Do we still need the aminoglycosides?

International Journal of Antimicrobial Agents 33 (2009) 201–205

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag

Review

Do we still need the aminoglycosides? Emanuele Durante-Mangoni a , Alexandros Grammatikos b,c , Riccardo Utili a , Matthew E. Falagas b,d,e,∗ a

Unit of Infectious & Transplant Medicine, 2nd University of Naples, Monaldi Hospital, Naples, Italy Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece c Department of Medicine, ‘G. Gennimatas’ Hospital, Thessaloniki, Greece d Department of Medicine, ‘Henry Dunant’ Hospital, Athens, Greece e Department of Medicine, Tufts University School of Medicine, Boston, MA, USA b

a r t i c l e

i n f o

Keywords: Aminoglycosides Infections Gram-negative bacteria Antibiotics

a b s t r a c t Since the introduction into clinical practice of the aminoglycoside class of antibiotics, a number of other antimicrobial agents with improved safety profile have entered the market. Studies have failed to demonstrate the superiority of aminoglycoside-containing regimens in a number of infection settings. This has raised doubts regarding the actual clinical utility of aminoglycosides. However, the recent emergence of infections due to Gram-negative bacterial strains with advanced patterns of antimicrobial resistance has prompted physicians to reconsider these ‘old’ antibacterial agents. This revived interest in the use of aminoglycosides has brought back to light the debate on the two major issues related to these compounds, namely the spectrum of antimicrobial susceptibility and toxicity. Although some of the aminoglycosides retain activity against the majority of Gram-negative clinical bacterial isolates in many parts of the world, the relatively frequent occurrence of nephrotoxicity and ototoxicity during aminoglycoside treatment make physicians reluctant to use these compounds in everyday practice. We believe that recent advances in the understanding of the effect of various dosage schedules of aminoglycosides on toxicity combined with the retained (to a considerable degree) activity against the majority of Gram-negative bacterial isolates make this class of antibiotics still valuable in today’s clinical practice. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction The aminoglycosides are one of the oldest classes of antimicrobials. Streptomycin was the first, introduced into the therapeutic armamentarium in the 1940s. The newer semisynthetic derivatives of the aminoglycoside family entered clinical use almost 30 years ago but, since then, no additional molecule of this class has been developed. In contrast, numerous antimicrobial compounds of other antibiotic classes with good antimicrobial coverage, such as ␤-lactams, have entered clinical use during the last decades. The question therefore arises as to whether we still need the aminoglycosides in the modern era of antimicrobial treatment. In this review, we shall briefly cover this issue, highlighting the current evidence for and against the use of aminoglycosides in clinical practice.

∗ Corresponding author at: Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece. Tel.: +30 694 611 0000; fax: +30 210 683 9605. E-mail address: [email protected] (M.E. Falagas).

2. Spectrum of antimicrobial activity and mechanism of action The aminoglycosides are a group of antibiotics either derived from Streptomyces spp. (streptomycin, neomycin and tobramycin) or Micromonospora spp. (gentamicin) or synthesised in vitro (netilmicin, amikacin, arbekacin and isepamicin). They exhibit antimicrobial activity against a wide spectrum of different microorganisms, including Gram-positive and Gram-negative bacteria, mycobacteria and protozoa. In clinical practice the molecules most frequently prescribed at present are gentamicin, tobramycin and amikacin, whilst streptomycin remains an important tool in the treatment of tuberculosis, brucellosis, tularaemia and plague. Paromomycin and spectinomycin have been used to treat intestinal protozoal pathogens and Neisseria gonorrhoeae infections, respectively. Classically, gentamicin is often used in combination with a cell wall-active agent for susceptible (i.e., non-high-level resistant) enterococcal infections, whilst tobramycin and amikacin retain the highest anti-Pseudomonas activity within the class, and arbekacin is successfully employed in Japan against meticillin-resistant Staphylococcus aureus (MRSA). Aminoglycosides are transported across

0924-8579/$ – see front matter © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2008.09.001

202

E. Durante-Mangoni et al. / International Journal of Antimicrobial Agents 33 (2009) 201–205

the cytoplasmic membrane in an oxygen-dependent manner, thus they display no activity against anaerobes. The aminoglycosides exert their activity by binding to the aminoacyl site of 16S ribosomal RNA (rRNA) within the 30S ribosomal subunit [1,2]. They are characterised by a rapid bactericidal activity and, as a class, they seem to have synergistic activity with ␤-lactams and other cell wall-active agents [3] as well as a highly concentration-dependent antimicrobial effect. Moreover, they have been consistently shown to possess a significant post-antibiotic effect. This accounts for the persistent suppression of bacterial growth up to 7.5 h after the drug has been cleared and has been described both for Gram-negative bacilli and S. aureus, but not other Gram-positive cocci [4]. The major adverse effects of aminoglycosides are dosedependent nephrotoxicity and ototoxicity, with impairment of both vestibular and hearing functions. Neuromuscular blockade is a rare but serious adverse effect that may occur in patients with disease states and/or concomitant drug therapy that interfere with neuromuscular transmission. Finally, hypersensitivity reactions, nausea, vomiting, headache, tremor, arthralgias and hypotension have also been reported.

3. Mechanisms of resistance As mentioned earlier, the mechanism of action of aminoglycosides involves penetration within the target cell and direct interference with bacterial protein synthesis via binding to the 30S ribosomal subunit. However, the binding site within the active site of the 30S subunit differs for individual molecules. Thus, resistance more commonly develops against single molecules rather than all members of the class. Moreover, on-treatment development of resistance to aminoglycosides is rather rare, especially if they are used in combination with other antibiotics. Several aminoglycoside resistance mechanisms have been characterised [2]. Individual bacterial species, including enterococci and anaerobes, are intrinsically resistant to relatively low levels of aminoglycoside; in fact, owing to their facultative anaerobic metabolism, these bacteria show minimum inhibitory concentrations (MICs) of aminoglycosides ranging from 4 mg/L to 256 mg/L, but are normally susceptible to higher drug levels. Intrinsically susceptible bacteria may produce inactivating enzymes [5–7], which may be encoded by plasmids or associated with transposable elements [8]. When these aminoglycoside-modifying enzymes, including acetyltransferases, phosphotransferases and nucleotidyltransferases, are produced from plasmid-encoded resistance genes, the MIC of enterococci and certain Gram-negative bacteria increases up to 500–2000 mg/L, conferring the so-called high-level resistance to aminoglycosides, mostly gentamicin. In contrast, resistance to high levels of streptomycin is due to mutational changes in ribosomal proteins. Decreased accumulation of the drug is another major mechanism of resistance [9]. Bacteria may express efflux systems that result in reduced aminoglycoside accumulation within the cell [10]. At present, a large proportion of Pseudomonas, Acinetobacter and Burkholderia spp. show resistance to aminoglycosides owing to production of highly efficient multidrug efflux systems capable of actively pumping out the drug from the cell. Methylation of the 16S rRNA within the 30S subunit in species such as Pseudomonas, Acinetobacter, Escherichia coli, and Klebsiella impairs aminoglycoside binding, thereby blocking their antimicrobial activity. rRNA methylation is a self-protection mechanism developed by actinomycetes to resist self-produced aminoglycosides. Methylation at nucleotides G1405 and A1408 in the A-site hampers binding of the aminoglycoside to the 30S ribosome. armA

and rmtA–D genes encoding 16S rRNA methylases are located on transposons and can be easily spread to different bacterial species such as Pseudomonas, Acinetobacter and several Enterobacteriaceae, conferring high-level resistance to gentamicin, tobramycin, amikacin and arbekacin but not streptomycin. Co-expression of 16S rRNA methylase and metallo-␤-lactamases (CTX-M, SHV) gives to Pseudomonas and Acinetobacter spp. the multidrug-resistant (MDR) trait so often encountered in clinical practice and accounting for failure of carbapenems and aminoglycosides [8,11]. 4. Pharmacokinetics/pharmacodynamics Aminoglycoside antimicrobial activity appears to be mostly concentration-dependent. Concentration-dependent killing refers to the ability of higher concentrations of aminoglycosides (relative to the organism’s MIC) to induce a more rapid and extensive killing of the pathogen [12]. Time–kill studies of the bactericidal activity of tobramycin against Pseudomonas aeruginosa have clearly shown that increasing concentrations from 0.25× up to 64× the strain MIC produces progressively greater extents of bacterial killing even after a few hours of exposure [13]. Elevated peak concentrations enhance efficacy whilst lower trough concentrations reduce the incidence of nephrotoxicity. Once-daily administration of the total dose therefore appears to be the best approach to achieve these optimal concentrations and results in improved efficacy and toxicity outcomes [14]. However, the killing profile of individual aminoglycosides may actually differ according to the bacterial strain considered. Indeed, increasing the concentration above 2× MIC does not appear to improve further the extent of bacterial killing against S. aureus [15]. In this setting, gentamicin appears to exert its activity through a time-dependent mechanism. This may explain why in staphylococcal endocarditis multiple daily dosing schedules appear to be preferable [16]. Therefore, according to current evidence, aminoglycosides should be administered as a single daily dose in Gram-negative infections and as multiple doses (two to three) in Gram-positive infections. Aminoglycosides show poor penetration into the cerebrospinal fluid, biliary tree and bronchial secretions, whilst they concentrate very efficiently within the urine. 5. Current indications for use 5.1. General concepts The most frequent clinical use of aminoglycosides is empirical therapy of serious infections such as septicaemia, nosocomial respiratory tract infections, complicated urinary tract infections (UTIs) and complicated intra-abdominal infections caused by aerobic Gram-negative bacilli. However, in long-term treatment, once an organism has been identified and susceptibilities have been determined, aminoglycosides are often discontinued in favour of less toxic options. Owing to the emergence of MDR organisms, aminoglycosides have recently been re-evaluated as active agents along with the polymyxins [17]. This is particularly true in the setting of serious infections due to extended-spectrum ␤-lactamase (ESBL)producing Enterobacteriaceae, Pseudomonas and Acinetobacter spp., including nosocomial pneumonia and UTIs. Many authors recommend that aminoglycoside antibiotics should be administered in combination with other antimicrobial agents, such as ␤-lactams. Indeed, aminoglycoside interaction with cell wall-active agents has been repeatedly confirmed in the laboratory: proven synergism exists with ampicillin against enterococci, as ampicillin enhances uptake of the aminoglycoside

E. Durante-Mangoni et al. / International Journal of Antimicrobial Agents 33 (2009) 201–205

by disrupting the peptidoglycan cell wall, which is normally impermeable to aminoglycosides. A potential benefit may also exist for Enterobacteriaceae, Pseudomonas and staphylococci, as addition of an aminoglycoside may prevent development of resistance to the ␤-lactam agent. In contrast, antagonism appears to be observed between glycopeptides and aminoglycosides in MRSA infections owing to induction of aminoglycoside acetyltransferase and phosphotransferase enzymes. Despite scientific support of the notion of synergism, clinical trials attempting to compare the efficacy of ␤-lactam/aminoglycoside combination treatments with that of ␤-lactam monotherapy have failed to confirm its value. In these trials, combination treatment is associated with an equal number of treatment failures, whilst it is related to a higher incidence of adverse events [18–23]. The aminoglycoside/␤-lactam combination does not appear to be associated with a lower incidence of resistance development or a better outcome in P. aeruginosa infections either [18]. Although only a few trials have been carried out on the efficacy of aminoglycoside monotherapy in comparison with combination treatment, it appears that such monotherapy is better suited for the treatment of UTIs [24]. 5.2. Aminoglycosides in lower respiratory tract infection Aminoglycosides are no longer among the preferred antimicrobial agents for the treatment of pneumonia. This is essentially due to three major reasons: (1) a low concentration of these drugs within the alveolar lining fluid of the lungs [25]; (2) inactivation of aminoglycosides by the acidic pH present within the inflamed lung tissue; (3) high risk of nephrotoxicity in otherwise often critically ill patients. The 2007 Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines include an aminoglycoside, as a second-line option, only in cases of suspected or documented Pseudomonas pneumonia, especially in fluoroquinolone-experienced subjects [26]. 5.3. Aminoglycosides in infective endocarditis (IE) Aminoglycosides have long been a mainstay of treatment of IE. Gentamicin, together with cell wall-active agents, is included in most of the treatment regimens recommended by the current guidelines. The addition of gentamicin to penicillin appears to exert a synergistic bactericidal effect in in vitro and experimental models of both viridans group streptococcal and staphylococcal endocarditis. However, the benefits of this regimen are yet to be proven in clinical practice. Indeed, several lines of evidence show that the use of gentamicin may not add an appreciable favourable effect and may even be associated with higher rates of adverse events [19]. According to current recommendations, combination treatment with penicillin and gentamicin can be used for 2 weeks ␤-lactam in place of standard 4-week monotherapy for streptococcal native valve IE. The recommendations for the use of gentamicin are even more stringent in prosthetic valve streptococcal IE, where this molecule should be added for the first 2 weeks in cases due to penicillin-susceptible strains and for the whole 6-week period in cases due to penicillin-non-susceptible strains [16]. The true feasibility of such a long-lasting gentamicin regimen in patients commonly characterised by reduced renal function is, however, poorly demonstrated. In staphylococcal native valve IE, although addition of gentamicin to a ␤-lactam reduces the duration of bacteraemia by ca. 1 day in human studies, this combination does not improve mortality or complication rates but increases renal toxicity. Therefore, in this setting gentamicin should be added to a cell wall-active agent for no longer than the initial 3–5 days of treatment in cases

203

due to susceptible strains (meticillin-susceptible S. aureus) [16]. When staphylococcal infection involves a prosthetic intracardiac structure, addition of gentamicin is recommended for the initial 2 weeks of therapy. However, very little clinical data are available to support this contention as well. A meta-analysis of five wellconducted clinical trials comparing ␤-lactam monotherapy with a combination of an aminoglycoside and a ␤-lactam in IE has been performed recently [19]. Outcomes evaluated were cure rates, need for surgery and nephrotoxicity. Combination therapy did not positively affect any outcome but it did significantly increase the rates of renal adverse effects. Finally, in IE cases due to non-high-level resistant enterococci, appropriate killing might be exploited by the synergistic combination of a cell wall-active agent and gentamicin. 5.4. Aminoglycosides in urinary tract infections Aminoglycosides reach concentrations in the urine 25–100-fold that of serum. Approximately 99% of the administered dose is eliminated unchanged in the urine, primarily via glomerular filtration. Therefore, aminoglycosides are a very potent tool in the treatment of complicated UTIs. In an era when resistance against many commonly used first-line antibiotics for UTIs is spreading rapidly, aminoglycosides could prove of significant value in this particular setting. It should be noted that the half-life of aminoglycosides is prolonged in patients with decreased renal function, thus caution should be exercised in these cases. 6. Evaluation of the evidence for the need of aminoglycosides in current clinical practice There are two important issues that discourage physicians from using aminoglycosides more extensively than they do in current clinical practice: the advanced pattern of antimicrobial resistance of today’s clinical isolates in many parts of the world; and the toxicity of this class of antibiotics. This is reflected in the drop in the recorded use of aminoglycosides in recent years. Thus, what emerges as an important question for the clinician is whether these problems are indeed serious enough to make the choice of aminoglycosides an unattractive one in most instances. The SENTRY antimicrobial resistance surveillance programme shows that aminoglycosides still retain good activity against most Gram-negative fermenting bacilli such as E. coli, Klebsiella pneumoniae and Enterobacter spp. [27,28]. Susceptibility rates of these bacteria to amikacin averaged 97.3%, to gentamicin 90.6% and to tobramycin 89.8% in a recent global SENTRY report [27]. In fact, amikacin’s exceptionally good activity rates were only found to be surpassed by the carbapenem class of antibiotic compounds in the above studies. The semisynthetic aminoglycoside derivative isepamycin appears to fare even better against these bacteria; some reports attribute to this drug activity rates approaching 100% [29]. Some aminoglycosides show considerable in vitro activity against all three Gram-negative pathogens currently ranked among the top bacterial threats, namely Acinetobacter baumannii, P. aeruginosa and ESBL-producing Enterobacteriaceae (e.g., K. pneumoniae and E. coli) [30]. Resistance rates of non-fermenting Gram-negative pathogens, such as P. aeruginosa and Acinetobacter spp., to amikacin appear to be acceptably low in most parts of the world [9,31,32]. Unfortunately, neither gentamicin nor tobramycin any more appear to be very effective against these pathogens [9,31]. Of clinical importance, compared with other classes of antibiotic compounds, aminoglycosides are still among the few classes (together with carbapenems and polymyxins) that retain activity against the great majority of MDR Gram-negative bacterial strains

204

E. Durante-Mangoni et al. / International Journal of Antimicrobial Agents 33 (2009) 201–205

[33]. The inclusion of most Gram-negative bacteria in the antimicrobial spectrum of aminoglycosides has made them one of the most commonly used classes of antibiotics against the emerging epidemic of MDR Gram-negative bacterial strains. Also, aminoglycosides appear to exhibit a sufficiently good activity against Stenotrophomonas maltophilia, a non-fermenting Gram-negative pathogen that is not as widespread yet but that is anticipated to become a more common threat in the future [34]. A critical evaluation of the data presented above suggests that, as yet, the issue of resistance does not appear to constitute a significant problem for most aminoglycosides. Moreover, resistance development during treatment is not a common phenomenon. Furthermore, it is anticipated that aminoglycoside derivatives which will, at least partially, address the resistance and toxicity issues of the currently available molecules could be produced in the future. The production of the semisynthetic compounds isepamycin, dibekacin, amikacin and netilmicin in the 1970s and 1980s supports these expectations. In the effort to increase the potency and antimicrobial spectrum of this class of antibiotic compounds, one of the primary targets is the inactivating enzymes. The recent development of X-ray crystallographic techniques provides hope that the structure and mode of action of these enzymes will be more thoroughly understood in the future, allowing for the development of compounds that will inhibit their action. The second major issue associated with the use of aminoglycosides is toxicity, particularly nephrotoxicity and ototoxicity. In recent years, large steps have been taken towards addressing this problem, some of the most important ones being the implementation of close monitoring strategies of renal function and once-daily dosing regimens. The improved safety of once-daily dosing has been widely demonstrated in several settings and, recently, also in critically ill patients [35,36]. Quantitation of the urinary excretion of renal tubular cell-derived enzymes (e.g., alanine aminopeptidase or N-acetyl-␤-d-glucosaminidase) is emerging as a highly sensitive and specific method to early detect aminoglycoside-induced renal damage [37]. Our better understanding of the pathogenetic mechanisms that underlie renal damage during aminoglycoside treatment is expected to aid this goal further [38]. Interesting studies have been carried out recently on the relationship between circadian rhythms, dietary protein intake, hypoalbuminaemia and aminoglycoside nephrotoxicity [39]. In addition, several compounds are currently being tested for their effect in reducing toxicity, including antioxidants, which lower free radical levels, and daptomycin or poly-l-aspartate, which reduce the ability of aminoglycosides to interact with phospholipids. Finally, the recognition that ototoxicity could be associated with genetic factors has opened novel research pathways that could lead to the development of methods or compounds that will overcome this common adverse event.

7. Conclusions Despite the development of several new antibiotic agents following the introduction of aminoglycosides, these antibiotics remain valuable weapons in our antimicrobial armamentarium. Particularly in today’s era of infections due to MDR and pandrugresistant bacteria [40], aminoglycosides take an even more vital role, especially in the treatment of serious Gram-negative nosocomial infections. Still, it should be acknowledged that the use of aminoglycosides comes with a number of significant problems. Thus, until novel derivatives with improved characteristics are produced, physicians are advised to apply caution when using these drugs. Furthermore, evidence is accumulating to suggest that some of the current common clinical indications of aminoglycosides,

in particular within combination antimicrobial schedules, are not evidence-based and should be critically revised. More clinical studies are needed to be carried out in the future in order to elucidate further the properties of these compounds and allow them to be used more effectively in everyday clinical practice. Funding: No funding sources. Competing interests: None declared. Ethical approval: Not required.

References [1] Fourmy D, Recht MI, Blanchard SC, Puglisi JD. Structure of the A site of Escherichia coli 16S ribosomal RNA complexed with an aminoglycoside antibiotic. Science 1996;274:1367–71. [2] Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM. Aminoglycosides: activity and resistance. Antimicrob Agents Chemother 1999;43:727–37. [3] Allan JD, Moellering Jr RC. Management of infections caused by Gram-negative bacilli: the role of antimicrobial combinations. Rev Infect Dis 1985;7(Suppl 4):S559–71. [4] Novelli A, Mazzei T, Fallani S, Cassetta MI, Conti S. In vitro postantibiotic effect and postantibiotic leukocyte enhancement of tobramycin. J Chemother 1995;7:355–62. [5] Davies J, Wright GD. Bacterial resistance to aminoglycoside antibiotics. Trends Microbiol 1997;5:234–40. [6] Daigle DM, McKay GA, Wright GD. Inhibition of aminoglycoside antibiotic resistance enzymes by protein kinase inhibitors. J Biol Chem 1997;272:24755–8. [7] Hon WC, McKay GA, Thompson PR, Sweet RM, Yang DS, Wright GD, et al. Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases. Cell 1997;89:887–95. [8] Doi Y, Arakawa Y. 16S ribosomal RNA methylation: emerging resistance mechanism against aminoglycosides. Clin Infect Dis 2007;45:88–94. [9] Poole K. Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005;49:479–87. [10] Westbrock-Wadman S, Sherman DR, Hickey MJ, Coulter SN, Zhu YQ, Warrener P, et al. Characterization of a Pseudomonas aeruginosa efflux pump contributing to aminoglycoside impermeability. Antimicrob Agents Chemother 1999;43:2975–83. [11] Yokoyama K, Doi Y, Yamane K, Kurokawa H, Shibata N, Shibayama K, et al. Acquisition of 16S rRNA methylase gene in Pseudomonas aeruginosa. Lancet 2003;362:1888–93. [12] McLean AJ, IoannidesDemos LL, Li SC, Bastone EB, Spicer WJ. Bactericidal effect of gentamicin peak concentration provides a rationale for administration of bolus doses. J Antimicrob Chemother 1993;32:301–5. [13] Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1–10 [Quiz 11-12]. [14] Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother 1997;39:677–86. [15] Tam VH, Kabbara S, Vo G, Schilling AN, Coyle EA. Comparative pharmacodynamics of gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa. Antimicrob Agents Chemother 2006;50:2626–31. [16] Baddour LM, Wilson WR, Bayer AS, Fowler Jr VG, Bolger AF, Levison ME, et al. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia; American Heart Association; Infectious Diseases Society of America. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005;111:e394–434. [17] Drusano GL, Ambrose PG, Bhavnani SM, Bertino JS, Nafziger AN, Louie A. Back to the future: using aminoglycosides again and how to dose them optimally. Clin Infect Dis 2007;45:753–60. [18] Bliziotis IA, Samonis G, Vardakas KZ, Chrysanthopoulou S, Falagas ME. Effect of aminoglycoside and beta-lactam combination therapy versus beta-lactam monotherapy on the emergence of antimicrobial resistance: a meta-analysis of randomized, controlled trials. Clin Infect Dis 2005;41:149–58. [19] Falagas ME, Matthaiou DK, Bliziotis IA. The role of aminoglycosides in combination with a beta-lactam for the treatment of bacterial endocarditis: a meta-analysis of comparative trials. J Antimicrob Chemother 2006;57:639–47. [20] Falagas ME, Matthaiou DK, Karveli EA, Peppas G. Meta-analysis: randomized controlled trials of clindamycin/aminoglycoside vs. beta-lactam monotherapy for the treatment of intra-abdominal infections. Aliment Pharmacol Ther 2007;25:537–56. [21] Leibovici L, Paul M, Poznanski O, Drucker M, Samra Z, Konigsberger H, et al. Monotherapy versus beta-lactam–aminoglycoside combination treatment for Gram-negative bacteremia: a prospective, observational study. Antimicrob Agents Chemother 1997;41:1127–33.

E. Durante-Mangoni et al. / International Journal of Antimicrobial Agents 33 (2009) 201–205 [22] Paul M, Silbiger I, Grozinsky S, Soares-Weiser K, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam–aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev 2006;1:CD003344. [23] Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam–aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ 2003;326:1111. [24] Vidal L, Gafter-Gvili A, Borok S, Fraser A, Leibovici L, Paul M. Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2007;60:247–57. [25] Panidis D, Markantonis SL, Boutzouka E, Karatzas S, Baltopoulos G. Penetration of gentamicin into the alveolar lining fluid of critically ill patients with ventilator-associated pneumonia. Chest 2005;128:545–52. [26] Mandell L. Treatment of community-acquired pneumonia down under versus the United States: is it really that different? Clin Infect Dis 2008;46:1522–4. [27] Sader HS, Biedenbach DJ, Jones RN. Global patterns of susceptibility for 21 commonly utilized antimicrobial agents tested against 48,440 Enterobacteriaceae in the SENTRY Antimicrobial Surveillance Program (1997–2001). Diagn Microbiol Infect Dis 2003;47:361–4. [28] Vargas LJ, Casselas JM, Gales A, Tomé G, Sader HS, Lanza A, et al. Survey of bloodstream infection isolates: SENTRY Antimicrobial Surveillance Program in Buenos Aires, Argentina (1997–2002). Rev Panam Infectol 2006;8:11–7. [29] Tsai TY, Chang SC, Hsueh PR, Feng NH, Wang JT. In vitro activity of isepamicin and other aminoglycosides against clinical isolates of Gram-negative bacteria causing nosocomial bloodstream infections. J Microbiol Immunol Infect 2007;40:481–6. [30] Infectious Diseases Society of America. Bad bugs, no drugs. As antibiotic discovery stagnates. . . a public health crisis brews. IDSA; 2004. http://www. idsociety.org/WorkArea/showcontent.aspx?id=5554 [accessed September 8, 2008]. [31] Gales AC, Jones RN, Turnidge J, Rennie R, Ramphal R. Characterization of Pseudomonas aeruginosa isolates: occurrence rates, antimicrobial susceptibility

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39] [40]

205

patterns, and molecular typing in the global SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis 2001;32(Suppl 2):S146–55. Jones RN, Sader HS, Beach ML. Contemporary in vitro spectrum of activity summary for antimicrobial agents tested against 18569 strains non-fermentative Gram-negative bacilli isolated in the SENTRY Antimicrobial Surveillance Program (1997–2001). Int J Antimicrob Agents 2003;22:551–6. Falagas ME, Rafailidis PI. Re-emergence of colistin in today’s world of multidrug-resistant organisms: personal perspectives. Expert Opin Invest Drugs 2008;17:973–81. Gales AC, Jones RN, Forward KR, Linares J, Sader HS, Verhoef J. Emerging importance of multidrug-resistant Acinetobacter species and Stenotrophomonas maltophilia as pathogens in seriously ill patients: geographic patterns, epidemiological features, and trends in the SENTRY Antimicrobial Surveillance Program (1997–1999). Clin Infect Dis 2001;32(Suppl 2): S104–13. Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995;39:650–5. Olsen KM, Rudis MI, Rebuck JA, Hara J, Gelmont D, Mehdian R, et al. Effect of once-daily dosing vs. multiple daily dosing of tobramycin on enzyme markers of nephrotoxicity. Crit Care Med 2004;32:1678–82. Tulkens PM. Pharmacokinetic and toxicological evaluation of a once-daily regimen versus conventional schedules of netilmicin and amikacin. J Antimicrob Chemother 1991;27(Suppl C):49–61. Martinez-Salgado C, Lopez-Hernandez FJ, Lopez-Novoa JM. Glomerular nephrotoxicity of aminoglycosides. Toxicol Appl Pharmacol 2007;223: 86–98. Beauchamp D, Labrecque G. Chronobiology and chronotoxicology of antibiotics and aminoglycosides. Adv Drug Deliv Rev 2007;59:896–903. Falagas ME, Bliziotis IA. Pandrug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era? Int J Antimicrob Agents 2007;29:630–6.