1. Aminoglycosides Maressa Santarossa, PharmD, BCPS, BCIDP
Pharmacology and Therapeutics
September 10, 2019

2. Learning Objectives Mechanisms of action and resistance
Spectrum of activity
Synergy between cell wall active agents and aminoglycosides
PK/PD and dosing principles
Traditional vs. extended-interval dosing strategies
Clinical uses
Adverse effects

3. Aminoglycosides Streptomycin (1943) Neomycin (1949) Kanamycin (1957)
Paromomycin (1959)
Gentamicin (1963)
Tobramycin (1968)
Amikacin (1972)
Netilmicin (1975)
Plazomicin (2018)

4. Mechanism of Action
Irreversibly bind to 30S ribosomal subunit of susceptible bacteria resulting in inhibition of protein synthesis
Cell entry is oxygen-dependent

5. Mechanisms of Resistance
Synthesis of AG modifying enzymes
Plasmid-mediated
>50 AG altering enzymes
Cause acetyl-, adenyl-, or phosphorylation
Altered AG uptake
Loss of porin channel
Efflux pump
Change in ribosomal binding site/target modification

6. Spectrum of Activity Gentamicin
Gram-negative
E. coli
K. pneumoniae
Proteus
Citrobacter
Enterobacter
Morganella
Serratia
Pseudomonas
Gram-positive
Enterococcus
S. aureus
Viridans Streptococcus
S. pyogenes

7. Spectrum of Activity Tobramycin
Gram-negative
Similar to gentamicin BUT
More active against Pseudomonas
Slightly less active against other gram-negatives

8. LUMC Antibiogram 2018 Gram-Negatives
Percentage of organisms susceptible to antimicrobials
Organism
Amp/Sul
Cefz
Ceftr
Ctaz
Cefp
Gent
Mero
Cip
Pip/Taz
Tobr
T/S
A. baumannii 67 40 59 48 51 62 -
E. cloacae 69 91 98 97 68 89
E. coli 46 82 85 86 99 66 92 84
K. pneumoniae 65 75 83 94 95 77
P. mirabilis 70
100 96 74
P. aeruginosa 87 88 78
S. marcescens 60

9. Spectrum of Activity Amikacin
Gram-negative
Generally, most active against nosocomial gram-negatives (except vs tobra for Pseudomonas, most of the time)
Mycobacterial
M. tuberculosis
Atypical mycobacteria
Others
Nocardia

10. Spectrum of Activity Streptomycin
Gram-positive
Enterococcus
Mycobacterial
M. tuberculosis
Less atypical mycobacteria than amikacin

11. Synergy Synergy between cell wall active agents and AGs
Likely due to enhanced AG uptake

12. Pharmacokinetics Poor oral absorption Volume of distribution ~ 0.3L/kg
Low protein binding (~10%)
High water solubility
Distribution sites:
Low in CSF, bronchial secretions, bile (30%), vitreous humor (40%)
Pleural, pericardial, ascitic, synovial fluid ~50% of serum
High in urine

13. Pharmacokinetics
99% renally eliminated (urine conc ~ x serum conc)
30-40% removed by hemodialysis
Linear PK

14. Pharmacodynamics Concentration-dependent killing
PK/PD parameter: peak/MIC (goal ≥ 8 – 10)

15. PK/PD Parameters Associated with Antibiotic Efficacy
Peak:MIC
Fluoroquinolones
Aminoglycosides
Daptomycin
AUC:MIC
Fluoroquinolones
Vancomycin
Concentration
MIC
Time > MIC
Macrolides
Clindamycin
-lactams
Time (hours)
Craig WA, Clin Infect Dis 1998;26:1

16. Dosing Gentamicin and Tobramycin
Gram-negative infections
Traditional (multiple daily doses) dosing
2 – 2.5 mg/kg q8h for normal renal function
Goal levels: peak 5-10 (depending on site of infection); trough < 2
Extended interval (once-daily) dosing
5 – 7 mg/kg/day for normal renal function
Goal levels: peak 15 – 20; trough < 1

17. Dosing Amikacin Gram-negative infections
Traditional (multiple daily doses) dosing
5 mg/kg q8h for normal renal function
Goal levels: peak (depending on site of infection); trough < 5
Extended interval (once-daily) dosing
mg/kg/day for normal renal function
Goal levels: peak ; trough < 2

18. Dosing Gram-positive infections
Gentamicin 1 mg/kg q8h for normal renal function
Goal levels: peak 3-4; trough < 1
Streptomycin 5 – 10 mg/kg q 12 – 24h
Goal levels not defined (high peaks not needed, closely monitor troughs with goal concentration of < 1-2 to minimize toxicity)

19. Dosing Mycobacterial infections
Amikacin/streptomycin
Standard dose: 15 mg/kg/day
Goal levels: peak 30-40, trough <2
High-dose: 25 mg/kg 3 times/weekly
Goal levels: peak 70-80, trough <1

20. Traditional vs. Extended-Interval Dosing
Traditional dosing (MDD)
Approximately same daily dose given every 8 to 12 hours
Extended-interval dosing (ODA)
One large dose given at an interval no less than every 24 hours

21. Rationale for Extended-Interval Dosing
Concentration-dependent bactericidal activity
Post-antibiotic effect (PAE)
Adaptive resistance
Minimize toxicities
Nephrotoxicity
Ototoxicity
Cost savings
Efficacy

22. Concentration-Dependent Bactericidal Activity: Aminoglycoside Peak/MIC Ratio
Response ratio
Maximum Peak/MIC ratio
100 80 60 40 20
Adapted from Moore RD et al. J Infect Dis. 1987;155:93-99

23. Concentration-Dependent Bactericidal Activity: Aminoglycoside Peak/MIC Ratio
Relative odds
95% CI
<2
1.00
2 to <4
1.63
0.84 – 3.16
4 to <6
1.83
1.09 – 3.03
6 to <8
4.35
2.53 – 7.46
8 to <10
6.49
3.56 – 11.82
>10
8.41
4.62 – 15.33
Adapted from Moore RD et al. J Infect Dis. 1987;155:93-99

24. Postantibiotic Effect
Persistent suppression of bacterial growth after drug concentration falls below the MIC of targeted organism
Factors that impact PAE:
Organism
Drug concentration
Duration of drug exposure
Antimicrobial combinations
PAE range for AGs: 0.5 – 7.5h
Lacy et al., Clin Infect Dis 1998;27:23; Spivey, Clin Pharm 1992;11:865

25. Adaptive Resistance
Decreased drug uptake that occurs in bacteria that survive an initial, suboptimal AG dose
Increased drug-free time may protect the bactericidal activity of AGs
Adaptive resistance is characterized by a temporary down-regulation of drug uptake into the bacteria. It is thought to decrease AG efficacy b/c it turns off the energy-dependent AG transport systems after the first dose. If drug concs. Remain constant, adaptive resistance may occur. Administration of large, infrequent doses allows for concs to fall to minimal levels and up-regulation or reactivation of the transport system, leading to increased activity and decreased resistance.
Lacy et al., Clin Infect Dis 1998;27:23

26. Decreased Nephrotoxicity
Related to intracellular accumulation of drug in the renal cortex
Uptake of AGs into proximal tubule cells is saturable at clinically achieved concentrations
Animal studies have shown that continuous infusion AG results in higher renal cortical concentrations compared with a single daily injection regimen
Murry KR et al, Pharmacotherapy 1999;19:1252; Swan SK, Sem Nephrol 1997;17:27

27. Decreased Nephrotoxicity Renal Accumulation of AGs
Methods
N=25 pts with renal cancer partly involving one kidney
24h prior to nephrectomy, pts randomized to receive:
Gentamicin 4.5 mg/kg as a 30m or 24h infusion
Netilmicin 5 mg/kg as a 30m or 24h infusion
Monitored AG PK prior to nephrectomy
Tissue AG concentrations obtained from excised kidney
Verpooten GA et al, Clin Pharmacol Ther 1989;45:22

28. Decreased Nephrotoxicity Renal Accumulation of AGs
Results
PK consistent with existing data for AG PK in pts with normal renal function
Renal cortical drug levels were 30% and 50% higher in the CI groups for netilmicin and gentamicin, respectively
Verpooten GA et al, Clin Pharmacol Ther 1989;45:22

29. Decreased Ototoxicity?
Uptake of AGs into different inner ear tissues does not correlate with the degree of ototoxicity
Sparse data for risk of ototoxicity based on dosing regimen
Animal studies—conflicting data (dosing regimen vs. total daily dose)
Human data—specific threshold for peak or trough concentrations that confer highest risk for ototoxicity has not been identified; severe damage may occur with normal concentrations and/or may be related to total drug exposure
Mattie H et al, J Antimicrob Chemother 1989;24:281

30. Safety Meta-Analyses Study Studies reviewed Patients (nephro/oto)
Nephrotoxicity
Otoxicity
Galloe 1995 16
1200 ND
Barza 1996 21
3091
ODA better
Ferriols-Lisart 1996 18
2317
Freeman 1996 35
1603
Not studied
Hatala 1996 14
1625
Trend favoring ODA
Munckhof 1996 19
2881
Ali 1997 26
2035
Bailey 1997 20
2163
Hatala 1997 4
422

31. Cost Savings Decreased pharmacy preparation time
Decreased nursing administration time
Potentially decreased drug concentration monitoring

32. Efficacy Meta-Analyses
Study
Studies reviewed
Patients
Clinical response
Galloe 1995 16
1200 ND
Barza 1996 21
3091
Trend favoring ODA
Ferriols-Lisart 1996 18
2317
ODA better
Freeman 1996 35
1603
Hatala 1996 14
1625
Munckhof 1996 19
2881
Ali 1997 26
2035
Bailey 1997 20
2163
Hatala 1997 4
422

33. Summary: How to dose Gram-negative or mycobacterial infection
HIGH dose less frequently (once daily is shortest interval)
Gentamicin/tobramycin 5-7 mg/kg/day for normal renal function
Amikacin mg/kg/day for normal renal function
Gram-positive infection
Low dose more frequently
Gentamicin 1 mg/kg q8h for normal renal function

34. Clinical Uses Gram-negative infections (gent, tobra, amikacin)
In combination with beta-lactams to treat resistant and/or serious infections
Empiric treatment of sepsis, especially from a urinary source
Bloodstream, intraabdominal infections, skin/soft tissue infections
Need to use high dose if giving for pneumonia
Rarely used as monotherapy

35. Clinical Uses Gram-positive infections (mostly gent, some strepto)
In combination with beta-lactams (ampicillin or nafcillin) or vancomycin for severe infections (enterococcal or staphylococcal endocarditis)
High peak concentrations are not necessary so low dose is sufficient

36. Clinical Uses Mycobacterial infections (amikacin, streptomycin)
In combination with multiple antimycobacterial agents
High dose less frequently (similar to dosing for gram-negative infections)

37. Toxicities Nephrotoxicity Incidence: 9 – 15%
Gent > tobra > amik > strepto
AG-induced renal tubular necrosis is reversible
Risk factors: prolonged, elevated trough concentrations, prolonged therapy, underlying renal insufficiency, advanced age, hypovolemia, concomitant nephrotoxins
Kahlmeter G, J Antimicrob Chemother 1984;13(Suppl A):9.

38. Toxicities Ototoxicity Incidence: 3 – 14%
AGs may cause cochlear and vestibular damage
Cochlear: amik > gent > tobra
Vestibular: strepto > gent > amik > tobra
Damage may occur before symptoms appear
Usually irreversible (may appear after the end of treatment)
Risk factors: increased age, prolonged AG course,
?increased serum concentrations, ?genetic factors
Kahlmeter G, J Antimicrob Chemother 1984;13(Suppl A):9.
Ariano RE, Ann Pharmacol 2008;42:1282.

39. New drug approval: Plazomicin (Zemdri®)
FDA approved June 2018 for adults with cUTI, including pyelonephritis (did not get approved for bloodstream infections)
Boxed warnings for nephrotoxicity (3.6%) and ototoxicity (0.3%)
Dosing: 15 mg/kg q24h + renal dose adjustments
Compared to meropenem in clinical trials
AUC:MIC correlates with efficacy
Variable activity against P. aeruginosa
In-vitro activity against ESBL, KPC, OXA-48

40. Conclusions
Aminoglycosides are a vital component of the antibacterial armamentarium, however, they may cause serious adverse effects
It is possible to optimize PK/PD to enhance bacterial kill and minimize toxicity
“Get in and get out!”

41. Aminoglycosides Maressa Santarossa, PharmD, BCPS, BCIDP
Pharmacology and Therapeutics
September 10, 2019