Nontraditional Therapy for Stenotrophomonas maltophilia Infections: Ending the Sulfuring

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1 Nontraditional Therapy for Stenotrophomonas maltophilia Infections: Ending the Sulfuring Reese Cosimi, Pharm.D., BCPS PGY2 Infectious Diseases Pharmacy Resident South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy The University of Texas Health Science Center at San Antonio December 9, 2016 Objectives 1. Recognize risk factors and clinical characteristics associated with Stenotrophomonas maltophilia infection 2. Explain mechanisms of Stenotrophomonas maltophilia antimicrobial resistance and its resultant limited susceptibility to traditional agents 3. Recommend optimal antimicrobial therapy for Stenotrophomonas maltophilia in a patient who is not a candidate for trimethoprim-sulfamethoxazole Cosimi 1

2 Background I. History of Stenotrophomonas maltophilia 1 A. Initially isolated from pleural fluid B. Taxonomically reclassified on multiple occasions Figure 1: Nomenclature 1, Bacterium bookeri 1960 Pseudomonas maltophilia 1981 Xanthomonas maltophilia 1993 Stenotrophomonas maltophilia II. Epidemiology A. Incidence 1. Infections due to S. maltophilia occur in 7.4 to 37.7 patients in 10,000 at risk for opportunistic infections 3 2. Isolated in 30% of cystic fibrosis patient sputum cultures 4 B. Mortality 1. Difficult to determine true mortality for several reasons 1 a. Low pathogenicity makes infection versus colonization unclear b. Isolation of S. maltophilia most commonly occurs in critically ill patients c. Poor association with infection and worse clinical outcomes 2. Overall mortality from acute respiratory tract infections was found to be 20.3% though multiple confounders were present 5 a. No evidence of lung consolidation in 70% of patients b. Administration of an antibiotic against S. maltophilia had no effect on outcomes c. Concomitant nosocomial pathogens were present in >30% of patients 3. Attributable mortality with bacteremia is 26.7% and treatment of S. maltophilia improved survival in this population 6 C. Common sources of S. maltophilia 1 1. Soil and plant roots 2. Contaminated fluids a. Dialysate b. Contact solution c. Chlorhexidine d. Sink drains and handwashing soap e. Ice machines Cosimi 2

3 D. Patients at highest risk for isolation of S. maltophilia are those with multiple comorbidities Table 1: Risk Factors 1,6 Malignancy Indwelling devices Chronic respiratory disease Immunocompromised host Prior antibiotic use Prolonged hospitalization ICU admission Chronic conditions E. Typical infectious presentation 1,7 1. Majority of infections are polymicrobial 2. Pneumonia, bacteremia and catheter-related blood stream infections are most common 3. COPD and cystic fibrosis exacerbations, skin and soft tissue infections, osteomyelitis, meningitis, and intraabdominal infections are also seen III. Microbiology 1 A. Yellow colony cultures B. Gram-negative bacilli with polar flagella C. Non-lactose fermenter D. Obligate aerobe E. Oxidase negative F. High affinity to form biofilm on plastic devices Figure 3: Biofilm Formation 9 Cosimi 3

4 G. Clinical and Laboratory Standards Institute (CLSI) breakpoints Table 2: Breakpoints 10 Drug Susceptible Intermediate Resistant TMP-SXT 2/ /76 Minocycline Levofloxacin Ceftazidime TMP-SMX = trimethoprim-sulfamethoxazole IV. Pharmacotherapy A. High rates of intrinsic resistance makes antibiotic selection difficult TMP-SMX is considered treatment of choice Historical data supporting alternative/combination therapy was lacking B. S. maltophilia hospital-acquired pneumonia or ventilator-associated pneumonia 1. Infectious Diseases Society of America (IDSA) makes no recommendations Original in vitro studies demonstrated highest susceptibility with TMP-SMX which supported its utility 11,14,15 C. S. maltophilia catheter-related blood stream infections 1. IDSA guidelines recommend removal of infected device plus TMP-SMX administration Recommendation based on original high susceptibility of TMP-SMX plus evidence that receipt of appropriate therapy decreased mortality by up to 45% 11,17 D. Clinical data using TMP-SMX is lacking ventilator-associated pneumonia patients = 13% mortality bacteremia patients = 0% mortality patients with all infection types = 30.8% mortality 20 V. Pharmacology of agents active against S. maltophilia Table 3: Pharmacology 2 TMP-SMX 16,22 Minocycline 23 Levofloxacin 24 Dose 3-5mg/kg every 8 100mg twice 750mg daily hours daily Route IV or oral IV or oral IV or oral Distribution Vd (L/kg) Cmax (mg/l) Protein Bound (%) TMP: 2; SMX: 0.36 TMP: 3.4; SMX: 46.3 TMP: 44; SMX: Metabolism Hepatic Hepatic None Renal Elimination (%) TMP: Adverse Drug Reactions SMX: Hypersensitivity Nephrotoxicity Hemolytic anemia Thrombocytopenia Hyperkalemia GI upset Hepatotoxicity Photosensitivity Vd = Volume of distribution; CDI = Clostridium difficile infection Tendon rupture CDI Neurotoxicity Prolonged QT Cosimi 4

5 VI. In vitro susceptibility and resistance mechanisms A. Gram-negative pathogens often have multiple intrinsic and acquired mechanisms of resistance 25 Figure 4: Mechanisms of Resistance 26 Figure 4: Mechanisms of Resistance 26 Fluoroquinolones Tetracyclines Beta-lactams Aminoglycoside B. S. maltophilia is resistant to many antimicrobials commonly used for gram-negative infections TMP-SMX 28 a. Mechanism: acquired mobile sul-genes increase bacterial fitness against TMP-SMX b. Increasing prevalence noted worldwide 2. Beta-lactams a. Mechanism: two types of inducible beta-lactamases i. Metallo-beta-lactamase (L1) ii. Clavulanate sensitive cephalosporinase (L2) b. Resistance: All penicillins, cephalosporins and carbapenems c. Ceftazidime and ticarcillin-clavulanate may retain susceptibility though low clinical cure rates have been reported (50 and 60%, respectively) 3. Aminoglycosides a. Mechanism: enzymatic inactivation via acetyltransferase b. Resistance: All aminoglycosides 4. Fluoroquinolones 29 a. Mechanism: efflux pumps and decreased uptake b. Resistance: All fluoroquinolones c. Only levofloxacin has susceptibility breakpoints d. In vitro moxifloxacin is most susceptible but may not equate in vivo 5. Tetracyclines 30 a. Mechanism: efflux pumps and decreased uptake b. Resistance: All tetracyclines Cosimi 5

6 C. Previous antimicrobial exposure significantly increases risk for expression of resistance 11 Table 4: Recent Antibiotic Susceptibility Drug Percent Susceptible (%) Minocycline TMP-SMX 12,31,33-34, Levofloxacin 31-35, Tigecycline Moxifloxacin 12, Ticarcillin-clavulanate 12,34, Piperacillin Ceftazidime 12,31-34, Colistin Ciprofloxacin Gentamicin 32 2 *Antimicrobials without breakpoints required extrapolation from other organisms or drugs in many of these studies VII. Why use alternative agents? A. Hypersensitivity in up to 2% of patients 39 B. Adverse drug reactions in up to 13% of cases 40 C. Thrice daily dosing increases workload and volume burden 21 D. IV formulation drug shortages may take place (most recent: 2014) 41 E. Contraindications to therapy History of sulfonamide- or TMP-induced thrombocytopenia 2. Age <2 months 3. Hepatic damage 4. Megaloblastic anemia due to folate insufficiency 5. Renal insufficiency F. Increasing resistance seen in 30-40% of isolates worldwide 11,28 VIII. Which alternative agent? A. Minocycline and levofloxacin are most attractive alternatives to TMP-SMX 1. High susceptibility rates 2. More favorable adverse drug reaction profiles 3. In vitro analyses demonstrate efficacy IX. Clinical Question A. Do clinical data support non-tmp-smx based therapy as an alternative to TMP-SMX? B. Which situations may it be utilized? Cosimi 6

7 Literature Review Wang YL, Scipione MR, Dubrovskaya Y, Papadopoulos J. Monotherapy with fluoroquinolone or trimethoprim-sulfamethoxazole for treatment of Stenotrophomonas maltophilia infections. Antimicrob Agents Chemother. 2014;58(1): Objective Assess efficacy of fluoroquinolone monotherapy vs. TMP-SMX in S. maltophilia infections Methods Study Design Retrospective review of patients treated with either a fluoroquinolone (ciprofloxacin or levofloxacin) or TMP-SMX for S. maltophilia infections Location: NYU Langone Medical Center, New York, NY Susceptibility breakpoint source: not reported Population Inclusion Criteria Exclusion Criteria 18 years Received combination therapy Positive S. maltophilia culture Clinical signs/symptoms of nosocomial infection Received S. maltophilia treatment for 48 hours Endpoints Microbiological cure and clinical response at end of therapy (EOT), in-hospital mortality, 30-day mortality and nonsusceptible isolates within 30 days of EOT Microbiological cure definition: no growth from same site at or prior to EOT Statistical Categorical data analyzed with chi-squared or Fisher s exact test Analyses Continuous data analyzed with Student s T test or Mann-Whitney U test P-value of <0.05 indicated statistical significance Multivariate logistic regression Results Enrollment 98 patients were included in the review including 35 patients on TMP-SMX and Baseline Characteristics 63 patients on a fluoroquinolone (48 levofloxacin; 15 ciprofloxacin) Characteristic Fluoroquinolone TMP-SMX (n=63) (n=35) Age (mean ± SD) 69±15 73±15 -- Most common underlying conditions, n(%) Major surgery Malignancy (solid organ) Coronary Artery Disease Diabetes mellitus Mechanical ventilation Intra-abdominal drain Most common sites of infection, n(%) Pulmonary Skin/skin structure Urine Intra-abdominal Bacteremia 28 (44) 24 (38) 26 (41) 26 (41) 17 (27) 1 (2) 38 (60) 9 (14) 6 (10) 5 (8) 5 (8) 14 (40) 14 (40) 11 (31) 9 (26) 12 (34) 6 (17) 17 (49) 10 (29) 3 (9) 4 (11) 1 (3) P-value < Prior antibiotic use, n(%) 54 (86) 28 (80) 0.46 ICU Admission, n(%) 17 (27) 6 (17) 0.27 Cosimi 7

8 Length of stay prior to culture, days, median (IQR) Days to treatment, days, median (IQR) Polymicrobial infection, n(%) 53 (84) Pseudmonas spp. 8 (28) Enterococcus spp. 10 (40) Methicillin-resistant 11 (44) Staphylococcus aureus IQR = Interquartile range Results Outcome Fluoroquinolone (n=63) Microbiological cure at 6 (1-19) 4 (0-11) (2-4) 3 (2-5) (63) 2 (22) 5 (38) 3 (31) TMP-SMX P-value (n=35) 23/37 (62%) 13/20 (65%) 0.83 EOT, n(%) In-hospital mortality, (n%) 16/63 (25%) 7/35 (20%) day mortality, n(%) 16/52 (31%) 6/27 (22%) 0.42 Clinical success at EOT, n(%) 27/52 (52%) 17/28 (61%) 0.45 Non-susceptible isolate within 30 11/37 (30%) 4/20 (20%) 0.43 days of EOT, n(%) Duration of therapy, days, median 9 (2-38) 8 (2-28) (IQR) Length of stay, days, median (IQR) 25 (15-37) 16 (8-42) 0.97 Multivariate analysis identified risk factors for increased mortality: o ICU admission (odds ratio, 8.2; 95% confidence interval, ; p = 0.005) o Recent chemotherapy administration (odds ratio, 6.2; 95% confidence interval, ; p = 0.037) High rates of resistance were reported after prior exposure to antibiotics in patients with follow-up cultures o TMP-SMX exposure resulted in 2/7 (24%) resistance to TMP-SMX and 2/5 (40%) resistance to levofloxacin o Fluoroquinolone exposure resulted in 0/11 (0%) resistance to TMP-SMX 10/14 (71%) resistance to levofloxacin and Author s When an alternative to TMP-SMX is required, fluoroquinolones may be used an Conclusions alternative option Discussion Critique Strengths Limitations Take-home Points Combination therapy was an exclusion to the study Follow-up susceptibility testing conducted Adjusted for confounding factors Small retrospective analysis Low proportion of patients could be evaluated for all endpoints Minimal bacteremia patients included in study Resistant isolates excluded No differentiation between colonization and infection Fluoroquinolones may be as efficacious as TMP-SMX in initial treatment of S. maltophilia infections Resistance may develop on therapy but may be more common with fluoroquinolones Cosimi 8

9 Cho SY, Kang C, Kim J, et al. Can levofloxacin be a useful alternative to trimethoprimsulfamethoxazole for treating Stenotrophomonas maltophilia bacteremia? Antimicrob Agents Chemother. 2014;58(1): Objective Compare clinical outcomes of TMP-SMX with levofloxacin against S. maltophilia bacteremia Methods Study Design Retrospective review evaluating outcomes of adult patients receiving either TMP-SMX or levofloxacin for S. maltophilia bacteremia Location: Samsung Medical Center, Seoul, South Korea Susceptibility breakpoint source: CLSI Population Inclusion Criteria Exclusion Criteria 18 years Received either IV TMP-SMX or levofloxacin for S. maltophilia bacteremia for >48 hours Isolate resistant to prescribed therapeutic agent Endpoints Primary objective: Overall 30-day mortality Secondary objectives: Length of stay, adverse events and bacteremia recurrence Statistical Analyses Categorical variables: Fisher s exact test and chi-squared Continuous variables: Student s t test Statistical significance defined as p value <0.05 Multivariate logistic regression utilized to evaluate effects of therapy with levofloxacin Results Enrollment Of 203 patients identified with S. maltophilia 86 were included in the study. TMP-SMX was administered to 51 patients and levofloxacin to 35 patients Rates of susceptibility to initial S. maltophilia isolates were 96.1% for TMP- SMX and 87.1% for levofloxacin Baseline Characteristics Characteristic TMP-SMX Levofloxacin P value (n=51) (n=35) Age, median (IQR) 56 (40-67) 61 (49-68) Gender, male, n(%) 28 (54.9) 28 (80) Source of bacteremia, n(%) Definite catheter-related Possible catheter-related Intrabdominal Pneumonia Underlying disease, n(%) Hematologic malignancy Solid tumor Liver cirrhosis Diabetes mellitus Cardiovascular disease Comorbid conditions, n(%) Central venous catheter Chemotherapy Neutropenia 12 (23.5) 11 (21.6) 14 (27.5) 9 (17.6) 29 (56.9) 16 (31.4) 9 (17.6) 8 (15.7) 8 (15.7) 5 (14.3) 11 (31.4) 11 (31.4) 5 (14.3) 15 (44.1) 16 (45.7) 5 (14.3) 5 (14.3) 8 (22.9) (76.5) 30 (58.8) 25 (49) 22 (62.9) 17 (48.6) 13 (37.1) Catheter removed, n(%) 21 (53.8) 11 (50) Cosimi 9

10 Charlson Comorbidity Index, 2 (2-3) 2 (2-3) median (IQR) Septic shock 13 (25.5) 7 (20) Polymicrobial bacteremia 12 (23.5) 5 (14.3) Combination therapy 9 (17.6) 3 (8.6) Typical daily dose 15-20mg/kg 750mg -- Results Outcome TMP-SMX Levofloxacin P value (n=51) (n=35) 30-day mortality, n(%) 14 (27.5) 7 (20) Length of stay, days, median 23 (12-51) 27 (15-52) (IQR) Adverse events, n(%) 12 (23.5) 0 (0) Recurrent bacteremia, n (%) 6 (11.9) 2 (5.7) Author s Conclusions No difference noted in 30-day mortality with TMP-SMX versus levofloxacin upon exclusion of patients with combination therapy or polymicrobial infections (29% versus 18.5%; p=0.351) Multivariate analysis identified risk factors associated with increased mortality: o Septic shock (odds ratio, 6.19; 95% confidence interval, ; p = 0.004) o Pneumonia (odds ratio, 5.33; 95% confidence interval, ; p = 0.015) Most common adverse events with TMP-SMX reported were rash, cytopenia and hepatotoxicity Half of the recurrent bacteremia isolates were notably resistant to levofloxacin Though clinical trials are needed, levofloxacin may be useful in treating S. maltophilia infections Discussion Critique Strengths Limitations Cohort compared standard of care with levofloxacin Follow-up susceptibility testing conducted Regression analysis conducted to adjust for confounders Only evaluated bacteremia patients Small retrospective analysis Resistant isolates excluded No differentiation between colonization and infection 30-day mortality may not correlate with infection outcomes Take-home Points Levofloxacin may be used for S. maltophilia bacteremia Susceptibility should be determined prior to use as levofloxacin resistance is more common than TMP-SMX Cosimi 10

11 Jacobson S, Noa LJ, Wallace MR, Bowman MC. Clinical outcomes using minocycline for Stenotrophomonas maltophilia infections. J Antimicrob Chemother DOI: /jac/dkw Objective Evaluate efficacy of minocycline for S. maltophilia infections Methods Study Design Retrospective review of patients receiving minocycline for S. maltophilia infections Location: Orlando Regional Medical Center / Orlando Health, Orlando, FL Susceptibility breakpoint source: CLSI Population Inclusion Criteria Exclusion Criteria 18 years Treated with minocycline monoor combination therapy for S. maltophilia Endpoints Clinical failure: Statistical Analyses o o <48 hours of minocycline therapy Pregnant women In-hospital death within 30 days of initial positive culture Clinical deterioration plus one or more of the following: Isolation of S. maltophilia from the same site at follow-up Receipt of an additional antibiotic with in vitro activity against S. maltophilia Partial clinical success: o Lack of clinical deterioration plus one or more of the following: Isolation of S. maltophilia from the same site at follow-up Receipt of additional antibiotics with activity for S. maltophilia Complete clinical success: none of the above Descriptive statistics Results Enrollment 93 of 119 identified patients receiving minocycline for S. maltophilia were included in the review Baseline Characteristics Characteristic Cohort (n=93) ICU, n(%) 49 (53) Mean APACHE II Score, mean (SD) 15 (±6.6) Initial minocycline MIC 4mg/L, n(%) 4mg/L <4mg/L 93 (100) 7 (7.5) 86 (92.5) Infection Type, n(%) Pneumonia Bacteremia 59 (63) 14 (15) Initial Dose 100mg every 12 hours (1 patient received higher dose) Results Outcome Cohort (n=93) Clinical Failure, n(%) 17 (18) Partial Clinical Success, n(%) 22 (24) Complete Clinical Success, n(%) 54 (58) Cosimi 11

12 Patients more likely to fail therapy: o S. maltophilia minocycline MIC 4mg/L (29.4% vs. 2.6%, p=0.004) o Higher mean APACHE II score (18.1 vs. 14.3, p<0.05) Four patients (9%) on minocycline monotherapy reported clinical failure o 3 deaths; 1 had persistently positive cultures with clinical deterioration o All 4 patients had infections with other microorganisms Author s Minocycline may be an appropriate alternative agent for the treatment of S. Conclusions maltophilia but randomized clinical trials are needed Discussion Critique Strengths Limitations Results supported by existing Retrospective analysis literature Included patients on combination Susceptibility testing conducted therapy without specifying agents for correlation with clinical Concomitant infections were outcomes Patients evaluated for partial common in patients with clinical failure clinical success No differentiation between colonization and infection 30-day mortality may not Take-home Points correlate with infection outcomes Minocycline seems to be effective for the treatment of S. maltophilia infections Less clinically ill patients with lower minocycline MICs may benefit most from minocycline therapy Hand E, Davis H, Kim T, Duhon B. Monotherapy with minocycline or trimethoprim/sulfamethoxazole for treatment of Stenotrophomonas maltophilia infections. J Antimicrob Chemother. 2016;71: Objective Evaluate efficacy of minocycline monotherapy vs. TMP-SMX in the treatment of S. maltophilia infections Methods Study Design Retrospective review of patients receiving either minocycline or TMP-SMX for S. maltophilia infections Location: University Hospital, San Antonio, TX Susceptibility breakpoint source: CLSI Population Inclusion Criteria Exclusion Criteria 1 positive culture for S. maltophilia Received 48 hours of minocycline or TMP-SMX as monotherapy Pregnant Incarcerated Received concominant antibiotics with in vitro activity against S. maltophilia during first 48 hours Endpoints Rates of treatment failure in patients with S. maltophilia treated with minocycline vs. TMP-SMX monotherapy Treatment failure definition: Cosimi 12

13 o Isolation of S. maltophilia from same site within 30 days o In-hospital death within 30 days of initial S. maltophilia isolate o Receipt of concomitant antibiotic with in vitro activity against S. maltophilia Statistical Demographics and outcomes: descriptive statistics Analyses Continuous data: Mann-Whitney U-test Nominal data: Chi-squared test Logistic regression analyses conducted to account for confounders P-value of <0.05 indicated statistical significance Results Enrollment 45 patients were included in the review including 23 patients on minocycline and 22 patients on TMP-SMX Baseline Characteristic Minocycline TMP-SMX P-value Characteristics (n=23) (n=22) Age, years, mean (range) 54 (18-81) 49 (8-84) 0.42 Most common comorbid condition, n(%) Mechanical ventilation Chronic lung disease Recent ARI Immunosuppression Malignancy Solid Organ Transplant Most common culture site, n(%) Sputum Broncheoalveolar lavage Blood Leukocytosis upon culture isolation, n(%) 13 (57) 12 (52) 10 (43.5) 8 (35) 8 (35) 6 (26) 9 (39) 7 (30) 1 (5) 10 (45) 2 (9) 2 (9) 3 (14) 3 (14) 2 (9) 8 (36) 5 (23) 1 (5) (52) 12 (55) -- Fever upon culture isolation, n(%) 7 (30) 12 (55) -- ICU Admission, n(%) 17 (74) 14 (64) -- Polymicrobial infections, n(%) P. aeruginosa S. aureus 15 (64) 8 (34) 3 (13) 18 (82) 7 (32) 4 (18) Average daily dose 200mg 8.5mg/kg -- Susceptibility to treatment 23 (100) 22 (100) -- regimen at initiation, n(%) Results Outcome Minocycline TMP-SMX P-value (n=23) (n=22) Treatment failure, n(%) 7 (30) 9 (41) 0.67 S. maltophilia isolated at followup, 5/10 (50) 7/11 (63) 0.75 n(%) Length of stay, days, median 41 (6-136) ) 0.35 (range) 30-day in-hospital mortality, n(%) 2 (8.7) 2 (9) -- Duration of therapy, days, median (range) 13 (4-32) 7 (3-15) Cosimi 13

14 No development of resistance to minocycline was noted upon follow-up cultures and susceptibilities Author s Based on the findings of this study, it is reasonable to use minocycline for S. Conclusions maltophilia infections Discussion Critique Strengths Limitations Evaluated solely monotherapy Small retrospective review with patients inadequate power Cohort compared minocycline to Concomitant infections were standard of care common Adjusted for baseline differences Minimal bacteremia patients Follow-up susceptibility testing conducted Attempted to assess colonization versus infection Take-home Points Minocycline has similar clinical success compared with TMP-SMX for the treatment of S. maltophilia infections and may be used as first-line or alternative therapy for this indication Cosimi 14

15 Conclusions I. Summary A. Evidence continues to grow supporting use of minocycline or fluoroquinolones in the treatment of S. maltophilia B. Levofloxacin is the preferred fluoroquinolone for S. maltophilia based on the presence of CLSI breakpoints and existing clinical data C. Nontraditional therapies may provide equal efficacy as TMP-SMX with more convenient dosing regimens and improved safety profiles II. Recommendations A. TMP-SMX should remain primary therapy for S. maltophilia infections at this time though minocycline susceptibility data supports its use empirically B. When TMP-SMX is not clinically suitable due to contraindications, intolerance, resistant isolates or volume overload, minocycline should be used preferentially to levofloxacin in the treatment of S. maltophilia infections due to the following: 1. Higher rates of susceptibility 2. Better barrier to resistance 3. Superior safety profile 4. Theoretical pharmacokinetic advantages Cosimi 15

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