Aminoglycoside Versus Carbapenem Or Piperacillin/Tazobactam treatment For Bloodstream Infections Of Urinary Source Caused By Gram-Negative Extend Spectrum Beta-lactamase Producing Enterobacteriaceae

Design

Single center, retrospective cohort study

N= 218

Objective

To evaluate the efficacy and safety of aminoglycoside monotherapy as definitive treatment in Extend Spectrum Beta-lactamase Producing Enterobacteriaceae (ESBL-EB) bacteremia of urinary origin

Study Groups

Carbapenem or Piperacillin/Tazobactam (n= 85)

Aminoglycoside (n=108)

Inclusion Criteria

Positive blood culture for ESBL-EB, positive urine culture for ESBL-EB, clinical diagnosis of urinary tract infection (UTI) or pyelonephritis or urosepsis, treated with an aminoglycoside, carbapenem or piperacillin/tazobactam for >48 hours

Exclusion Criteria

Other sources of bacteremia, resistance to the antibiotic given, polymicrobial bacteremia, did not complete 48 h of appropriate treatment due to death or other reasons

Methods

Patients were grouped according to the treatment they received: aminoglycoside versus carbapenem or piperacillin/tazobactam in an intention to treat manner. Patient charts were summarized in a tabular manner regarding past and present medical history and treatment. Severe sepsis and septic shock were defined as sepsis with at least one organ dysfunction or tissue hypoperfusion, and sepsis with hypoperfusion not responsive to fluid resuscitation, in accordance with the Surviving Sepsis Campaign definitions. Urine cultures were followed up to 90 days to assess recurrence of bacteriuria.

Duration

January 1, 2014 to December 31, 2017

Outcome Measures

Primary: 30-day mortality

Secondary: Combined 30-day mortality or therapy switch or bacteriuria recurrence with the same bacteria in 90 days

Safety: Acute Kidney Injury (AKI) 14 days after presentation, AKI at 14 days or treatment switch due to safety problems or concerns

Baseline Characteristics

Aminoglycoside (n=108)

Carbapenem or Piperacillin/Tazobactam (n= 85)

Age, years

Male

Dwelling

Home

Long-term Care Facility

76 (70.4%)

32 (29.6%)

56 (65.9%)

29 (34.1%)

Function

Independent 

Partially Dependent

Dependent

30 (27.8%)

13 (12.0%)

65 (60.2%) 

37 (43.5%)

14 (16.5%)

34 (40.0%)

0.02

Immunocompromised

Glomerular filtration rate, mL/min

Vascular catheter

Urinary Hardware

Urinary catheter

Nephrostomy

28 (25.9%)

1 (0.9%)

24 (28.2%)

4 (4.7%)

Nephrolithiasis

14 (13%)

17 (20.0%)

Antibiotic treatment in ≤6 months

Cephalosporins

β-lactam/β-lactamase inhibitor

Aminoglycosides

Carbapenems

Quinolones

49 (45.4%)

16 (14.8%)

18 (16.7%)

4 (3.7%)

21 (19.4%) 

37 (43.5%)

16 (18.8%)

6 (7.1%)

11 (12.9%)

12 (14.1)

0.050

0.028

Hospitalization in ≤6 months

Hospitalization Length of Stay ≤6 months, days

Bacteria

E. coli

Klebsiella spp.

other Enterobacteriaceae

76 (70.4%)

20 (18.5%)

12 (11.1%)

42 (49.4%)

30 (35.3%)

13 (15.3%)

0.010

Results

Endpoint

Aminoglycoside (n = 108)

Carbapenem or piperacillin/ tazobactam (n = 85)

Adjusted Odds Ratio (95% Confidence Interval)

Adjusted Risk Difference (95% Confidence Interval)

30-day Mortality

30-Day Mortality or Treatment Switch

Recurrence of bacteriuria in ≤90 days *

AKI 14 days after starting treatment

AKI 14 days after starting treatment or treatment switch due to toxicity

Primary and secondary efficacy outcomes with adjustment for the variables: age, sex, baseline GFR, immunocompromised state, dementia, Charlson comorbidity score, nosocomial infection, and time to appropriate treatment. Safety outcomes were not adjusted 

AKI 14 days after starting treatment: Non-Adjusted Odds Ratio (95% Confidence Interval): 1.95 (0.51 to 7.45); Non-Adjusted Risk Difference (95% Confidence Interval): -5.24 (-14.83 to 4.34)

AKI 14 days after starting treatment or treatment switch due to toxicity: Non-Adjusted Odds Ratio (95% Confidence Interval): 3.38 (0.93 to 12.26); Non-Adjusted Risk Difference (95% Confidence Interval): -12.14 (-22.78 to -1.5)

* Patients who had a follow-up urine culture, N=58 

Adverse Events

See Result

Study Author Conclusions

Our results support aminoglycoside treatment as a legitimate option for treating ESBL-EB BSI of urinary source, particularly in E. coli infections and in patients without severe sepsis or septic shock. The results support the efficacy and safety of aminoglycoside therapy. This approach supports avoiding excessive use of carbapenems without compromising efficacy and safety of treatment.

InpharmD Researcher Critique

This study has several limitations, including the inherent selection bias of a retrospective design and difficulties in fully adjusting for this bias. The retrospective nature also limited the ability to handle missing data and track patient outcomes. Dosages were not included for any study group, which may affect the interpretation of results. Additionally, the findings may not be generalizable to immunocompromised patients and the comparison of treatments may be influenced by varying efficacy reported in other studies.

Combination Therapy with Aminoglycoside in Bacteremiasdue to ESBL-Producing Enterobacteriaceae in ICU

Design

Retrospective observational cohort study (France)

N= 307

Objective

To evaluate the efficacy of empirical aminoglycoside in critically ill patients with bloodstream infections caused by extended-spectrum β-lactamase producing Enterobacteriaceae (ESBL-E BSI)

Study Groups

With aminoglycoside (n = 169)

Without aminoglycoside (n = 138)

Inclusion Criteria

Adults with blood culture(s) yielding ESBL-E within 24 hours prior to ICU admission or during the ICU stay

Exclusion Criteria

Patients with missing data on empirical antimicrobial prescriptions, patients who received aminoglycosides only as definitive treatment

Methods

Key data recorded included demographics, ICU admission reasons, underlying conditions, immunodeficiency, and illness severity (Simplified Acute Physiology Score II [SAPS II] and Sepsis-related Organ Failure Assessment [SOFA] scores). Immunodeficiency was defined as neoplasia, neutropenia, immunosuppressive therapy, or AIDS. At bloodstream infection (BSI) diagnosis, prior antimicrobial use, extended-spectrum β-lactamase producing Enterobacteriaceae  (ESBL-E) colonization, length of stay, severity, and presence of shock were noted.

Antimicrobial treatments were categorized as empirical (before culture results) or definitive (post-culture), with appropriateness based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. Empirical treatment was considered timely if started within 24 hours. De-escalation involved narrowing antibiotic spectrum. Continuous or extended infusion was used for betalactam/betalactamase inhibitor combinations (BLBLI), third generation cephalosporins (3GC), and carbapenems.

Patients were monitored until death or ICU release. Clinical cure was defined as symptom resolution, negative cultures, and no further antibiotic need. Antibiotic adequacy, ventilation duration, catecholamine use, ICU stay post-BSI, microbiologic success, and multidrug-resistant bacteria acquisition were assessed. Microbiologic success meant pathogen clearance from blood cultures. Recurrence or persistence was evaluated at follow-up.

Duration

January 1, 2011 to January 1, 2018

Outcome Measures

Mortality on day 30

Baseline Characteristics

Without aminoglycoside (n = 138)

With aminoglycoside (n = 169)

Age, years

Male

SOFA score

Comorbidity

Diabetes

Renal insufficiency

30.4%

11.6% 

29.2%

10.7% 

Immunodeficiency

Immunosuppressive therapy in the last 3 months

Transplantation

Solid cancer

Hematological malignancy

49 (35.5%)

7 (5.1%)

6 (4.3%)

22 (15.9%)

14 (10.1%)

83 (49.1%)

25 (14.8%)

16 (9.5%)

22 (13%)

20 (11.8%)

Admission

Medical

Scheduled surgical

Unscheduled surgical

110 (79.7%)

2 (1.4%)

14 (10.1%)

145 (85.8%)

0 (0)

20 (11.8%)

Origin of the infection

Urinary tract

Intra-abdominal infection

Catheter related infection

Respiratory tract

Bone infection

Other

13 (9.4%)

24 (17.4%)

32 (23.2%)

53 (38.4%)

5 (3.6%)

10 

25 (14.8%)

29 (17.2%)

30 (17.8%)

75 (44.4%)

0 (0)

6 

Etiology

Klebsiella sp.

Enterobacter sp.

E. coli

Other §

87 (63%)

30 (21.7%)

19 (13.8%)

2 (1.5%) 

97 (57.4)

31 (18.3)

33 (19.5)

8 (4.7%)

§ Serratia sp. (n = 5), Proteus sp. (n = 3), Citrobacter sp. (n = 2). 

Results

Endpoint

Without aminoglycoside (n = 138)

With aminoglycoside (n = 169)

p-value

Amikacin was the most prescribed aminoglycoside (83%). The average treatment duration was 1.6 days, with drug monitoring conducted in 39% of patients.

Multivariate analysis identified age ≥70 (odds ratio [OR] 2.67), solid organ transplantation (OR 5.2), nosocomial infection (OR 8.67), vasoactive drug use by day 2 (OR 3.61), ARDS (OR 2.42), and acute renal failure (OR 2.49) as independent mortality predictors. Empirical aminoglycoside use was not linked to 30-day mortality (OR 1.05).

Adverse Events

See result

Study Author Conclusions

In intensive care unit (ICU) patients with ESBL-E BSI, empirical treatment with aminoglycoside was frequent. It demonstrated no impact on mortality, despite increasing treatment appropriateness.

InpharmD Researcher Critique

The small sample size may lead to a type II error, where larger studies could reveal additional findings. Being retrospective, there may be unmeasured differences in patients receiving aminoglycoside combination therapy, though multivariate analysis adjusted for confounders. Additionally, therapeutic drug monitoring was performed in less than half of the patients, and underdosing could have contributed to the lack of observed clinical benefit. Prior studies show high-dose aminoglycosides often fail to achieve target concentrations, which are linked to better outcomes. Future prospective studies with high doses and routine drug monitoring are needed to confirm optimal dosing. 

Combination therapy with an aminoglycoside for Staphylococcus aureus endocarditis and/or persistent bacteremia is associated with a decreased rate of recurrent bacteremia: a cohort study

Design

Retrospective cohort study

N= 87

Objective

Study Groups

Aminoglycoside use (n= 49)

No aminoglycoside use (n= 38)

Inclusion Criteria

Patients who had sustained bacteremia with blood cultures positive for Staphylococcus aureus for ≥72 hours (positive blood cultures on a minimum of two separate dates at least 72 hours apart); met the modified Duke criteria for the diagnosis of definite Staphylococcus aureus infective endocarditis

Exclusion Criteria

Patients with ≥72 hours of bacteremia (but without the diagnosis of definite infective endocarditis) treated with any aminoglycoside therapy during the first 72 hours of bacteremia

Methods

Investigators collected clinical data that included demographic details such as age, sex, and race, along with information on co-morbid conditions like diabetes mellitus, intravenous drug use, chronic kidney disease (stage 2 or higher with a glomerular filtration rate ≤ 89 mL/min/1.73 m²), and end-stage renal disease requiring dialysis. They also recorded chronic steroid use (defined as daily steroid use greater than 5 mg of prednisone or its equivalent), the Charlson Index score, treatment specifics for Staphylococcus aureus bacteremia (including the type, dose, and duration of any antistaphylococcal antibiotics), the presence of an indwelling central venous catheter at the time of bacteremia and its removal date, as well as any admissions to the intensive care unit during the bacteremia episode.

Duration

January 1997 to December 2007

Outcome Measures

Primary outcome: The incidence of recurrent (either relapse or re-infection) S. aureus bacteremia

Secondary outcomes: the total duration of bacteremia, 6-month all-cause mortality, incidence of complications of persistent bacteremia or infective endocarditis, and incident renal failure in the 6 months following the initial bacteremia 

Baseline Characteristics

Aminoglycoside use (n=49)

No aminoglycoside use (n=38)

Age, years (range)

Male

Race 

Black 

33 (67%)

26 (68%)

Inclusion criteria

Endocarditis

Bacteremia

DM

IVDU

CKD

ESRD

HIV

ESLD

MRSA isolate

ICU stay during bacteremia

29 (59%)

31 (63%)

22 (45%)

9 (18%)

7 (14%)

16 (33%)

5 (10%)

2 (4%)

27 (55%)

32 (65%) 

15 (39%)

28 (74%)

20 (53%)

5 (13%)

9 (24%)

6 (16%)

2 (5%)

4 (11%)

21 (55%)

21 (55%)

Charlson index (range)

Abbreviations: DM= diabetes mellitus, IVDU= current intravenous drug use, CKD= chronic kidney disease, ESRD= end-stage renal disease on dialysis, HIV= human immunodeficiency virus, ESLD= end-stage liver disease, MRSA= methicillin-resistant Staphylococcus aureus, ICU= intensive care unit

For baseline characteristics with a range, values are presented as Median (range) 

Results

Endpoint

Aminoglycoside use (n=49)

No aminoglycoside use (n=38)

p-Value

Incidence of recurrent bacteremia 

6-month all-cause mortality

Complication rate

Incident of renal failure

The median overall duration of bacteremia was 5 days (range 1–41 days), with no significant difference between the groups treated with and without an aminoglycoside (median 5 days for both groups, p= 0.49).

Outcomes for 6-month all-cause mortality and and incidence of complications of persistent bacteremia or infective endocarditis were not  not statisitically significant in difference.

Adverse Events

See results 

Study Author Conclusions

InpharmD Researcher Critique

Impact of combination therapy with aminoglycosides on the outcome of ICU-acquired bacteraemias

Design

Retrospective analysis 

N= 48 

Objective

Study Groups

Aminoglycoside not received (n= 30)

Aminoglycoside received (n= 18)

Inclusion Criteria

Patients who developed Intensive care unit (ICU)-acquired bacteremia during their stay in the ICU

Exclusion Criteria

Not explicitly stated 

Methods

Investigators collected data on all antibiotics administered during the month prior to the onset of bacteremia in patients. ICU-acquired bacteremia was defined as occurring more than 48 hours after admission, with coagulase-negative staphylococci confirmed by two positive blood cultures showing the same antibiogram. Infection sources were classified into categories such as lower respiratory tract, intra-abdominal, and more. Secondary bacteremia was identified when an episode developed after a documented infection with the same microorganism elsewhere.

Variables related to antibiotic therapy included the time from the first positive blood culture to the first antibiotic administration, the antimicrobial agents used, and the administration schedule of aminoglycosides. Toxicity was indicated by trough levels over 2 mcg/mL. Antibiotic therapy was deemed adapted if it followed guidelines and adequate if it included at least one effective antibiotic.

Duration

Outcome Measures

Primary outcome: 28-day survival

Secondary outcomes: Number of days without mechanical ventilation, without vasopressive drugs, without renal replacement therapy (RRT) and with ICU discharge on day 28 from bacteremia

Baseline Characteristics

Aminoglycoside not received (n= 30)

Aminoglycoside received (n= 18)*

Age, years

Female

Comorbidities

Cardiac disease

Diabetes mellitus

COPD

Chronic liver failure

Chronic alcoholism

Chronic renal failure

Non-hematologic malignancy

Hematologic malignancy

Immunosuppression

Cardiac failure

Renal failure

Respiratory failure

Coagulation failure

Hepatic failure

Neurologic failure

8 (26%)

7 (23%)

11 (37%)

5 (16%)

10 (33%)

2 (7%)

3 (10%)

3 (10%)

5 (16%)

7 (23%)

7 (23%)

29 (96%)

2 (7%)

3 (10%)

2 (7%)

4 (32%)

8 (44%)

11 (61%)

0

4 (22%)

1 (6%)

1 (6%) 

0

0

3 (16%)

1 (6%)

17 (94%)

0

0

2 (11%)

Temperature, °C

Leukocyte count, /mm³

Platelet count, 1,000/mm³

Creatinine, mg/L

CRP, mg/L

Abbreviations: COPD= chronic obstructive pulmonary disease; CRP=  c-reactive protein 

*18 out of 48 patients (37.5%) received combination therapy with an aminoglycoside, including 12 with amikacin and six with gentamicin. The mean number of aminoglycoside injections was 2.1 ± 1.2. Aminoglycosides were more commonly used in Gram-negative than Gram-positive bacteremias (43% vs. 23%).

For all patients, the most common portal of entry for infections was catheter-related bacteremia, accounting for 52% of all cases. The predominant microorganisms identified were Staphylococcus aureus (33%) and Enterobacteriaceae (27%). No instances of polybacterial bacteremia were observed.

Results

Endpoint

Aminoglycoside not received (n= 30)

Aminoglycoside received (n= 18)

p-Value

Prognosis on day 28

Number of days alive free from mechanical ventilation

Number of days alive free from vasopressors

Number of days alive free from RRT

Number of days alive away from ICU

5.5 ±9.2

11.3 ± 12.4

5.4 ± 9.4

3.2 ± 6.6

12.5 ± 9.3

19.3 ± 10.5

28

11.3 ± 8.9

0.02

0.18

0.17

0.002 

ICU death

Patients discharged from ICU on day 28

Bacteremia complications

Multivariate analysis revealed that patients treated with aminoglycosides were six times less likely to die than those not treated with aminoglycosides (confidence interval 1.3–28.9; p= 0.02).

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique

While the findings suggest that combination therapy with an aminoglycoside for ICU-acquired bacteraemias may potentially increase survival, the study’s retrospective design and small sample size may limit generalizability. Additionally, it was noted that patients not receiving aminoglycosides had a greater rate of hepatic failure, this could have potentially been a factor associated with high mortality and may have confounded the overall findings.

Retrospective, observational cohort study

N= 4,863 episodes

To evaluate the influence of empirical therapy with a beta-lactam alone versus a beta-lactam-aminoglycoside combination on the prognosis of bacteremia due to Gram-negative microorganisms

Beta-lactam (n= 4,185)

Beta-lactam + aminoglycoside (n= 678)

Patients with monomicrobial bacteremia due to aerobic or facultative Gram-negative microorganisms admitted between January 1997 and December 2008

Exclusion Criteria

Data were collected from patients in Spain identified to have received empirical therapy with either beta-lactam alone or a beta-lactam-aminoglycoside combination. Empirical therapy included antibiotics administered before microbiological data were available. Therapy was considered appropriate if at least one antibiotic had in vitro activity against the isolate and was given at the correct dosage and via an appropriate route. Specific dosages were not recorded, but local guidelines during the study recommended single daily doses of 5-7 mg/kg for gentamicin and tobramycin, and 15 mg/kg for amikacin in patients with normal renal function.

January 1997 to December 2008

30-day mortality

Beta-lactam + aminoglycoside (n= 678)

Age ≥65 years

Male

Place of acquisition

Community

Hospital

Health care related

191 (28%)

306 (45%)

181 (27%) 

2,782 (67%)

1,052 (25%)

351 (8%) 

Ultimately/finally fatal underlying disease

Source of infection

Unknown

Urinary tract

IV catheter

Pneumonia

Intraabdominal

Biliary tract

Skin/soft tissues

Other

219 (32%)

124 (18%)

128 (19%)

82 (12%)

30 (4%)

47 (7%)

29 (4%)

19 (3%)

651 (16%)

2,111 (50%)

291 (7%)

167 (4%)

246 (6%)

504 (12%)

103 (3%)

112 (3%)

Factors associated with mortality

2 (1.6-2.6)

Place of acquisition

Community

Hospital

Health care related

1

1.5 (1.2-1.9)

0.9 (0.6-1.4)

2.5 (1.9-3.2)

1.9 (1.4-2.6)

1.5 (1.1-2)

8.8 (7-11)

2.8 (1.9-4.1)

1.8 (1.3-2.5)

OR= odds ratio; CI= confidence interval

Amikacin was the most prescribed aminoglycoside (591 episodes, 87%), followed by gentamicin (56 episodes, 8%) and tobramycin (31 episodes, 5%). Aminoglycosides were combined with antipseudomonal beta-lactams in 78% of cases.

Out of the reported episodes, 467 (10%) resulted in fatalities.

Subgroup analysis showed that combination therapy independently protected against episodes with shock (OR 0.6; 95% CI 0.4-0.9) or neutropenia (OR 0.5; 95% CI 0.3-0.9).

Not specifically reported

In conclusion, we have been unable to demonstrate an overall significant association between β-lactam-aminoglycoside combination therapy and survival in patients with Gram-negative bacteremia. However, a survival advantage cannot be discarded for episodes presenting shock or neutropenia, and therefore, in patients with these conditions the empirical use of combination therapy may still be justified. Combination therapy also should be considered for patients at risk of being infected with resistant organisms, if only to increase the appropriateness of empirical therapy. In regard to these issues it is of note that a retrospective study with multiple subgroup analysis cannot generate firm conclusions, hence further studies would be needed to definitively support these contentions.

The study’s limitations include its retrospective design, potential confounding factors, lack of detailed adverse event reporting, and unspecified exclusion criteria, which may affect the generalizability and safety assessment of the findings.

Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic

Design

Prospective cohort study of safety data from a randomized controlled trial (RCT)

N= 236

Objective

To evaluate the association between initial low-dose gentamicin and nephrotoxicity in patients with Staphylococcus aureus bacteremia and native valve infective endocarditis

Study Groups

Received gentamicin (n= 130)

Did not receive gentamicin (n= 106)

Inclusion Criteria

Exclusion Criteria

Not explicitly stated

Methods

Patients in the RCT were randomized to receive either daptomycin monotherapy or standard therapy consisting of vancomycin (1 g every 12 hours with dose adjustment) or an antistaphylococcal penicillin (nafcillin, oxacillin, or flucloxacillin; 2 g every 4 hours), depending on the methicillin susceptibility of the causative organism.

Patients in the standard therapy group, as well as those with a high likelihood of left-side endocarditis who received daptomycin, were also given initial low-dose gentamicin (1 mg/kg every 8 hours, with dose adjustment) for the first 4 days of treatment. Additionally, medications administered before enrollment were reviewed to determine which patients received initial low-dose gentamicin within 2 days prior to randomization.

Duration

Median gentamicin duration: 5 days (range 1–7 days) in vancomycin-treated patients; 4 days (range 2–12 days) in patients treated with antistaphylococcal penicillins

Outcome Measures

Baseline Characteristics

Received gentamicin (n= 130)

Did not receive gentamicin (n= 106)

Age, years (range)

Male

Creatine clearance, mL/min (range)

Risk factor

Diabetes mellitus

HIV infection

SIRS

46 (35%)

3 (2%)

100 (77%)

40 (38%)

6 (6%)

77 (73%)

Study agent

Daptomycin

Antistaphylococcal penicillins

Vancomycin

22 (17%)

59 (45%)

49 (38%)

98 (92%)

4 (4%)

4 (4%)

Recipient of concomitant nephrotoxic drugs*

ACE-Is or ARBs

NSAIDs or COX-2 inhibitors

Amphotericin B

High-dose gentamicin

36 (28%)

36 (28%)

0

6 (5%)

1 (1%) 

42 (40%)

20 (19%)

1 (1%) 

3 (3%)

4 (4%)

Initial low-dose gentamicin before study enrollment

Median days (range)

Daily dose, mg/kg (range)

43 (33%)

2.0 (1–12)

2.9 (0.9–5.6)

Initial low-dose gentamicin as a study drug 

Days (range)

Daily dose, mg/kg (range)

109 (84%)

4.0 (1–12)

2.1 (0.8–3.5) 

Abbrevtions: ACE-Is, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; COX-2, cyclooxygenase 2; NA, not applicable; NSAIDs, nonsteroidal anti-inflammatory drugs; SIRS, systemic inflammatory response syndrome

*Patient received the agent ≤7 days before study enrollment until the occurrence of either a clinically significant decrease in creatine clearance or the day before the last day of study treatment, whichever came first. 

For baseline characteristics with a range, values are presented as Median (range)

Results

Endpoint

Received gentamicin (n= 122)*

Did not receive gentamicin (n= 100)*

p-value

Clinically significant decrease in CrCl

Sustained 50% decrease in CrCl

Sustained 25% decrease in CrCl

Discontinuation of use of study medication because of renal events

* Number of patients with both baseline and at least 1 post-baseline value during treatment

Adverse Events

Study Author Conclusions

Initial low-dose gentamicin as part of therapy for S. aureus bacteremia and native valve infective endocarditis is nephrotoxic and should not be used routinely, given the minimal existing data supporting its benefit.

InpharmD Researcher Critique

The findings from this study are derived from a randomized, controlled trial not specifically designed to assess gentamicin's effects on renal dysfunction. However, the secondary analyses suggest a consistent association between gentamicin and renal impairment. While these insights are valuable, caution is warranted in interpreting the results. 

Outcomes of empiric aminoglycoside monotherapy  for Pseudomonas aeruginosa bacteremia

Design

Single-center, retrospective, cohort study

N= 103

Objective

To assess the outcomes of patients treated with functional aminoglycoside monotherapy for the empiric treatment of Pseudomonas aeruginosa bacteremia

Study Groups

Inappropriate empiric therapy (n= 45)

Appropriate empiric monotherapy (n= 58)

Inclusion Criteria

≥18 years old, positive blood culture for P. aeruginosa, hospitalized for ≥48 hours after index culture

Exclusion Criteria

Received >1 active antibiotic 

Methods

Patients included were stratified based upon the receipt of appropriate versus inappropriate empiric antibiotic therapy and subsequently stratified into function aminoglycoside monotherapy versus beta-lactam monotherapy use. 

Appropriate empiric antibiotic therapy was defined as the administration of antipseudomonal antibiotic(s) within 24 hours of positive index blood culture, which was shown to be active against the isolate. Functional aminoglycoside monotherapy was defined as the administration of an aminoglycoside as the only active agent given empirically for >1 dose and a minimum of 48 hours of therapy. Inappropriate empiric antibiotic therapy was defined as no active agent given empirically.

Duration

January 2002 to December 2015

Outcome Measures

Baseline Characteristics

All patients (N= 103)^∗

Age, years

≤63

>63

10/53 (18.9%)

11/50 (22%) 

Sex

Female

Male

8/39 (20.5%)

13/64 (20.3%)

Race

White

Non-white

11/58 (19%)

10/43 (23.3%)

Length of hospital stay, days

≤20

>20

6/54 (11.1%)

15/49 (30.6%)

APACHE II score

≤15

>15

6/54 (11.1%)

15/49 (30.6%)

Source of bacteremia

Line

Lungs

Urinary tract

Wound

Abdomen

2/8 (25%)

5/23 (21.7%)

1/19 (5.3%)

2/11 (18.2%)

6/15 (40%)

^∗Baseline characteristics presented as 30-day mortality stratified to different demographic/clinical variables (n/N), with patients who expired (n) and overall patient population (N) values provided. 

APACHE II, Acute Physiology and Chronic Health Evaluation II 

Results

Among the 12 patients who received aminoglycosides as functional monotherapy, the following treatments were given: amikacin (5 patients; dose range: 4.3–7.3 mg/kg), tobramycin (6 patients; dose range: 1.9–4.2 mg/kg), and gentamicin (1 patient; dose: 1.5 mg/kg). Among these, 3 patients received extended-interval dosing and 9 received traditional dosing (5 had end-stage renal disease). 

Overall 45 (43.7%) of patients received inappropriate empiric therapy, with 58 (56.3%) of patients receiving appropriate empiric (functional) monotherapy. There was no significant difference in 30-day mortality among patients who received functional aminoglycoside monotherapy versus inappropriate empiric therapy (33.3% versus 24.4%; p= 0.71). The rate of 30-day mortality in the functional aminoglycoside monotherapy group was more than double the mortality rate of the beta-lactam monotherapy group, although this was not found to be statistically significant (33.3% versus 13%; p= 0.19).

Adverse Events

N/A 

Study Author Conclusions

Patients who received functional aminoglycoside monotherapy had less favorable outcomes compared to patients who received beta-lactam monotherapy for the empiric treatment of P. aeruginosa bacteremia. This poses a significant therapeutic challenge as aminoglycosides remain one of our last-line agents for multidrug-resistant P. aeruginosa infections. The best evidence-based approach to advance medical care of patients should consider an optimal balance of clinical benefits and potential risk of nephrotoxicity associated with aminoglycosides.

InpharmD Researcher Critique

This study could not control for antimicrobial prescribing practices or separate patients based on the source of bacteremia and multidrug-resistant phenotypes due to its retrospective design. The effects of aminoglycoside dosing and duration on outcomes were not specifically evaluated, and therapeutic drug monitoring was not routinely done, which may have caused variability in drug exposure and effectiveness. Differences in susceptibility thresholds also suggest that some patients might not have received appropriate empiric therapy, which could have impacted the results.

Aminoglycosides for Treatment of Bacteremia Due to Carbapenem-Resistant Klebsiella pneumoniae

Design

Single-center, retrospective study

N= 33

Objective

To review our clinical experience with aminoglycosides as primary therapy for carbapenem-resistant (CR) K. pneumoniae bacteremia

Study Groups

Amenable bacteremia (n= 16)

Unamenable bacteremia (n= 17)

Inclusion Criteria

Patients with bacteremia who were initially treated with an aminoglycoside for >3 days

Exclusion Criteria

Patients that died after 1 day of aminoglycoside therapy

Methods

Patients with normal renal function were ordered standard extended-interval aminoglycoside doses based on the Hartford nomogram. Adjustments were made for those with renal impairment in accordance with current guidelines. Bacteremia was classified as primary or secondary based on independent reviews conducted by two investigators. Sources of bacteremia were categorized as amenable or unamenable to achieving reliable aminoglycoside pharmacokinetics (PK) at the site. Amenable sites included primary bacteremia, urine, and soft tissues, while unamenable sites encompassed the abdominal cavity, respiratory tract, and bone.

Duration

February 2010 to September 2014

Outcome Measures

Primary outcomes: Clinical success defined as survival at 30 days following the onset of CR K. pneumoniae bacteremia

Secondary outcomes: Fatal or nonfatal underlying disease, resolution of signs and symptoms of infection, sterilization of blood cultures within 7 days of treatment initiation, completion of planned antimicrobial therapy, and the absence of recurrent CR K. pneumoniae infections within 30 days

Baseline Characteristics

All patients^∗

(N= 33)

APACHE II score (range)

Primary bacteremia

Secondary bacteremia sites

Abdomen

Respiratory tract

Urinary tract

Soft tissue

Bone

14 (42%)

2 (6%)

2 (6%)

1 (3%)

1 (3%)

CR. K pneumoniae strain-typed isolates

ST-258

KPC-2

KPC-3

28/31 (90%)

25/31 (81%)

4/31 (13%) 

Infections amendable to reliable aminoglycoside PK

16 (48%)

Gentamicin monotherapy treatment

Gentamicin susceptibility

10 (37%)

32 (97%)

∗All included patients were adults, with the majority of the patient population (52%) >60 years old

APACHE II, acute physiology and chronic health evaluation II ST, strain type; KPC, Klebsiella pneumoniae carbapenemase

Results

Endpoint

Amenable bacteremia

(n= 16)

Unamenable bacteremia

(n= 17)

p-value

Sources of bacteremia

12/16 (75%)

Survival rates at 14 and 30 days were 78% and 70%, respectively. Clinical success was achieved in 54% of patients, with a higher association of clinical success seen in patients with primary rather than secondary bacteremia (10/13 [77%] versus 8/20 [40%]; p= 0.07)., amendable compared to unamendable (12-16 [75%] versus 6/17 [35%]; p= 0.037), and APACHE II scores of <20 compared to ≥20 (14/22 [64%] versus 4/11 [36%]; p= 0.16). Success rates were higher in patients with underlying diseases considered nonfatal compared to fatal (13/17 [76%] versus 5/16 [31%); p= 0.015). 

Overall clinical success rate was 78% (14/18) for patients in whom >2 factors (amendable source, APACHE II score <20, and/or nonfatal underlying disease) linked to favorable outcomes were present compared to 27% (4/15) for other patients (p= 0.005). The clinical success rate was 100% (8/8) for patients in whom all 3 favorable factors, compared to 40% (10/25) for others (p= 0.004).

Adverse Events

A total of 9 patients developed an acute kidney injury during aminoglycoside therapy, with one patient requiring renal replacement therapy. One patient developed a recurrent bloodstream infection while on gentamicin monotherapy due to an aminoglycoside-resistant CR K. pneumonia strain 11 days from initial bacteremia development. 

Study Author Conclusions

In conclusion, despite a small sample size, our study provides much-needed insight into the potential roles for aminoglycoside treatment against CR K. pneumoniae bacteremia. As new agents against CR K. pneumoniae and other highly drug-resistant Gramnegative bacteria enter the clinic, it will be imperative to employ them judiciously to preserve their long-termutility. In this regard, it is critical to understand where older agents, like aminoglycosides, have useful roles. Moving forward, it will be important to determine if aminoglycosides can be used in combination with newer agents to improve efficacy and limit the emergence of resistance.

InpharmD Researcher Critique

Study limitations include small sample size and retrospective lens, the dosing parameters for aminoglycosides were not reported, and variations in baseline comorbidities and previous antibiotic use contributing to potential resistance were not evaluated. As the majority of patients had developed bacteremia secondary to an intra-abdominal infection, generalizability to aminoglycoside efficacy outside of this patient population is limited.