, clindamycin, and erythromycin. Large skin lesions generally are aspirated or drained by incision. However, in patients with chronic indolent infection, skin ulcers of the extremities or other pressure-induced infections, infections following surgery or trauma, and histotoxic necrotizing infection, the "educated-guess" approach may not be sufficient. A large number of potential pathogens in addition to S. aureus and various species of streptococci may be involved in such infections; these pathogens include Enterobacteriaceae, Pseudomonas species, and anaerobes. These infections are influenced by the local epidemiology (geographic area), previous antimicrobial therapy, previous surgical procedures, type of wound care, and host defense status. Ideally, the provision of optimal antimicrobial therapy requires that an appropriate culture be performed before therapy is initiated. Culture of a specimen from the area of a closed infection such as an abscess is straightforward. Specimens obtained by aspiration or by incision and drainage are acceptable. However, cultures of samples obtained from cutaneous ulcers and open surgical or traumatic wounds, may not represent the true nature of the infection. Sapico et al. [3] and
Reprints and correspondence: Dr. Thomas M. File, Jr., 75 Arch Street, Suite 105, Akron, Ohio 44304. Reviews of Infectious D6eases 1991;13(Suppl 9):S73~ © 1991 by The University of Chicago. AU rights reserved. 0162-Q886/9l/l304-0017$02.00
Lee at al. [4] have shown that the results of cultures of deep tissue specimens obtained by curettage or needle aspiration
achieve a much greater correlation with the true pathogens than do cultures of superficial swab specimens. For patients with diabetic foot infections, Wheat et al. [5] have demonstrated that appropriately obtained specimens often include fewer organisms than do inappropriately obtained specimens and, therefore, permit the use of more specific antimicrobial therapy. This paper presents multicenter experience with ticarcillinclavulanate and summarizes the clinical and microbiologic efficacyof the combination. The data presented are from published clinical trials of ticarcillin-clavulanate as therapy for bacterial skin and soft tissue infections. It must be acknowledged that there are limitations to the comparability of the results of these studies. When an antimicrobial agent is evaluated for its efficacy, the results of treatment are judged by the clinical and microbiologic response. The objective measurement of microbiologic status is difficult for many patients who have an ulcer or open wound because of the poor reliability of the results of initial cultures. Ideally, for open wounds, a deep wound or open wound biopsy specimen should be obtained for culture to avoid contaminated areas. Unfortunately, no standard recommendations of culture have been accepted. In addition, the evaluation of efficacy has to include interventions other than antimicrobial therapy, such as the role of surgery, local wound care, and the status of the host. For most of the studies published, much of this information is lacking.
TIcarcillin-Clavulanate Therapy for Skin and Soft TIssue Infections Ticarcillin-clavulanate is active in vitro against the vast majority of pathogens involved in skin and soft tissue infections [6]. The addition of the {j-lactamase inhibitor clavulanate to ticarcillin expands its activity to include methicillin-sensitive staphylococci and significantly increases its activity against Bacteroidesfragilis and other anaerobes. Studies by Cuchural
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 5, 2015
TIcarcillin-elavulanate is active in vitro against the vast majority of pathogens involved in skin and soft tissue infections. A compilation of six controlled clinical trials of ticarcillin-clavulanate for treatment of skin infections showed a satisfactory clinical response in 175 (93%) of 189cases. The bacteriologic response included eradication of Staphylococcus aureus, Enterococcus species, Enterobacteriaceae, and Pseudomonas aeruginosa in 88%, 75%, 88%, and 77% of cases, respectively. In addition, the records of 17 patients with diabetic foot infections who were treated with ticarcillin-clavulanate as monotherapy in controlled trials are reviewed. Eight of these infections were cured and eight were improved at the end of therapy. The available clinical data suggest that ticarcillin-elavulanate is effective antimicrobial therapy for skin infections.
S734
File and Tan
Table 1. Clinical efficacy of ticarcillin-clavulanate as therapy for skin infections in six clinical trials.
Author [reference]
No. of patients with satisfactory clinical response*/ total no. of patients (%)
Pankey et al. [12]
10/12 (83)
LeFrock et al. [13] Rao et al. [14]
71/76 (93) 30/33 (91)
Tan et al. [15]
17/18 (94)
Timmes [16]
13/14 (93)
Johnson et al. [17] Total
34/36 (94)
Remarks Efficacy of 75 % for eight cefazolin-treated controls Noncomparative Efficacy of 89 % for 36 moxalactam-treated controls Efficacy of 81 % for 16 moxalactam-treated controls Surgical wound infections Efficacy of 80% for 10 moxalactam-treated controls Noncomparative
175/189 (93)
NOTE. Cellulitis, skin abscesses, infected wounds, and ulcer infections of the extremities were treated. The dose was 3.1 g (3 g of ticarcillin and 0.1 g of clavulanate), and the usual dosing interval was every 6 hours (range, 4-8 hours). * Satisfactory clinical response includes cure and improvement.
known if any of these isolates produced the Richmond and Sykes classes I and IV 13 -lactamases that are not inhibited by clavulanic acid [6]. Tan et al. [15] observed one isolate of P. aeruginosa recovered from the site of a diabetic foot infection that persisted despite clinical improvement; the MIC before therapy was 32 ILg/mL, and the MIC at the end oftherapy was >128 ILg/mL. The development of resistance in P. aeruginosa during therapy with other broad-spectrum 13-lactam agents has also been observed [19]. Data are available for 410 pathogens evaluated in 215 infections of skin structures included for evaluation in all clinical trials of ticarcillin-clavulanate preceding its release (data supplied by Beecham Laboratories, Bristol, TN; table 3). Cellulitis, skin abscesses, infected surgical wounds, and other infections were treated. Eradication of 91.5% of all pathogens and of 89 % of ticarcillin-resistant pathogens occurred. Because S. aureus is considered to be the most common pathogen involved in skin infections, it is important to evaluate the efficacy of ticarcillin-clavulanate against this pathogen specifically. Table 4 shows the clinical and bacteriologic results of all cases of monomicrobial skin infections caused by S. aureus that were included in the clinical trials of ticarcillin-clavulanate preceding its release (data supplied by 1.W. Alexander, Beecham Laboratories). A satisfactory clinical response was observed in 95 % of patients and the only clinical failures were due to "failure to surgically drain cutaneous abscesses." Bacteriologic eradication occurred in 36 of
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 5, 2015
et al. [7] have documented in vitro activity of ticarcillinclavulanate against the B. fragilis group of pathogens. The addition of clavulanate to ticarcillin also enhances activity against certain gram-negative pathogens, such as Klebsiella species: Although clavulanate does not inhibit the 13-lactamases found in Pseudomonas aeruginosa, most Enterobacter species, and Citrobacter species, organisms that may be involved in mixed soft tissue infections or postoperative infections, ticarcillin itself is relatively active against these organisms. Ticarcillin has "moderate" (intermediate) activity against most isolates of Enterococcus faecalis (usual MIC, 32-64 ILg/mL) [8]. The addition of clavulanate does not affect the activity ofticarcillin against most isolates of enterococci. However, rare 13-lactamase-producing isolates that would be anticipated to be susceptible to the combination of ticarcillin and clavulanate have been reported. Pharmacokinetic studies evaluating antibiotic levels in thread fluid and blister fluid indicate that they are adequate for the treatment of infections caused by a wide variety of skin pathogens, including S. aureus, Enterobacteriaceae, P. aeruginosa, and other gram-negative aerobic and anaerobic bacteria [9, 10]. Furthermore, experimental animal studies have documented the in vivo bactericidal effectof ticarcillin-clavulanate for soft tissue infections due to staphylococci and Bacteroides species [11]. The efficacy of ticarcillin-clavulanate in the therapy for skin and soft tissue infections has been evaluated in previously published clinical trials. The clinical efficacy of ticarcillinclavulanate in six clinical trials is summarized in table 1 [12-17]. Cellulitis, skin abscesses, infected wounds, and ulcer infections of the extremities were treated. The usual dose ofthe combination used in these studies was 3.1 g (3 g of ticarcillin and 0.1 g of clavulanate), and the usual dosing interval was 6 hours (range, 4-8 hours). The clinical response was satisfactory (cure or significant improvement) in 175 (93 %) of 189 of the cases in a compilation of these clinical trials. Many of these trials were comparative, and in the individual studies, the patients who received ticarcillin-clavulanate responded as well as or slightly better than the treated controls. In most cases the comparative agent was a first-generation cephalosporin (cefazolin) or a third-generation cephalosporin (moxalactam). LeFrock et al. [13] commented that surgical drainage, debridement, and frequent changes of dressing are necessary to achieve good results. In general, ticarcillinclavulanate was well tolerated and exhibited a safety profile similar to that of ticarcillin [18]. The bacteriologic efficacy of ticarcillin-clavulanate in four of these clinical trials for which complete bacteriologic data were available for analysis is included in table 2. The great majority of patients included in these trials had polymicrobial infections. S. aureus, Enterococcus species, Enterobacteriaceae, and P. aeruginosa were eradicated in 88 %, 75 %, 88 %, and 77% of the infections, respectively. LeFrock et al. [13] noted that one isolate each of Enterobacter, Klebsiella, and Citrobacter acquired resistance to the combination. It is not
RID 1991;13 (Suppl 9)
Ticarcillin-Clavulanate for Skin Infections
RID 1991;13 (Suppl 9)
S735
Table 2. Bacteriologic efficacy of ticarcillin-elavulanate as therapy for skin infections in four clinical trials. No. of isolates in indicated study Pankey et al. [12]
Pathogen
7
S. aureus Coagulase-negative staphylococci ~-Hemolytic streptococci Enterococcus species Enterobacteriaceae P. aeruginosa
5 2 1 12 2
LeFrock et al. [13]
Tan et al. [15]
39 7 13 12 52* 6
14 7
5 7 8 5t
* Acquired resistance was noted for one isolate each of Enterobacter species,
Timmes [16] 6 5 5
No. of pathogens eradicated/total no. of pathogens (%) 58/66 21/24 24/25 15/20 64/73 10/13
(88) (88) (96) (75) (88) (77)
Klebsiella species, and Citrobacter species.
t Acquired resistance was noted for one isolate.
Table 3. Bacteriologic efficacy of ticarcillin-clavulanate as therapy for 215 infections of skin structures included for evaluation in all clinical trials preceding release of the combination. No. of indicated strain eradicated/ no. of evaluable strains All strains
Pathogen S. aureus S. epidermidis Enterococcus species Streptococcus pyogenes Streptococcus species Escherichia coli Klebsiella species Proteus species Enterobacter species Citrobacter species Serratia marcescens
Other Enterobacteriaceae P. aeruginosa Other aerobes Anaerobes Total NOTE.
91/104 27/31 27/33 41/41 28/30 20/21 12/12 29/31 19/20 5/6 3/3 10/11 17/20 21/22 25/25 375/410 (91.5%)
Data supplied by Beecham Laboratories.
Ticarcillinresistant strains 69/78 13/16 1/1 2/2 3/3 7/7 2/2 2/3 1/1
1/1 4/4 105/118 (89.0%)
Table 4. Efficacy of ticarcillin-clavulanate therapy for monomicrobial skin infections due to S. aureus in multicenter trials preceding release of the combination. Characteristic
Value
No. of patients Mean age (y) Diagnosis (no. of patients) Cellulitis Abscess Other Underlying condition (no. of patients) Diabetes Drug use Malignancy Surgical wound Mean days of therapy Response (no. of patients [%]) Satisfactory clinical Satisfactory bacteriologic
43 45 22 11 10 9
5 4
5 11 41 (95)* 39 (91)t
NOTE. Data supplied by Beecham Laboratories. * Cure, 36 patients; improvement, five patients. t Eradication, 36 patients; effective (bacteriologic reduction to colonization), three patients.
Table 5. Ticarcillin-clavulanate therapy for diabetic foot infections in multicenter investigations. Results
Characteristic Total no. of evaluable patients Mean age (y) Clinical response (no. of patients) Cure Improvement Failure Bacteriological response (no. of pathogens eradicated/total no. of pathogens) S. aureus ~-Hemolytic streptococci Coagulase-negative staphylococci Enterococcus species Enterobacteriaceae P. aeruginosa Anaerobes Other pathogens Total NOTE.
17 (nine males) 59 (27-83) 8 8 1
6/9 3/3 6/7 2/5
16/17 3/5 6/6 2/2 44/54 (81 %)
Data are from Tan et al. [15] and from Beecham Laboratories.
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43 cases; three additional cases were classified as "effective" because the number of organisms was reduced to a few colonies in clinically cured infections. These organisms were considered by the investigator to represent colonization. No large controlled trials of ticarcillin-clavulanate as monotherapy for mixed necrotizing infections have been done. However, data for 17patients with diabetic foot infections who were treated with ticarcillin-clavulanate as monotherapy in controlled trials are tabulated in table 5. Cases include nine from our own experience and an additional eight that were on file at Beecham Laboratories (data supplied by G. W. Reedy). Thirteen infections were polymicrobial, and an average of 3.8 pathogens were isolated per infection. The mean duration of therapy for all 17 patients was 12 days. Eight of the infections were considered to be cured, and eight were improved (defined as substantial diminution in the severity
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References
1. Finch R. Skin and soft-tissue infections. Lancet 1988;1:164-7 2. Swartz MN. Cellulitis andsuperficialinfections. In: Mandell GL, Douglas RG, Bennett IE, eds. Principles and practice of infectious diseases. 2nd ed, New York: John Wiley and Sons, 1985:598-609 3. Sapico FL, Canawati HN, Witte JL, Montogomerie JZ, Wagner FW Jr, Bessman AN. Quantitative aerobic and anaerobic bacteriology of infected diabetic feet. J Clin Microbiol 1980;12:413-20 4. Lee P-C, Turnidge J, McDonald PJ. Fine-needle aspiration biopsy in diagnosis of soft tissue infections. J Clin Microbiol 1985;22:80-3 5. Wheat U, Allen SD, Henry M, Kernek CB, Siders JA, Kuebler T, Fineberg N, Norton J. Diabetic foot infections: bacteriologic analysis. 'Arch Intern Med 1986;146:1935--40 6, Neu HC, ed. Beta-lactamaseinhibition: therapeutic advances, Am J Med 1985;75(Suppl 5B):1-195 7. Cuchural GJ Jr, Thlly FP, Jacobus NV, Aldridge K, Cleary T, Finegold SM, Hill G, Iannini P, O'Keefe JP, Pierson C, Crook D, Russo T, Hecht D. Susceptibility of the Bacteroidesfragilis group in the United States: analysis by site of isolation. Antimicrob Agents Chemother 1988;32:717-22 8. Pulverer G, Peters G, Kunstmann G. In-vitro activity ofticarcillin with and without clavulanic acid against clinical isolates of gram-positive and gram-negative bacteria. J Antimicrob Chemother 1986;17(Suppl C):1-5 9. Bennett S, Wise R, Weston D, Dent 1. Pharmacokinetics and tissue penetration of ticarcillin combined with clavulanic acid. Antimicrob Agents Chemother 1983;23:831-4 10. Walstad RA, HelIum KB, Thurmann-Nielsen E, Dale LG. Pharmacokinetics and tissue penetration of timentin: a simultaneous study of serum, urine, lymph, suction blister and subcutaneous thread fluid. J Antimicrob Chemother 1986;17(Suppl C):71-SO 11. Boon RJ, Beale AS, SutherlandR. Bactericidal effects ticarcillin-davulanic acid against ~-lactamase-producing bacteria in vivo.AntimicrobAgents Chemother 1986;29:838-44 12. Pankey GA, Katner HP, Valainis GT, Clarkson MJ, Cortez LM, Dalovisio JR. Overview of bacterial infections of the skin and soft tissue and clinical experience with ticarcillin plus clavulanate potassium in their treatment. Am J Med 1985;79(Suppl 5B):I06-15 13. LeFrock JL, Johnson ES, Smith LG, Rosenberg E. Noncomparative trial of ticarcillin plus clavulanic acid in skin and soft tissue infections. Am J Med 1985;79(Suppl 5B):122-5 14. Rao B, See RC, Chuah SK, Bansal MB, Lou MA, Thadepalli H. Ticarcillin plus clavulanic acid versus moxalaetam in the treatment of skin and soft tissue infections. Am J Med 1985;79(Suppl 5B):126-9 15. ThoJS, File TM, Salstrom S-1. Timentin versus moxalactam in the treatment of skin and soft tissue infections. Am J Med 1985;79(Suppl 5B):13Q-3 16. Timmes J1. Comparative study of ticarcillin plus clavulanate potassium and moxalactam in the treatment of surgical infections of the soft tissue. Am J Med 1985;79(Suppl 5B):134-5 17. Johnson CC, Reinhardt 1F, \¥cillaceSL, Terpenning MS, Helsel CL, Mulligan ME, Finegold SM, George WL. Safety and efficacy of ticarcillin plus clavulanic acid in the treatment of infections of soft tissue, bone, and joint. Am J Med 1985;79(Suppl 5B):136--40 18. Croydon EAP, Hermoso C. An evaluation of the safety and tolerance of Timentin, J Antimicrob Chemother 1986;17(Suppl C):233--4O 19. Calandra G, Ricci F, Wang C, Brown K. Cross-resistance and imipenem [letter]. Lancet 1986;2:340-1 20. Calandra GB, Gaupp W, Brown KR. Imipenem/cilastatin treatment of lower extremity skin and soft tissue infections in diabetics. Scand J Infect Dis Suppl 1987;52:15-9
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of presenting signsand symptoms) at the end of therapy. The rate of satisfactory clinical response was94 %. Of 54 pretherapy pathogens, 44 (81%) were eradicated. These pathogens included S. aureus, {j-hemolytic streptococci,coagulase-negativestaphylococci, Enterococcus species, Enterobacteriaceae, P. aeruginosa, anaerobes, and other pathogens. The single patient in whom treatment failed had very poor vascularity in the infected foot, which had cutaneous evidence of gangrenous tissue and required amputation. It is difficult to compare various antibioticregimens in the therapy for diabeticfoot infections since the response of such infections is dependent on factors such as the status of vascularity, presenceof gangrene, adequate surgical debridement, control of the levelof blood sugar, and presence of underlying osteomyelitis. Nevertheless, it is of interest to compare the results with ticarcillin-clavulanate with those recently reported for imipenem-eilastatinin the treatment of skin and soft tissue infections of the lower extremities in diabetics. Calandra et al. [20] reviewed 94 cases of evaluable skin and soft tissue infectionsof the lower extremities in diabetic patients treated in the United States with imipenem-cilastatin and for which the data were in the files of Merck Sharp & Dohme's Research Laboratory (West Point, PA) by August 1986. Seventy-two patientshad footinfections. More thanonehalf of these patients failed to respond to previous antibiotic therapy. The mean duration of therapy with imipenem-cilastatin was 14days, and most patientsweretreated with 2 glday. The clinicaland bacteriologicoutcomesof these studies were similar to those for ticarcillin-elavulanate. Calandra et al. reported satisfactory clinical results in 92 % of the patients (47% cure and 45% improvement) and eradication of 79% of the pathogens. All eight clinical failures occurred in patients who either required amputation or for whom amputation was predicted at the time of clinical evaluation. In summary, the results of available clinical trials suggest that ticarcillin-clavulanate is effective antimicrobial therapy for skin infections. The broad-spectrum coverage of the combination, whichincludes Staphylococcus species (methicillinsensitive), gram-negative bacilli(including Enterobacteriaceae and Pseudomonas) and anaerobes, makes this an ideal empiric agent for postoperative wound infections, bite-wound infections, and mixed aerobic/anaerobic necrotizing skin infections. The real utility of a broad-spectrum antimicrobial agentsuchas ticarcillin-elavulanate can be basedon its efficacy in the therapy for difficult-to-treatsevere infections, such as secondarily infected diabetic footulcers and other necrotizing infections.Clinical experience in this area, as well as further controlledstudies, will providebetter information concerning the use of this agent in patients with such infections.
RID 1991;13 (Suppl 9)
