Aminoglycoside Antibiotics 2h5w3l

Click to edit Master subtitle style

 The aminoglycoside antibiotics are widely used for the treatment of severe gram-negative infections such as pneumonia or bacteremia, often in combination with a β-lactam antibiotic.  Aminoglycosides are also used for gram-positive infections such as infective endocarditis in combination with penicillins when antibiotic synergy is required for optimal killing.  Aminoglycoside antibiotics are bactericidal, and the drugs exhibit concentrationdependent bacterial killing.

Antibiotics with concentration-dependent killing characteristically bacteria at a faster rate when drug concentrations are higher. Also, aminoglycosides have a concentrationdependent postantibiotic effect. The postantibiotic effect is the phenomenon of continued bacterial killing even though serum concentrations have fallen below the minimum inhibitory concentration (MIC)

Aminoglycoside (AGL)

Stretomyces Suffix -mycin

Micromonospora Suffix -micin

Streptomycin

Paromomycin

Gentamicin

Neomycin

Tobramycin

Netilmicin

Amikacin

• Most bacterial species are sensitive – aminoglycoside concentration varies widely among species.

• Intracellular concentration is dependent upon a transport system located in the cell membrane – Oxygen-dependent system ordinarily transports polyamines and is absent in anaerobes

• Therefore, only clinically useful against organisms growing in aerobic conditions.

• Bactericidal (irreversible) inhibitors of protein synthesis • Penetration of bacterial cell wall is partly dependent on O2-dependent active transport • Minimal activity against strict anaerobes • Transport is enhanced by cell wall synthesis inhibitors – Antimicrobial synergism

• •

Bind to 30S ribosomal unit Interfere with protein synthesis 1. Block formation of initiation complex 2. Cause misreading of the code on the mRNA template 3. Inhibit translocation

• Resistant due to failure to penetrate into the cell – Streptococci, including S. pneumoniae – Enterococci

• Resistant due to failure to penetrate into the cell – Streptococci, including S. pneumoniae – Enterococci

• Plasmid-mediated formation of inactivating enzymes – Primary mechanism of resistance – Varying susceptibility to the enzyme

• Plasmid-mediated formation of inactivating enzymes – Group transferases • Catalyze the acetylation of amine functions • Transfer of phosphoryl or adenyl groups to the O2 atoms of hydroxyl groups on the aminoglycoside

• Plasmid-mediated formation of inactivating enzymes – Netilmicin is less susceptible and is active against more strains of organisms

• Plasmid-mediated formation of inactivating enzymes – Transferases produced by enterococci can inactivate • Amikacin • Gentamicin • Tobramycin • Not streptomycin

Parenteral

 Septicemia, bone and t infections, skin and soft tissue infections, respiratory tract infections, postoperative and intra-abdominal infections  Tuberculosis and other mycobacterial diseases

: streptomycin, kanamycin, amikacin  In vitro synergism - AGs + extended spectrum penicillin with antipseudomonal activity or + β-lactam antibiotic/carbapenem or + expanded-spectrum penicillin - Gentamicin (or Streptomycin) + penicillin G (or ampicillin) for Enterococci



Oral

Kanamycin, Neomycin: preoperative intestinal antisepsis Paromomycin: intestinal amebiasis, various parasitic infections 

Inhalation Tobramycin, Gentamicin : bronchopulmonary Ps.

aeruginosa

infections in cystic fibrosis

GENTAMICIN, TOBRAMYCIN, and AMIKACIN • Used for the following but is not the drug of choice – H. influenzae – M. catarrhalis – Shigella species

• Serious infections caused by aerobic gram (-) bacteria – – – –

E. coli Klebsiella Providencia Serratia

Enterobacter Proteus Pseudomonas

ANTIBACTERIAL SYNERGY • Not effective for gram (+) cocci when used alone • Combination of aminoglycoside and cell wall synthesis inhibitors • Combined with penicillin in the treatment – Pseudomonal – Listerial – Enterococcal infections

STREPTOMYCIN • Tuberculosis • Plague • Tularemia • Multi-drug-resistant (MDR) strains of M. tb resistant to streptomycin maybe susceptible to amikacin SPECTINOMYCIN • Aminocylitol related to aminoglycosides • Back-up drug • Intramuscular as single dose for gonorrhea

NEOMYCIN • Used topically • Locally – In the GIT – Eliminate bacterial flora

NETILMICIN • Reserved for serious infections resistant to other aminoglycosides

Drug

Use

Streptomycin



(Streptomycin Sulfate ® )

Second-choice medications: for tuberculosis (TB)  streptococcal endocarditis (with B- lactam)  enterococcal endocarditis ( with penicillins )

Paromomycin



( Humatin ®)

Neomycin ( mycifrdish ®)

Tobramycin ( Nebcin ®) , (Tobi®)

Gentamicin ( garamycin ®)

Intestinal infections Ttt of hepatic encephalopathy  Ttt of amebiasis

prophylaxis GI surgery  prevention of hepatic encephalopathy & hypercholesterolemia 

Ttt of systemic infection  respiratory tract infection 

Ttt

of systemic infection  life threatening infection  eye infection

( Amikin ® )

Respiratory tract infection  Skin infection  Urinary tract infection  Blood, abdomen or bones infection

Netilmicin



Amikacin

( NETROMYCIN ®)



septicemia  Lower respiratory tract infection  Urinary tract infection  peritonitis and endometritis

Drug

Streptomycin

Dose regimen

Available dosage form

(if creatinine clerance > 90ml/min)

( all aminglycosides have very poor absorption from G.I.T )

I.V 25-30 mg/weak ( tuberculosis )

I.V , I.M

(Streptomycin Sulfate ® )

Paromomycin

Oral 500 mg po tid x7d

Oral

( Humatin ®)

( mycifrdish ®)

Oral For hepatic encephalopathy : 4-12 gm/d As prophylactic in GI surgery : 1.0 gm po x3 with erythromycin

Tobramycin

I.V 5.1 ( 7 if critically ill ) mg/kg q24h

Neomycin

Oral , topical It is not given intravenously, as it is extremely nephrotoxic

I.V , I.M , inhalation (Tobi®)

( Nebcin ®)

Gentamicin

I.V 5.1 ( 7 if critically ill ) mg/kg q24h

I.V , I.M , Topical

( garamycin ®)

Amikacin

I.V 15mg/kg q24h

I.V , I.M

I.V 6.5 mg/kg q24h

I.V , I.M

( Amikin ® )

Netilmicin ( NETROMYCIN ®)

The lowest ototoxic AGL

• Tobramycin is superior to gentamicin for ttt of P.aeruginosa . • Gentamicin is the preferred AGL used in combination ttt of enterococcal endocarditis ( with ampicillin or vancomycin). • Streptomycin has the greatest activity of all the AGL against M.tuberculosis. • Capreomycin is an AGL use as alternative drug to ttt mycobacterial infection • Streptomycin & gentamicin are drugs of choice to ttt tularemia • Streptomycin is drug of choice to ttt plague & brucellosis

A. OTOTOXICITY • Auditory or vestibular damage (or both) maybe irreversible –

Auditory impairment • Amikacin and kanamycin – Vestibular dysfunction • Gentamicin and tobramycin

•

Risk is proportionate to the plasma levels –

• •

High if dosage is not modified in renal dysfunction

Increased with the use of loop diuretics Contraindicated in pregnancy

B. NEPHROTOXICITY • Acute tubular necrosis • Reversible • Most nephrotoxic – Gentamicin and tobramycin

• •

More common in elderly patients Patients concurrently receiving – Amphotericin B – Cephalosporins – Vancomycin

C. NEUROMUSCULAR BLOCKADE • Rare • Curare-like block may occur at high doses – Respiratory paralysis

• •

Reversible Treatment – Calcium – Neostigmine – Ventilatory

D. SKIN REACTIONS • Neomycin – Allergic skin reactions like dermatitis

Pharmacokinetics

Bioavailability 1. Oral: 0.2% 2. Intramuscular: complete, rapid 3. Aerosol: 1.5% to 34%

• Duration of distribution : 30 min. after the end of infusion • Total protein binding: 0% to 30% • Distribution sites Good

Synovial fluid, Urogenital tissue

Moderate

Placenta

Poor

Eye, Renal cyst

Limited

Bone, Bronchial tree, CSF

Variable

Saliva

• Renal excretion 70% to 100%

• Breast-feeding Controversial

• Bile Variable Some studies - biliary concentrations equal to or greater than that of serum. No correlation between liver function and drug excretion in the bile.

For Adult: There are two main principles for the use of the SDD of AGL: 1.

2.

Since the AGL bactericidal effect is related to peak concentrations, higher doses will achieve a higher peak concentration and ensure efficacy of therapy. With this dosing, it is possible to achieve the desired peak:MIC ratio. SDD may reduce the frequency of nephrotoxicity since low or undetectable trough concentrations will be attained. Dose ranges from 3 to 7mg/kg/day for gentamicin & tobramycin.

For children: The use of SDD of AGL in children has some limitation because of: 1. 2. 3. 4.

Rapid AGL clearance. Unknown duration of post-antibiotic effect. Safety concerns. Limited clinical and efficacy data.

•

SDD relatively contraindications :

1. S.aureus or Enterococcal infection. 2. Bacterial pneumonia with pathogen having high MIC.

•

Toxicity with SDD:

1. Endotoxin like reactions with SDD AGL’s therapy: - many patients develop rigors, fever, tachycardia. 2. Ototoxicity: develop vestibular dysfunction with high dose. 3. Nephrotoxicity decreased with the use of SDD AGL’s.

N.B: - SDD of AGL not for every infection, pathogen, or patient. - Must have therapeutic goal based on pathogen susceptibility & location of infection. - PK’s remain useful tool to screen patients & to establish desired x:MIC ratio.

AGL dose depend on IBW & cretinine clerance. Formula: 1. Creatinine clerance : = (140-age)(IBW in kg) / (72)(Scr)=ml/min x 0.85 for CrCl of women 2. Ideal Body Weight (IBW) : males: 50kg + 2.3kg per inch over 5’= weight in kg females: 45kg +2.3kg per inch over 5’= weight in kg 3. Obesity adjustment : use if Actual Body Weight (ABW) is >30% above IBW. To calculate adjusted dosing weight in kg : IBW+ 0.4 (ABW-IBW) = adjusted weight .

The pharmacokinetic dosing method

The Hull and Sarubbi nomogram

Literature-based recommended dosing

The goal of initial dosing of aminoglycosides is to compute the best dose possible for the patient given their set of disease states and conditions that influence aminoglycoside pharmacokinetics and the site and severity of the infection.

In order to do this, pharmacokinetic parameters for the patient will be estimated using average parameters measured in other patients with similar disease state and condition profiles.

For patients who do not have disease states or conditions that alter volume of distribution, the only two patient-specific factors that change when using the pharmacokinetic dosing method is patient weight and creatinine clearance. Because of this, it is possible to make a simple nomogram to handle uncomplicated patients with a standard volume of distribution (Table 4-3).

Because of the large amount of variability in aminoglycoside pharmacokinetics, even when concurrent disease states and conditions are identified, many clinicians believe that the use of standard aminoglycoside doses for pediatric patients is warranted In general, the expected aminoglycoside steady-state serum concentrations used to compute these doses were similar to those for adults given conventional dosing.

Suggested initial aminoglycoside doses for various pediatric patients are listed in the Effects of Disease States and Conditions on Aminoglycoside Pharmacokinetics and Dosing section.

Clinical PharmacoKinetics Parameters

• Therapeutic plasma concentration Gentamicin, Tobramycin Peak 4-8 mg/L Trough<2 mg/L Amikacin  Peak 20-30 mg/L Trough <10mg/L

• Vd 0.25 L/kg • Cl

Normal renal function equal to Clcr Functionally anephric patients 0.0043 L/kg/hr Surgically anephric patients 0.0021 L/kg/hr Hemodialysis 1.8 L/hr

• T½ Normal renal function 2-3 hr Functionally anephric patients 30-60 hr

1) Ke 

Ln C1 / C2 t

T1 / 2 

0.693 Ke Dose Cmax

Conc.

C1 C2 ti n

t1

t τ

Time

( Dose tin)  S  F  1  e  Ketin   e  Ket 1 2) Vd  C1  Ke  1  e  Ke  Vd Dose Cmax

Conc.

C1 C2 ti n

t1

t

τ Time

1) Interval

 new

 eakdesired  1   Ln   tin Ke  Ctroughdesired 

2) Dose Vd  eakdesired  Ke  tin  (1  e Ke ) Dosenew  S  F  (1  e Ketin )  e Ket 1

Decide whether the following are appropriate: • Use alone or in combination with another antibiotic • Dose and Interval • Need for therapeutic serum concentration drug monitoring 1. Will aminoglycoside levels be needed? 2. What type of study if any is needed 3. How many and when should levels be obtained • How should patient be monitored • Duration of therapy

Aminoglycoside serum concentration time data (ASCTD) available: • No ASCT data available 1. Far more common situation 2. General rule for conventional aminoglycoside therapy (Assume adult with normal renal function) - Daily dose for gentamicin or tobramycin ~ 5 mg/kg/d *Amount per dose ~ 1.5 mg / kg - Daily dose for amikacin ~ 15 mg/kg/d *Amount per dose ~ 5 to 7.5 mg / kg

Parameters required for • evaluation: • Age • Height in inches • Weight • Serum creatinine

Patient weight: a. Actual body weight (ABW) b. Lean body weight (LBW) in Kg 1. Males = 50 + 2.3 (# inches over 5 feet) 2. Female = 45 + 2.3 (# inches over 5 feet) 3. Note if LBW > ABW use ABW c. Dosing body weight (DBW) 1. For patients >30% over LBW 2. DBW = LBW + 0.4 (ABW – LBW)

• Calculated Creatinine Clearance(Crcl) in ml/min Method of Cockcroft and Gault Male = ((140 – Age )* LBW) / (72* Scr) Female = 0.85 ((140 – Age )* LBW) / (72* Scr) • Transform Crcl into Kd using Detli method Kd (Hr-1) = 0.0024 (Crcl) + 0.01

• Peak concentrations should be ~ 10 x MIC of the likely bacterial pathogen • Troughs should be as low as possible given the circumstances surrounding the patient • Dose should be evaluated on a mg/kg/day basis and mg/kg per dose basis using the appropriate body weight parameter • Dosing interval should be ~ 2 to 3 T1/2’s plus the hour for drug infusion • Try to limit total course of therapy to < 5 days to reduce risk of nephrotoxicity or ototoxicity

• General requirements are that patient’s renal function and fluid status be stable • Trough / Peak Option - Patient must be at steady state *Received drug for 3-5 T1/2’s - If t1/2 is short in relation to doing interval, the likelihood of having measurable trough is low - Nurse has istered drug on time and on schedule during the 3 to 5 T1/2 period - Note: If patient seriously ill with impaired renal function, clinician may not be able to wait for steadystate

• Impact of preventing aminoglycoside toxicity through TDM (traditional dosing) –TDM can reduce nephrotoxicityfrom 19.2% to 7.9% (retrospective) –TDM reduces significantly nephrotoxicity from 14.4 to 8% and from 9.5 to 5.6 (prospective) • Nephrotoxicityin once-daily istration occurs at a higher frequency (> 15%) in at risk patients – Long duration of therapy, high doses – Elderly – Co-existing liver/renal dysfunction – Co-istration nephrotoxicdrugs (vancomycin), volume depletion, furosemide

• Should always factor in the clinical condition of the patient • The likely bacterial pathogen and level of sensitivity to chosen aminoglycoside • The location of infection and how well the aminoglycoside is likely to concentrate at that site • Anticipate future - Renal & fluid status - Likely duration of therapy

Bauer, Larry A.2008. Applied Clinical Pharmacokinetics Second Edition. Washington : MacGrawHill Medical Bauer, Larry A. Clinical Pharmacokinetics Handbook. Washington : MacGrawHill Medical