SUPPLEMENT ARTICLE Carbapenem-Resistance in Gram-Negative Bacilli and Intravenous : An Antimicrobial Stewardship Approach at the Detroit Medical Center Jason M. Pogue, 1,2 Anupama Neelakanta, 2 Ryan P. Mynatt, 3 Sarit Sharma, 2 Paul Lephart, 2,4 and Keith S. Kaye 2,5 1 Department of Pharmacy, Sinai-Grace Hospital, Detroit Medical Center, 2 Wayne State University School of Medicine, Detroit, 3 Department of Pharmacy, Detroit Receiving Hospital, Detroit Medical Center, 4 Detroit Medical Center University Laboratories, and 5 Department of Internal Medicine, Division of Infectious Diseases, Detroit Medical Center, Michigan In the era of carbapenem-resistance in Acinobacter baumannii and Enterobacteriaceae, there are limited treatment options for these pathogens. It is essential that clinicians fully assess all available therapeutic alternatives for these multidrug-resistant organisms. We herein describe the approach of the antimicrobial stewardship team at the Detroit Medical Center (DMC) for the evaluation and use of intravenous (IV) minocycline for the treatment of these resistant organisms, given potential advantages of IV minocycline over tigecycline and doxycycline. In vitro analyses at the DMC demonstrated good activity against A. baumannii (78% susceptibility), including 74% of carbapenem-resistant strains, but limited activity against our carbapenem-resistant K. pneumoniae (12% susceptibility.) Based in part on these results, IV minocycline was added to the formulary, primarily for the treatment of carbapenem-resistant A. baumannii. Early experience has been positive: 6/9 (67%) of patients who received IV minocycline had infections due to these organisms cured, including 6/7 (86%) who received doses of 200 mg twice daily. Keywords. minocycline; tetracycline; colistin; multidrug-resistant; A. baumannii. Rapidly increasing rates of carbapenem-resistance in Acinetobacter baumannii and Klebsiella pneumoniae have been described worldwide, and the Detroit Medical Center (DMC) has not been immune to this troublesome trend. Reddy and colleagues reported that carbapenem resistance rates in A. baumannii at DMC skyrocketed from 1% in 2003 to 58% in 2008 [1]. The rate of carbapenem resistance in A. baumannii peaked at 69% in 2009 and has since leveled off at approximately 60%. The DMC has simultaneously seen the Correspondence: Jason M. Pogue, PharmD, BCPS-ID, Clinical Pharmacist, Infectious Diseases, Sinai-Grace Hospital; Detroit Medical Center, Clinical Assistant Professor of Medicine, Wayne State University School of Medicine, 6071 W Outer Dr, Detroit, MI 48235 (jpogue@dmc.org). Clinical Infectious Diseases 2014;59(S6):S388 93 The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. DOI: 10.1093/cid/ciu594 introduction of carbapenem resistance in K. pneumoniae, primarily due to the introduction of K. pneumoniae carbapenemase (KPC) producing strains. Approximately 5% of K. pneumoniae strains isolated at the DMC are resistant to carbapenems, with KPC being the primary mechanism. This rise in resistance has been troublesome as currently available treatment options are scarce and associated with significant clinical limitations. Polymyxins remain the mainstay of therapy for the treatment of these organisms as their unique mechanism of action on the outer membrane of susceptible gram-negative organisms leads to rapid bactericidal activity. In addition, this action on the outer membrane serves as the proposed mechanism for synergy that is demonstrated with many other antimicrobial agents. Colistin, formulated as its inactive prodrug colistimethate sodium, remains the primary polymyxin used for these organisms in the United States and worldwide. Unfortunately, in Stewardship Approach to IV CID 2014:59 (Suppl 6) S388
part due to suboptimal pharmacokinetics [2, 3], unclear dosing recommendations, heteroresistance in both A. baumannii and K. pneumoniae [4, 5], and a relatively narrow therapeutic index, this agent has significant limitations and often is not recommended as monotherapy. Polymyxin B, the other commercially available polymyxin, appears to have more favorable and straightforward pharmacokinetics [6], but has similar safety and efficacy limitations. Tigecycline, a glycylcycline derivative of minocycline has excellent in vitro activity against both carbapenem-resistant A. baumannii (CRAB) and carbapenem-resistant K. pneumoniae (CRKP) [7]. However, the utility of tigecycline for invasive infections is limited by its pharmacokinetics. The high degree of lipophilicity leads to suboptimal blood concentrations, with a maximum serum concentration of <1 µg/ml [8]. Breakthrough s have been described in patients treated with tigecycline for A. baumannii infections [9]. Additionally, tigecycline failed to demonstrate non-inferiority compared to imipenem in a double-blind, randomized controlled trial for the treatment of hospital acquired pneumonia [10], with suboptimal drug levels in the epithelial lining fluid being suggested as a possible cause for its poor performance [11]. Furthermore, tigecycline has minimal renal elimination, and was inferior to aminoglycosides for the treatment of urinary tract infections due to CRKP [12]. Because infections due to CRAB and CRKP are most commonly seen in the lungs, blood, and urine, the role of tigecycline in the treatment of these resistant pathogens remains unclear and its efficacy uncertain. The other antimicrobial class that is commonly considered as a potential treatment option due to having somewhat reliable in vitro activity against these organisms is the aminoglycosides. Tobramycin has significant activity against A. baumannii [1], and amikacin and gentamicin often have activity against CRKP. Tobramycin has been shown to be equivalent to colistin for the treatment of CRAB infections; however, these data are significantly limited by the fact that they include patients who were colonized rather than infected [13]. Additionally, metaanalyses have reported that aminoglycosides are inferior to comparator agents and should not be used as monotherapy for infections that occur outside of the urinary tract [14]. While fosfomycin often offers activity against these pathogens, in the United States it is only formulated as a 3 gram oral sachet and is not suitable for systemic infections. The possible utility of other tetracyclines, notably minocycline, are often overlooked, and will be discussed in detail below. DEVELOPMENT OF CRAB GUIDELINES AT THE DMC In 2009, during the peak of the CRAB outbreak at the DMC, the Antimicrobial Subcommittee developed institutional guidelines for the treatment of invasive infections due to CRAB. In accordance with expert recommendations and the available literature, colistin was positioned as the backbone of the antimicrobial regimens. However, due to the aforementioned issues with colistin monotherapy (notably the narrow therapeutic index, unclear dosing recommendations, and extensive heteroresistance), it was recommended that combination therapy with either a second active agent (ie, tigecycline or tobramycin) or a highly synergistic agent (meropenem or rifampin) be used. No particular combination regimen was preferred at the time, as data supporting a particular combination regimen were lacking. Common practice was to combine colistin with rifampin due to excellent in vitro synergy and to minimize utilization of broad-spectrum gram-negative agents. EVALUATION OF MINOCYCLINE In 2009 an intravenous (IV) formulation of minocycline previously approved by the US Food and Drug Administration (FDA) in the 1970s was reintroduced into the US market to address increasing drug resistance to current first-line agents. Case series were published regarding its use for the treatment of ventilator-associated pneumonia due to CRAB. Two analyses reported clinical success in 35/43 (81%) patients who received minocycline or doxycycline regimens, including 11/13 who received monotherapy [15, 16]. At this time the DMC formulary included both IV and per oral (PO) doxycycline but did not include minocycline. Doxycycline was primarily used for treatment of community-acquired respiratory tract infection. Due to the increase in carbapenem resistance at DMC, the Antimicrobial Subcommittee reevaluated minocycline in 2011. Although doxycycline was considered as a potential treatment option for CRAB, the interest in minocycline stemmed from data demonstrating that minocycline was highly active against CRAB and most importantly, that it was more active than doxycycline against A. baumannii (90% vs 31% respectively) [17]. The subcommittee was particularly interested in minocycline as a potential alternative to tigecycline given its pharmacokinetic advantage in the blood, where it achieved higher serum concentrations (2.1 to 6.6 µg/mlwiththe200mgivdose)[18]; and its FDA-approved indication for treatment of infections due to Acinetobacter spp. as well as for urinary tract infections [19]. Additionally, with the availability of both IV and PO minocycline formulations, and the relatively high bioavailability of the oral formulation, the ability to switch from IV to PO routes with minocycline was attractive. Based on this information, the DMC Antimicrobial Subcommittee reviewed minocycline for formulary addition in September of 2011. The subcommittee also evaluated the role of minocycline in the treatment of CRKP infections. S389 CID 2014:59 (Suppl 6) Pogue et al
IN VITRO SUSCEPTIBILITY OF MINOCYCLINE AT THE DMC VERSUS CRAB AND CRKP In order to evaluate the potential role of minocycline at the DMC, susceptibility to minocycline was analyzed via Etest for arepresentativesampleofa. baumannii (including carbapenem-resistant strains) and carbapenem-resistant K. pneumoniae (largely KPC-producing strains) in 2011. Susceptibility testing via the Etest methodology for minocycline was performed according to package insert guidelines, which indicated reading of isolates at 16 20 hours and at the time of complete inhibition of growth [20]. Clinical Laboratory Standards Institute (CLSI) breakpoints were used to determine susceptibility (susceptible at minimum inhibitory concentrations [MICs] 4 µg/ml, intermediate at MICs = 8 µg/ml, resistant at MICs 16 µg/ml) [21]. demonstrated good activity against A.baumannii, including CRAB with >70% of isolates being susceptible (Table 1); however, it showed only limited activity against the CRKP at our institution, with a susceptibility rate of only 12%, with the vast majority of isolates having an MIC of 8 µg/ml. FORMULARY DECISION ON MINOCYCLINE, SEPTEMBER 2011 Based on the efficacy data, the higher blood concentrations, and in vitro susceptibility results, the Antimicrobial Subcommittee decided to bring both minocycline formulations (IV and PO) onto the formulary at the DMC, primarily for the treatment of CRAB. Furthermore, through collaboration with the clinical microbiology laboratory, a process was developed where all non-urinary CRAB isolates would undergo automatic reflex Etest susceptibility testing for minocycline, similar to a process already in place for colistin testing. Due to the limited susceptibility of CRKP, reflex testing was not routinely performed for CRKP but testing would be available upon clinician request. UPDATING THE DMC CRAB GUIDELINES Around the time that minocycline was added to the formulary in September 2011, our group published an analysis identifying risk factors for colistin-associated nephrotoxicity in which we reported that patients who were coadministered rifampin with colistin were at a 3-fold increased risk for nephrotoxicity compared to those who did not receive rifampin [22]. The subcommittee revised the CRAB guidelines and developed more specific recommendations, placing colistin + meropenem as the preferred regimen, and either colistin + tigecycline or colistin + minocycline as second-line regimens. Due to toxicity concerns, colistin + tobramycin and colistin + rifampin were positioned as less desirable options. The guidelines were also updated to state that if a tetracycline-based regimen was used for s due to CRAB, the minocyclinebased combination was favored over the tigecycline regimen. was recommended to be dosed at 200 mg twice daily in order to optimize serum concentrations. EARLY EXPERIENCE WITH INTRAVENOUS MINOCYCLINE Since bringing IV minocycline to formulary, 9 patients have been treated with minocycline for infection due to carbapenem-resistant gram-negative bacilli. Case summaries for those patients are summarized in Table 2. Use has mainly been for s (n = 5) or pneumonia (n = 3), with 1 patient having both a pneumonia and. Six patients have received IV minocycline for CRAB infections, 2 for KPC-producing pathogens, and 1 for a coinfection with both organisms. Seven patients received a dose of 200 mg every 12 hours, whereas 2 were dosed at 100 mg every 12 hours. was combined with colistin in 6 cases, ampicillin/sulbactam in 1 case, tobramycin in 1 case, and used as monotherapy in 1 case. Clinical cure was achieved in 6/9 (67%) patients receiving minocycline including 6/7 (86%) who received 200 mg twice daily. Clinical cure was demonstrated in 4/6 (67%) patients with and 3/4 (75%) patients with pneumonia. Microbiological cure occurred in 5/ 7 (71%) patients in whom repeat microbiologic testing was performed, including 5/5 (100%) who received the higher dose of 200 mg twice daily. The lone patient who received monotherapy for pneumonia and a postoperative surgical site infection with A. baumannii had both clinical and microbiological cure. Table 1. In Vitro Activity of Against Clinical Isolates of Acinetobacter baumannii and Carbapenem-Resistant Klebsiella pneumoniae at Detroit Medical Center in 2011 Organism Susceptible Intermediate Resistant MIC 50 (mcg/ml) MIC 90 (mcg/ml) A. baumannii (all, n = 54) 42/54 (78%) 9/54 (17%) 3/54 (6%) 4 8 CRAB (n = 31) 23/31 (74%) 8/31 (26%) 0/31 (0%) 4 8 Carbapenem-susceptible A.baumannii (n = 23) 19/23 (83%) 1/23 (4%) 3/23 (13%) 4 16 CRKP (n = 59) 7/59 (12%) 29/59 (49%) 23/59 (39%) 8 32 Abbreviations: CRAB, Carbapenem-resistant A. baumannii; CRKP, Carbapenem-resistant K. pneumoniae; MIC, minimum inhibitory concentration. Stewardship Approach to IV CID 2014:59 (Suppl 6) S390
S391 CID 2014:59 (Suppl 6) Pogue et al Table 2. Clinical Information of Patients Treated With IV at Detroit Medical Center Pt Demographics Infection Requiring IV 1 50 y/o male Acinetobacter baumannii Degree Dose and Duration 100 mg BID (minocycline MIC = 4) 6 d 2 51 y/o male A. baumannii pneumonia 100 mg BID (minocycline MIC = 2) 6 d 3 56 y/o female A. baumannii pneumonia 200 mg BID (minocycline MIC = 2) 7 d 4 45 y/o male A. baumannii pneumonia and surgical site infection 5 74 y/o male A. baumannii aspiration pneumonia and due to KPC-producing K. pneumoniae 6 72 y/o male KPC-producing K. pneumoniae secondary to UTI Septic shock None 200 mg BID (minocycline MIC = 2 in wound, 4 in sputum) 13 d 200 mg BID 9 d (minocycline MIC to A. baumannii =4, tetracycline MIC for KPC = 2) 200 mg BID 4 d (tetracycline MIC 4) Concomitant Antibiotics for Infection Requiring Microbiological Cure a Clinical Cure b Comments Colistin 6 d No No Pt developed BSI (unknown source) while on tigecycline which was active in vitro. Therapy was switched to meropenem + tobramycin empirically; and then colistin + minocycline based on microbiological results. Patient never cleared clinical cultures and went to hospice care and expired. Colistin 6 d No No Pneumonia clinically worsened over the next 48 72 h after starting colistin/minocycline, requiring intubation. Patient also developed an intracranial hemorrhage and expired in the hospital. Colistin 7 d Not repeated Yes Duration stopped at 7 d due to development of acute kidney injury (likely secondary to colistin). Completed an additional week of cefepime for concomitant P. aeruginosa pneumonia and was discharged. None Not repeated Yes Patient responded well to therapy and was ultimately discharged to a rehab facility to heal from wounds from motor vehicle accident. Colistin + Meropenem 9 d as well (meropenem MIC for KPC was >8) Meropenem + Tobramycin 4 d (meropenem and tobramycin MIC s both 4 mcg/ml. Meropenem dose 1000 mg q6h, tobramycin for target peaks of 20 mcg/ml) Respiratory: not repeated Blood: Yes Yes Pt arrived from long term care facility with polymicrobial with MRSA and KPC due to an infected PICC line. Patient also had aspiration pneumonia with A. baumannii. PICC line was removed and patient was successfully managed and discharged in stable condition back to LTCF. MRSA was managed with daptomycin (vancomycin MIC of 2 mcg/ml.) Yes Yes Patient with urosepsis; initially started on triple antibiotic therapy. Patient was discharged in good condition after 4 d of combination therapy, and was to continue tobramycin monotherapy for 10 more days after discharge.
Table 2 continued. Stewardship Approach to IV CID 2014:59 (Suppl 6) S392 Pt Demographics Infection Requiring IV 7 35 y/o male A. baumannii bloodstream infection (secondary to PICC) 8 80 y/o female KPC-producing K. pneumoniae secondary to above the knee amputation site (KPC-producing K. pneumoniae also isolated from this site) 9 49 y/o female A. baumannii bloodstream infection (PICC line associated) Degree Severe sepsis Dose and Duration 200 mg BID 11 d (MIC = 4) 200 mg BID 4 d (MIC = 4) Second course: 200 mg BID 7 d Concomitant Antibiotics for Infection Requiring Ampicillin/Sulbactam 11 d (isolate intermediate, dose 3 g IV q4h) Amikacin 4 d Colistin 7d Microbiological Cure a Clinical Cure b Comments Yes Yes Patient responded to therapy and was discharged to a LTCF. PICC line was removed as a part of patient care. Yes (blood) No Patient initially treated with Amikacin + minocycline IV; then switched to colistin + trimethoprim/ sulfamethoxazole. Three days after switch patient experienced cardiac arrest, was resuscitated but experienced subsequent renal failure. TMP/SMX was stopped and minocycline IV was re-instituted, but patient was made comfort measures only and expired. 200 mg BID 4 d Colistin 4 d Yes Yes Pt responded well to therapy and was sent to nursing home to complete 10 d course of the combination. Abbreviations: BID, twice daily; IV, intravenous; KPC, Klebsiella pneumoniae Carbapenemase; LTCF, long-term care facility; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; PICC, peripherally inserted central catheter; TMP-SMX, trimethoprim/sulfamethoxazole. a Microbiological cure defined as cultures being repeated from the site of infection and clearance of the organism of interest. b Clinical cure defined as resolution of signs and symptoms of the infection requiring minocycline.
was well tolerated. Two patients developed acute kidney injury, which was presumed to be related to colistin and not to minocycline. No patients reported vestibular toxicity. DISCUSSION As rates of carbapenem resistance in A.baumannii and Enterobacteriaceae continue to rise and antimicrobial options for infections due to these pathogens remain limited, antimicrobial stewardship programs must find ways to optimize currently available therapeutic options., particularly for the treatment of CRAB, has many attractive qualities compared to other tetracyclines with regards to antimicrobial activity (compared to doxycycline) and pharmacokinetics (compared to tigecycline). Although the efficacy data presented in this report are limited, minocycline was used safely and effectively. The rate of success was particularly notable in light of the fact that minocycline in our series was frequently being used as salvage therapy after patients failed multiple other antibiotic regimens. was used as combination therapy in all but 1 patient. It is interesting to note that when the maximum dose of 200 mg twice daily was used, clinical cure was achieved in 6/7 patients as compared to 0/2 patients who received 100 mg twice daily, the current recommended dose. The only patient who received monotherapy (at a dose of 200 mg twice daily) had both clinical and microbiological cure of pneumonia due to A. baumannii. Further analysis is warranted to determine whether or not the higher dose of 200 mg twice daily, and associated higher concentrations are associated with favorable clinical outcomes. Notes Supplement sponsorship. This article appears as part of the supplement for the Treatment of Multidrug-Resistant Acinetobacter baumannii, sponsored by The Medicines Company. Potential conflicts of interest. K. S. K. is a consultant for Rempex Pharmaceuticals, The Medicines Company, and Achaogen; consultant, grant recipient and member of the speaker s bureau of Pfizer. K. S. K. is supported by the National Institute of Allergy and Infectious Diseases (NIAID; DMID protocol number 10-0065). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Reddy T, Chopra T, Marchaim D, et al. Trends in antimicrobial resistance of Acinetobacter baumannii isolates from a metropolitan Detroit health system. Antimicrob Agents Chemother 2010; 54:2235 8. 2. Plachouras D, Karvanen M, Friberg LE, et al. 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