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Tigecycline Use in Cancer Patients With Serious Infections

A Report on 110 Cases From a Single Institution

Chemaly, Roy F. MD, MPH; Hanmod, Santosh S. MD; Jiang, Ying MS; Rathod, Dhanesh B. MD; Mulanovich, Victor MD; Adachi, Javier A. MD; Rolston, Kenneth V. MD; Raad, Issam I. MD; Hachem, Ray Y. MD

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doi: 10.1097/MD.0b013e3181af01fc
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Abstract

INTRODUCTION

The management of hospital- and community-acquired bacterial infections is becoming a significant challenge for health care providers. Because of the increased prevalence of multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, and extended-spectrum β-lactamases, which produce carbapenem-resistant Gram-negative organisms, it is challenging to choose the appropriate empiric antimicrobial therapy.4,16,41,44 Increased morbidity and mortality, hospital length of stay, and medical care costs are all associated with multidrug-resistant organisms.33 Delay of appropriate empiric antimicrobial therapy is known to increase morbidity and mortality among affected patients,1,10,18,27,31 and inadequate therapy has been found to be associated with excess mortality and increased duration of hospitalization.15,17,36,37

There is a high rate of resistance to commonly used antimicrobial agents, including β-lactams (penicillins and cephalosporins), fluoroquinolones, macrolides, and glycopeptides, which may reduce the effectiveness of these drugs.41,44 Antibiotic stewardship programs have been successful not only in limiting resistance, but also in minimizing several other unintended consequences of antimicrobial agent use, including toxicity, the selection (emergence) of some pathogenic organisms (such as Clostridium difficile), and health care costs, without adversely affecting quality of care.9 Linezolid, quinupristin-dalfopristin, and daptomycin have provided additional treatment options for infections due to resistant Gram-positive organisms.29 However, severe myalgia and arthralgia, myelosuppression, and thrombocytopenia may limit the usefulness of these drugs.2,20,25,30 Furthermore, emerging resistance has been documented for these agents; thus, options for treating these infections are limited.16,34

Tigecycline is a glycylcycline that has come into clinical use at a critical time and appears to be a welcome asset to the current armamentarium. Derived from minocycline, glycylcyclines share a binding site on the 30S ribosomal subunit with tetracyclines.43 They also bind to a region of the A site that is unique to glycylcyclines and prevents the elongation of peptide chains by blocking the entry of new amino acyl transfer RNA.41 Glycylcyclines bind to ribosomes 5 times more strongly than do tetracyclines, and they have structural modifications at the C-9 position of minocycline.6,29,44 This distinct mechanism of action probably overcomes the common resistance mechanisms described for tetracyclines, which are mainly ribosomal protection and efflux.4,16,41

Several in vitro studies have shown that tigecycline is effective against a wide range of bacteria. Tigecycline has been found to be active, with high potency, against many Gram-positive cocci, including Staph. aureus irrespective of methicillin susceptibility; coagulase-negative staphylococci; vancomycin-resistant staphylococci and enterococci; penicillin-resistant Streptococcus pneumoniae; glycopeptides-resistant enterococci; and intracellular bacteria (Mycoplasma species, Chlamydia species, and Legionella species).41,44 Tigecycline's in vitro Gram-negative activity covers Enterobacteriaceae (Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumonia, and Serratia marcescens) including strains that produce extended-spectrum β-lactams (E. coli, K. oxytoca, and K. pneumonia); Haemophilus influenzae; Acinetobacter baumannii; Stenotrophomonas maltophilia; and anaerobes, including most strains of Bacteroides fragilis. However, Pseudomonas aeruginosa, Proteus species, and Providencia species have not been found to be susceptible to tigecycline.16,41 Very few antibiotics available at this time demonstrate such a broad spectrum of activity against multidrug-resistant Gram-positive and Gram-negative organisms.16,19,41

Several studies have shown that tigecycline is effective in the treatment of complicated skin and skin structure and intraabdominal infections,8,11,12 and in June 2005, Tigecycline was approved by the United States Food and Drug Administration (FDA) for intravenous use in the treatment of complicated intraabdominal infections and complicated skin and skin structure infections, including those caused by MRSA.29,38 This was based on a large number of studies involving a large number of patients in Phase II and III studies. More than 1100 subjects were enrolled to study complicated skin and skin structure infections. Tigecycline was found to be effective in 86.5% of the cases compared with 88.6% in the control arm, where subjects received aztreonam and vancomycin. For infections involving MRSA, however, it was found to be effective in 78.4% compared with 76.5%, respectively. For complicated intraabdominal infections, more than 1600 subjects were enrolled, and the efficacy rate for tigecycline was found to be 86.1% compared with 86.2% in the control group, where imipenem-cilastin was used.38 However, tigecycline is being used to treat a range of infections, including infections in sites like the respiratory tract and blood stream, when multidrug-resistant organisms are encountered or suspected, despite the paucity of efficacy data outside its approved indications. Authors of a 2008 study3 evaluated the role of tigecycline for treatment of infections due to multidrug-resistant Gram-negative organisms and found that pre-treatment minimum inhibitory concentration (MIC) for A. baumannii can be a predictor of clinical outcome of the infection, and 1 isolate became fully resistant to tigecycline during therapy. Furthermore, few patients had persistent bacteremia with A. baumannii, E. coli, and K. pneumoniae despite continuous treatment with tigecycline. This raises concerns regarding the use of tigecycline for the treatment of such infections and others that are not included in the FDA official labeling of this drug until more data are available.40

On the other hand, multidrug-resistant Gram-positive organisms like MRSA are known to be an increasingly common cause of nosocomial infections including complicated skin and skin structure infections, intraabdominal infections, and pneumonia. The list of antibiotics ineffective against them continues to expand. This can be attributed to incomplete and improper care of such infections, which leads to an increase in the resistance among them.42 Tigecycline is known to have in vitro activity against Gram-positive organisms including MRSA; however, clinical data are scarce. A 2008 published Phase III trial12 comparing the efficacy and safety of tigecycline to vancomycin in patients with MRSA infections found similar clinical cure rates in both arms; however, most of the enrolled patients infected with MRSA had either complicated skin and skin structure infection or complicated intraabdominal infections. Fifteen patients with vancomycin-resistant enterococci infections were enrolled in the trial to compare tigecycline with linezolid, but no conclusion could be drawn because of the small sample size. Importantly, there were no new safety concerns for tigecycline in the trial.

Data on the effectiveness and safety of tigecycline in immunocompromised patients, particularly in cancer patients, are still lacking. Thus, we report herein our experience with tigecycline in cancer patients with serious infections treated at our institution.

METHODS

In the current retrospective study, we searched the pharmacy database for all consecutive cancer patients who had been treated with tigecycline for more than 48 hours between June 2005 and September 2006 at The University of Texas M. D. Anderson Cancer Center. We collected the following data from the electronic medical records for all patients: demographics; cancer type; hematopoietic stem cell transplantation status; infection risk factors, including diabetes, splenectomy, and use of immunosuppressive therapy such as chemotherapy, radiotherapy, or steroids within 4 weeks before the onset of infection; prior antimicrobial history, including the use of antibacterials and antifungals for more than 72 hours within 4 weeks before the start of tigecycline therapy; and prior infection history within 3 months before tigecycline use. We also collected data on tigecycline use, including source of infection, reason for use, duration of use, and adverse events; and radiographic, pathologic, microbiologic, and antibacterial sensitivity data when available, before and after the start of tigecycline therapy. Data on concurrent treatments with tigecycline (such as concomitant antibacterials and steroids), intensive care unit (ICU) transfers, and ventilator support were recorded. Outcomes were recorded as complete response, partial response, or failure to respond. The cause of death was identified if the patient died during the course of treatment. Each patient was followed up to 60 days from the date of termination of tigecycline therapy. The institutional review board approved a Waiver of Informed Consent and a Waiver of Authorization, because this was a retrospective data review that involved no diagnostic or therapeutic intervention, and no direct patient contact.

Definitions

Neutropenia was defined as an absolute neutrophil count of less than 500 cells per microliter of blood.

Lymphopenia was defined as an absolute lymphocyte count of less than 200 cells per microliter of blood.

An overall complete clinical response was defined as the complete resolution of signs and symptoms and complete radiologic and/or microbiologic recovery at the end of tigecycline therapy. For patients with non-microbiologically documented infections and for patients with infections due to organisms resistant to or known not to respond to tigecycline, like P. aeruginosa, clinical cure was defined as resolution of signs and symptoms of the infection with radiologic response when appropriate.

Failure to respond was defined as no significant change in or progression of clinical signs and symptoms, with no radiologic and/or microbiologic recovery or death due to infection at the end of tigecycline therapy. For patients with non-microbiologically documented infections, failure to respond was defined as progression of clinical signs and symptoms and/or no radiologic response when appropriate, or death during tigecycline therapy.

Statistical Analysis

Categorical variables were compared using the chi-square or Fisher exact test, as appropriate. Continuous variables were compared using t tests or Wilcoxon rank-sum tests. In addition, a survival analysis was performed for certain groups of patients. The Kaplan-Meier approach was used to estimate the overall survival probability for each group, and a log-rank test was used for the comparison. All tests were 2-sided, at a significance level of 0.05. Statistical analyses were performed using SAS software version 9.1 (SAS Institute, Cary, NC).

RESULTS

Patient Characteristics

The current study included 110 patients (70 men and 40 women) (Table 1). The median patient age was 58 years (range, 18-81 yr). Sixty-four patients had hematologic malignancies, and 46 had solid tumors. Twenty-seven of the 64 (42%) patients with hematologic malignancies had undergone hematopoietic stem cell transplantation; 11 of these had acute (5 patients) or chronic (6 patients) graft-versus-host disease. The 4 most common malignancies in patients with solid tumors were gastrointestinal (14 patients), head and neck (9 patients), genitourinary (7 patients), and lung (6 patients). Forty-four (40%) patients had undergone chemotherapy within 1 month of acquiring the infection, and 13 (12%) had received a high dose of steroids. Thirty-one patients (28%) had neutropenia. Sixty-two (56%) were in the ICU at the start of tigecycline therapy; 44 (71%) of these patients had pneumonia. Forty-five (41%) patients required ventilator support. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score before the start of tigecycline therapy was 15 (range, 7-34).

TABLE 1
TABLE 1:
Characteristics of 110 Patients

Tigecycline Use

All patients received an initial loading dose of 100 mg, followed by 50 mg administered intravenously every 12 hours. The underlying infections for which tigecycline was given were pneumonia in 66 patients (microbiologically documented in 22 patients Table 2), bacteremia in 19 patients (Table 3), complicated intraabdominal infections in 9 patients, and complicated skin and skin structure infections in 7 patients; the remaining 9 had fever of undetermined origin (3 patients), gastroenteritis (2 patients), septic shock (2 patients), urinary tract infection (1 patient), or pharyngitis (1 patient). The mean duration of therapy was 11 days (range, 3-35 d). In 106 (96%) patients, tigecycline was given as second-line therapy. Ninety-five (86%) patients were on other antibacterial agents and 55 (50%) were on antifungal agents before starting tigecycline. In 56 (51%) patients, tigecycline was given as empirical therapy for infections that did not respond to other antibiotics; in the remaining patients, therapy was given the following reasons: organisms resistant to other antibiotics in 34 (31%) patients, allergy to other antibiotics (β-lactam, meropenem, metronidazole, or vancomycin) in 13 (12%) patients, thrombocytopenia with linezolid in 2 (2%) patients, leukopenia with vancomycin in 1 (1%) patient, and primary therapy for complicated intraabdominal or wound infections in 4 (4%) patients. Most (107; 97%) patients underwent concurrent antibiotic treatment with tigecycline; 101 (92%) of these patients were on 1 or more antipseudomonal drugs.

TABLE 2
TABLE 2:
Demographics and Clinical Outcomes of 22 Patients With Microbiologically Documented Pneumonia Treated With Tigecycline
TABLE 3
TABLE 3:
Demographics and Clinical Outcomes of 19 Patients With Bacteremia Treated With Tigecycline

Microbiology

Fifty (45%) patients had microbiologically documented infections; the remaining 60 patients had negative cultures at initiation of tigecycline therapy (Table 4). Seventy-three percent of patients with non-microbiologically documented infections had pneumonia. MRSA (5), E. coli (4), and coagulase-negative staphylococci (4) were the most commonly isolated organisms in the 19 patients with bacteremia (Table 5). S. maltophilia and enterococci were the most common organisms (5 each), followed by MRSA (4 cases), in patients with pneumonia. S. maltophilia was the most common organism isolated in patients with complicated skin and skin structure infections and intraabdominal infections (3 of 9). Twelve (11%) patients had an associated P. aeruginosa infection, isolated from the same or a different site of infection.

TABLE 4
TABLE 4:
Infections by Diagnosis and Microbiologic Documentation Status
TABLE 5
TABLE 5:
Isolates of Microbiologically Documented Infections

Safety and Tolerability

Forty-three (39%) patients had been receiving antiemetics before the start of tigecycline therapy. Of the 42 patients who had not been on antiemetics or ventilator support at the start of therapy, 2 (5%) experienced mild nausea, and 1 (2%) experienced nausea and vomiting. Only 4 (4%) of the total 110 patients experienced diarrhea on tigecycline, all of whom were negative for C. difficile toxin in stools.

Clinical Outcome

A complete clinical response was noted in 70 (64%) patients; however, this response rate varied significantly among patient groups (Table 6). A total of 66 patients had pneumonia, 22 (33%) of whom had microbiologically documented infection (Table 2) and the rest were treated empirically. Eight (12%) of the patients had ventilator-associated pneumonia. Clinical response was noted in 33 (51%) of the 65 patients with pneumonia and documented outcomes. Forty-four (67%) patients with pneumonia required ICU admission, and 38 (58%) required ventilator support. Twenty-nine (44%) of the 66 patients with pneumonia died; in most cases the cause of death was multiorgan failure and pneumonia of unknown etiology.

TABLE 6
TABLE 6:
Complete Clinical Response Rates in Patients While on Tigecycline

Fifteen (79%) of the 19 patients with bacteremia had a complete clinical and microbiologic response (Tables 3 and 6), compared with 33 (51%) of the 65 patients with pneumonia and documented outcomes, and 21 (84%) of the 25 patients with other infections (complicated skin and skin structure infections, intraabdominal, fever of undetermined origin, urinary tract infection, gastroenteritis, septicemic shock, and pharyngitis). Patients with pneumonia had a significantly lower clinical response rate compared to patients with other infections (51% vs. 84%; p = 0.0039) and patients with bacteremia (51% vs. 79%; p = 0.029), respectively. Patients with ventilator-associated pneumonia had a 37% response rate (3 of 8); however, this was not statistically different from that of patients with non-ventilator-associated pneumonia. Patients with microbiologically documented infections had a significantly higher clinical response rate than patients with non-microbiologically documented infections (73% vs. 55%; p = 0.047) (Table 6). The clinical outcome of patients with polymicrobial infections was not significantly different from that of patients with monomicrobial infections (78% vs. 71%; p = 0.6). In patients with documented microbiology, a complete clinical response was seen in 80% of the patients (33 of 41) with no associated P. aeruginosa infection. However, in patients with an associated P. aeruginosa infection, 50% (6 of 12) showed clinical response (p = 0.06); although most patients (83% in each group) were on 1 or more antipseudomonal drugs.

No statistically significant difference was found in the clinical outcomes of patients who started tigecycline therapy early (within 48 h of diagnosis of infection) and those who started late (>48 h after diagnosis of infection) (Table 6). Of the 40 patients who did not respond to treatment, 36 died of active infection during or immediately after tigecycline therapy. The cause of death was respiratory or multiorgan failure in 33 patients, (92%); 6 of these patients had an invasive multidrug-resistant P. aeruginosa infection, and 2 had invasive aspergillosis. The remaining 3 patients died of acute myocardial infarction, acute pulmonary embolism, or acute gastrointestinal graft-versus-host disease with active infection. It is noteworthy that of the 12 patients with an associated P. aeruginosa infection, 6 died with the infection as an attributable or contributing cause, compared with 6 of the 42 patients with no associated P. aeruginosa infection (50% vs. 14%; p = 0.016).

Patients with pneumonia had a significantly higher mortality rate compared with patients with bacteremia (44% vs. 16%; p = 0.026) and patients with other infections (44% vs. 16%; p = 0.013), respectively. During the 60 days of follow-up after the date of clinical response, patients with pneumonia had significantly shorter survival durations than patients with other infections (p = 0.008) and patients with bacteremia (p = 0.012) (Figure 1).

FIGURE 1
FIGURE 1:
Kaplan-Meier survival curves of patients with pneumonia, bacteremia, and other infections (p = 0.0024).

DISCUSSION

We studied the safety and effectiveness of tigecycline in a large number of cancer patients. Most of the patients were critically ill, either with progressive or refractory malignancy, requiring ICU care, or with severe neutropenia with high APACHE II scores. In most patients, tigecycline was not given for FDA-approved conditions and indications. The mean clinical response rate was 64%; this rate was higher in patients with bacteremia (79%) and other infections (84%), and lower (51%) in patients with pneumonia. The clinical response rate was higher in patients with microbiologically documented infections (73%) than in those with non-microbiologically documented infections (55%). Associated P. aeruginosa infections also seemed to affect the overall outcome. Patients with associated multidrug-resistant P. aeruginosa infections had lower clinical response rates and higher mortality rates than patients without this infection.

Although limited clinical data on the effectiveness of tigecycline in patients with pneumonia have been published so far, various studies have reported high penetration of tigecycline in lung tissue.8,28,39 In the current study, patients with pneumonia had lower clinical response rates than patients with bacteremia or other infections. This could be explained in part because these patients were sicker, requiring ICU care (67%) and/or ventilator support (58%), and also because they had non-microbiologically documented infections (67%). In vitro findings have demonstrated reduced efficacy of tigecycline against some organisms know to cause ventilator-associated pneumonia including K. pneumoniae (MIC of 0.25-2 mg/L) and Entercoccus species (MIC of 0.6-2 mg/L). Higher MICs lead to increased failure of treatment with tigecycline in these infections.7,19 Several clinical studies have demonstrated similar findings, particularly on the emergence of resistance of A. baumannii to tigecycline.3,24,26,32 In the current study only 1 of the 8 cases of ventilator-associated pneumonia was secondary to A. baumannii, and this patient responded to tigecycline therapy.

Patients with bacteremia had a relatively high clinical response rate (79%). Data from a pooled analysis of Phase III clinical trials have showed an 82%-83% complete cure rate in patients with associated blood stream infections.4,11,35 However, most of our patients were on concomitant antimicrobial agents; therefore, it is difficult to attribute the response exclusively to tigecycline. It is important to note that tigecycline achieves higher concentration in sites such as skin and skin structure and bile compared to bloodstream.14,29 At the recommended dosage, tigecycline is known to achieve low mean peak serum concentrations (0.63 ± 0.28 mg/L).3,24 This raises concern regarding its effectiveness as a therapeutic agent for the treatment of bloodstream infections even against organisms susceptible to it, but more so for blood stream infections caused by organisms with MICs of ≥1 mg/L, particularly when it is used as monotherapy. This is an important consideration when treating bloodstream infections due to A. baumannii, which are known to have high tigecycline MICs (≥1 mg/L).24 No patients in the current study had A. baumannii isolated from the blood stream.

Sixteen patients (15%) had complicated intraabdominal infection or skin and skin structure infection. The complete clinical response rate was high (88%) in these patients. This finding is similar to those of many Phase III clinical studies, which have shown complete cure rates of 80%-90% in such patients.4,11,13,23

Overall, tigecycline was safe in our patient population. The most common side effects associated with tigecycline use are nausea, vomiting, and diarrhea;4,13,23 dizziness and hyperpigmentation of the skin are rare.21 Phase III clinical trials have reported nausea in 30% of patients, vomiting in 20%, and diarrhea in 13%.21 In the current study, only 5% of patients experienced mild nausea; 2% had vomiting and 4% had diarrhea. No patients developed C. difficile infection. This finding is consistent with those of Phase III clinical trials that have found that despite the broad-spectrum activity of tigecycline, it is not associated with an increased risk for C. difficile infection.4,23,40 In vitro studies have also concluded similar findings, and this may be explained by the potent activity of tigecycline against C. difficile. The MIC of tigecycline against all strains of C. difficile was found to be 0.06 mg/L, which is much lower then the peak concentration reached in the gut.5 No serious adverse events were noted that could be attributed to tigecycline use, considering the retrospective nature of our study.

To our knowledge, this is the first study to evaluate the effectiveness of tigecycline in a large number of cancer patients with complicated infections. However, this was a retrospective observational study; thus no control group was available. Therapeutic decisions were made by individual physicians, with no uniform guidelines. Most patients were on other concomitant antibiotics besides tigecycline; therefore, it is difficult to attribute clinical responses exclusively to tigecycline. Another limitation of this study is that we had no susceptibility data for tigecycline. Finally, this work was supported by a grant from the manufacturer of the drug being studied, which may lead to the perception of bias.

In conclusion, tigecycline appears to be a safe antimicrobial agent in critically ill patients with intractable infections that do not respond to other antibiotics. Along with antipseudomonal drugs, it is a good empirical treatment of choice in patients who are critically ill and have serious infections. However, patients with refractory pneumonia have a relatively low clinical response rate. The efficacy and safety of tigecycline in health care-associated pneumonia must be further evaluated in clinical trials.

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