Update on new medicinal applications of gentamicin: Evidence-based review

Journal of the Formosan Medical Association (2014) 113, 72e82

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.jfma-online.com

REVIEW ARTICLE

Update on new medicinal applications of gentamicin: Evidence-based review Changhua Chen a,*, Yumin Chen b, Pinpin Wu c, Baoyuan Chen b a

Division of Infectious Diseases, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan b Department of Pharmacy, Changhua Christian Hospital, Changhua, Taiwan c Division of General Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan Received 21 June 2013; received in revised form 19 August 2013; accepted 3 October 2013

KEYWORDS evidence-based; gentamicin; medicinal application; review

Gentamicin (GM) was discovered in 1963 and was introduced into parenteral usage in 1971. Since then, GM has been widely used in medicinal applications. The Food and Drug Administration of the United States approved the routine prescription of GM to treat the following infectious disorders: infection due to Klebsiella pneumoniae, Escherichia coli, Serratia marcescens, Citrobacter spp., Enterobacteriaceae spp., Pseudomonas spp.; Staphylococcus infectious disease; bacterial meningitis; bacterial sepsis of newborns; bacterial septicemia; infection of the eye, bone, skin and/or subcutaneous tissue; infective endocarditis; peritoneal dialysiseassociated peritonitis due to Pseudomonas and other gram-negative organisms; peritonitis due to gastrointestinal tract infections; respiratory tract infections; and urinary tract infectious disease. GM is an old antibiotic and is used widely beyond its FDA-labeled indications as follows: actinomycotic infection; Staphylococcus saprophyticus bacteremia with pyelonephritis; appendicitis; cystic fibrosis; diverticulitis; adjunct regimen for febrile neutropenia; female genital infection; uterine infection; postnatal infection; necrotizing enterocolitis in fetus or newborn; osteomyelitis; pelvic inflammatory disease; plague; gonorrhea; tularemia; prophylaxis of post-cholecystectomy infection, transrectal prostate biopsy, and postetympanostomy-related infection; malignant otitis externa; and intratympanically or transtympanically for Me ´nie `re’s disease. GM is also used in combination regimens, such as with beta-lactam antibiotics to treat mixed infection and with bacteriophage to treat Staphylococcus aureus infections. It is also added to medical materials, such as GM-loaded cement spacers for osteomyelitis and prosthetic jointeassociated infections. Overall, there are many medicinal applications for GM. To reduce the development of GM-resistant bacteria and to

Conflicts of interest: The authors have no conflicts of interest relevant to this article. * Corresponding author. Division of Infectious Diseases, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanhsiau Street, Changhua, Taiwan. E-mail address: [email protected] (C. Chen). 0929-6646/$ - see front matter Copyright ª 2013, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved. http://dx.doi.org/10.1016/j.jfma.2013.10.002

Applications of gentamicin

73 maintain its effectiveness, GM should be used only to treat or prevent infections that are proven or strongly suspected as being caused by susceptible bacteria. In the future, we believe that GM will be used more widely in combination therapy and applied to medical materials for clinical applications. A definitive, appropriately powered study of this antibiotic and its clinical applications is now required, especially in terms of its effectiveness, safety, and cost. Copyright ª 2013, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.

Introduction Gentamicin (GM) is an aminoglycoside that is widely used in clinical conditions to fair clinical response. It was isolated from Micromonospora in 1963, proving to be a breakthrough in the treatment of gram-negative (GN) bacillary infections, including those caused by Pseudomonas aeruginosa. It was introduced into parenteral usage in 1971. GM has been widely used in medicinal applications since then. In the past 50 years, the clinical outcome of GM use has mostly been good, but the opposite was sometimes true. Due to the progression of pharmaceuticals, the prescription of GM has decreased. Based on clinical experience where the response to GM is good, the United States (US) Food and Drug Administration (FDA) approved the use of GM for treating the following infectious disorders1: infection by Klebsiella pneumoniae, Escherichia coli, Serratia marcescens, Citrobacter spp., Enterobacteriaceae spp., or Pseudomonas spp.; Staphylococcus infectious disease; bacterial meningitis; bacterial sepsis of newborns; bacterial septicemia; infection of the eye, bone, skin, and/or subcutaneous tissue; infective endocarditis; peritoneal dialysis-associated peritonitis due to Pseudomonas and other GN organisms; peritonitis due to gastrointestinal tract infections; respiratory tract infection; and urinary tract infectious disease. GM is also used widely beyond its FDA-labeled indications as follows1: actinomycotic infection; Staphylococcus saprophyticus bacteremia with pyelonephritis; appendicitis; cystic fibrosis (CF); diverticulitis; adjunct regimen for febrile neutropenia; female genital infection; uterine infection; peripartum and postnatal infection; necrotizing enterocolitis in the fetus or newborn; osteomyelitis; pelvic inflammatory disease; plague; gonorrhea; tularemia; prophylaxis of post-cholecystectomy infection, transrectal prostate biopsy, and post-tympanostomy-related infection; malignant otitis externa; and intratympanically or transtympanically for Me ´nie `re’s disease (MD). GM is also used in combination regimens, such as with beta-lactam antibiotics, to treat mixed infections and with bacteriophage to treat Staphylococcus aureus infections. GM is also added to medical materials, such as GM-loaded cement spacers for osteomyelitis and prosthetic joint-associated infections (PJIs). The application of GM has changed in recent years. This review aims to provide physicians and pharmacists with a review of GM and its role in the treatment of infectious diseases, with a focus on its medicinal applications. There is more than 50 years’ worth of cumulative clinical experience behind GM; as less adverse reactions are reported, and it is inexpensive and convenient, GM continues to play an important role in the treatment and

prophylaxis of infectious and non-infectious diseases, even in the face of patient-centered treatment, quality of medical care in general, resistant microorganisms, costbenefit limitations, and overall medical expenses. GM exerts concentration-dependent bactericidal actions and is active against a wide range of aerobic GN bacilli. GM is also active against staphylococci and certain mycobacteria. It is effective even when the bacterial inoculum is large, and resistance rarely develops during the course of treatment. Due to its potency, GM is used as prophylaxis and treatment in a variety of clinical situations. Over the course of half a century, GM has been used in the treatment and prophylaxis of infectious and non-infectious diseases that constitute more than 40 clinical conditions. We have divided the use of GM into FDA-approved and non-FDAapproved labeling indications.1 These indications are summarized in Supplement 1. Its FDA-approved labeling indications included at least 18 clinical conditions and the non-FDA-approved labeling indications include at least 27 clinical conditions. As the clinical data were limited, the use of GM for these non-FDA-approved labeling indications was controversial. However, clinical studies in this field over the past decade have reported fair responses in the accumulated clinical experiences of GM; therefore, the use of GM in the above clinical conditions has been accepted. Over the past 50 years, GM was sometimes used for nonFDA-approved labeling indications because of bad clinical responses to traditional treatment, the availability of preliminary results only (e.g., the results of clinical experience or from animal studies but not approved by the FDA), and low medical cost. Due to limited evidence-based information, the use of GM for such indications was controversial. As clinical studies from the past 10 years have reported fair responses to the accumulative clinical experiences of GM, it remains an important option for the above clinical conditions. We reviewed the literature from the past 10 years, and summarized the clinical conditions in Tables 1 and 2.3,7,8,11,21,22,24e26,28e30,34,36,40e42,45,50,52,53,56,61,62,65, 68,72,76 We divided the indications for GM according to dosage form, and describe the indications and review articles in accordance with this division in the following sections.

Parenteral GM S. saprophyticus is generally susceptible to most antibiotics, including penicillin (PEN).2 Forrest et al2 demonstrated significantly high failure rates for single-dose PEN therapy. In our clinical experience, GM is one option that can be used to treat S. saprophyticus infection.3 Bartonella quintana

74 Table 1

C. Chen et al. Medicinal applications of gentamicin (GM) today and in the future.

Administration

Medicinal application

Parenteral

Bacteremia - Staphylococcus saprophyticus bacteremia - Bartonella quintana bacteremia Neonatal sepsis Gynecological infection - Intrapartum chorioamnionitis Eye diseases - Cataract surgery Coagulation disorders Ear diseases - Me ´nie `re’s disease - Preoperative vestibular ablation Postoperative prophylaxis - Intra-abdominal infections Nasal infection - Pediatric chronic rhinosinusitis Surgical site infection - Colorectal surgical site infection - Anal fistula surgical site infection - Pilonidal sinus wound infection - Sternal wound infection - Hidradenitis suppurativa Diabetic foot infections Cutaneous leishmaniasis Peritoneal dialysis catheter exit site infections and peritonitis in uremia Infected arthroplasty Local infection in non-cystic fibrosis bronchiectasis Carbapenem-resistant Klebsiella pneumoniae carriage Brucellosis Plague

Lavage

GM-collagen sponge

Topical GM-loaded cement spacers Nebulized Oral

infection of humans was first described during World War I as being responsible for trench fever,4 and recent reports have indicated a reemergence of B. quintana infections among the homeless populations in cities in both Europe and the US.5,6 Foucault et al7 conducted a randomized clinical trial and demonstrated the efficiency of the combination of doxycycline (DOX) and GM in eradicating B. quintana bacteremia. The efficiency of this combination in eradicating B. quintana bacteremia may prevent the occurrence of B. quintana endocarditis efficiently. Neonatal sepsis is a life-threatening infection of the newborn. Zaidi’s study found that treatment failure was significantly higher with trimethoprim-sulfamethoxazole (TMP-SMX)-GM as compared with PEN-GM, and the outpatient therapy with injectable antibiotics is an effective option when hospitalization of sick infants is unfeasible. Procaine PEN-GM was superior to TMP-SMX-GM. Ceftriaxone is more expensive, and may be less effective.8Also, PEN or ampicillin plus GM might be a preferred empirical regimen in neonatal sepsis as compared to other antibiotics. However, limited sample sizes and poor evidence suggest that further research is required to support this conclusion. Chorioamnionitis can be associated with prolonged or premature rupture of the membranes or a primary cause of premature labor, and Nasef and colleagues9 found that chorioamnionitis was associated with motor, cognitive, and

language developmental delay. Intrapartum treatment with ampicillin and GM reduces maternal febrile morbidity, and length of stay when compared with postpartum treatment alone.10 Lyell and colleagues11 concluded that daily GM appeared to be as effective as 8-hour GM for the treatment of intrapartum chorioamnionitis, without differences in maternal or neonatal morbidities. Mitra et al12 reported that cure rates of combination therapy with once-daily GM ranged from 88% to 94% in peripartum infection of the uterus and postnatal infection. Phacoemulsification with intraocular lens implantation is currently the most common ophthalmic surgical procedure, and endophthalmitis continues to be a sight-threatening complication of cataract surgery, despite advances in surgical techniques.13 Perioperative antibiotic prophylaxis may reduce the risk of endophthalmitis.14,15 Therefore, intracameral triamcinolone acetonide injections following cataract surgery would prevent postoperative endophthalmitis.16 Ahmed et al17 also showed that intracameral triamcinolone acetonide and GM appears to be a promising treatment option for the control of postoperative inflammation following cataract surgery. The typical symptoms of MD can be managed using medical therapy that allows control of the disease in as many as two-thirds of patients.18 An ablative approach is recommended when treatment cannot reduce the recurrent spells

Evidence-based review of applications of gentamicin.

Application

Author

Purpose

Population/patient sample

Methodology/design

Evidence levela

Parenteral Bacteremia

Foucault et al

20 Patients

Open, randomized trial

Level B, Class II b 7

Bacteremia

Chen

Case report

Level C

3

Neonatal sepsis

Zaidi et al

To evaluate treatment of chronic Bartonella quintana bacteremia Describe the clinical experience To compare failure rates for possible serious bacterial infection

A randomized, case-control study

Level B, Class IIa

8

Gynecological infection

Lyell et al

Randomized, controlled trial

Level A, Class I

11

Ear diseases

Casani et al

Open, prospective, randomized, controlled study

Level B, Class IIa

22

Ear diseases

Delgado et al

A longitudinal, prospective, descriptive study

Level B, Class IIa

24

Ear diseases

Postema et al

A prospective, double-blind, randomized, placebocontrolled clinical trial

Level B, Class IIa

25

Ear diseases

Casani et al

Open, prospective study

Level B, Class IIa

21

Ear diseases

Stokroos and Kingma

Ear diseases

Tjernstro ¨m et al

Ear diseases

Magnusson et al

Larvage Postoperative prophylaxis

Buimer et al

Ref

1 Patient with Staphylococcus saprophyticus bacteremia 434 Patients in total; 145 in penicillin-gentamicin group, 145 in ceftriaxone group, and 143 in trimethoprimsulfamethoxazole-gentamicin group To assess effectiveness for 126 Patients were enrolled, intrapartum chorioamnionitis of whom 63 received daily gentamicin and 63 received 8-hour gentamicin To determine the efficacy and 60 Patients safety of low dose intratympanic gentamicin To analyze intratympanic 71 Patients gentamicin injection in Me ´nie `re’s disease To determine the 28 Patients with Me ´nie `re’s effectiveness in patients with disease according to the Menie American Academy of `re’s disease Otolaryngology-Head and Neck Surgery criteria To determine the effects on 60 Patients Menie `re’s disease To determine the efficacy on 22 Patients with Me ´nie `re’s Menie disease according to the `re’s disease AAO-HNS criteria To access the effect of 41 Patients postural sway To access the effect of 12 patients hearing function

Prospective, double-blind, randomized, clinical trial

Level B, Class IIa

26

Prospective, case-control Prospective, case-control

Level B, Class IIb

29

Level C

28

To investigate postoperative infections

Prospective, randomized study

Level B, Class IIb

49

200 Patients

randomized, study randomized, study

Applications of gentamicin

Table 2

GMecollagen sponge (continued on next page)

75

76

Table 2 (continued ) Author

Purpose

Population/patient sample

Methodology/design

Evidence levela

Ref

Surgical site infection

Rutten and Nijhuis

221 Patients

Randomized, case-controlled trial

Level B, Class IIa

36

Surgical site infection

Bennett-Guerrero et al

602 Patients

34

Schimmer et al

Level B, Class IIa

45

Surgical site infection

Yetim et al

Large, multicenter randomized, placebocontrolled clinical trial Controlled, prospective, randomized, double-blind, single-center study Randomized, case-control study.

Level B, Class II

Surgical site infection

Level B, Class IIa

40

Surgical site infection

Andersson et al

161 Patients

Randomized, controlled study Level B, Class IIa

42

Diabetic foot infections

Lipsky et al

To confirm the efficacy of GM collagen sponge in postoperative wound infection rates To confirm the effective prophylaxis of surgical site infection To investigate the efficacy in reducing sternal wound complications To determine the effect on healing, infection and recurrence, after pilonidal sinus surgery. To analyze the effect of reducing the wound infection rate and recurrences To determine the safety and potential benefit of treating diabetic foot infections of moderate severity

56 Patients

Randomized, controlled, multicenter, clinical trial

Level B, Class IIa

50

Topical Cutaneous leishmaniasis

Ben Salah et al

Assess the efficacious treatment for cutaneous leishmaniasis To evaluate the efficacy of peritoneum lavage

375 Patients

Prospective, double-blind, randomized, clinical trial

Level B, Class IIa

52

103 Patients analyzed: 51 in Group 1 and 52 in Group 2

Prospective, randomized, case-control study

Level B, Class IIa

30

Koo et al

Survey the safety of using in endoscopy

77% (158/206) urologic units were surveyed

Structured questionnaire

Level C Class III

56

Davenport

To assess the effectiveness in 2975 Patients reducing catheter exit site infections and peritonitis rates

Prospective, randomized, case-control study

Level B, Class IIb

53

Holzer et al

To evaluate the efficacy of a new gentamicin collagen fleece

Controlled, multicenter trial

Level B, Class IIa

41

Peritoneal dialysis catheter exit site infections and peritonitis in uremia Carbapenem-resistant Klebsiella pneumoniae carriage Peritoneal dialysis catheter exit site infections and peritonitis in uremia GM-loaded cement spacers Infected arthroplasty

Ruiz-Tovar et al

720 Patients

80 Patients

103 Patients

C. Chen et al.

Application

Nebulized Decrease local infection in non-cystic fibrosis bronchiectasis Oral Carbapenem-resistant Klebsiella pneumoniae carriage

Springer et al

To assess the systemic safety 34 Patients (36 knees) were and potential adverse effects enrolled after an infected total knee replacement

Prospective, randomized, case-control study

Level C, class IIb

61

Murray et al

To assess the efficacy in patients with non-cystic fibrosis bronchiectasis

65 Patients

Prospective, randomized, case-control study

Level B, Class IIb

62

Saidel-Odes et al

To assess the effectiveness of selective digestive decontamination for eradicating carbapenemresistant Klebsiella pneumoniae (CRKP) oropharyngeal and gastrointestinal carriage To investigate for treatment of Leishmania major cutaneous leishmaniasis To compare the efficacy in human brucellosis Evaluate for treating human brucellosis To evaluate for plague

40 Patients in total, 20 Patients per group

Randomized, double-blind, placebo-controlled trial

Level B, Class IIa

65

92 Patients

Randomized, double blind, vehicle-controlled study

Level B, Class II

52

162 Patients

Prospective, randomized, case-control study Prospective, randomized study Randomized, comparative, open-label, clinical trial

Level B, Class IIb

72

Level B, Class IIb

68

Level C, Class IIb

76

Brucellosis

Ben Salah et al

Brucellosis

Roushan et al

Brucellosis

Hasanjani Roushan et al Mwengee et al

Plague

97 Patients 65 Patients

Applications of gentamicin

Infected arthroplasty

Classification of recommendations: Class I: Conditions for which there is evidence, general agreement, or both that a given procedure or treatment is useful and effective. Class II: Conditions for which there is conflicting evidence, a divergence of opinion, or both about the usefulness/efficacy of a procedure or treatment. Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. Class IIb: Usefulness/efficacy is less well established by evidence/opinion. Class III: Conditions for which there is evidence, general agreement, or both that the procedure/treatment is not useful/effective and in some cases may be harmful. Level of evidence: Level of evidence A: data derived from multiple randomized clinical trials. Level of evidence B: data derived from a single randomized trial or nonrandomized studies. Level of evidence C: consensus opinion of experts. GM Z gentamicin. a Evidence-based scoring system.

77

78 of vertigo. The advent of less invasive procedures, such as intratympanic therapy (IT), has greatly changed the treatment approach to refractory MD. Several articles on IT steroids for MD have reported positive19 and negative results.20 Casani et al21 demonstrated that a combination of GM and fibrin glue permitted a reduction in the number of administrations in patients with intractable unilateral MD in 2005, and his study produced evidence that supported the hypothesis that IT delivery of low-dose GM was a relatively safe and effective therapy for the treatment of intractable MD, providing superior vertigo control as compared with IT dexamethasone (IT GM vs. IT dexamethasone, 93.5% vs. 61%, respectively), and was associated with a very low incidence of hearing impairment (12.5%) in 2012.22 The results are approved by many studies.23e26 An acute vestibular lesion causes the well-known symptoms of vestibular loss, featuring vertigo, nausea, and ataxia, and this process has been demonstrated as being dependent on cerebellar function.27 The approach of Magnusson and colleagues,28 which combined a vestibular prehabilitation program (PREHAB) with pre-surgery GM ablation of vestibular function, suggests the possibility of reducing morbidity in patients in whom intracranial surgery will induce acute vestibular loss. Results from Tjernstro ¨m et al29 indicated that pretreating patients who have remaining vestibular function with GM prior to ablative surgery benefits not only postoperative wellbeing as previously described, but also the long-term learning of how to withstand perturbed postural control.29

GM solution Typically, an antibiotic lavage consists of perioperative or peritoneal irrigation to prevent infectious diseases. According to the literature, there are two conditions in which GM solution would be effective. Many surgeons have adopted the use of peritoneal lavage in abdominal surgeries. Generally, this consists of peritoneal irrigation with a varied volume of 0.9% sodium chloride. The effects of lavage have been widely studied for the management of patients with bacterial peritonitis and reduction of the morbidity and mortality of intraabdominal infections. The use of clindamycin-GM solution in peritoneal lavage was associated with a lower incidence of intra-abdominal abscesses and wound infections in a study by Ruiz-Tovar et al.30 The prospective, randomized, double-blind study of Wei et al31 was designed to compare the efficacy and outcome of daily saline irrigation versus saline with GM for treating chronic rhinosinusitis. The high tolerance, compliance, and effectiveness of once-daily intranasal GM irrigation supported its use as a first-line treatment for pediatric chronic rhinosinusitis prior to when surgical intervention was considered.

GM-collagen sponge GM-collagen sponges have been used since the 1990s; recent publications have reported their application in most surgical site and diabetic wound infections. Surgical site infection (SSI) is one of the most common healthcare-associated infections among surgical patients,

C. Chen et al. and it is estimated that SSIs develop in 2e5% of the >30 million patients who undergo surgical procedures each year.32,33 Many surgeons believe that local use of antibiotics is a new essential method for postoperative reduction of wound complications. The GM-collagen sponge, an implantable topical antibiotic agent, is approved for surgical implantation in 54 countries,34 and it was developed to prevent and treat wound infections by providing high GM concentrations locally, avoiding the high systemic concentrations associated with the risk of toxic adverse reactions, such as nephrotoxicity.35 Several studies suggest that the sponge may be effective in the prevention and treatment of infections after general surgery.36e38 In this review, we found that the GM-collagen sponge was used in at least five different SSIs, and the SSIs were caused by a reduction of wound complications post-surgery. A study by Rutten and Nijhuis36 showed that 221 patients who underwent colorectal surgery and received a sponge had 70% less SSI as compared with those who did not receive a sponge (18.4% vs. 5.6%, respectively; p < 0.01). However, Bennett-Guerrero et al34 showed that the GM-collagen sponge was not effective for preventing SSI in patients who had undergone colorectal surgery. Endoanal advancement flap repair is widely used in sphincter-preserving surgery for anal fistula, but a major problem is the high recurrence rate due to local infection of the flap. However, a study by Gustafsson and Graf39 demonstrated that the primary recurrence rate of endoanal advancement flap repair for anal fistula was 61%, and healing was not significantly improved by local application of the GM-collagen sponge. A study by Yetim et al40 concluded that the implantation of a GM-collagen sponge in the wound area in pilonidal sinus decreased the rate of infection and recurrence and shortened hospital stay. Holzer et al41 provide evidence that supports the use of the GM-collagen sponge for treating pilonidal sinuses. However, Andersson et al42 showed that there were no significant differences in the rates of wound infection, wound healing, or recurrences when a GM-collagen sponge was added to the surgical treatment of pilonidal disease with excision and primary midline suture. In open cardiac surgery, sternal wound infection (SWI) continues to be one of the most serious postoperative complications, with significant associated costs, lengthened hospital stay, and increased mortality.43,44 The controlled, prospective, randomized, double-blind single-center study of Schimmer et al45 demonstrated that routine prophylactic retrosternal use of a GM-collagen sponge in patients undergoing cardiac surgery significantly reduced deep SWIs. Other studies provide evidence that supports the use of the GMcollagen sponge for the prevention of postoperative SWIs in patients undergoing cardiac surgery.46,47 Godbole et al concluded that most randomized controlled trials (RCTs) have been performed with GM-collagen sponges for sternal closure, and the most recent multicenter RCT showed no benefit of GM-collagen sponges in elective surgery (coronary artery bypass grafting and/or valve surgery) in high-risk patients with diabetes, obesity, or both. GM-collagen is unlikely to reduce SWIs in high-risk patients and polymicrobial infections.48 However, additional large, high-quality RCTs are warranted to further elucidate this field.

Applications of gentamicin Hidradenitis suppurativa is a chronic recurrent inflammatory disease of the apocrine sweat glands. Controversy remains regarding the appropriate treatment for hidradenitis suppurativa. Buimer and colleagues49 demonstrated that excision of hidradenitis lesions with primary closure over a GM-collagen sponge reduces the number of postoperative complications and results in a clean, fast-healing wound. The use of a GM-collagen sponge with excision and primary closure was recommended. The pilot study of Lipsky and associates50 reported that topical application of the GM-collagen sponge appeared safe and might improve clinical and microbiological outcomes of diabetic foot infections of moderate severity when combined with standard care. The pilot data suggested that a larger trial of this treatment was warranted.

Topical GM This dosage form is the earliest form in which GM was applied; most of the conditions were related to wound care. The literature contains two clinical situations that provided good clinical evidence for this use of topical GM. Leishmania, a genus of trypanosomatid protozoa, is endemic in 98 countries or territories worldwide, and the annual incidence of cutaneous leishmaniasis (CL) globally is 1.0e1.5 million cases.51 Ben Salah et al52 developed a cream called WR279,396 that contained 15% paromomycin sulfate plus 0.5% GM sulfate in a complex base to aid drug penetration. They provided evidence of the efficacy of paromomycin-GM and paromomycin alone for ulcerative Leishmania major disease. They also demonstrated that the efficacy of either of two creams containing 15% paromomycin with and without 0.5% GM was superior to that of a vehicle-control cream for treating ulcerative CL caused by L. major in Tunisia.52 Peritonitis is the major cause of peritoneal dialysis technique failure. Davenport et al53 reported that topical GM reduces both effect of exit site infections (ESIs) and peritonitis rates, but this review of routine clinical practice determined that although topical mupirocin reduced overall ESI rates and that combination regimen of topical mupirocin with GM reduced S. aureus ESIs, neither regimens reduced overall peritonitis rates.

GM-loaded cement spacers PJI is one of the most frequent complications in total hip arthroplasty and total knee arthroplasty, and is often associated with significant morbidity and increased medical costs.54 The current standard surgical procedure in managing prosthetic hip infections is staged exchange arthroplasty.55 The use of antibiotic-loaded cement spacers (ALCS) to treat PJIs has gained popularity over recent decades, with reported infection eradication rates ranging from 90% to 100%.56e59 ALCS not only function as a temporary hip joint implant, but can also be utilized for direct local antibiotic delivery.60 Vancomycin plus GM is the preferred regimen in the composition of ALCS. Therefore, the utilization of this regimen raises the concern of systemic safety. Another study by Springer and colleagues61

79 reported that no patient exhibited any clinical evidence of acute renal insufficiency, failure, or other systemic side effects of GM, hence using high-dose vancomycin and GM antibiotic spacers to treat patients with infected total knee arthroplasty appeared clinically safe.

Nebulized GM Bronchiectasis is a chronic debilitating disease with few evidence-based long-term treatments. Murray and colleagues62 conducted an RCT to assess the efficacy of nebulized GM therapy in patients with non-CF bronchiectasis and reported that regular long-term nebulized GM was of significant benefit in non-CF bronchiectasis, but that continuous treatment was required to ensure ongoing efficacy. Such infections are difficult to eradicate with systemic antibiotics, because the structural abnormalities in the bronchial wall reduce their bactericidal effect at this level.62

Oral GM The carbapenem-resistant K. pneumoniae (CRKP) harboring K. pneumoniae carbapenemase are resistant to almost all available antimicrobial agents.63,64 Saidel-Odes and associates65 showed that selective decontamination of the digestive tract (SDD) is the only evidence-based approach that prevents infection and mortality in critically ill patients hospitalized in the intensive care unit.65 As an enteral antimicrobial approach, an SDD regimen containing GM could be a suitable decolonization therapy for selected patients colonized with CRKP, such as transplant recipients or immunocompromized patients pending chemotherapy, and patients who require major intestinal or oropharyngeal surgery.66 Brucellosis is an important public health problem worldwide.66,67 When GM and DOX were used for 7 days and 45 days, respectively, the rates of success in three studies were between 86% and 94.8%.68e70 The efficacy of 5-day GM plus 8-week DOX administration was 100% in children with brucellosis.71 As the efficacy of this regimen in adult brucellosis had not been determined, Roushan and associates72 found that the efficacy of the 5-day GM plus 8-week DOX treatment was not superior to that of 2-week streptomycin plus 45-day DOX. Plague is a natural infection of rodents caused by the bacterium Yersinia pestis.73,74 A recent retrospective analysis of human cases of plague was recently reported,75 but there has not been a controlled prospective assessment of human infection. Mwengee et al76 conducted their trial to test the efficacy and safety of GM for the plague. GM and DOX were effective therapies for adult and pediatric plague, with high rates of favorable responses and low rates of adverse events.

Recommended dosing and route of administration based on new medicinal applications of GM Optimization of aminoglycoside dosing to ensure maximal efficacy and minimal toxicity is essential. The best

80 predictors of efficacy are the ratios of peak aminoglycoside plasma concentration or area under the curve to the minimum inhibitory concentration. Hence, dosing regimens that maximize these are expected to maximize efficacy and prevent emergence of resistant strains.77 The recommended dosing and route of administration, and potential adverse drug reactions based on new medicinal application of GM are described. With regards to parenteral GM for intratympanic GM instillation, we recommended instilling 30 mg/mL GM solution (GM solution of 40 mg/mL diluted to 30 mg/mL with 7% sodium bicarbonate solution) to fill the tympanic cavity once a day for 5 sequential days according to Takai et al,78 and complications were not mentioned by either study, nor were adverse effects (apart from hearing loss).79 Concerning lavage with GM solution, we recommended intraperitoneal irrigation with a solution of 240 mg GM and 600 mg clindamycin according to Ruiz-Tovar et al.30 In the matter of GM-collagen sponge, we recommended 130 mg of GM and 280 mg of collagen in 100 cm2 (5 cm  20 cm) sponge according to a study by Bennett-Guerrero et al,34 and no case of verified or suspected allergic or other adverse reaction to GM or bovine collagen was identified.80 Regarding topical GM, we recommended 0.5% GM cream according to Ben Salah et al.52 There were no cases of clinically significant tinnitus or vertigo, or changes in serum creatinine levels, and adverse events occurred in 1% of patients, the most common being erythema and skin irritation.52 Concerning the GM-loaded cement spacers, we recommended 4 g of vancomycin and 4.8 g of GM per batch of cement and generally use two to four batches of cement in one spacer according to Springer et al,61 and it is thought that although local concentrations increase immediately after implantation, the concentration in the serum and urine remain low, with little systemic effects of toxicity.61 Relating to nebulized GM, we recommended twice-daily nebulized 80 mg GM according to Murray et al,62 but 21.9% (7 of 32 patients) reported bronchospasm in the total cohort originally allocated.61 Concerning oral GM, we recommended oral solutions of GM (80 mg, 4 times per day) according to the study by Saidel-Odes et al.65

Summary Despite the glut of newly developed antibiotics in the current century, GM still plays a role in medicinal applications. As the availability of less toxic agents means that it is usually not used alone to treat staphylococcal infections, GM possesses appreciable activity against Staphylococci. By contrast, a beta-lactam antibiotic or vancomycin is often combined with GM to treat serious staphylococcal infections, to take advantage of their synergistic actions and the increased rate of bactericidal action. GM is commonly used in combination with cell wall-active agents, such as betalactams and vancomycin in the therapy of enterococcal endocarditis. As mentioned previously, GM may be used for inhalational therapy, primarily in the management of Pseudomonas aeruginosa in CF patients. GM is available in ophthalmic ointment and solution form to treat a variety of ophthalmic infections, including blepharitis, conjunctivitis, keratitis, and corneal ulcers, and is available as topical

C. Chen et al. ointment or cream preparations to treat dermatologic infections, such as impetigo contagiosa, acne, and seborrheic dermatitis. GM has been used in combination with paromomycin to treat exotic infections caused by Francisella tularensis (tularemia), Y. pestis (plague), and Brucella spp. (brucellosis). This antibiotic added into medical materials produces good clinical effects in medicinal applications, such as sponge, cement, and a solution form. In the future, GM will be more widely used in combination therapy and applied to medical materials for clinical application; most of those indications have yet to be approved by the FDA. It would now be appropriate to carry out a definitive, suitably powered study of the clinical applications of GM, especially in terms of its effectiveness, safety, and cost.

Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jfma.2013.10.002.

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