REVIEW REPORT SPECIAL For reprint orders, please contact: [email protected]
Is minocycline a solution for multidrugresistant Acinetobacter baumannii?
Ioannis K Neonakis*,1, Demetrios A Spandidos2 & Efthimia Petinaki3
ABSTRACT: Minocycline is an old, safe, second-line antimicrobial agent that has drawn attention over the last few years as a possible therapeutic option against multidrug-resistant Acinetobacter baumannii (MDR‑AB) clinical isolates. Recent in vitro and in vivo results indicate that minocycline is a valid, alternative treatment option for minocycline-susceptible MDR‑AB. Although effective alone, its administration as monotherapy should be avoided. Combinations with other antimicrobials can reduce the MIC of each component, present synergism and minimize the risk for drug resistance. Owing to its limited solubility in urine, it should be avoided for urinary pathogens. The present article reports all available information regarding its use as a therapeutic option against MDR‑AB. Background Acinetobacter species are non-motile, oxidase-negative Gram-negative coccobacilli. Based on DNA–DNA hybridization and nutritional characteristics, numerous different groups (genomo species) were distinguished within the genus Acinetobacter. Among them, genomospecies 1 is the type species Acinetobacter calcoaceticus and genomospecies 2 is Acinetobacter baumannii and includes those isolates previously referred to as A. calcoacetiticus var anitratus. The members of these groups are sometimes characterized as ‘A. calcoaceticus–A. baumannii complex’ or ‘saccharolytic Acinetobacter’. The most common Acinetobacter species isolated from human clinical samples is A. baummannii. Over the last few years, A. baummannii has started to be considered as one of the most dangerous nosocomial pathogens [1] . Although it is a low-virulence pathogen that can be easily confronted with no relapses using only a single course of an active antimicrobial agent, it has the ability to easily acquire and incorporate serious resistance mechanisms [2,3] . Multidrug-resistant A. baumannii (MDR‑AB; i.e., isolates resistant to quinolones, aminoglycosides and β-lactams, including carbapenems) isolates are being increasingly reported worldwide, causing serious nosocomial infections associated with increased morbidity and mortality [4] . As our armamentarium against these MDR‑AB isolates has become extremely limited, the use of old, second-line antimicrobials has attracted new interest. In the present study, we review the available information concerning the use of minocycline as an alternative therapeutic option for minocycline-susceptible MDR‑AB. Minocycline is a compound that was derived in the late 1960s by structural modification of the tetracycline molecule. Minocycline has a longer half-life, better daily dosage schedule, better oral absorption and the ability to overcome most tetracycline-resistance mechanisms [5] . Minocycline is a different molecule when compared with tetracycline, and these two agents should always be examined and approached separately. Minocycline is usually administered orally; however, it can also be used intravenously [5,6] . It should be noted that the intravenous formulation was brought
KEYWORDS
• carbapenem resistance • colistin • minocycline • multidrug-resistant
Acinetobacter baumannii • tetracycline • ventilatorassociated pneumonia
Department of Microbiology, University Hospital of Heraklion, Heraklion, Crete, Greece Department of Laboratory Medicine, Medical School, University of Crete, Heraklion, Crete, Greece 3 Department of Microbiology, Medical School, University of Thessaly, Larissa, Greece *Author for correspondence: Tel.: +30 2810 392601; Fax: +30 210 7252922; [email protected] 1 2
10.2217/FMB.13.167 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(3), 299–305
part of
ISSN 1746-0913
299
Special Report Neonakis, Spandidos & Petinaki back into production in the USA, specifically because of the MDR‑AB problem. Minocycline binds to bacterial ribosome leading to wide-range structural changes in the 16S rRNA, thus preventing the association of aminoacyl-tRNA with the bacterial ribosome leading to inhibition of bacterial protein synthesis [7] . It acts both against Gram-positive and Gram-negative bacteria and, although bacteriostatic, it is generally considered clinically effective for the treatment of acne vulgaris, urethral/cervical infections and respiratory infections in seriously ill hospitalized patients [8] . Owing to its increased lipophilicity, it transverses cell membranes and easily penetrates various tissues such as the prostate or CNS [9] . On the other hand, its solubility in urine is limited and, in general, it is not the antimicrobial of choice for urinary pathogens. The side effects of minocycline are mild and transient and are usually confined to gastrointestinal symptoms, CNS effects (e.g., lightheadedness, dizziness and vertigo), hyperpigmentation, hypersensitivity and autoimmune effects [8] . Minocycline is very well tolerated and overall adverse events are rare. In a systematic review by Smith et al., it is estimated that, from January 1998 to August 2003 in the USA, the rate of overall adverse events was only 72 cases per million of new minocycline prescriptions [8] . Although other researchers report higher rates of adverse events [10,11] , it is generally accepted that minocycline is a safe and well-tolerated antimicrobial. The broad antibacterial effect of minocycline against both Gram-positive cocci and Gramnegative bacilli was detected very early [12] . Several subsequent studies in the 1970s revealed its high in vitro and in vivo activity against clinical isolates of A. calcoacetiticus var. anitratus/A. baumannii [13–15] . In one study, using agar dilution tests, it was shown that minocycline was two- to four-times more potent than gentamicin or polymyxin and eight-times more potent than tetracycline against A. baumanni [14] . In the same study, it was further demonstrated that minocycline was more active than gentamicin or polymyxin against lethal infections produced by strains of A. baumannii in mice. In particular, on the basis of subcutaneous dosage requirements (mg/kg) for protection against the Acinetobacter infections, minocycline was one- to four-times as active as gentamicin and 0.2- to 1.5-times as active as polymyxin. On the basis of median effective peak serum concentrations (μg/ml) for protection against the Acinetobacter infections, minocycline
300
Future Microbiol. (2014) 9(3)
was also found to be superior to gentamicin and polymyxin and, in all cases, its concentration was less than 2 μg/ml, a concentration that is clinically achievable [14] . The results of these initial studies strongly suggested that minocycline represents a useful option for the treatment of infections by A. baumannii. However, over time, the use of minocycline against this pathogen was limited mainly due to its bacteriostatic properties and the introduction of new and more potent agents. This practice has continued until recently when the lack of viable treatment alternatives against multidrug-resistant pathogens has led us to re-examine forgotten antimicrobials. In vitro results Recently, additional information arose on the in vitro effectiveness of minocycline, either alone or in combination with other antimicrobials against A. baumanni. In 2007, Hawley et al. reported the susceptibilities of 142 A. baumannii isolates (95 from wounded US soldiers who were deployed overseas) to 13 antimicrobial agents, as determined by broth microdilution [16] . The most active agents were found to be minocycline and colistin. The susceptibility rates for minocycline were 98 and 97% for nondeployed and deployed personnel, respectively, whereas the rates for imipenem were much lower at 87 and
Is minocycline a solution for multidrugresistant Acinetobacter baumannii?
Ioannis K Neonakis*,1, Demetrios A Spandidos2 & Efthimia Petinaki3
ABSTRACT: Minocycline is an old, safe, second-line antimicrobial agent that has drawn attention over the last few years as a possible therapeutic option against multidrug-resistant Acinetobacter baumannii (MDR‑AB) clinical isolates. Recent in vitro and in vivo results indicate that minocycline is a valid, alternative treatment option for minocycline-susceptible MDR‑AB. Although effective alone, its administration as monotherapy should be avoided. Combinations with other antimicrobials can reduce the MIC of each component, present synergism and minimize the risk for drug resistance. Owing to its limited solubility in urine, it should be avoided for urinary pathogens. The present article reports all available information regarding its use as a therapeutic option against MDR‑AB. Background Acinetobacter species are non-motile, oxidase-negative Gram-negative coccobacilli. Based on DNA–DNA hybridization and nutritional characteristics, numerous different groups (genomo species) were distinguished within the genus Acinetobacter. Among them, genomospecies 1 is the type species Acinetobacter calcoaceticus and genomospecies 2 is Acinetobacter baumannii and includes those isolates previously referred to as A. calcoacetiticus var anitratus. The members of these groups are sometimes characterized as ‘A. calcoaceticus–A. baumannii complex’ or ‘saccharolytic Acinetobacter’. The most common Acinetobacter species isolated from human clinical samples is A. baummannii. Over the last few years, A. baummannii has started to be considered as one of the most dangerous nosocomial pathogens [1] . Although it is a low-virulence pathogen that can be easily confronted with no relapses using only a single course of an active antimicrobial agent, it has the ability to easily acquire and incorporate serious resistance mechanisms [2,3] . Multidrug-resistant A. baumannii (MDR‑AB; i.e., isolates resistant to quinolones, aminoglycosides and β-lactams, including carbapenems) isolates are being increasingly reported worldwide, causing serious nosocomial infections associated with increased morbidity and mortality [4] . As our armamentarium against these MDR‑AB isolates has become extremely limited, the use of old, second-line antimicrobials has attracted new interest. In the present study, we review the available information concerning the use of minocycline as an alternative therapeutic option for minocycline-susceptible MDR‑AB. Minocycline is a compound that was derived in the late 1960s by structural modification of the tetracycline molecule. Minocycline has a longer half-life, better daily dosage schedule, better oral absorption and the ability to overcome most tetracycline-resistance mechanisms [5] . Minocycline is a different molecule when compared with tetracycline, and these two agents should always be examined and approached separately. Minocycline is usually administered orally; however, it can also be used intravenously [5,6] . It should be noted that the intravenous formulation was brought
KEYWORDS
• carbapenem resistance • colistin • minocycline • multidrug-resistant
Acinetobacter baumannii • tetracycline • ventilatorassociated pneumonia
Department of Microbiology, University Hospital of Heraklion, Heraklion, Crete, Greece Department of Laboratory Medicine, Medical School, University of Crete, Heraklion, Crete, Greece 3 Department of Microbiology, Medical School, University of Thessaly, Larissa, Greece *Author for correspondence: Tel.: +30 2810 392601; Fax: +30 210 7252922; [email protected] 1 2
10.2217/FMB.13.167 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(3), 299–305
part of
ISSN 1746-0913
299
Special Report Neonakis, Spandidos & Petinaki back into production in the USA, specifically because of the MDR‑AB problem. Minocycline binds to bacterial ribosome leading to wide-range structural changes in the 16S rRNA, thus preventing the association of aminoacyl-tRNA with the bacterial ribosome leading to inhibition of bacterial protein synthesis [7] . It acts both against Gram-positive and Gram-negative bacteria and, although bacteriostatic, it is generally considered clinically effective for the treatment of acne vulgaris, urethral/cervical infections and respiratory infections in seriously ill hospitalized patients [8] . Owing to its increased lipophilicity, it transverses cell membranes and easily penetrates various tissues such as the prostate or CNS [9] . On the other hand, its solubility in urine is limited and, in general, it is not the antimicrobial of choice for urinary pathogens. The side effects of minocycline are mild and transient and are usually confined to gastrointestinal symptoms, CNS effects (e.g., lightheadedness, dizziness and vertigo), hyperpigmentation, hypersensitivity and autoimmune effects [8] . Minocycline is very well tolerated and overall adverse events are rare. In a systematic review by Smith et al., it is estimated that, from January 1998 to August 2003 in the USA, the rate of overall adverse events was only 72 cases per million of new minocycline prescriptions [8] . Although other researchers report higher rates of adverse events [10,11] , it is generally accepted that minocycline is a safe and well-tolerated antimicrobial. The broad antibacterial effect of minocycline against both Gram-positive cocci and Gramnegative bacilli was detected very early [12] . Several subsequent studies in the 1970s revealed its high in vitro and in vivo activity against clinical isolates of A. calcoacetiticus var. anitratus/A. baumannii [13–15] . In one study, using agar dilution tests, it was shown that minocycline was two- to four-times more potent than gentamicin or polymyxin and eight-times more potent than tetracycline against A. baumanni [14] . In the same study, it was further demonstrated that minocycline was more active than gentamicin or polymyxin against lethal infections produced by strains of A. baumannii in mice. In particular, on the basis of subcutaneous dosage requirements (mg/kg) for protection against the Acinetobacter infections, minocycline was one- to four-times as active as gentamicin and 0.2- to 1.5-times as active as polymyxin. On the basis of median effective peak serum concentrations (μg/ml) for protection against the Acinetobacter infections, minocycline
300
Future Microbiol. (2014) 9(3)
was also found to be superior to gentamicin and polymyxin and, in all cases, its concentration was less than 2 μg/ml, a concentration that is clinically achievable [14] . The results of these initial studies strongly suggested that minocycline represents a useful option for the treatment of infections by A. baumannii. However, over time, the use of minocycline against this pathogen was limited mainly due to its bacteriostatic properties and the introduction of new and more potent agents. This practice has continued until recently when the lack of viable treatment alternatives against multidrug-resistant pathogens has led us to re-examine forgotten antimicrobials. In vitro results Recently, additional information arose on the in vitro effectiveness of minocycline, either alone or in combination with other antimicrobials against A. baumanni. In 2007, Hawley et al. reported the susceptibilities of 142 A. baumannii isolates (95 from wounded US soldiers who were deployed overseas) to 13 antimicrobial agents, as determined by broth microdilution [16] . The most active agents were found to be minocycline and colistin. The susceptibility rates for minocycline were 98 and 97% for nondeployed and deployed personnel, respectively, whereas the rates for imipenem were much lower at 87 and
