Aminoglycosides: how should we use them in the 21st century?

REVIEW URRENT C OPINION

Aminoglycosides: how should we use them in the 21st century? Justin Jackson a, Caroline Chen b, and Kirsty Buising a,b,c

Purpose of review Aminoglycoside antibiotics (AGAs) have proved an invaluable part of our antimicrobial armamentarium since their introduction into practice over 60 years ago. This review summarizes recent developments, defining their role in the context of the current global epidemic of antibiotic resistance, raising awareness of their toxicity profile, and highlighting current data on their utility as synergistic agents. Recent findings Clinicians are facing an unprecedented threat from antibiotic resistance, resulting in an increased reliance on the addition of an AGA to provide adequate empirical cover in cases of severe sepsis. Concurrently, an increased awareness of the potential for severe disability, particularly from vestibular toxicity, has restrained directed therapy of AGAs to situations in which there are no appropriate alternatives. Their role as synergistic agents in the treatment of enterococcal endocarditis is currently under reevaluation, and new data have emerged on combination therapy for Pseudomonas aeruginosa bacteremia. AGAs are themselves coming under increasing threat from resistance, predominately from aminoglycoside modifying enzymes (mediating selective resistance) and 16S rRNA methyltransferases (conferring class-wide resistance). New agents and the development of alternate ways to circumvent resistance are likely to have important roles in future clinical care. Summary Aminoglycosides retain an invaluable but well defined role, and will remain important agents into the foreseeable future. Keywords aminoglycosides, endocarditis, gentamicin, Gram-negative, sepsis, vestibular toxicity

INTRODUCTION Since the discovery of streptomycin in 1944, aminoglycoside antibiotics (AGAs) have proved invaluable in the treatment of a wide range of infectious diseases. They have a broad spectrum of activity, are rapidly bactericidal, and are relatively inexpensive to produce. These advantages must be weighed against their poor penetration into certain tissues and their potential for serious adverse effects. Owing to the introduction of efficacious and less toxic alternatives, particularly broad-spectrum b-lactam antibiotics (BLAs) and fluoroquinolones, the use of AGAs has been in decline. However, the recent global spread of resistant pathogens has led to resurgence of interest in their clinical use.

BASIS OF ANTIMICROBIAL ACTION AGAs are polycationic compounds that electrostatically bind to negatively charged residues on the outer membrane of Gram-negative bacteria [1,2]. www.co-infectiousdiseases.com

Transport across the bacterial cytoplasmic membrane is an oxygen-dependent process, explaining why AGAs are poorly active in anaerobic environments such as abscess cavities [3]. This step is inhibited by an elevated osmolarity and low pH, which may affect the activity of AGAs in the lung. AGAs bind to the 30S subunit of prokaryotic ribosomes and induce a conformational change in the A-site of the 16S rRNA [4]. This allows noncognate tRNA to bind, resulting in high levels of mistranslation [5,6 ]. The faulty proteins produced then stimulate free radical formation and cell death [7]. &

a

Department of Infectious Diseases, St Vincent’s Hospital, bVictorian Infectious Disease Service, The Royal Melbourne Hospital and cThe University of Melbourne, Melbourne, Victoria, Australia Correspondence to Kirsty Buising, Associate Professor, The University of Melbourne, Grattan Street, Parkville, Victoria 3050, Australia. Tel: +61 393427212; e-mail: [email protected] Curr Opin Infect Dis 2013, 26:516–525 DOI:10.1097/QCO.0000000000000012 Volume 26 Number 6 December 2013

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Aminoglycoside use in the 21st century Jackson et al.

KEY POINTS AGAs remain effective drugs in the treatment of a broad range of pathogens, and have an important place in the empiric treatment of severe Gramnegative sepsis. Significant toxicities limit their place in therapy. Vestibular and cochlear toxicity are unpredictable, usually irreversible and often go unrecognized. Use in treatment of mild infections, such as urinary tract infections and surgical prophylaxis, should be minimized when other safer alternatives are available. Resistance to AGAs from AMEs is often specific to either gentamicin/tobramycin or amikacin, whereas 16S rRNA methyltransferases confer classwide resistance. New aminoglycosides are of great interest, some with improved toxicity profiles, and may have important roles in future clinical care.

(ESBL) producing strains of Enterobacteriaceae. They more commonly mediate selective resistance against gentamicin and tobramycin but not amikacin [5,15 ,16 ]. Recent surveillance studies suggest that amikacin is one of the most active agents against Gram-negative pathogens both in the Asia-Pacific region and in the United States [17–19]. Both AMEs and 16S-RMTases circulate widely in Asia; the latter enzymes have the ability to confer resistance to all aminoglycosides in current clinical use, as well as newer agents like arbekacin and plazomicin [20]. Genes encoding AGA resistance often exist on plasmids together with fluoroquinolone resistance determinants and genes for ESBLs or metallo-b-lactamases [21–23]. It is thus imperative for clinicians to keep abreast of relevant epidemiology in order to inform appropriate empiric prescribing decisions. &

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TOXICITY AMINOGLYCOSIDE RESISTANCE The most common mechanism of bacterial resistance to AGAs is modification of the antibiotic itself by aminoglycoside modifying enzymes (AMEs). This generally confers substrate-specific resistance with resistance to some but not all AGAs. The most broadspectrum AGA resistance is conferred by enzymatic modification of the ribosomal target via 16S rRNA methyltransferase (16S-RMTase) enzymes. This confers resistance to all clinically available AGAs. Other resistance mechanisms of importance include the following: mutations of the 16S rRNA (particularly in mycobacteria) [8,9]; efflux pumps (particularly in Pseudomonas aeruginosa) [10–12]; and extracellular DNA shielding in biofilms [13 ]. Induction and expression of resistant genes that encode the aminoglycoside AAC and AAD family of AMEs has recently been shown to be under the control of an aminoglycoside-binding riboswitch [14 ]. Riboswitches are small RNA domains within mRNA that allow direct autoregulation of gene expression by binding small molecules. In this case, the aminoglycoside binds to the riboswitch, inducing a conformational change and subsequent translation of the resistance gene. It is noteworthy that this riboswitch sequence is highly conserved, widely distributed, and is as an integral part of the resistance plasmids that confer multidrug resistance. Research to date has not yielded a clinical useful AME inhibitor, and the AGA-riboswitch offers another possible pharmacological target. AMEs of the AAC (60 ) enzyme class are commonly seen in extended-spectrum b-lactamase &

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The toxicities associated with aminoglycoside therapy are their major drawback in therapeutic use. In this section, we discuss current data on cochlear toxicity, vestibular toxicity, nephrotoxicity, and neuromuscular toxicity in turn, as well as providing guidance in relation to minimizing toxicity.

Cochlear toxicity Aminoglycosides bind to the human mitochondrial ribosome, disrupting normal metabolism and resulting in the generation of reactive oxygen species lethal to the inner-ear hair cells [24]. Cochlear toxicity, which manifests as high-frequency hearing loss, occurs in a treatment-duration-dependent fashion in the majority. However, an idiosyncratic form of toxicity resulting in profound and irreversible hearing loss even after very low exposures is recognized to affect genetically predisposed individuals, such as those with the A1555G mitoribosome mutation [25]. Cochlear toxicity is described in patients of any age, but longer treatment durations and advanced age are associated with increased risk [26,27,28 ,29]. Amikacin appears to cause higher rates of cochlear toxicity relative to other AGAs. Aspirin has been shown to protect against gentamicin-related hearing loss [30], as has coadministration of N-acetylcysteine in hemodialysis patients [31]. The background incidence of ototoxicity depends on duration of therapy and whether formal testing is undertaken, but occurs in up to 25% of those treated [32]. Apramycin, an AGA licensed for veterinary practice, has minimal affinity for eukaryotic ribosomes, including those with the A1555G

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mutation, and does not appear to cause toxicity to hair cells in animal models [33 ]. &&

Vestibular toxicity Increasingly, clinicians are becoming aware of the profound and disabling effects of aminoglycosideinduced vestibular toxicity [34]. There is a wide spectrum of disease manifestation, ranging from subclinical to a severe idiosyncratic form. Symptom onset may be sudden and without warning, rendering patients unable to walk or visually fixate on objects. In the largest summary to date, the overall incidence was reported at 2.2% of AGA recipients [35]. The incidence rate on formal testing is much higher, and data suggest that, apart from idiosyncratic toxicity, there is likely to be a dose-dependent relationship. For example, the incidence in a pediatric cohort was discovered to be 17% on formal testing, and was only detected in those receiving a cumulative amikacin dose greater than 1200 mg/kg [28 ]. The diagnosis of vestibular toxicity is often missed because of a number of factors. First, patients uncommonly present with nystagmus or vertigo. Rather, bilateral vestibulopathy results in disequilibrium and oscillopsia [36]. Secondly, hearing loss is not a marker of vestibulopathy – reports suggest that there is usually no overlap [28 ,37 ]. Thirdly, AGAs accumulate in the inner ear and can be detected for 6–12 months following administration, so symptoms may begin many months after AGA cessation and discharge home from hospital. Finally, there is often an absence of formal testing or prolonged patient follow-up. There is no threshold dose or duration of treatment that defines increased risk – in a recent case series of 103 patients with severe AGA-induced vestibulopathy, 6% occurred after administration of a single dose [37 ]. In addition, cases can occur when serum levels are within the acceptable therapeutic range. Reports have followed inhaled tobramycin [38,39], intraperitoneal administration [40], and topical eardrop administration [41]. Streptomycin and gentamicin seem to pose the highest risk of vestibulotoxicity, followed by amikacin, then tobramycin and netilmicin least of all [36]. &&

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administration, and cases have been attributed to gentamicin-loaded bone cement and beads for prosthetic joint infections [44,45]. Nephrotoxicity is usually reversible [46], although progression to anuric renal failure has been uncommonly observed. Careful serum drug monitoring is advised and an increasing trough level may be an early indication of toxicity [16 ]. &&

Neuromuscular toxicity Although uncommon, neuromuscular toxicity of AGAs has been long recognized, and is potentiated by diseases such as myasthenia gravis, concomitant administration of muscle relaxants, botulism, and hypocalcemia [47,48].

Minimizing toxicity Administration of AGAs should be avoided wherever possible in high-risk patients, which includes the elderly, those with a family history of AGAinduced cochlear or vestibular toxicity, and people with preexisting renal dysfunction, balance difficulties, or hearing impairment [49,50 ]. Coadministration of nephrotoxic and/or ototoxic drugs as well as muscle relaxants should be avoided, and serum creatinine and creatinine clearance should be closely monitored throughout the course. Wherever possible, patients should be informed that there is chance of balance or hearing problems and asked to report these to medical staff immediately should they occur. In our view, patients in whom aminoglycoside therapy is intended for more than 5 days should have regular bedside vestibular function tests as well as formal audiometry [37 ,51]. Formal vestibular function testing should also be considered, particularly where therapy is likely to be prolonged. Monitoring is much more difficult in critically ill patients, and there is no reliable method of early detection. AGA use should be restricted to appropriate clinical indications (for a summary of the authors’ suggested indications for AGA use in clinical practice, refer to Table 1). When possible, many experts suggest limiting the total duration of AGA therapy to 3–5 days in order to minimize rates of toxicity [49,52]. &&

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DOSING AND MONITORING Nephrotoxicity Nephrotoxicity occurs in 10–25% of aminoglycoside courses. Recognized risk factors include older age, preexisting renal dysfunction, concomitant nephrotoxic drugs, prolonged duration of AGA therapy, and higher doses [42]. There is some suggestion that patients with cystic fibrosis may be less susceptible to AGA-induced nephrotoxicity [43]. Nephrotoxicity is not limited to intravenous 518


Aminoglycosides have a narrow therapeutic index, and individualized patient dosing with careful serum level monitoring is critical. The two pharmacokinetic–pharmacodynamic predictors best associated with aminoglycoside efficacy are the ratio of area under the curve to minimum inhibitory concentration (AUC : MIC), and the ratio of peak serum concentration to minimum inhibitory concentration (Cmax : MIC) [53–55]. Volume 26 Number 6 December 2013


Aminoglycoside use in the 21st century Jackson et al. Table 1. Summary of suggested uses for aminoglycosides Category

Established indications

Areas of ongoing debate

Routine use not suggested

Gram-negative infections

Empirical therapy in severe sepsis with appropriate epidemiologya; directed therapy for MDR pathogens in which there is no suitable alternative

Combination therapy for Pseudomonas aeruginosa bacteremia; surgical antibiotic prophylaxis; impregnated surgical devices; enteric ESBL decolonization; inhaled therapy for cystic fibrosis

Empirical therapy for mild infections where less toxic alternatives available; directed therapy in which there are suitable less toxic alternatives; routine use prior to urinary catheter insertion

Enterococcal endocarditis; streptococcal endocarditis

S. aureus bacteremia and endocarditis; Listeria meningitis

Synergistic use in Gram-positive infections Zoonotic infections

Significant infection with Yersinia pestis, Francisella tularensis, and Brucella and Bartonella spp.

Mycobacteria and other Actinomycetales

Directed therapy for MDR pathogens in which there are no suitable alternatives

Protozoal infections

Leishmaniasis; amebiasis

ESBL, extended-spectrum b-lactamase; MDR, multidrug resistant. a Appropriate epidemiology is defined by situations in which there is an unacceptable risk of resistance to broad-spectrum b-lactam antibiotics and likelihood that aminoglycoside antibiotics will provide additional antimicrobial cover.

Increasing evidence suggests that AGAs should be administered as a once daily dose (ODD), taking advantage of their concentration-dependent bactericidal effect as well as their postantibiotic effect [49]. Some evidence suggests clinical outcomes may be improved and nephrotoxicity reduced with ODD, although other studies have shown no difference compared with multiple daily dosing (MDD) [56–59]. ODD in antibiotic courses of less than 10 days may be particularly beneficial in delaying or preventing renal impairment, whereas rates of nephrotoxicity seem to be equivalent in longer courses [49]. Dosing in patients with renal impairment is problematic, and expert advice should be sought. Although there is emerging evidence that ODD is as efficacious as MDD in the treatment of enterococcal endocarditis, many experts still remain cautious about recommending its use for this indication [60,61 ]. Monitoring is required when the treatment duration exceeds 24–48 h, and differs according to the administration method [50 ]. Dosage adjustment based on set ‘trough’ and ‘peak’ serum levels has traditionally been utilized for MDD, and has been continued for ODD by many institutions [16 ]. This method has, however, been criticized for potentially leading to delays in appropriate dosage regimens and incorrect dosing adjustments [62]. A variety of computerized pharmacokinetic modeling programs are available to accurately determine the AUC. Of these, Bayesian estimate programs, incorporating a combination of patient-specific characteristics as well as population data, are &

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preferred. The main drawback of computer programs is the level of skill required in data entry and interpretation, and such programs should be managed by nominated local experts such as a clinical pharmacologist [63].

SPECTRUM OF ACTIVITY Aminoglycosides are active against aerobic Gramnegative organisms including most Enterobacteriaceae, Pseudomonas, and Acinetobacter species. They lack significant activity against Burkholderia cepacia, Stenotrophomonas maltophilia, and Pasturella multocida as well as anaerobic organisms. Gram-positive organisms are relatively resistant to aminoglycosides, and their use against these organisms is usually restricted to a synergistic role alongside BLAs. Arbekacin is an AGA with particular activity against methicillin-resistant Staphylococcus aureus (MRSA) [64 ]. Aerobic organisms belonging to the order Actinomycetales, including Mycobacterium, Nocardia, Gordonia, Tsukamurella, and Rhodococcus, are often susceptible to certain AGAs [65–67]. Paromomycin has activity against protozoa, cestodes, and Leishmania [68]. &

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USE IN CLINICAL PRACTICE Although AGAs have a long history of use in clinical practice, with certain established clinical indications, there remain important areas of uncertainty and debate. In this section, we focus on recent data informing these debated clinical indications, as well



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as discussing prophylaxis, emerging clinical uses, and novel aminoglycoside antibiotics.

Established clinical indications Aminoglycoside therapy has an established role in the treatment of Gram-negative zoonotic pathogens that are often resistant to many other agents, and is indicated for Yersinia pestis [69]; Brucella and Bartonella infection [70–72]; and Francisella tularensis [73]. Streptomycin has traditionally been the agent of choice, although gentamicin is now widely used [73,74]. AGAs are bactericidal against these organisms, and there have been reports of treatment failures with the use of alternate antibiotics [70,75]. Aminoglycosides, particularly amikacin, may serve as an integral component of therapeutic regimens for Mycobacteria and Nocardia species. This is particularly important when alternatives are limited, as, for example, in multidrug resistant (MDR) tuberculosis. Paramomycin is utilized in its poorly absorbed oral form for the treatment of amoebiasis and giardiasis, as well as topically for cutaneous leishmaniasis and intravenously for visceral leishmaniasis [68,76].

Debated indications: role in Gram-negative infections Observational studies suggest that AGAs may be associated with increased mortality compared with BLA therapy when used to treat Gram-negative infections from sources other than the urinary tract [77]. AGA therapy targeting Gram-negative organisms with an elevated MIC, even when it remains within the susceptible range, may have an extremely narrow therapeutic index [78]. This difficulty is compounded in sites of poor tissue penetration and an acidic pH, such as inflamed lung tissue or abscess cavities, and clinical efficacy may be difficult to achieve without an unacceptably high risk of toxicity. Clinical studies have borne out these concerns, demonstrating that AGAs are associated with higher mortality compared to BLAs for the treatment of pulmonary infections [79] and P. aeruginosa bacteremia [80–82], and higher rates of clinical failures and nephrotoxicity for intra-abdominal infections [83,84]. Therefore, AGAs are not recommended for these indications unless there are no available alternatives. AGAs achieve concentrations in the urine 25–100-fold that of serum, and remain above the MIC for most Gram-negative bacilli for at least 4 days following the last dose, so if used, short durations may be suitable [49,85]. However, because of their potential toxicity they are not recommended as 520


first-line agents if alternatives are available. AGAs are effective in eradicating carbapenem-resistant Klebsiella pneumoniae from urine [86]. As such, they retain an important role as directed monotherapy for urinary tract infections due to MDR pathogens, or as empiric therapy for severe infections from a urinary source. There is ongoing debate about whether AGAs are synergistic in vivo if combined with BLA for Gram-negative infections. Substantial randomized controlled trial evidence describes no advantage to combination therapy for septic patients overall [87], or those with febrile neutropenia specifically [88], and comes at the cost of increased toxicity. Neither do current studies support combination therapy for the treatment of P. aeruginosa bacteremia. In the ã et al. [89 ] reported largest cohort to date, Pen 632 episodes without demonstration of a significant advantage over monotherapy. When these results were updated with an earlier meta-analysis [90], there was still no demonstrated advantage to appropriate combination therapy in either the empirical or definitive stages of treatment [91 ]. Confidence intervals remain wide, however, and the authors do not dismiss a possible benefit for this indication. Another possible rationale for combination therapy is to protect against the development of future resistant pathogens, although to date this has not been borne out in clinical studies [92]. Patients with septic shock present a unique group worthy of consideration. It is clear that appropriate empirical antibiotic therapy for patients with septic shock saves lives [80,82]. For the reasons discussed above, an AGA should not be used as monotherapy for this indication. However, in patients with severe sepsis and a high risk of mortality without appropriate empiric antibiotic treatment, the addition of an AGA is recommended when epidemiological data suggest unacceptable rates of BLA resistance and where the AGA is likely to broaden empiric cover (Fig. 1). The choice of AGA should be guided by current epidemiological data, remembering that rates of resistance vary among specific AGAs (see Aminoglycoside resistance, above). If local AGA resistance is high, alternative companion drug(s), such as colistin, may be more appropriate. Once antibiotic susceptibility patterns are known, the AGA should be stopped if there is a less toxic alternative. &&

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Debated indications: synergistic treatment for Gram-positive infections The synergistic role of aminoglycosides for the treatment of Gram-positive infections remains controversial. It has long been known that penicillin is Volume 26 Number 6 December 2013


Aminoglycoside use in the 21st century Jackson et al.

Aminoglycoside antibiotics (AGAs) have a place as short-term empiric therapy for patients with in combination with beta lactam antibiotics in settings where: 1.

The patient is at high risk of mortality if initial therapy is inappropriate (e.g. septic shock);

2.

There is concern (based on epidemiological data) about resistance of the likely causative bacterial pathogen(s) to beta lactam antibiotics and the addition of an AGA is likely to broaden the spectrum of bacterial cover.

The choice of AGA should be guided by relevant epidemiology and if AGA resistance is high, an alternative drug(s) may be more appropriate. If microbiological investigations do not confirm that a resistant pathogen is present (usually known by 48–72 hours) the AGA should be stopped and a less toxic alternative antibiotic should be used.

FIGURE 1. Role of aminoglycosides in the empiric management of sepsis. AGAs, aminoglycoside antibiotics; BLAs, b-lactam antibiotics.

only bacteriostatic against enterococci, and clinical cure rates for enterococcal infective endocarditis are significantly improved with combined BLA–AGA therapy [93]. More recently this practice has been challenged by increasing rates of high-level aminoglycoside resistance among enterococci, and concerns over aminoglycoside toxicity [94]. In a prospective cohort of patients with Enterococcus faecalis infective endocarditis, the synergistic combination of ceftriaxone–ampicillin compared favorably to gentamicin–ampicillin, with no significant difference in outcomes [95 ]. Emerging data have also questioned the necessity of 4–6 weeks duration of gentamicin. Two observational studies from Sweden reported cure rates comparable with standard duration with only 2 weeks of AGA therapy [61 ,96]. Although these studies are not randomized and have wide confidence intervals, they provide therapeutic alternatives where aminoglycosides are inappropriate or contraindicated [97,98]. Many clinicians are now minimizing the duration of AGAs and/or substituting with ceftriaxone to adopt aminoglycoside free regimens in an effort to minimize toxicity, particularly in patients with risk factors (see Minimizing toxicity, above). There are limited clinical data to support the use of aminoglycosides in combination with b-lactams for staphylococcal and streptococcal infective endocarditis [99,100]. The use of AGA in Staphylococcus aureus endocarditis is now largely discouraged as it appears to increase nephrotoxicity without improving clinical outcomes [101]. Regarding streptococcal infective endocarditis, current guidelines recommend for treatment of native valve endocarditis caused by streptococci with higher MICs to penicillin that at least the first 2 weeks include gentamicin &&

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[102]. Gentamicin-free regimens are available for fully susceptible strains. It is unknown whether ceftriaxone (in place of gentamicin) may have a similar synergistic role for viridans streptococci infective endocarditis for isolates with an elevated penicillin MIC, or indeed whether ceftriaxone monotherapy may be adequate. A number of recent studies have reminded us of the higher rates of nephrotoxicity associated with gentamicin use in infective endocarditis [60,101]. In keeping with the most recent British guidelines, we recommend against the routine use of gentamicin for S. aureus infective endocarditis and advise careful consideration prior to its use in viridans streptococcal infective endocarditis [103]. Regarding Listeria infection, AGAs are no longer recommended in the treatment of Listeria meningoencephalitis, as the combination of ampicillin with cotrimoxazole appears to be superior [104,105].

Prophylaxis Gentamicin is generally inexpensive and has, in the past, been widely adopted for use as prophylaxis prior to medical procedures, typically intra-abdominal or urological surgery. In recent times, the risk versus benefit has been reassessed. Wherever alternative less toxic agents are available, many centers are choosing to move away from AGAs. Some observational studies have described increased incidence of renal impairment perioperatively in patients receiving gentamicin as part of surgical prophylaxis, but conflicting reports have also emerged [106]. Awareness of toxicity risks and the local epidemiology of pathogens in surgical site infections should guide choices.



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The practice of administering gentamicin prior to elective urinary catheter insertion and/or removal can lead to widespread gentamicin overuse and it is generally not recommended [107]. The risk of harm from the AGA, even though it is small, likely outweighs the benefit in most settings.

Emerging clinical uses Two recent trials have exploited the poor oral bioavailability of AGAs by using them as part of an oral decolonization strategy for patients carrying ESBLproducing bacteria in their gut. In one study neomycin was used combined with colistin [108], whereas in another oral gentamicin was used with oral polymyxin in an attempt to decolonize patients carrying carbapenemase-producing bacteria [109]. In both studies, temporary suppression of colonization was achieved, presenting possible options in people prior to predictable periods of high risk for infection such as chemotherapy or transplantation. Similarly, AGAs have been used in ventilated patients in the intensive care as part of selective digestive decolonization strategies to reduce ventilator-associated pneumonia [110]. Inhaled tobramycin has been used for people with cystic fibrosis who are colonized with P. aeruginosa. Its use appears to be associated with small but statistically significant improvement in lung function for these patients and reduced microbiologic density of pathogen in the short term [111,112]. The long-term clinical benefit is less certain [113]. There is little evidence supporting use in people with noncystic fibrosis chronic lung disease to date. The use of inhaled AGAs for treatment of severe hospital-acquired pneumonia and ventilator-associated pneumonia is an emerging area, and further information is awaited with interest as new delivery devices are explored. Gentamicin has been used in several surgical devices including gentamicin impregnated spacers or polymethylmethacrylate beads used to fill anatomical spaces [114]. Similarly resorbable gentamicin-containing collagen implants have been developed to prevent surgical site infections [115]. The evidence supporting such use is still not clear.

New aminoglycoside antibiotics Arbekacin is a derivative of dibekacin, which in turn is derived from kanamycin. It is approved for human use in some countries and has good activity against Pseudomonas, Acinetobacter, and interestingly also against MRSA [116]. Plazomicin (previously called ACHN 490) is derived from sisomicin and importantly is not affected by many of the AMEs, including the AAC (60 ) type. It holds promise as being 522


clinically useful for some very resistant pathogens, including some carbapenemase producing bacteria that often carry AMEs, and it is currently in phase 3 trials [117,118]. Both plazomicin and arbekacin are inhibited by the 16S RMTases [119–121]. As discussed above, apramycin may have an improved toxicity profile compared with AGAs in current clinical use. In addition, it has been found to be the only aminoglycoside with activity against organisms harboring the 16S-RMTases gene [120], and has superior activity against mycobacteria, but it is still primarily a veterinary drug and human trial data are lacking [33 ]. &&

CONCLUSION AGAs form an essential part of our antimicrobial armamentarium, particularly in an era of increasing BLA and fluoroquinolone resistance. Resistance to AGAs themselves poses a grave threat, necessitating the rediscovery of older agents and development of new means to circumvent resistant mechanisms. Concurrently, there is increased recognition that the consequences of AGA toxicity, particularly idiosyncratic vestibular toxicity, can be devastating for patients. As such, we advocate limiting their role to empirical therapy in which the addition of an AGA may be life-saving, or to directed therapy in which there are no suitable alternatives. Their choice as synergistic agents in Gram-positive infections is currently being reevaluated. Despite seven decades of clinical experience, these and many other important questions remain to be answered, and we await further research developments with interest. Acknowledgements We gratefully acknowledge the assistance of colleagues in the Infectious Diseases Department at St Vincent’s Hospital, Melbourne, in the preparation of this manuscript. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Kotra LP, Haddad J, Mobashery S. Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance. Antimicrob Agents Chemother 2000; 44:3249–3256. 2. Taber HW, Mueller J, Miller P, Arrow A. Bacterial uptake of aminoglycoside antibiotics. Microbiol Rev 1987; 51:439–457. 3. Jana S, Deb J. Molecular understanding of aminoglycoside action and resistance. Appl Microbiol Biotechnol 2006; 70:140–150.

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Aminoglycoside use in the 21st century Jackson et al. 4. Bryan L, Kwan S. Roles of ribosomal binding, membrane potential, and electron transport in bacterial uptake of streptomycin and gentamicin. Antimicrob Agents Chemother 1983; 23:835–845. 5. Ramirez MS, Tolmasky ME. Aminoglycoside modifying enzymes. Drug Resist Updat 2010; 13:151–171. 6. Becker B, Cooper MA. Aminoglycoside antibiotics in the 21st century. ACS & Chem Biol 2012; 8:105–115. An excellent review on aminoglycosides, focusing on resistance mechanisms. 7. Kohanski MA, Dwyer DJ, Wierzbowski J, et al. Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death. Cell 2008; 135:679–690. 8. Prammananan T, Sander P, Brown BA, et al. A single 16S ribosomal RNA substitution is responsible for resistance to amikacin and other 2-deoxystreptamine aminoglycosides in Mycobacterium abscessus and Mycobacterium chelonae. J Infect Dis 1998; 177:1573–1581. 9. Nessar R, Reyrat JM, Murray A, Gicquel B. Genetic analysis of new 16S rRNA mutations conferring aminoglycoside resistance in Mycobacterium abscessus. J Antimicrob Chemother 2011; 66:1719–1724. 10. Li X-Z, Nikaido H, Poole K. Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1995; 39:1948– 1953. 11. Poole K. Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005; 49:479–487. 12. Poole K. Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 2005; 56:20–51. 13. Chiang W-C, Nilsson M, Jensen PØ, et al. Extracellular DNA shields against & aminoglycosides in Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother 2013; 57:2352–2361. Fascinating study on the role of extracellular DNA as a key constituent of the matrix of microbial biofilms and functioning as a protective shield against antibiotics. 14. Jia X, Zhang J, Sun W, et al. Riboswitch control of aminoglycoside antibiotic && resistance. 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Trends in susceptibility of selected Gram-negative bacilli isolated from intra-abdominal infections in North America: SMART 2005–2010. Diagn Microbiol Infect Dis 2013; 76:379– 381. 19. Bouchillon SK, Badal RE, Hoban DJ, Hawser SP. Antimicrobial susceptibility of inpatient urinary tract isolates of Gram-negative bacilli in the United States: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) Program: 20092011. Clin Ther 2013; 35:872–877. 20. Livermore DM. Current epidemiology and growing resistance of Gramnegative pathogens. Korean J Intern Med 2012; 27:128–142. 21. Fritsche TR, Castanheira M, Miller GH, et al. Detection of methyltransferases conferring high-level resistance to aminoglycosides in Enterobacteriaceae from Europe, North America, and Latin America. Antimicrob Agents Chemother 2008; 52:1843–1845. 22. Jiang Y, Yu D, Wei Z, et al. Complete nucleotide sequence of Klebsiella pneumoniae multidrug resistance plasmid pKP048, carrying blaKPC-2, blaDHA-1, qnrB4, and armA. Antimicrob Agents Chemother 2010; 54:3967–3969. 23. Wachino J, Arakawa Y. Exogenously acquired 16S rRNA methyltransferases found in aminoglycoside-resistant pathogenic Gram-negative bacteria: an update. Drug Resist Updat 2012; 15:133–148. 24. Jensen-Smith HC, Hallworth R, Nichols MG. Gentamicin rapidly inhibits mitochondrial metabolism in high-frequency cochlear outer hair cells. PloS ONE 2012; 7:e38471. 25. Fischel-Ghodsian N. Genetic factors in aminoglycoside toxicity. Pharmacogenomics 2005; 6:27–36. 26. Seddon JA, Godfrey-Faussett P, Jacobs K, et al. Hearing loss in patients on treatment for drug-resistant tuberculosis. Eur Respir J 2012; 40:1277– 1286. 27. Harris T, Bardien S, Schaaf HS, et al. Aminoglycoside: induced hearing loss in HIV-positive and HIV-negative multidrug-resistant tuberculosis patients. S Afr Med J 2012; 102:363–365. 28. Chen KS, Bach A, Shoup A, Winick NJ. Hearing loss and vestibular && dysfunction among children with cancer after receiving aminoglycosides. Pediatr Blood Cancer 2013; 60:1772–1777. A very important study, highlighting the presence of cochlear and vestibular toxicity in the pediatric population, that toxicity may occur in a dose-dependent fashion and the importance of formal testing.

29. Zimmerman E, Lahav A. Ototoxicity in preterm infants: effects of genetics, aminoglycosides, and loud environmental noise. J Perinatol 2012; 33:3–8. 30. Sha S-H, Qiu J-H, Schacht J. Aspirin to prevent gentamicin-induced hearing loss. N Engl J Med 2006; 354:1856–1857. 31. Feldman L, Efrati S, Eviatar E, et al. Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine. Kidney Int 2007; 72:359–363. 32. Huth M, Alharazneh AM, Ricci A, et al. Gentamicin ototoxicity requires functional mechanotransducer channels. Otolaryngol Head Neck Surgery 2011; 145:94–194. 33. Matt T, Ng CL, Lang K, et al. Dissociation of antibacterial activity and && aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin. Proc Natl Acad Sci 2012; 109:10984–10989. This article provides original data on apramycin, a promising aminoglycoside that is currently confined to veterinary use. 34. Minor LB. Gentamicin-induced bilateral vestibular hypofunction. JAMA 1998; 279:541–544. 35. Kahlmeter G, Dahlager JI. Aminoglycoside toxicity – a review of clinical studies published between 1975 and 1982. J Antimicrob Chemother 1984; 13:9–22. 36. Ariano RE, Zelenitsky SA, Kassum DA. Aminoglycoside-induced vestibular injury: maintaining a sense of balance. Ann Pharmacother 2008; 42:1282– 1289. 37. Ahmed RM, Hannigan IP, MacDougall HG, et al. Gentamicin ototoxicity: a && 23-year selected case series of 103 patients. Med J Aust 2012; 196:701– 710. This cohort study provides important data on aminoglycoside use and severe vestibular toxicity. 38. Edson RS, Brey RH, McDonald TJ, et al. Vestibular toxicity due to inhaled tobramycin in a patient with renal insufficiency. Mayo Clinic Proc 2004; 79:1185–1191. 39. Ahya VN, Doyle AM, Mendez JD, et al. Renal and vestibular toxicity due to inhaled tobramycin in a lung transplant recipient. J Heart Lung Transplant 2005; 24:932–935. 40. Chong TK, Piraino B, Bernardini J. Vestibular toxicity due to gentamicin in peritoneal dialysis patients. Perit Dial Int 1991; 11:152–155. 41. Marais J, Rutka J. Ototoxicity and topical eardrops. Clin Otolaryngol Allied Sci 1998; 23:360–367. 42. Lopez-Novoa JM, Quiros Y, Vicente L, et al. New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int 2010; 79:33–45. 43. Massie J, Cranswick N. Pharmacokinetic profile of once daily intravenous tobramycin in children with cystic fibrosis. J Paediatr Child Health 2006; 42:601–605. 44. de Klaver PA, Hendriks JG, van Onzenoort HA, et al. Gentamicin serum concentrations in patients with gentamicin – PMMA beads for infected hip joints: a prospective observational cohort study. Ther Drug Monit 2012; 34:67–71. 45. Kalil GZ, Ernst EJ, Johnson SJ, et al. Systemic exposure to aminoglycosides following knee and hip arthroplasty with aminoglycoside-loaded bone cement implants. Ann Pharmacother 2012; 46:929–934. 46. Florescu MC, Lyden E, Murphy PJ, et al. Long-term effect of chronic intravenous and inhaled nephrotoxic antibiotic treatment on the renal function of patients with cystic fibrosis. Hemodial Int 2012; 16:414–419. 47. Pasquale TR, Tan JS. Nonantimicrobial effects of antibacterial agents. Clin Infect Dis 2005; 40:127–135. 48. Sansthan BU. Tetany in kala azar patients treated with paromomycin. Indian J Med Res 2008; 127:489–493. 49. Craig WA. Optimizing aminoglycoside use. Crit Care Clin 2011; 27:107– 121. 50. Poulikakos P, Falagas ME. Aminoglycoside therapy in infectious diseases. && Expert Opin Pharmacother 2013; 1–13. An excellent review article on aminoglycoside therapy. 51. Fetter M. Assessing vestibular function: which tests, when? J Neurol 2000; 247:335–342. 52. Sun H-Y, Fujitani S, Quintiliani R, Victor LY. Pneumonia due to Pseudomonas aeruginosa Part II: antimicrobial resistance, pharmacodynamic concepts, and antibiotic therapy. CHEST J 2011; 139:1172–1185. 53. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987; 155:93–99. 54. Zelenitsky SA, Harding GK, Sun S, et al. Treatment and outcome of Pseudomonas aeruginosa bacteraemia: an antibiotic pharmacodynamic analysis. J Antimicrob Chemother 2003; 52:668–674. 55. Turnidge J. Pharmacodynamics and dosing of aminoglycosides. Infect Dis Clin North Am 2003; 17:503–528. 56. Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997; 24:796–809. 57. Bailey TC, Little JR, Littenberg B, et al. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997; 24:786–795. 58. Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. Br Med J 1996; 312:338–344.



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Antimicrobial agents 59. Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother 1996; 37:645–663. 60. Buchholtz K, Larsen CT, Schaadt B, et al. Once versus twice daily gentamicin dosing for infective endocarditis: a randomized clinical trial. Cardiology 2011; 119:65–71. 61. Dahl A, Rasmussen RV, Bundgaard H, et al. Enterococcus faecalis infective & endocarditis: a pilot study of the relationship between duration of gentamicin treatment and outcome. Circulation 2013; 127:1810–1817. An important study comparing 14–28 days of gentamicin therapy for E. faecalis infective endocarditis 62. Avent M, Rogers B, Cheng A, Paterson D. Current use of aminoglycosides: indications, pharmacokinetics and monitoring for toxicity. Intern Med J 2011; 41:441–449. 63. Leong C, Buising K, Richards M, et al. Providing guidelines and education is not enough: an audit of gentamicin use at The Royal Melbourne Hospital. Intern Med J 2006; 36:37–42. 64. Hwang J-H, Lee J-H, Moon M-K, et al. The usefulness of arbekacin compared & to vancomycin. Eur J Clin Microbiol Infect Dis 2012; 31:1663–1666. Original data on arbekacin, an aminoglycoside antibiotic with activity against MRSA. 65. Savini V, Fazii P, Favaro M, et al. Tuberculosis-like pneumonias by the aerobic actinomycetes Rhodococcus, Tsukamurella and Gordonia. Microbes Infect 2012; 14:401–410. 66. Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc 2012; 87:403–407. 67. Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis. N Engl J Med 2013; 368:745–755. 68. Davidson RN, den Boer M, Ritmeijer K. Paromomycin. Trans R Soc Trop Med Hyg 2009; 103:653–660. 69. Butler T. Plague into the 21st century. Clin Infect Dis 2009; 49:736–742. 70. Rolain J-M, Maurin M, Raoult D. Bactericidal effect of antibiotics on Bartonella and Brucella spp.: clinical implications. J Antimicrob Chemother 2000; 46:811–814. 71. Biswas S, Rolain JM. Bartonella infection: treatment and drug resistance. Future Microbiol 2010; 5:1719–1731. 72. Koruk ST, Erdem H, Koruk I, et al. Management of Brucella endocarditis: results of the Gulhane study. Int J Antimicrob Agents 2012; 40:145–150. 73. Hepburn MJ, Simpson AJ. Tularemia: current diagnosis and treatment options. Expert Rev Anti Infect Ther 2008; 6:231–240. 74. Mwengee W, Butler T, Mgema S, et al. Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzania. Clin Infect Dis 2006; 42:614–621. 75. Jackson J, McGregor A, Cooley L, et al. Francisella tularensis subspecies holarctica, Tasmania, Australia, 2011. Emerg Infect Dis 2012; 18:1484– 1486. 76. Ben Salah A, Ben Messaoud N, Guedri E, et al. Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med 2013; 368:524–532. 77. Vidal L, Gafter-Gvili A, Borok S, et al. Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2007; 60:247–257. 78. Drusano GL, Ambrose PG, Bhavnani SM, et al. Back to the future: using aminoglycosides again and how to dose them optimally. Clin Infect Dis 2007; 45:753–760. 79. Crabtree TD, Pelletier SJ, Gleason TG, et al. Analysis of aminoglycosides in the treatment of Gram-negative infections in surgical patients. Arch Surg 1999; 134:1293–1298. 80. Leibovici L, Paul M, Poznanski O, et al. Monotherapy versus beta-lactamaminoglycoside combination treatment for Gram-negative bacteremia: a prospective, observational study. Antimicrob Agents Chemother 1997; 41:1127–1133. 81. Kuikka A, Valtonen VV. Factors associated with improved outcome of Pseudomonas aeruginosa bacteremia in a Finnish university hospital. Eur J Clin Microbiol Infect Dis 1998; 17:701–708. 82. Morata L, Cobos-Trigueros N, Martıńez JA, et al. Influence of multidrug resistance and appropriate empirical therapy on the 30-day mortality rate of Pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother 2012; 56:4833–4837. 83. Bailey JA, Virgo KS, DiPiro JT, et al. Aminoglycosides for intra-abdominal infection: equal to the challenge? Surg Infect 2002; 3:315–335. 84. Falagas M, Matthaiou D, Karveli E, Peppas G. Meta-analysis: randomized controlled trials of clindamycin/aminoglycoside vs. b-lactam monotherapy for the treatment of intra-abdominal infections. Aliment Pharmacol Ther 2007; 25:537–556. 85. Wood M, Farrell W. Comparison of urinary excretion of tobramycin and gentamicin in adults. J Infect Dis 1976; 134:S133–S138. 86. Satlin MJ, Kubin CJ, Blumenthal JS, et al. Comparative effectiveness of aminoglycosides, polymyxin B, and tigecycline for clearance of carbapenemresistant Klebsiella pneumoniae from urine. Antimicrob Agents Chemother 2011; 55:5893–5899. 87. Marcus R, Paul M, Elphick H, Leibovici L. Clinical implications of b-lactam– aminoglycoside synergism: systematic review of randomised trials. Int J Antimicrob Agents 2011; 37:491–503.

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88. Paul M, Soares-Weiser K, Leibovici L. b-Lactam monotherapy versus b lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. Br Med J 2003; 326:1111. 89. Penã C, Suarez C, Ocampo-Sosa A, et al. Effect of adequate single-drug vs && combination antimicrobial therapy on mortality in Pseudomonas aeruginosa bloodstream infections: a post hoc analysis of a prospective cohort. Clin Infect Dis 2013; 57:208–216. This study provides prospective data on the role of combination therapy for the largest cohort of patients with P. aeruginosa bacteremia to date. 90. Vardakas KZ, Tansarli GS, Bliziotis IA, Falagas ME. b-Lactam plus aminoglycoside or fluoroquinolone combination versus b-lactam monotherapy for Pseudomonas aeruginosa infections: A meta-analysis. Int J Antimicrob Agents 2013; 41:301–310. 91. Paul M, Leibovici L. Combination therapy for Pseudomonas aeruginosa & bacteremia: where do we stand? [editorial commentary]. Clin Infect Dis 2013; 57:217–220. Excellent commentary on P. aeruginosa bacteremia. 92. Bliziotis IA, Samonis G, Vardakas KZ, et al. Effect of aminoglycoside and blactam combination therapy versus b-lactam monotherapy on the emergence of antimicrobial resistance: a meta-analysis of randomized, controlled trials. Clin Infect Dis 2005; 41:149–158. 93. Geraci JE, Martin WJ. Antibiotic therapy of bacterial endocarditis VI. Subacute enterococcal endocarditis: clinical, pathologic and therapeutic consideration of 33 cases. Circulation 1954; 10:173–194. 94. Miro JM, Pericas JM, del Rio A. A new era for treating Enterococcus faecalis endocarditis: ampicillin plus short-course gentamicin or ampicillin plus ceftriaxone: that is the question! Circulation 2013; 127:1763–1766. 95. Fernańdez-Hidalgo N, Almirante B, Gavalda` J, et al. Ampicillin plus ceftriax&& one is as effective as ampicillin plus gentamicin for treating Enterococcus faecalis infective endocarditis. Clin Infect Dis 2013; 56:1261–1268. A landmark article providing clinical evidence on the efficacy of ceftriaxone– ampicillin in the treatment of E. faecalis infective endocarditis. 96. Olaison L. Enterococcal endocarditis in Sweden, 1995–1999: can shorter therapy with aminoglycosides be used? Clin Infect Dis 2002; 34:159–166. 97. Munita JM, Arias CA, Murray BE. Enterococcus faecalis infective endocarditis: is it time to abandon aminoglycosides? [editorial commentary]. Clin Infect Dis 2013; 56:1269–1272. 98. Solla DJF. Effectiveness of ampicillin plus ceftriaxone compared to ampicillin plus gentamicin for treating Enterococcus faecalis infective endocarditis: a noninferiority question not yet properly investigated. Clin Infect Dis 2013; 57:768. 99. Leibovici L, Vidal L, Paul M. Aminoglycoside drugs in clinical practice: an evidence-based approach. J Antimicrob Chemother 2009; 63:246–251. 100. Falagas ME, Matthaiou DK, Bliziotis IA. The role of aminoglycosides in combination with a b-lactam for the treatment of bacterial endocarditis: a meta-analysis of comparative trials. J Antimicrob Chemother 2006; 57:639– 647. 101. Cosgrove SE, Vigliani GA, Campion M, et al. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis 2009; 48:713–721. 102. Baddour LM, Wilson WR, Bayer AS, et al. 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–e434. 103. Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012; 67:269–289. 104. Merle-Melet M, Dossou-Gbete L, Maurer P, et al. Is amoxicillin-cotrimoxazole the most appropriate antibiotic regimen for listeria meningoencephalitis? Review of 22 cases and the literature. J Infect 1996; 33:79–85. 105. Mitja` O, Pigrau C, Ruiz I, et al. Predictors of mortality and impact of aminoglycosides on outcome in listeriosis in a retrospective cohort study. J Antimicrob Chemother 2009; 64:416–423. 106. Challagundla SR, Knox D, Hawkins A, et al. Renal impairment after high-dose flucloxacillin and single-dose gentamicin prophylaxis in patients undergoing elective hip and knee replacement. Nephrol Dial Transplant 2013; 28:612– 619. 107. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:625–663. 108. Huttner B, Haustein T, Uçkay I, et al. Decolonization of intestinal carriage of extended-spectrum b-lactamase-producing Enterobacteriaceae with oral colistin and neomycin: a randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother 2013; 68:2375–2382. 109. Saidel-Odes L, Polachek H, Peled N, et al. A randomized, double-blind, placebo-controlled trial of selective digestive decontamination using oral gentamicin and oral polymyxin E for eradication of carbapenem-resistant Klebsiella pneumoniae carriage. Infect Control Hosp Epidemiol 2012; 33:14–19.

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Aminoglycoside use in the 21st century Jackson et al. 110. de Smet AMG, Bonten MJ, Kluytmans JA. For whom should we use selective decontamination of the digestive tract? Curr Opin Infect Dis 2012; 25:211– 217. 111. Hodson M, Gallagher C, Govan J. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J 2002; 20:658– 664. 112. Maíz L, Giroń RM, Olveira C, et al. Inhaled antibiotics for the treatment of chronic bronchopulmonary Pseudomonas aeruginosa infection in cystic fibrosis: systematic review of randomised controlled trials. Expert Opin Pharmacother 2013; 14:1135–1149. 113. Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev 2009; 4:CD004197. 114. Barth RE, Vogely HC, Hoepelman AI, Peters EJ. ‘To bead or not to bead?’ Treatment of osteomyelitis and prosthetic joint-associated infections with gentamicin bead chains. Int J Antimicrob Agents 2011; 38:371– 375. 115. Chang WK, Srinivasa S, MacCormick AD, Hill AG. Gentamicin-collagen implants to reduce surgical site infection: systematic review and metaanalysis of randomized trials. Ann Surg 2013; 258:59–65.

116. Sato R, Tanigawara Y, Kaku M, et al. Pharmacokinetic-pharmacodynamic relationship of arbekacin for treatment of patients infected with methicillinresistant Staphylococcus aureus. Antimicrob Agents Chemother 2006; 50:3763–3769. 117. Landman D, Babu E, Shah N, et al. Activity of a novel aminoglycoside, ACHN490, against clinical isolates of Escherichia coli and Klebsiella pneumoniae from New York City. J Antimicrob Chemother 2010; 65:2123–2127. 118. Landman D, Kelly P, Ba¨cker M, et al. Antimicrobial activity of a novel aminoglycoside, ACHN-490, against Acinetobacter baumannii and Pseudomonas aeruginosa from New York City. J Antimicrob Chemother 2011; 66:332–334. 119. Endimiani A, Hujer KM, Hujer AM, et al. ACHN-490, a neoglycoside with potent in vitro activity against multidrug-resistant Klebsiella pneumoniae isolates. Antimicrob Agents Chemother 2009; 53:4504–4507. 120. Livermore D, Mushtaq S, Warner M, et al. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother 2011; 66:48–53. 121. Zhanel GG, Lawson CD, Zelenitsky S, et al. Comparison of the nextgeneration aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev Anti Infective Ther 2012; 10:459–473.



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How should we advise heart failure patients on exercise and what should we tell them?

Laminitis in the 21st century.

Pallidotomy in the 21st century.

[Strabology in the 21st century].

Science in the 21st century.

Malnutrition in the 21st century.

We need a Public Health Act fit for 21st century.

Transplant in the 21st century.

How we developed a trainee-led book group as a supplementary education tool for psychiatric training in the 21st century.

Leprosy in the 21st century.

Tobacco in the 21st century.

Informing 21st-Century Risk Assessments with 21st-Century Science.

False positive chlamydia results in pregnancy: should we retest them?

How long should we treat?

21st Century Cell Culture for 21st Century Toxicology.

Nursing theory: the 21st century.

How should we address the pipeline problem?

New Technologies: Should we Embrace them so Fast?: Reply.

Training for the 21st century?

New Technologies: Should we Embrace them so Fast?

Serum liver enzymes--should we count on them?

Urodynamics in pelvic organ prolapse: when are they helpful and how do we use them?

Urodynamics in male LUTS: when are they necessary and how do we use them?

College student health in the 21st century.