Available via license: CC BY-NC-ND 4.0
Content may be subject to copyright.
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 Administra-
tion of the United States approved the routine prescription of GM to treat the following infec-
tious 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; peri-
tonitis 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 neutro-
penia; female genital infection; uterine infection; postnatal infection; necrotizing enteroco-
litis 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 Staphylo-
coccus 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: changhua@cch.org.tw (C. Chen).
0929-6646/$ - see front matter Copyright ª2013, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.
http://dx.doi.org/10.1016/j.jfma.2013.10.002
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.jfma-online.com
Journal of the Formosan Medical Association (2014) 113,72e82
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 ª2013, 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 Admin-
istration (FDA) approved the use of GM for treating the
following infectious disorders
1
: infection by Klebsiella
pneumoniae,Escherichia coli,Serratia marcescens,Cit-
robacter spp., Enterobacteriaceae spp., or Pseudomonas
spp.; Staphylococcus infectious disease; bacterial meningi-
tis; bacterial sepsis of newborns; bacterial septicemia;
infection of the eye, bone, skin, and/or subcutaneous tissue;
infective endocarditis; peritoneal dialysis-associated peri-
tonitis due to Pseudomonas and other GN organisms; peri-
tonitis due to gastrointestinal tract infections; respiratory
tract infection; and urinary tract infectious disease. GM is
also used widely beyond its FDA-labeled indications as fol-
lows
1
: actinomycotic infection; Staphylococcus saprophyti-
cus bacteremia with pyelonephritis; appendicitis; cystic
fibrosis (CF); diverticulitis; adjunct regimen for febrile
neutropenia; female genital infection; uterine infection;
peripartum and postnatal infection; necrotizing enteroco-
litis in the fetus or newborn; osteomyelitis; pelvic inflam-
matory disease; plague; gonorrhea; tularemia; prophylaxis
of post-cholecystectomy infection, transrectal prostate bi-
opsy, 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 Staphylo-
coccus aureus infections. GM is also added to medical ma-
terials, such as GM-loaded cement spacers for osteomyelitis
and prosthetic joint-associated infections (PJIs). The appli-
cation 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 in-
fectious diseases, with a focus on its medicinal applica-
tions. 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 con-
tinues 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, cost-
benefit 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 mycobac-
teria. 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-FDA-
approved 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 non-
FDA-approved labeling indications because of bad clinical
responses to traditional treatment, the availability of pre-
liminary 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 informa-
tion, 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 condi-
tions. 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 ar-
ticles 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 al
2
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
Applications of gentamicin 73
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 al
7
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 eradi-
cating 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 outpa-
tient 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.
8
Also, PEN or
ampicillin plus GM might be a preferred empirical regimen
in neonatal sepsis as compared to other antibiotics. How-
ever, 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 colleagues
9
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 colleagues
11
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 al
12
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 sur-
gical techniques.
13
Perioperative antibiotic prophylaxis
may reduce the risk of endophthalmitis.
14,15
Therefore,
intracameral triamcinolone acetonide injections following
cataract surgery would prevent postoperative endoph-
thalmitis.
16
Ahmed et al
17
also showed that intracameral
triamcinolone acetonide and GM appears to be a promising
treatment option for the control of postoperative inflam-
mation following cataract surgery.
The typical symptoms of MD can be managed using med-
ical therapy that allows control of the disease in as many as
two-thirds of patients.
18
An ablative approach is recom-
mended when treatment cannot reduce the recurrent spells
Table 1 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
Lavage Postoperative prophylaxis
- Intra-abdominal infections
Nasal infection
- Pediatric chronic rhinosinusitis
GM-collagen sponge Surgical site infection
- Colorectal surgical site infection
- Anal fistula surgical site infection
- Pilonidal sinus wound infection
- Sternal wound infection
- Hidradenitis suppurativa
Diabetic foot infections
Topical Cutaneous leishmaniasis
Peritoneal dialysis catheter exit site infections and peritonitis in uremia
GM-loaded cement spacers Infected arthroplasty
Nebulized Local infection in non-cystic fibrosis bronchiectasis
Oral Carbapenem-resistant Klebsiella pneumoniae carriage
Brucellosis
Plague
74 C. Chen et al.
Table 2 Evidence-based review of applications of gentamicin.
Application Author Purpose Population/patient sample Methodology/design Evidence level
a
Ref
Parenteral
Bacteremia Foucault et al To evaluate treatment of
chronic Bartonella quintana
bacteremia
20 Patients Open, randomized trial Level B, Class II b 7
Bacteremia Chen Describe the clinical
experience
1 Patient with Staphylococcus
saprophyticus bacteremia
Case report Level C 3
Neonatal sepsis Zaidi et al To compare failure rates for
possible serious bacterial
infection
434 Patients in total; 145 in
penicillin-gentamicin group,
145 in ceftriaxone group, and
143 in trimethoprim-
sulfamethoxazole-gentamicin
group
A randomized, case-control
study
Level B, Class IIa 8
Gynecological infection Lyell et al To assess effectiveness for
intrapartum chorioamnionitis
126 Patients were enrolled,
of whom 63 received daily
gentamicin and 63 received
8-hour gentamicin
Randomized, controlled trial Level A, Class I 11
Ear diseases Casani et al To determine the efficacy and
safety of low dose
intratympanic gentamicin
60 Patients Open, prospective,
randomized, controlled study
Level B, Class IIa 22
Ear diseases Delgado et al To analyze intratympanic
gentamicin injection in
Me
´nie`re’s disease
71 Patients A longitudinal, prospective,
descriptive study
Level B, Class IIa 24
Ear diseases Postema et al To determine the
effectiveness in patients with
Menie
`re’s disease
28 Patients with Me
´nie
`re’s
disease according to the
American Academy of
Otolaryngology-Head and
Neck Surgery criteria
A prospective, double-blind,
randomized, placebo-
controlled clinical trial
Level B, Class IIa 25
Ear diseases Casani et al To determine the effects on
Menie
`re’s disease
60 Patients Open, prospective study Level B, Class IIa 21
Ear diseases Stokroos and
Kingma
To determine the efficacy on
Menie
`re’s disease
22 Patients with Me
´nie
`re’s
disease according to the
AAO-HNS criteria
Prospective, double-blind,
randomized, clinical trial
Level B, Class IIa 26
Ear diseases Tjernstro
¨m et al To access the effect of
postural sway
41 Patients Prospective, randomized,
case-control study
Level B, Class IIb 29
Ear diseases Magnusson et al To access the effect of
hearing function
12 patients Prospective, randomized,
case-control study
Level C 28
Larvage
Postoperative prophylaxis Buimer et al To investigate postoperative
infections
200 Patients Prospective, randomized
study
Level B, Class IIb 49
GMecollagen sponge
(continued on next page)
Applications of gentamicin 75
Table 2 (continued)
Application Author Purpose Population/patient sample Methodology/design Evidence level
a
Ref
Surgical site infection Rutten and Nijhuis To confirm the efficacy of GM
collagen sponge in
postoperative wound
infection rates
221 Patients Randomized, case-controlled
trial
Level B, Class IIa 36
Surgical site infection Bennett-Guerrero
et al
To confirm the effective
prophylaxis of surgical site
infection
602 Patients Large, multicenter
randomized, placebo-
controlled clinical trial
Level B, Class II 34
Surgical site infection Schimmer et al To investigate the efficacy in
reducing sternal wound
complications
720 Patients Controlled, prospective,
randomized, double-blind,
single-center study
Level B, Class IIa 45
Surgical site infection Yetim et al To determine the effect on
healing, infection and
recurrence, after pilonidal
sinus surgery.
80 Patients Randomized, case-control
study.
Level B, Class IIa 40
Surgical site infection Andersson et al To analyze the effect of
reducing the wound infection
rate and recurrences
161 Patients Randomized, controlled study Level B, Class IIa 42
Diabetic foot infections Lipsky et al 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
375 Patients Prospective, double-blind,
randomized, clinical trial
Level B, Class IIa 52
Peritoneal dialysis catheter
exit site infections and
peritonitis in uremia
Ruiz-Tovar et al To evaluate the efficacy of
peritoneum lavage
103 Patients analyzed: 51 in
Group 1 and 52 in Group 2
Prospective, randomized,
case-control study
Level B, Class IIa 30
Carbapenem-resistant
Klebsiella pneumoniae
carriage
Koo et al Survey the safety of using in
endoscopy
77% (158/206) urologic units
were surveyed
Structured questionnaire Level C Class III 56
Peritoneal dialysis catheter
exit site infections and
peritonitis in uremia
Davenport To assess the effectiveness in
reducing catheter exit site
infections and peritonitis
rates
2975 Patients Prospective, randomized,
case-control study
Level B, Class IIb 53
GM-loaded cement spacers
Infected arthroplasty Holzer et al To evaluate the efficacy of a
new gentamicin collagen
fleece
103 Patients Controlled, multicenter trial Level B, Class IIa 41
76 C. Chen et al.
Infected arthroplasty Springer et al To assess the systemic safety
and potential adverse effects
after an infected total knee
replacement
34 Patients (36 knees) were
enrolled
Prospective, randomized,
case-control study
Level C, class IIb 61
Nebulized
Decrease local infection in
non-cystic fibrosis
bronchiectasis
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
Oral
Carbapenem-resistant
Klebsiella pneumoniae
carriage
Saidel-Odes et al To assess the effectiveness of
selective digestive
decontamination for
eradicating carbapenem-
resistant Klebsiella
pneumoniae (CRKP)
oropharyngeal and
gastrointestinal carriage
40 Patients in total, 20
Patients per group
Randomized, double-blind,
placebo-controlled trial
Level B, Class IIa 65
Brucellosis Ben Salah et al To investigate for treatment
of Leishmania major
cutaneous leishmaniasis
92 Patients Randomized, double blind,
vehicle-controlled study
Level B, Class II 52
Brucellosis Roushan et al To compare the efficacy in
human brucellosis
162 Patients Prospective, randomized,
case-control study
Level B, Class IIb 72
Brucellosis Hasanjani Roushan
et al
Evaluate for treating human
brucellosis
97 Patients Prospective, randomized
study
Level B, Class IIb 68
Plague Mwengee et al To evaluate for plague 65 Patients Randomized, comparative,
open-label, clinical trial
Level C, Class IIb 76
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 Zgentamicin.
a
Evidence-based scoring system.
Applications of gentamicin 77
of vertigo. The advent of less invasive procedures, such as
intratympanic therapy (IT), has greatly changed the treat-
ment approach to refractory MD. Several articles on IT ste-
roids for MD have reported positive
19
and negative results.
20
Casani et al
21
demonstrated that a combination of GM and
fibrin glue permitted a reduction in the number of adminis-
trations in patients with intractable unilateral MD in 2005,
and his study produced evidence that supported the hy-
pothesis 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 al
29
indicated that pretreating patients who have
remaining vestibular function with GM prior to ablative
surgery benefits not only postoperative wellbeing as pre-
viously 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. Ac-
cording 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 intra-
abdominal 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 al
31
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 rhinosi-
nusitis 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,
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 sur-
gical 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 concen-
trations 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 Nijhuis
36
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 al
34
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 Graf
39
demonstrated that the primary recurrence rate of endoa-
nal 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 al
40
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 al
41
provide evidence
that supports the use of the GM-collagen sponge for
treating pilonidal sinuses. However, Andersson et al
42
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 com-
plications, with significant associated costs, lengthened
hospital stay, and increased mortality.
43,44
The controlled,
prospective, randomized, double-blind single-center study
of Schimmer et al
45
demonstrated that routine prophylactic
retrosternal use of a GM-collagen sponge in patients under-
going cardiac surgery significantly reduced deep SWIs. Other
studies provide evidence that supports the use of the GM-
collagen 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 pa-
tients with diabetes, obesity, or both. GM-collagen is un-
likely to reduce SWIs in high-risk patients and polymicrobial
infections.
48
However, additional large, high-quality RCTs
are warranted to further elucidate this field.
78 C. Chen et al.
Hidradenitis suppurativa is a chronic recurrent inflam-
matory disease of the apocrine sweat glands. Controversy
remains regarding the appropriate treatment for hidrade-
nitis suppurativa. Buimer and colleagues
49
demonstrated
that excision of hidradenitis lesions with primary closure
over a GM-collagen sponge reduces the number of post-
operative 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 associates
50
reported that
topical application of the GM-collagen sponge appeared
safe and might improve clinical and microbiological out-
comes of diabetic foot infections of moderate severity
when combined with standard care. The pilot data sug-
gested 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 al
52
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% paro-
momycin 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 al
53
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 over-
all 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 man-
aging prosthetic hip infections is staged exchange arthro-
plasty.
55
The use of antibiotic-loaded cement spacers
(ALCS) to treat PJIs has gained popularity over recent de-
cades, with reported infection eradication rates ranging
from 90% to 100%.
56e59
ALCS not only function as a tem-
porary 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 sys-
temic safety. Another study by Springer and colleagues
61
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 col-
leagues
62
conducted an RCT to assess the efficacy of nebu-
lized GM therapy in patients with non-CF bronchiectasis and
reported that regular long-term nebulized GM was of sig-
nificant benefit in non-CF bronchiectasis, but that contin-
uous treatment was required to ensure ongoing efficacy.
Such infections are difficult to eradicate with systemic an-
tibiotics, because the structural abnormalities in the bron-
chial 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 asso-
ciates
65
showed that selective decontamination of the
digestive tract (SDD) is the only evidence-based approach
that prevents infection and mortality in critically ill pa-
tients 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 associ-
ates
72
found that the efficacy of the 5-day GM plus 8-week
DOX treatment was not superior to that of 2-week strep-
tomycin 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 al
76
conducted their trial
to test the efficacy and safety of GM for the plague. GM and
DOX were effective therapies for adult and pediatric pla-
gue, 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
Applications of gentamicin 79
predictors of efficacy are the ratios of peak aminoglycoside
plasma concentration or area under the curve to the min-
imum inhibitory concentration. Hence, dosing regimens
that maximize these are expected to maximize efficacy and
prevent emergence of resistant strains.
77
The recom-
mended 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 so-
lution (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
Con-
cerning lavage with GM solution, we recommended intra-
peritoneal 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 cm
2
(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 irri-
tation.
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 rec-
ommended 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 cur-
rent 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 pos-
sesses 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 beta-
lactams and vancomycin in the therapy of enterococcal
endocarditis. As mentioned previously, GM may be used for
inhalational therapy, primarily in the management of Pseu-
domonas 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
ointment or cream preparations to treat dermatologic in-
fections, such as impetigo contagiosa, acne, and seborrheic
dermatitis. GM has been used in combination with paromo-
mycin to treat exotic infections caused by Francisella
tularensis (tularemia), Y. pest is (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 appli-
cation; most of those indications have yet to be approved by
the FDA. It would now be appropriate to carry out a defini-
tive, 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.
References
1. Gentamicin. In: Dosing and Therapeutic Tools Database
[Internet database]. Truven Health Analytics Inc.:
Micromedex 2.0. http://www.micromedexsolutions.com/
micromedex2/librarian/ND_T/evidencexpert/ND_PR/
evidencexpert/CS/1C4E99/ND_AppProduct/evidencexpert/
DUPLICATIONSHIELDSYNC/894342/ND_PG/evidencexpert/
ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/
evidencexpert.DisplayDrugpointDocument?docIdZ250830&
contentSetIdZ100&titleZGentamicin+Sulfate&services
TitleZGentamicin+Sulfate&topicIdZdosingAndIndications
Section&subtopicIdZfdaSection#TopOfPage. [accessed
29.04.13].
2. Forrest GN, Mehta S, Weekes E, Lincalis DP, Johnson JK,
Venezia RA. Impact of rapid in situ hybridization testing on
coagulase-negative staphylococci positive blood cultures.
J Antimicrob Chemother 2006;58:154e8 [PMID: 16636084].
3. Chen CH. Staphylococcus saprophyticus bacteremia with
pyelonephritis cured by GM. J Formos Med Assoc 2013 in
press.
4. Raoult D, Roux V. The body louse as a vector of reemerging
human diseases. Clin Infect Dis 1999;29:888e911.
5. Spach DH, Kanter AS, Dougherty MJ, Larson AM, Coyle MB,
Brenner DJ, et al. Bartonella (Rochalimaea) quintana
bacteremia in inner-city patients with chronic alcoholism. N
Engl J Med 1995;332:424e8.
6. Stein A, Raoult D. Return of trench fever. Lancet 1995;345:
450e1.
7. Foucault C, Raoult D, Brouqui P. Randomized open trial of
gentamicin and doxycycline for eradication of Bartonella
quintana from blood in patients with chronic bacteremia.
Antimicrob Agents Chemother 2003;47:2204e7.
8. Zaidi AK, Tikmani SS, Warraich HJ, Darmstadt GL, Bhutta ZA,
Sultana S, et al. Community-based treatment of serious bac-
terial infections in newborns and young infants: a randomized
controlled trial assessing three antibiotic regimens. Pediatr
Infect Dis J 2012;31:667e72.
9. Nasef N, Shabaan AE, Schurr P, Iaboni D, Choudhury J,
Church P, et al. Effect of clinical and histological cho-
rioamnionitis on the outcome of preterm infants. Am J Peri-
natol 2013;30:59e68.
10. Gibbs RS, Dinsmoor MJ, Newton ER, Ramamurthy RS. A ran-
domized trial of intrapartum versus immediate postpartum
80 C. Chen et al.
treatment of women with intra-amniotic infection. Obstet
Gynecol 1988;72:823e8.
11. Lyell DJ, Pullen K, Fuh K, Zamah AM, Caughey AB, Benitz W,
et al. Daily compared with 8-hour gentamicin for the treat-
ment of intrapartum chorioamnionitis: a randomized
controlled trial. Obstet Gynecol 2010;115:344e9.
12. Mitra AG, Whitten MK, Laurent SL, Anderson WE. A random-
ized, prospective study comparing once-daily gentamicin
versus thrice-daily gentamicin in the treatment of puerperal
infection. Am J Obstet Gynecol 1997;177:786e92.
13. Olson RJ. Reducing the risk of postoperative endophthalmitis.
Surv Ophthalmol 2004;49:S55.
14. Lehmann OJ, Roberts CJ, Ikram K, Campbell MJ, McGill JI.
Association between nonadministration of subconjunctival
cefuroxime and postoperative endophthalmitis. J Cataract
Refract Surg 1997;23:889.
15. Montan PG, Wejde G, Koranyi G, Rylander M. Prophylactic
intracameral cefuroxime: efficacy in preventing endoph-
thalmitis after cataract surgery. J Cataract Refract Surg 2002;
28:977e81.
16. Gills JP. Filters and antibiotics in irrigating solution for cata-
ract surgery. J Cataract Refract Surg 1991;17:385.
17. Ahmed MS, Moly KN, Aziz MA. Use of povidone-iodine drop
instead of sub-conjunctival injection of dexamethasone and
gentamicin combination at the end of phacoemulsification
cataract surgery. Mymensingh Med J 2010;19:232e5.
18. Rauch SD. Clinical hints and precipitating factors in patients
suffering from Meniere’s disease. Otolaryngol Clin North Am
2010;43:1011e7.
19. Herraiz C, Plaza G, Aparicio JM, Gallego I, Marcos S, Ruiz C.
Transtympanic steroids for Meniere’s disease. Otol Neurotol
2010;31:162e7.
20. Dodson KM, Woodson E, Sismanis A. Intratympanic steroid
perfusion for the treatment of Meniere’s disease: a retro-
spective study. Ear Nose Throat J 2004;83:394e8.
21. Casani A, Nuti D, Franceschini SS, Gaudini E, Dallan I. Trans-
tympanic gentamicin and fibrin tissue adhesive for treatment
of unilateral Meniere’s disease: effects on vestibular func-
tion. Otolaryngol Head Neck Surg 2005;133:929e35.
22. Casani AP, Piaggi P, Cerchiai N, Seccia V, Franceschini SS,
Dallan I. Intratympanic treatment of intractable unilateral
Me
´nie`re disease gentamicin or dexamethasone? A randomized
controlled trial. Otolaryngol Head Neck Surg 2012;146:430e7.
23. Hsieh LC, Lin HC, Tsai HT, Ko YC, Shu MT, Lin LH. High-dose
intratympanic gentamicin instillations for treatment of
Meniere’s disease: long-term results. Acta Otolaryngol 2009;
129:1420e4.
24. Delgado LP, Rodrigo JF, Pen
˜a PA. Intratympanic gentamicin in
Me
´nie`re’s disease: our experience. J Laryngol Otol 2011;125:
363e9.
25. Postema RJ, Kingma CM, Wit HP, Albers FW, Van Der Laan BF.
Intratympanic gentamicin therapy for control of vertigo in
unilateral Menie
`re’s disease: a prospective, double-blind,
randomized, placebo-controlled trial. Acta Otolaryngol
2008;128:876e80.
26. Stokroos R, Kingma H. Selective vestibular ablation by intra-
tympanic gentamicin in patients with unilateral active
Me
´nie
`re’s disease: a prospective, double-blind, placebo-
controlled, randomized clinical trial. Acta Otolaryngol 2004;
124:172e5.
27. Vidal PP, de Waele C, Vibert N, Mu
¨hlethaler M. Vestibular
compensation revisited. Otolaryngol Head Neck Surg 1998;
119:34e42.
28. Magnusson M, Kahlon B, Karlberg M, Lindberg S, Siesjo
¨P.
Preoperative vestibular ablation with gentamicin and vestib-
ular ‘prehab’ enhance postoperative recovery after surgery
for pontine angle tumoursefirst report. Acta Otolaryngol
2007;127:1236e40.
29. Tjernstro
¨m F, Fransson PA, Kahlon B, Karlberg M, Lindberg S,
Siesjo
¨P, et al. Vestibular PREHAB and gentamicin before
schwannoma surgery may improve long-term postural func-
tion. J Neurol Neurosurg Psychiatry 2009;80:1254e60.
30. Ruiz-Tovar J, Santos J, Arroyo A, Llavero C, Arman
˜anzas L,
Lo
´pez-Delgado A, et al. Effect of peritoneal lavage with
clindamycin-gentamicin solution on infections after elective
colorectal cancer surgery. J Am Coll Surg 2012;214:202e7.
31. Wei JL, Sykes KJ, Johnson P, He J, Mayo MS. Safety and efficacy
of once-daily nasal irrigation for the treatment of pediatric
chronic rhinosinusitis. Laryngoscope 2011;121:1989e2000.
32. Horan TC, Gaynes RP, Martone WJ, Jarvis WR, Emori TG. CDC
definitions of nosocomial surgical site infections, 1992: a
modification of CDC definitions of surgical wound infections.
Infect Control Hosp Epidemiol 1992;13:606e8.
33. Sherertz RJ, Garibaldi RA, Marosok RD, Mayhall CG,
Scheckler WE, Berg R, et al. Consensus paper on the surveil-
lance of surgical wound infections. Am J Infect Control 1992;
20:263e70.
34. Bennett-Guerrero E, Pappas TN, Koltun WA, Fleshman JW,
Lin M, Mark DB, et al. Gentamicin-collagen sponge for infec-
tion prophylaxis in colorectal surgery. N Engl J Med 2010;363:
1038e49.
35. Friberg O, Jones I, Sjo
¨berg L, So
¨derquist B, Vikerfors T,
Ka
¨llman J. Antibiotic concentrations in serum and wound fluid
after local gentamicin or intravenous dicloxacillin prophylaxis
in cardiac surgery. Scand J Infect Dis 2003;35:251e4.
36. Rutten HJ, Nijhuis PH. Prevention of wound infection in
elective colorectal surgery by local application of a
gentamicin-containing collagen sponge. Eur J Surg Suppl
1997;578:31e5.
37. Guzma
´n Valdivia Gomez G, Guerrero TS, Lluck MC,
Delgado FJ. Effectiveness of collagen-gentamicin implant for
treatment of “dirty” abdominal wounds. World J Surg 1999;
23:123e7.
38. Nowacki MP, Rutkowski A, Oledzki J, Chwali
nski M. Prospec-
tive, randomized trial examining the role of gentamycin-
containing collagen sponge in the reduction of postoperative
morbidity in rectal cancer patients: early results and sur-
prising outcome at 3-year follow-up. Int J Colorectal Dis 2005;
20:114e20.
39. Gustafsson UM, Graf W. Randomized clinical trial of local
gentamicin-collagen treatment in advancement flap repair
for anal fistula. Br J Surg 2006;93:1202e7.
40. Yetim I, Ozkan OV, Dervis
‚oglu A, Erzurumlu K, Canbolant E.
Effect of gentamicin-absorbed collagen in wound healing in
pilonidal sinus surgery: a prospective randomized study. J Int
Med Res 2010;38:1029e33.
41. Holzer B, Gru
¨ssner U, Bru
¨ckner B, Houf M, Kiffner E,
Schildberg FW, et al. Efficacy and tolerance of a new genta-
micin collagen fleece (Septocoll) after surgical treatment of a
pilonidal sinus. Colorectal Dis 2003;5:222e7.
42. Andersson RE, Lukas G, Skullman S, Hugander A. Local
administration of antibiotics by gentamicin-collagen sponge
does not improve wound healing or reduce recurrence rate
after pilonidal excision with primary suture: a prospective
randomized controlled trial. World J Surg 2010;34:3042e8.
43. Friberg O, Dahlin LG, Levin LA, Magnusson A, Granfeldt H,
Ka
¨llman J, et al. Cost effectiveness of local collagen-
gentamicin as prophylaxis for sternal wound infections in
different risk groups. Scand Cardiovasc J 2006;40:117e25.
44. Mauermann WJ, Sampathkumar P, Thompson RL. Sternal wound
infections. Best Pract Res Clin Anaesthesiol 2008;22:423e36.
45. Schimmer C, O
¨zkur M, Sinha B, Hain J, Gorski A, Hager B,
et al. Gentamicin-collagen sponge reduces sternal wound
complications after heart surgery: a controlled, prospectively
randomized, double-blind study. J Thorac Cardiovasc Surg
2012;143:194e200.
Applications of gentamicin 81
46. Friberg O. Local collagen-gentamicin for prevention of sternal
wound infections: the LOGIP trial. APMIS 2007;115:1016e21.
47. Eklund AM, Valtonen M, Werkkala KA. Prophylaxis of sternal
wound infections with gentamicin-collagen implant: ran-
domized controlled study in cardiac surgery. J Hosp Infect
2005;59:108e12.
48. Godbole G, Pai V, Kolvekar S, Wilson A. Use of gentamicin-
collagen sponges in closure of sternal wounds in cardiotho-
racic surgery to reduce wound infections. Interact CardioVasc
Thorac Surg 2012;14:390e4.
49. Buimer MG, Ankersmit MF, Wobbes T, Klinkenbijl JH. Surgical
treatment of hidradenitis suppurativa with gentamicin sul-
fate: A prospective randomized study. Dermatol Surg 2008;
34:224e7.
50. Lipsky BA, Kuss M, Edmonds M, Reyzelman A, Sigal F. Topical
application of a gentamicin-collagen sponge combined with
systemic antibiotic therapy for the treatment of diabetic foot
infections of moderate severity a randomized, controlled,
multicenter clinical trial. J Am Podiatr Med Assoc 2012;102:
223e32.
51. Desjeux P. Human leishmaniases: epidemiology and public
health aspects. World Health Stat Q 1992;45:267e75.
52. Ben Salah A, Ben Messaoud N, Guedri E, Zaatour A, Ben
Alaya N, Bettaieb J, et al. Topical paromomycin with or
without gentamicin for cutaneous leishmaniasis. N Engl J Med
2013;368:524e32.
53. Davenport A., Pan Thames Renal Audit Peritoneal Dialysis
Group. Do topical antibiotics reduce exit site infection rates
and peritonitis episodes in peritoneal dialysis patients? The
Pan Thames Renal Audit. J Nephrol 2012;25:819e24.
54. Sculco TP. The economic impact of infected total joint
arthroplasty. Instr Course Lect 1993;42:349e51.
55. Salvati EA, Gonza
´lez Della Valle A, Masri BA, Duncan CP. The
infected total hip arthroplasty. Instr Course Lect 2003;52:
223e45.
56. Koo KH, Yang JW, Cho SH, Song HR, Park HB, Ha YC, et al.
Impregnation of vancomycin, gentamicin, and cefotaxime in a
cement spacer for two-stage cementless reconstruction in
infected total hip arthroplasty. J Arthroplasty 2001;16:882e92.
57. Yamamoto K, Miyagawa N, Masaoka T, Katori Y, Shishido T,
Imakiire A. Cement spacer loaded with antibiotics for infec-
ted implants of the hip joint. J Arthroplasty 2009;24:83e9.
58. Younger AS, Duncan CP, Masri BA, McGraw RW. The outcome of
two-stage arthroplasty using a custom-made interval spacer to
treat the infected hip. J Arthroplasty 1997;12:615e23.
59. Lieberman JR, Callaway GH, Salvati EA, Pellicci PM,
Brause BD. Treatment of the infected total hip arthroplasty
with a two-stage reimplantation protocol. Clin Orthop Relat
Res 1994;301:205e12.
60. Hsieh PH, Shih CH, Chang YH, Lee MS, Shih HN, Yang WE. Two-
stage revision hip arthroplasty for infection: comparison be-
tween the interim use of antibiotic-loaded cement beads and
a spacer prosthesis. J Bone Joint Surg Am 2004;86:1989e97.
61. Springer BD, Lee GC, Osmon D, Haidukewych GJ, Hanssen AD,
Jacofsky DJ. Systemic safety of high-dose antibiotic-loaded
cement spacers after resection of an infected total knee
arthroplasty. Clin Orthop Relat Res 2004;427:47e51.
62. Murray MP, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS,
Chalmers JD, et al. A randomized controlled trial of nebulized
gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir
Crit Care Med 2011;183:491e9.
63. Kochar S, Sheard T, Sharma R, Hui A, Tolentino E, Allen G,
et al. Success of an infection control program to reduce the
spread of carbapenem-resistant Klebsiella pneumoniae.
Infect Control Hosp Epidemiol 2009;30:447e52.
64. Centers for Disease Control and Prevention (CDC). Guidance
for control of infections with carbapenem-resistant or
carbapenemase-producing Enterobacteriaceae in acute care
facilities. MMWR Morb Mortal Wkly Rep 2009;58:256e60.
65. Saidel-Odes L, Polachek H, Peled N, Riesenberg K,
Schlaeffer F, Trabelsi Y, et al. A randomized, double-blind,
placebo-controlled trial of selective digestive decontamina-
tion using oral gentamicin and oral polymyxin E for eradica-
tion of carbapenem-resistant Klebsiella pneumoniae
carriage. Infect Control Hosp Epidemiol 2012;33:14e9.
66. Young EJ. An overview of human brucellosis. Clin Infect Dis
1995;21:283e9.
67. Colmenero JD, Reguera JM, Martos F, Sa
´nchez-De-Mora D,
Delgado M, Causse M, et al. Complications associated with
Brucella melitensis infection: a study of 530 cases. Medicine
1996;75:195e211.
68. Hasanjani Roushan MR, Mohraz M, Hajiahmadi M, Ramzani A,
Valayati AA. Efficacy of gentamicin plus doxycycline versus
streptomycin plus doxycycline in the treatment of brucellosis
in humans. Clin Infect Dis 2006;42:1075e80.
69. Solera J, Geijo P, Largo J, Rodriguez-Zapata M, Gijo
´nJ,
Martinez-Alfaro E, et al. A randomized, double-blind study to
assess the optimal duration of doxycycline treatment for
human brucellosis. Clin Infect Dis 2004;39:1776e82.
70. Solera J, Espinosa A, Martı
´nez-Alfaro E, Sa
´nchez L, Geijo P,
Navarro E, et al. Treatment of human brucellosis with doxy-
cycline and gentamicin. Antimicrob Agents Chemother 1997;
41:80e4.
71. Lubani MM, Dudin KI, Sharda DC, Ndhar DS, Araj GF, Hafez HA,
et al. A multicenter therapeutic study of 1100 children with
brucellosis. Pediatr Infect Dis J 1989;8:75e8.
72. Roushan MR, Amiri MJ, Janmohammadi N, Hadad MS,
Javanian M, Baiani M, et al. Comparison of the efficacy of
gentamicin for 5 days plus doxycycline for 8 weeks versus
streptomycin for 2 weeks plus doxycycline for 45 days in the
treatment of human brucellosis: a randomized clinical trial.
Antimicrob Agents Chemother 2010;65:1028e35.
73. Dennis DT, et al. Plague manual: epidemiology, distribution,
surveillance and control. Wkly Epidemiol Rec 1999 Dec
24e31;74(51e52):447 [PMID: 10635759].
74. Kool JL. Weinstein, Risk of person-to-person transmission of
pneumonic plague. Clin Infect Dis 2005;40:1166e72.
75. Boulanger LL, Ettestad P, Fogarty JD, Dennis DT, Romig D,
Mertz G. Gentamicin and tetracyclines for the treatment of
human plague: review of 75 cases in New Mexico, 1985e1999.
Clin Infect Dis 2004;38:663e9.
76. Mwengee W, Butler T, Mgema S, Mhina G, Almasi Y, Bradley C,
et al. Treatment of plague with gentamicin or doxycycline in a
randomized clinical trial in Tanzania. Clin Infect Dis 2006;42:
614e21.
77. Decker BS, Mohamed AN, Chambers M, Kraus MA, Moe SM,
Sowinski KM. Gentamicin pharmacokinetics and pharmaco-
dynamics during short-daily hemodialysis. Am J Nephrol 2012;
36:144e50.
78. Takai Y, Murofushi T, Ushio M, Iwasaki S. Recovery of sub-
jective visual horizontal after unilateral vestibular deaf-
ferentation by intratympanic instillation of gentamicin.
J Vestib Res 2006;16:69e73.
79. Pullens B, van Benthem PP. Intratympanic gentamicin for
Me
´nie
`re’s disease or syndrome. Cochrane Database Syst Rev
2011. CD008234.
80. Friberg O
¨,SvedjeholmR,So
¨derquist B, Granfeldt H, Vikerfors T,
Ka
¨llman J. Local gentamicin reduces sternal wound infections
after cardiac surgery: a randomizedcontrolled trial. Ann Thorac
Surg 2005;79:153e61.
82 C. Chen et al.
