Griffith, Matthew E. MD*; Yun, Heather C. MD†; Horvath, Lynn L. MD*; Murray, Clinton K. MD*
*Infectious Disease Service, Brooke Army Medical Center, Fort Sam Houston and †Infectious Disease Department, Wilford Hall Medical Center, Lackland Air Force Base, Fort Sam Houston, TX.
Disclaimers: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the US Department of the Army, US Department of the Air Force, the US Department of Defense or US government. The authors are employees of the US government, and this work was performed as part of their official duties. As such, there is no copyright to be transferred.
Address correspondence and reprint requests to Clinton K. Murray, MD, MAJ(P), MC, USA, Infectious Disease Service, MCHE-MDI, Brooke Army Medical Center, 3851 Roger Brooke Dr, Fort Sam Houston, TX 78234. E-mail: email@example.com.
The multidrug-resistant Acinetobacter baumannii-Acinetobactercal coaceticus complex (MDR-ABC) is a problematic cause of nosocomial infection worldwide.1 The organism's ability to easily acquire antimicrobial resistance, combined with a lack of further drug development, has led to an ever-shrinking armamentarium of effective antimicrobials.2 Although the carbapenems have long been considered the antimicrobials of choice for treating MDR-ABC infections, an increase in carbapenem resistance among MDR-ABC isolates has decreased the use of this class.3,4 This has forced many clinicians to use less conventional antimicrobials, such as colistin or tigecycline, which are unproven for this indication and may result in relatively high rates of toxicity.2
In our hospital, a US military facility that treats wounded service members, this problem is compounded by the fact that many of the MDR-ABC infections are wound infections with underlying bone fracture.3,5,6 Because these types of infections are often associated with poor bone healing and delayed union, most clinicians in our institution opt to treat these empirically as osteomyelitis.6 Osteomyelitis with MDR-ABC carries the added burden of requiring prolonged courses of antimicrobials.7 Treatment with carbapenems, colistin, or tigecycline thus requires prolonged parenteral therapy as no oral forms of these medications are available. This subjects the patient to the risks inherent to long-term intravenous access and may place the patient at an increased risk of adverse medication effects. Finding a safe antimicrobial that can be administered orally would greatly improve the care of these patients.
Minocycline has potential as a safe oral therapy. Its activity against Acinetobacter species both in vitro and in vivo has been known for many years, and it has been used clinically with success.8-10 Based on these data, our institution has begun to use minocycline in some patients with MDR-ABC infections. In this article, we report the outcomes of 8 patients who received minocycline as therapy for MDR-ABC traumatic wound infections.
MATERIALS AND METHODS
This study was a retrospective chart review of patients cared for at Brooke Army Medical Center in Fort Sam Houston, Texas, during 2005 and 2006. This study was approved by the institutional review board. Pharmacy records were used to identify all patients who received minocycline at any time during 2005 and 2006. Chart review of electronic inpatient and outpatient records was then performed to identify which of these patients received minocycline for a traumatic wound infection caused by MDR-ABC. Isolate identification was performed using standard microbiology techniques. Antimicrobial susceptibilities were performed using disk diffusion or broth microdilution testing per Clinical and Laboratory Standards Institute guidelines. Because a previous study revealed that MDR-ABC at our institution typically remains susceptible to minocycline, susceptibility testing for this drug was not routinely performed by the laboratory, unless requested by the attending physician.9 Multidrug resistance was defined as resistance to all commonly tested cephalosporins, β lactam/β-lactamase inhibitor combinations, and fluoroquinolones. A wound was considered infected if MDR-ABC was isolated from the wound in association with at least one of the following: fever (temperature >100.5°F), leukocyte count greater than 11,000 cells/mL, wound purulence, or poor wound healing, as described by the treating physician. Subjects were excluded if they received a course of therapy with another active antimicrobial before receiving minocycline. Information extracted from chart review included age, sex, site of infection, type of injury, type and duration of antimicrobial therapy received, presence of copathogens, outcome, and length of follow-up. For outcome, a case was defined as a treatment success if, at the time of last follow-up, a course of minocycline had been completed without complications, no further antimicrobial therapy directed against MDR-ABC was given after the minocycline, and there were no further signs of MDR-ABC infection as determined by symptoms, physical examination, and laboratory evaluation (laboratory markers examined were leukocyte count, erythrocyte sedimentation rate, and C-reactive protein).
A total of 8 patients received minocycline for a traumatic wound infection caused by MDR-ABC. The characteristics of these patients are listed in Table 1. All patients were men, aged 19 to 35 years. Four patients had open bone fractures, and 4 patients had traumatic amputations of a limb. Fixation devices were used on all 4 patients with open fractures. Two received external fixation devices, and 2 underwent internal fixation. The hardware was retained in all 4 of these patients. Two patients had proven osteomyelitis as determined by positive bone culture or characteristic bone histology. The remaining patients all had exposed bone in the wound bed. All patients received antimicrobial therapy for presumptive osteomyelitis. All patients underwent serial surgical debridement of wounds until there was no further nonviable or grossly infected tissue present. All patients received 100 mg of minocycline orally twice a day.
The antimicrobial susceptibility profiles for each patient are listed in Table 2. Six of the patients had carbapenem-resistant isolates at the beginning of therapy. The results of colistin susceptibility were available for 6 patients; all isolates tested were susceptible. All tested isolates were susceptible to minocycline. For 5 of the patients, minocycline was the only active agent used to treat their MDR-ABC infection. Two of these 5 received imipenem concurrently with their minocycline for treatment of copathogens, but their MDR-ABC isolates were resistant to imipenem. A sixth patient was treated with minocycline after developing renal toxicity after 2 weeks of colistin therapy. The seventh patient received imipenem for 6 weeks but relapsed with imipenem-resistant MDR-ABC and was subsequently treated with minocycline. The last patient received colistin for 9 days before being transitioned to minocycline because of his provider's preference.
Minocycline therapy resulted in clinical cure of the infection in 7 of the patients. The other patient was improving on minocycline, but developed eosinophilia and neutropenia attributable to the minocycline, which resolved after discontinuing the medication. Colistin was used to successfully complete his antimicrobial therapy. No other patient experienced an adverse effect that was attributable to minocycline therapy. The average length of follow-up for these successfully treated cases was approximately 6 weeks (range, 2 weeks-17 months).
In this report, we describe the use of minocycline in treating traumatic wound infections caused by MDR-ABC. Minocycline was successfully used in 7 of the 8 patients. Only 1 patient experienced adverse effects, and these reversed after stopping therapy. The successful use of minocycline in treating multidrug-resistant Acinetobacter baumannii pneumonia has been reported in the literature, but to our knowledge, ours is the first report regarding the use of minocycline for traumatic wound infections caused by this pathogen.10 Our experience builds on that reported by Wood et al10 and further supports the use of minocycline in treating MDR Acinetobacter infections. This safe and inexpensive drug would be an important addition to the scant armamentarium of available agents.
Minocycline has several characteristics that make it a rational alternative to the other agents often used to treat MDR Acinetobacter wound infections. It has exceptional oral bioavailability and excellent penetration into bone and soft tissues.11 Unlike imipenem, colistin, and tigecycline, the other available agents often used to treat MDR-ABC, minocycline can be given orally. Its antimicrobial spectrum is not as broad, thus decreasing the likelihood of Clostridium difficile-associated disease. Notably, minocycline often maintains activity against MDR-ABC isolates that are resistant to imipenem.9 Although not free of adverse effects, it has a long historical record of safety and is clearly less toxic than colistin.
The occurrence of minocycline-induced neutropenia and eosinophilia in 1 patient was somewhat surprising. Although these findings have been reported with minocycline use, they seem to be very rare.12 The more commonly reported adverse effects of minocycline use, such as gastrointestinal disturbance, skin or mucous membrane pigmentation, vestibular dysfunction, and hepatotoxicity, were not seen in this cohort.13
Our case series has 2 important limitations. Four of the patients received imipenem along with minocycline. Although testing revealed that the MDR-ABC isolates were resistant to imipenem in these cases, it is possible that it still maintained some activity in vivo or provided some synergy with minocycline, thus biasing our results in favor of minocycline therapy. That aside, we could find no reports of synergy between minocycline and imipenem reported in the literature. In addition, 3 of the patients did not receive concurrent therapy and still had successful outcomes. A more important limitation is that in most patients, coinfection with another pathogen was also present. The MDR-ABC is often considered a low-virulence pathogen. It is possible that in these cases of coinfection, it was not the primary pathogen, and clinical response was related more to appropriate treatment of the other pathogen(s) involved. It is our opinion that most clinicians would opt to treat MDR-ABC as a true pathogen in similar cases. In that respect, the low pathogenicity of MDR-ABC would actually be an argument to use a safe oral medicine, such as minocycline, instead of more broad-spectrum or toxic agents, such as colistin and imipenem.
Because MDR-ABC is a low-virulence pathogen, the infections are typically easy to treat if an antimicrobial agent with activity against the bacteria is available. In contrast to infections from other organisms such as Staphylococcus aureus, MDR-ABC wound infections in our institution are usually cured with a single course of an active antimicrobial and are not likely to relapse.5,6 Thus, the primary difficulty with MDR-ABC is finding an antimicrobial that retains activity against the pathogen, while not imparting an unacceptable risk of toxicity. It seems as if minocycline meets these criteria rather well.
In this report, we describe the successful treatment of MDR-ABC traumatic wound infections with minocycline. This suggests that minocycline may be an effective therapy for these infections. More studies, to include controlled trials, are needed to further determine the appropriate role of this agent in treating MDR-ABC.
1. Paterson DL. The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis. 2006;43:S43-S48.
2. Talbot GH, Bradley J, Edwards JE, et al. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Disease Society of America. Clin Infect Dis. 2006;42:657-668.
3. Murray CK, Hospenthal DR. Treatment of multidrug resistant Acinetobacter. Curr Opin Infect Dis. 2005;18:502-506.
4. Coelho JM, Turton JF, Kaufmann ME, et al. Occurrence of carbapenem-resistant Acinetobacter baumannii clones at multiple hospitals in London and southeast England. J Clin Microbiol. 2006;44:3623-3627.
5. Davis KA, Moran KA, McAllister CK, et al. Multidrug-resistant Acinetobacter extremity infections in soldiers. Emerg Infect Dis. 2005;11:1218-1224.
6. Johnson EN, Burns TC, Hayda RA, et al. Infectious complications of open type III tibial fractures among combat casualties. Clin Infect Dis. 2007;45:409-415.
7. Lazzarini L, Mader JT, Calhoun JH. Osteomyelitis in long bones. J Bone Joint Surg Am. 2004;86:2305-2318.
8. Kuck NA. In vitro and in vivo activities of minocycline and other antibiotics against Acinetobacter (Herellea-Mima). Antimicrob Agents Chemother. 1976;9:493-497.
9. Hawley JS, Murray CK, Griffith ME, et al. Susceptibility of Acinetobacter strains isolated from deployed US military personnel. Antimicrob Agents Chemother. 2007;51:376-378.
10. Wood GC, Hanes SD, Boucher BA, et al. Tetracyclines for treating multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia. Intensive Care Med. 2003;29:2072-2076.
11. Jonas M, Cunha BA. Minocycline. Ther Drug Monit. 1982;4:137-145.
12. Kaufmann D, Pichler W, Beer JH. Severe episode of high fever with rash, lymphadenopathy, neutropenia, and eosinophilia after minocycline therapy for acne. Arch Intern Med. 1994;154:1983-1984.
13. Smilack JD. The tetracyclines. Mayo Clin Proc. 1999;74:727-729.
© 2008 Lippincott Williams & Wilkins, Inc.