CHAPTER 45: A MINOGLYCOSIDES & SPECTINOMYCIN

“basta mga MYCIN = AMINOGLYCOSIDES”

Streptomycin
OUTLINE Usually in combination with other drugs
I Aminoglycosides
A General Properties of Aminoglycosides MECHANISM OF ACTION
i Physical and Chemical Properties ● MOA: Bacterial protein synthesis inhibitor at
ii Mechanism of Action 30s subunit
iii Mechanism of Resistance
iv Pharmacokinetics and Once-daily Dosing
● Irreversible inhibitors of protein synthesis
v Adverse Effects ○ First, penetrate via porin channels
vi Clinical Uses across the outer membrane to reach
B Streptomycin periplasmic space by passive diffusion
i Clinical Uses ○ Then, transport across cell membrane to
· Mycobacterial Infections cytoplasm by proton pump
· Nontuberculous Infections
ii Adverse Reactions
(oxygen-dependent process)
C Gentamicin ● 3 ways Aminoglycosides inhibit Protein
i Antimicrobial Activity
Synthesis
ii Clinical Uses ○ binds 30S-subunit ribosomal protein and
· Intramuscular or Intravenous Administration interference with initiation complex of
· Topical and Ocular Administration peptides formation
· Intrathecal Administration
iii Adverse Reactions
○ misreading of mRNA
○ breakup of polysomes into nonfunctional
D Tobramycin
monosomes.
i Intramuscular or Intravenous Administration
The MOA never forget that Bacterial protein synthesis
ii Inhaled and Ophthalmic Administration inhibitor at 30s subunit
E Amikacin MECHANISM OF RESISTANCE
F Netilmicin ● Production of a transferase enzyme that
G Neomycin, Kanamycin, & Paromomycin inactivates the aminoglycoside
i Antimicrobial Activity & Resistance ● Impaired entry of aminoglycoside into the cell
ii Pharmacokinetics ● Mutation of receptor protein on the 30S
iii Clinical Uses ribosomal subunit
iv Topical Administration
v Oral Administration
vi Intravenous and Intramuscular Administration PHARMACOKINETICS
vii Adverse Reactions ● absorbed very poorly in GI tract
H Plazomicin ● Administered parenterally or applied locally
II Spectinomycin ● Highly polar compounds that do not enter cells
readily
I. AMINOGLYCOSIDES ● Largely excreted from the CNS and eye
➢ Streptomycin ● Cleared by the kidney, and excretion is directly
➢ Gentamicin proportional to creatinine clearance
➢ Tobramycin
➢ Amikacin ONCE-DAILY DOSING
➢ Netilmicin ● 2 reasons why administration of entire daily
➢ Neomycin, Kanamycin & Paromomycin dose in a single injection may be preferred
➢ Plazomicin ○ 1. Concentration-dependent killing
Streptomyces - mycin ■ higher concentration kill a larger
Micromonospora - micin portion of bacteria and kill at a
more rapid rate
AMINOGLYCOSIDES ○ 2. Postantibiotic effect
● against aerobic gram-negative microorganism ■ antibacterial activity persists
● Water-soluble beyond the time during which
● stable in solution measureable drug is present
● more active in alkaline than acid pH ■ can last several hours

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 CHAPTER 45: Aminoglycosides & Spectinomycin
● Administering a single large dose has better ○ synergistic killing against certain
efficacy than when administered as multiple bacteria
smaller doses, also less toxic. ● Penicillin-aminoglycoside combination
● ADVANTAGES ○ used to achieve bactericidal activity in
○ repeated determination of serum treatment of enterococcal endocarditis
concentration are unnecessary unless ○ shorten duration of therapy for viridans
an aminoglycoside is given for more streptococcal endocarditis
than 3 days ○ due to toxicity, used less frequently
○ drug administered once a day rather
than 3 times a day in less labor Usually in combination= take note
intensive Aminoglycoside index- free; given 3 times every 8hrs;
○ more feasible for outpatient therapy depend of renal clearance
● Should be avoided if renal function is impaired to - patient with renal insufficiency doctors compute to
avoid accumulation and toxic levels know the drug concentration in the body even with renal
● Rapidly changing renal function must be failure
monitored to avoid overdosing or under dosing
STREPTOMYCIN
Remember POSTANTIBIOTIC EFFECT also true with ● second-line agent for treatment of tuberculosis
azithromycin, ni linger pa ang effect even if you stop ● isolated from the strain of streptomyces griseus
giving the antibiotic ● antimicrobial activity of streptomycin is typical of
that of other aminoglycosides
ADVERSE EFFECTS ● resistance has emerge in most species
● Adverse effects from aminoglycosides are both ● ribosomal resistance develop fast
time dependent and concentration-dependent ● limited usefulness as a single agent
● it occurs when:
○ more than 5 days of therapy MOA= Inhibitor of protein synthesis
○ at higher doses
○ in the elderly CLINICAL USES
○ in the setting of renal insufficiency ● Mycobacterial Infections
● Ototoxic ○ STreptomycin mainly used as a
○ Auditory damage second-line agent for treatment of
■ resulting in tinnitus and tuberculosis
high-frequency hearing loss ○ administered intramuscularly or
● MOST -Neomycin, intravenously
kanamycin, and ○ used only in combination with other
amikacin (auditory agents to prevent emergence of
damage) resistance
■ vestibular damage; vertigo, ● Nontuberculous infections
ataxia, and loss of balance ○ Plague, tularemia, and brucellosis
● MOST - Streptomycin ○ Administered intramuscularly
and gentamicin ○ Penicillin plus streptomycin is effective
(vestibulotoxic) for enterococcal endocarditis and
● Nephrotoxic 2-week therapy of viridans streptococcal
○ Result in rising serum creatinine levels endocarditis
○ Reduced creatinine clearance Mycobacterial: tuberculosis manang mycobacterium
○ Increase in through serum
aminoglycoside concentrations ADVERSE EFFECTS
■ earliest indication ● Hypersensitivity
○ MOST - Neomycin, tobramycin, and ○ Fever
gentamicin (Nephrotoxic) ○ Skin rashes
● Pain at the injection site
Doc: Basta ototoxic and nephrotoxic, mo affect sa ● Disturbance of vestibular function
hearing and kidney ○ Most serious toxic effect
Doc: Remember most vestibular toxic ○ Tends to be irreversible
Doc: All exhibits ototoxic; nephrotoxic; pero naa ray most ○ Vertigo
○ Loss of balance
CLINICAL USE ● Pregnancy
● Mostly use against aerobic gram-negative ○ Cause deafness in the newborn
bacteria Vestibular is balance
● most widely in combination with other agents:
B-lactam antibiotic or vancomycin, to treat other GENTAMICIN
drug-resistant organisms ● Isolated from Micromonospora purpurea

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 CHAPTER 45: Aminoglycosides & Spectinomycin
● effective against both gram-positive and
gram-negative organisms
● many of its properties resemble those of other
aminoglycosides
● Antimicrobial activity
○ Gentamicin sulfate- inhibits in vitro many
strains of staphylococci and
gram-negative bacteria, including P.
aeruginosa and Enterobacterioceae
MOA= Inhibitor of protein synthesis
RESISTANCE
● Streptococci and enterococci- relatively resistant
to gentamicin owing to failure of the drug to
penetrate into the cell
● Resistance rapidly emerges during monotherapy
owing to selection of permeability mutants
● Enterococcal enzyme that modifies gentamicin
is a bifunctional enzyme that also inactivates
amikacin, netilmicin, and tobramycin but not
streptomycin
CLINICAL USE
● Intramuscular or Intravenous administration
○ Gentamicin used mainly in severe
infections caused by gram-negative
bacteria that are likely to be resistant to
other drugs
■ P aeruginosa
■ Enterobacter sp
■ Acinetobacter sp
■ Serratia marcescens
■ Proteus sp
■ Klebsiella sp
○ Usually used in combination with a
second agent because
aminoglycoside alone may not be
effective for infections outside the
urinary tract
○ Pneumonia- penetration of infected lung
tissue is poor and local conditions of low
pH and low oxygen tension contribute to
limited activity
● Topical and Ocular administration
○ Creams
○ Ointments
○ Solutions
● Treatment of infected burns, wounds, or skin
lesions and in attempts to prevent intravenous
catheter infections
● Topical gentamicin is partly inactivated by
purulent exudates
● Gentamicin can be injected intraocularly for
treatment of certain eye infections.
● Intrathecal Administration
○ treatment of meningitis caused
gram-negative bacteria
○ neither intrathecal or intraventricular
gentamicin was beneficial in neonates
with meningitis
○ Intraventricular gentamicin was toxic
Intrathecal- sa brain not directly; beneath sa skull na
padulong na sa brain; membrane above sa brain e
inject; done rarely
Oral and almost entirely dili ma absorb, naa ra sa lumen,
that's why parenteral preparation is used
ADVERSE REACTIONS
● Ototoxicity
● Nephrotoxicity
TOBRAMYCIN
● antibiotic derived from Streptomyces tenebrarius
● has an antibacterial spectrum similar to that of
gentamicin
● some cross-resistance between gentamicin and
tobramycin
INTRAMUSCULAR OR INTRAVENOUS
ADMINISTRATION
● Traditionally it is divided into 3 equal amounts
and given every 8 hrs but now often given as a
single daily dose
○ monitoring blood levels in renal
insufficiency an essential guide to
proper dosing
● Gentamicin is slightly more active against S.
marcescens, whereas tobramycin is slightly
more active against P aeruginosa
● Enterococcus faecalis susceptible to both
gentamicin and tobramycin E faecium is
resistant to tobramycin
an ● Ototoxic and Nephrotoxic
○ Nephrotoxicity or tobramycin may be
slightly less than that of gentamicin
INHALED AND OPHTHALMIC ADMINISTRATION
● Formulated in solution for inhalation for
treatment of P aeruginosa lower respiratory tract
infections complicating cystic fibrosis
● Nephrotoxicity and Ototoxicity rarely occur.
● Caution to patients with:
○ pre existing renal disorder
○ vestibular disorder
○ hearing disorders
● Ophthalmic ointment and drops for the treatment
of superficial eye infections.
● These formulations result in minimal systemic
absorption and are unlikely to cause systemic
adverse effects.
Doc: Ophthalmic widely used para sa bag o giaank na
bata to prevent ophthalmia neonatorum - condition na
ma infected imong eyes by gonorrhea kay wala man ta
by kabalo basin ang mother naay gonorrhea or ang father
ba kaha unya natakdan and mother; makabuta kung ma
infect ang mata sa bata
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 CHAPTER 45: Aminoglycosides & Spectinomycin
Ibutang sa tanang bata
Sauna is Silver nitrate/ crede's prophylaxis (not anymore
use karun kay ready made naman ang tobramycin).
Tobramycin najud kasagaran ginahatag. Again silver
nitrate is being used nga ophthalmic nga solution, aka
crede’s prophylaxis.
AMIKACIN
● Semisynthetic derivative of kanamycin
● Resistant to many enzymes that inactivate
gentamicin and tobramycin
● Many Gram-negative bacteria, including many
strains of Proteus, Pseudomonas, Enterobacter,
and Serratia, are inhibited by 1-20 mcg/mL
amikacin in vitro.
● Strains of multidrug-resistant Mycobacterium
tuberculosis, including streptomycin-resistant
strains, are usually susceptible to amikacin.
● Kanamycin-resistant strains may be
cross-resistant to amikacin.
● Amikacin is nephrotoxic and ototoxic
(particularly for the auditory portion of the eighth
nerve).
● Adverse reaction: ototoxicity & nephrotoxicity
NETILMICIN
● Shares many characteristics with gentamicin
and tobramycin.
● The addition of an ethyl group to the 1-amino
position of the 2-deoxystreptamine ring sterically
protects the netilmicin molecule from enzymatic
degradation at the 3-amino (ring II) and
2-hydroxyl (ring III) positions.
● Netilmicin may be active against some
gentamicin-resistant and tobramycin-resistant
bacteria.
● Dosage and routes of administration are the
same as for gentamicin.
● Netilmicin is largely interchangeable with
gentamicin or tobramycin but is no longer
available in the US.
NEOMYCIN, KANAMYCIN, & PAROMOMYCIN
● Neomycin, kanamycin, and paromomycin
have similar pharmacologic properties.
ANTIMICROBIAL ACTIVITY & RESISTANCE
● Drugs of the neomycin group are active against
Gram-positive and Gram-negative bacteria,
and some mycobacteria.
● P aeruginosa and streptococci are generally
resistant.
● Mechanism of action and resistance are the
same as with other aminoglycosides.
● The former widespread use of these drugs in
bowel preparation for elective surgery
contributed to the selection of resistant
organisms and some outbreaks of enterocolitis
in hospitals.
● Cross resistance between kanamycin and
neomycin is complete and may result in
amikacin cross-resistance.
PHARMACOKINETICS
● Poorly absorbed from the GI.
● After oral administration, the intestinal flora is
suppressed or modified, and the drug is
excreted in the feces.
● Excretion of any absorbed drug is mainly
through glomerular filtration into the urine.
CLINICAL USES
● Neomycin
○ Limited to topical and oral use due to
toxicity associated with parenteral use
and higher resistance rates compared to
other aminoglycosides.
● Kanamycin
○ Use is limited to treatment of
multi-drug-resistant tuberculosis
○ Amikacin, an alternative agent and
others, is preferred.
○ No longer available in the US.
● Paromomycin
○ Effective against visceral leish-maniasis
when given parenterally.
○ Used for intestinal Entamoeba
histolytica infection.
○ Sometimes used for intestinal infections
with other parasites.
TOPICAL ADMINISTRATION
● Solutions (1-5 mg/mL) containing neomycin
have been used to infected surfaces or injected
into joints, the pleural cavity, tissue spaces, or
abscess cavities where infection is present.
Doc: Why is neomycin given for surgery? Di man kaha
ma absorb, for hepatic encephalopathy, why?
Shanley: Iyang i-reduce ang aerobic bowel flora nga
naay limited effect sa anaerobes.
Doc: Ang sulod sa atong GI tract, daghan ng kagaw.
(nawala ang connection sa rec lec)
– kay lagi damaged na ang liver. What will happen with
the use of your aminoglycoside? Diba iyang ipatay tung
mga kagaw, so ang kagaw cannot anymore convert the
protein into ammonia. Ang protein ma-converted into
ammonia. So ang imong kagaw, dili na sya maka
convert sa imong protein to ammonia so ma-minusan
imohang encepathy and cepalopathy, again that is the
purpose of giving your antibiotics, this aminoglycosides,
in cases of hepatic encephalopathy, and surgery.
Doc: Nvm the dosage. As long as it is given parenteral.
● Whether topical application for active infection
adds anything to appropriate systemic therapy is
questionable.
● Ointments, often formulated as a
neomycin-polymyxin-bacitracin combination,
can be applied to infected skin lesions or in the
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 CHAPTER 45: Aminoglycosides & Spectinomycin
nares for suppression of staphylococci but they
are largely ineffective.
ORAL ADMINISTRATION
● In preparation for elective bowel surgery, 1g of
neomycin may be given orally every 6-8 hrs for
1-2 days, often combined with 1g of
erythromycin base.
● This reduces the aerobic bowel flower with
little effect on anaerobes.
● In hepatic encephalopathy, coliform flora can be
suppressed by giving 1g every 6-8 hrs together
with reduced protein intake, thus reducing
ammonia production.
● Use of neomycin for hepatic encephalopathy
has been largely supplanted by lactulose and
other medications that are less toxic.
● Use of paromomycin for the treatment of
protozoal infections.
IV AND INTRAMUSCULAR (IM) ADMINISTRATION
● The standard dose of kanamycin is 15mg/kg/day
in two to three divided doses, whereas for
treatment of tuberculosis, 15 mg/kg is usually
given IM as a single daily dose.
ADVERSE REACTIONS
● All members of the neomycin group have
significant nephrotoxicity and ototoxicity.
● Auditory function is affected more than vestibular
function.
● Deafness may occur, especially in adults with
impaired renal function and prolonged elevation
of drug levels.
● The sudden absorption of postoperatively
instilled kanamycin from the peritoneal cavity
(3-5g) has resulted in curare-like
neuromuscular blockade and respiratory
arrest.
○ Calcium gluconate and neostigmine
can act as antidotes.
● Although hypersensitivity, prolonged application
of neomycin-containing ointments to skin and
eyes has resulted in severe allergic reactions.
PLAZOMICIN
● A new aminoglycoside under development/trial.
● It has been studied in phase II clinical trials for
treatment of urinary tract infections; phase III
clinical trials are underway for treatment of
carbapenem-resistant Enterobacteriaceae.
● It is a synthetic molecule derived from sisomicin,
an aminoglycoside no longer available.
II. SPECTINOMYCIN
SPECTINOMYCIN
● An aminocyclitol antibiotic that is structurally
related to aminoglycosides.
● Lacks amino sugars and glycosidic bonds.
● Active in vitro against many Gram-positive and
Gram-negative organisms.
● Used almost solely as an alternative treatment
for drug-resistant gonorrhea or gonorrhea in
penicillin-allergic patients.
● The majority of gonococcal isolates are inhibited
by 6 mcg/mL of spectinomycin.
● Strains of gonococci may be resistant to
spectinomycin, but there is no cross resistance
with other drugs used in gonorrhea.
● Notably, not recommended for treatment of
pharyngeal gonococcal infection due to high
failure rates regardless of in vitro susceptibility.
● Rapidly absorbed after intramuscular injection.
● The standard regimen is a single dose of 2-4 g/d
(40 mg/kg in children).
● There is pain at the injection site and
occasionally, fever and nausea.
● Nephrotoxicity and anemia have been observed
rarely.
● Spectinomycin is no longer available for use in
the USA but is still recommended elsewhere.
Summary
Derived from:
● Streptomyces (mycin): Streptomycin,
Tobramycin, Neomycin, Kanamycin, &
Paromomycin
● Micromonospora (micin): Gentamicin,
Amikacin, Netilmicin, and Plazomicin.
A. Prototype drug: Streptomycin
B. MOA: irreversible inhibitors of protein syn.
C. Uses: Treats infections caused by
gram-positive and gram negative organisms
D. Route: IM, IV, and Topical
E. Adverse Effects: Ototoxicity & Nephrotoxicity
Streptomycin and Gentamicin - ototoxic agents
Neomycin, Tobramycin & Gentamicin - nephrotoxic
agents
Doc: Be sure to know, sample brand names of those
medications. Sa board exam, there are some time it will
only mention the brand name (common in the PH). One
time I’ve read sa sample question sa Pharmacy board
exam, “The patient was taking Neozep…” So that’s why I
included them in your matching brand names.
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CHAPTER 45: Aminoglycosides & Spectinomycin