Retro-respective Evaluation of New Fixed Dose Combination of Antibiotics in Management of Severe Skin and Soft Tissue Infections – A Comparative Pharmacoeconomic Study

Study Background: Skin and soft tissue infections (SSTIs) are the second most common infection encountered in hospitals. Present study aims to comparatively analyze efficacy of new fixed dose combination (FDC) with teicoplanin case or need of concomitant therapy to treat sepsis. Overall cost involved in the infections management was estimated in INR. Results: A total of 314 confirmed SSTI cases out of 538 patients who met other study entrance criteria were further analyzed. Out of these 314 patients, empirical treatment with teicoplanin was received by 186 patients and 128 patients were treated with FDC empirically. Amidst all the patients, 132 (70.96%) of 186 from teicoplanin group and 102 (79.68%) of 128 from FDC group achieved clinical success. 26 / 128 (in FDC group) and 54 /186 (in Teicoplanin group) patients whose MIC falls in intermediate range failed to respond and tigecycline was added to ongoing therapy. Comparative cost expenditure analysis of the two drug treatment groups revealed that, the overall treatment cost for patients cured with empirical teicoplanin group was 92.83% more than that of FDC therapy. The strongest predictor of the increase in treatment costs was clinical failure. Similar trends were maintained for the patients cured with tigecycline additional therapy, with teicoplanin group accounting 56.63% more expenditure than FDC group. Conclusion: For the treatment of different types of SSTIs, the empirical intravenous FDC therapy was safe, well tolerated with higher efficacy including in infections caused by multidrug resistant strains (VRSA and GISA) than teicoplanin. Pharmacoeconomic analysis clearly shows that starting appropriate empirical antibiotic therapy has a large impact on the cost of treatment in management of SSTIs and preferring FDC empirically both as mono/combination therapy, can significantly reduce the cost involved in the treatment. Empirical use of FDC followed by correlating it with MIC values can prevent failure and SSTI turning in sepsis.


INTRODUCTION
Skin and soft tissue infections (SSTIs) can be defined as a suppurative microbial invasion of the epidermis and subcutaneous tissues that induce either a local or systemic host response. SSTIs are characterized by induration, erythema, warmth and pain or tenderness [1]. SSTIs have been classified as complicated or uncomplicated [2], with a range of severity from simple subcutaneous abscesses to severe necrotizing infections.
Uncomplicated infections are superficial, often self-limiting, and can usually be treated successfully by incision and drainage alone or in combination with oral antibiotics [3]. The complicated SSTIs (cSSTIs) extend to subcutaneous tissue, fascia, or muscle [4] and require complex treatment, combining careful selection of antimicrobials with expeditious surgical intervention. The main etiological agents implicated in SSTIs are the Gram-positive organisms, Staphylococcus aureus (S. aureus), and the beta-hemolytic streptococci (Groups A, B, C and G). Methicillin-resistant S. aureus (MRSA) infections have risen in prominence over the last 20 years, comprising 59% of S. aureus isolates in a recent study in the USA [5] and > 10% of isolates in 19 out of the 28 countries in the 2009 European Antimicrobial Resistance Survey [6].
Cellulitis is an acute, spreading, pyogenic inflammation of the lower dermis and associated subcutaneous tissue. It is a skin and soft tissue infection that results in high morbidity and severe financial costs to health-care providers worldwide [7].
Myositis or Idiopathic inflammatory myopathies are an important type of SSTIs present with muscle weakness [8]. Necrotizing myopathy (NM) has a multifactorial etiology; it may have an acute or subacute onset, can be severe, may have a seasonal variation or cancer association, and may be triggered by statins [9]. Necrotizing fasciitis (NF) is relatively uncommon, but life-threatening type of SSTIs, which tend to progress rapidly through the fascia planes, causing gradual destruction of the fascia at a rate reaching 2-3 cm/h. The infection progresses rapidly, and septic shock may ensue; hence, the mortality rate is high (median mortality 32.2%) [10]. Glycopeptides including teicoplanin and Vancomycin remains the most frequently prescribed treatment options for severe SSTIs especially for serious MRSA infections and are now the second most common antibiotic group used in hospitals to treat cephalosporin resistant gram positive infections [11]. Unfortunately, the cure rate for glycopeptides has been disappointing [12][13][14] with high mortality rates [12].
However, comparatively decreased mortality cases were reported by Wunderink et al. [15] in a clinical trial study and attributed the decreased mortality rates to the optimized glycopeptide dosing and overall improvement in the quality of care in patients with MRSA infections. The decreased cure rates with glycopeptides may be due to any previously reported reasons [16][17][18][19][20], which can limit the usefulness of teicoplanin/vancomycin mono therapy. All these aspects accentuates the need for new antibiotics. A new FDC of ceftriaxone + vancomycin + adjuvant (Vancoplus) is increasingly being used in Indian hospitals. Various reports of the in-vitro susceptibility studies [21][22][23][24][25] hints the possibility of this new FDC to overcome the hurdles of infections caused by MRSA, GISA and GRSA strains clinically. If effective in-vivo clinical success is achieved by this new FDC, it can be a potent alternative to mono therapy of either teicoplanin/vancomycin to treat infections caused by these multi-drug resistant strains. Therefore, current study was planned with objective to analyze if MIC correlates with clinical success and can empiric right choice of therapy prevent SSTI turning into sepsis. Further, the study also retrospectively evaluated cost of two therapies and cost driving factors.

Study Design Overview
The present study was a retrospective, observational analysis of the data collected from different tertiary care hospitals for the patients treated between March 2009 and August 2012. This study was carried out in accordance with the ethical principles of the Declaration of Helsinki and to the current norm for observational studies. Due to the retrospective nature of the design, informed consent was not taken.

Patient Selection
The patients were selected by going through their case history sheets of the hospitals. Hospitalized adult patients aged above 18 years, who were admitted between March 2009 and August 2012 were considered for the study. The other criteria for patients inclusion were; 1) patients with the primary diagnosis of SSTIs based on the clinical investigations and relevant signs and symptoms, 2) patients with identified baseline / super infection culture 3) patients in whom either FDC or teicoplanin were used at least for a period of >3 days 4) patients in whom adequate doses of the above said drugs were used and 5) patients who were hospitalized for more than 5 days.

Patient Analysis
Case history sheets of all the patients were reviewed and relevant information like patient age, gender, co-morbidities, culture identification tests, MIC values, antibiotic therapy, dose and duration, considering additional cover, the reasons for the additional cover and length of the hospital stay were recorded. Among all the case sheets analyzed, 314 patients which were given either FDC or teicoplanin and fulfilled the other above mentioned inclusion criteria were included for the analysis. The FDC dose used in the therapy was 3 g / 12 hrs, whereas for teicoplanin, an initial 3 loading doses of 400 mg / 12 hrs followed a maintenance dose of 400 mg every day. For tigecycline (used as additional cover), an initial loading dose of 100 mg was used followed by 50 mg / 12 hrs were used ( Fig. 1).

Initial Antibiotic Treatment and Outcomes
For better presentation and easy understanding, the patients analyzed retrospectively were broadly divided in to two groups; FDC grouppatients [128 (40.74%)] to whom FDC was administered empirically and Teicoplanin grouppatients [186 (59.24%)] which were on empirical teicoplanin therapy. The progress of the therapy was measured in terms of clinical improvement in signs and symptoms. After the initial microbiological assessment (after 3 days) and clinical progress (signs of improvement), the decision on whether to consider tigecycline additional cover was taken. The patients from both the groups, showing improvement with the empirical therapy were continued with the same regime and the patients with intermediate susceptibility and who failed to show significant clinical improvement (deteriorated) with mono therapy were given an additional cover of tigecycline.

Patient Evaluations and Definitions
All the patients enrolled into the study were thoroughly evaluated by examining the systemic signs of infection such as temperature >38°C, tachycardia (heart rate >90 beats per minute), tachypnea (respiratory rate >24 breaths per minute) or abnormal white blood cell count (>12 000 or <400 cells / µL), culture and sensitivity reports from the specimen sampled from the affected site, hematology and biochemistry including the levels of albumin, C-reactive protein (CRP), creatinine, alanine aminotransferase, hemoglobin, the leukocytes count, the platelet count and other relevant investigations on case to case basis. All the evaluations were done to derive a co-relation of lab results with clinical parameters. The lab parameters were also evaluated to rule out nephro-toxicity during course of treatment. Minimum inhibitory concentrations (MICs) of antibiotics for clinical isolates were determined by micro-broth dilution method according to the Clinical and Laboratory Standards Institute (CLSI). The assessment of microbiological response at patient level was based on the results of susceptibilities of the isolated pathogens and clinical outcome of the patients.

Clinical success
The patient's response was considered as clinical success when, the patient recovered with either first line empiric antibiotic therapy or a step down from the initial therapy.

Clinical failure
An individual case was defined as clinical failure when either the treatment was given an additional cover or when the death of patients occurred.

First line / empiric antibiotic therapy
It is defined as the regime started at the beginning before the availability of any culture data.

Second-line antibiotic therapy
It is defined as the addition of one or more antibiotics to the initial regime or as a complete or partial shift of the initial antibiotic with another parenteral antibiotic regime.

Susceptible
A MIC of ≤ 2 mg/L for teicoplanin and ≤ 8 mg/L for FDC was defined as susceptible.

Antibiotic Therapy Cost Analysis
An assessment of the direct cost of antibiotics was performed by multiplying the number of days of antibiotic therapy by the unit price of respective individual antibiotic and by the number doses per day, whereas the overall cost of antibiotic treatment for each patient was the sum of costs calculated for all parenteral antibiotics received by the patient during the hospitalization period. The unit price of antibiotics was based on maximum retail price (MRP) per unit of antibiotics. Hospitalization charges, laboratory tests, instrumental charges and overhead charges were calculated based on the average rate card of different hospitals in the vicinity. Costs incurred towards prior treatment procedures carried out and prior antibiotic therapies used before FDC and teicoplanin treatment were not included in analysis, as we assume they were independent of the adopted antibiotic therapy. Costs were expressed in Indian rupees (INR).

Patients and Demographic Characteristics
During the study period 538 patients were admitted out of which 314 patients were confirmed with SSTIs who met other study entrance criteria were further analyzed (Fig. 1). The baseline and demographic characteristics of the patients which were given either FDC (n=128) or teicoplanin (n=186) empirically are given in Table 1. Most of the baseline characteristics among the patients from both the groups were comparable. Male population was more when compared to their counter parts in both the groups with male: female ratio of 79:49 and 109:77 for FDC and teicoplanin groups respectively. The mean age of patients in FDC was 62.56 ± 11.54 and the same in patients belonging to teicoplanin group was 61.00 ± 10.05. The analysis of the disease severity data measured in terms of APACHE II score reveals that irrespective of the groups, majority of patients were having a score of <15. 86 (67.18%) out of 128 patients from FDC group were having APACHE II score of <15, whereas 123 (66.12%) patient out of 186 from teicoplanin group were having the severity score of <15. Among different types of SSTIs, there were 163 cases of cellulites (69 in FDC; 94 in teicoplanin group), 89 cases of myositis (38 in FDC; 51 in teicoplanin group) acardiovascular diseases nd 62 cases of necrotizing fasciitis (21 in FDC; 41 in teicoplanin group). Diabetes mellitus was the most common co-morbidity observed in patients from both the groups (49 in FDC; 76 in teicoplanin group) followed by chronic obstructive pulmonary disease (COPD) (31 in FDC; 41 in teicoplanin group), (24 in FDC; 31 in teicoplanin group), cirrhosis (25 in FDC; 24 in teicoplanin group), cancer (14 in FDC; 26 in teicoplanin group), chronic kidney disease (CKD) (12 in FDC; 20 in teicoplanin group) and least number of cases were observed with cerebrovascular diseases (08 in FDC; 09 in teicoplanin group) ( Table 1).

Clinical Response
Overall clinical response along with success among the subgroups is depicted in Table 2. Statistically significant difference was observed in overall clinical response among FDC and teicoplanin groups. Empirical FDC treatment with successful clinical response was observed in 102 (79.686%) patients out of 128 patients from FDC group. The mean treatment duration among these 102 patients was 7.64 days ± 0.69 (SD). For the remaining 26 patients, tigecycline additional cover was given to which 22 patients responded positively. The mean treatment duration for the 26 patients with tigecycline cover was 9.88 days ± 0.71 (SD). On the other hand, 132 patients out of 186 who were on teicoplanin empirically achieved clinical success with mean treatment duration 13.69 days ± 1.69 (SD). Out of the remaining 54 patients who were given tigecycline additional cover, only 37 patients achieved clinical success. The mean treatment duration for the 54 failure patients from teicoplanin group was 14.18 days ± 1.45 (SD).
Clinical response among the subgroups is depicted in Table 2. The clinical response in all the sub groups followed a similar pattern as that of a overall clinical response. Both the groups had lower cure rates in patients with higher APACHE II scores (FDC -73.80%; teicoplanin -63.49%) as compared to patients with APACHE II score of <15 (FDC -82.55%; teicoplanin -74.79%). FDC therapy had highest cure rates in cellulites (82.60%) followed by myositis (78.94%) and the least success was observed in necrotizing fasciitis (71.42%). However, teicoplanin had highest cure rates in myositis (72.54%), followed by almost similar cure rates for cellulites (70.21) and necrotizing fasciitis (70.73%). Even though, no noted difference among the groups was observed for S. aureus, Streptococcus pyogens and S. epidermidis caused SSTIs, significant differences were observed with GRSA and GISA caused SSTIs. Teicoplanin therapy failed completely in patients with GRSA and GISA infections where MIC values were ≥2 mcg/ml, where as FDC had a statistically significant higher clinical cure rates among GRSA (P value 0.0082) and GISA (P value 0.0018). SSTIs where MIC value was ≤8 mcg/ml. Co-morbidities did not have any significant difference among the clinical cure rates of both the groups except diabetes mellitus where FDC showed higher clinical efficacy. Clinical success among the FDC group patients with tigecycline additional cover had higher cure rates as compared with that of teicoplanin + tigecycline group. The detailed clinical response in all the subgroups with tigecycline additional cover is given in Table 2.

Antibiotic Therapy Cost Analysis
The cost expenditure for the patients considered in the study is depicted in

DISCUSSION
Skin and soft-tissue infections (SSTIs) encompass a broad set of conditions encountered frequently in clinical practice [3]. Among Gram positive pathogens, S. aureus continues to cause SSTIs in the community as well as invasive infections in the hospitalized patients [26]. Because many episodes of SSTIs are not cultured, the most common causes of SSTIs in general remain uncertain, although S. aureus and betahemolytic streptococci (BHS) are often suggested as being the most important causes [1,27,28]. In a recent Europe-wide survey, the most common organisms in SSTIs were S. aureus (71% cases) with 22.5 per cent being MRSA [26]. The antibiotic treatment choice for SSTIs mainly depends on clinical presentation of the patients and the type of the pathogens causing the infection. In probable Gram-positive infection where MRSA is suspected, treatment may include b-lactam/glycopeptide combinations, fluoroquinolones with enhanced Gram-positive activity such as moxifloxacin, co-trimoxazole or tigecycline [27,29]. However, the mainstay of treatment for serious MRSA infections has been the glycopeptides vancomycin and teicoplanin [30,31]. The present study comparatively analyzes the case history sheets of 314 patients diagnosed with different SSTIs and treated with either FDC or teicoplanin empirically.

CONCLUSIONS
Empirical intravenous FDC therapy seems to be safe, well tolerated and has higher efficacy than teicoplanin in treatment of different SSTIs caused by Gram positive pathogens, especially infected with hGISA, GRSA and MRSA. This retrospective study also sheds light on pharmaco-economic benefit associated with right empiric choice of antibiotic therapy and its close association with microbiological findings.