Chapter 118:
Infection
Treatment & Prophylaxis of Bacterial
The development of vaccine and antimicrobial agent that
prevent and cure bacterial infections was one of the twentieth
century’s major contributions to human longevidity and quality
of life.
Antimicrobial agent are among the most commonly prescribed
drugs, however their indiscriminate use drives up the cost of
health care, leads to a plethora of side effect & drug
interactions, and fosters the emergence of bacterial
resistance.
Rational Use of antibacterial agent (depends on mechanism of
action, pharmacokinetics, pharmacodynamics, toxicities,
interactions, bacterial strategies for resistance and bacterial
susceptibility in vitro plus the patient-associated parameter:
site of infection, immune & excretory status of the host and
appropriate therapeutic condition.
I. Mechanism of Action (MOA) – directed against unique
targets not present in mammalian cells
Goal: limit toxicity to the host & maximize chemotherapeutic
activity affecting invading microbes only.
Bactericidal drug – kill bacteria within it’s spectrum of activity
Bacteriostatic drug – inhibit bacterial growth
(Refer Basic Antibacterial Mechanism of Action Table 118-1,
page 790 depicted on Figure 118-1, page 791, or review
pharmacology handouts of Dra. Villar)
A. Inhibition of Cell Wall Synthesis
Cell wall – unique to bacteria which protect it from osmotic
rupture.
Peptidoglycan – structure conferring cell-wall rigidity &
resistance to osmotic pressure to both gram + (thick layer) & -
(thin layer) bacteria which composed of:
- backbone of 2 alternating sugars, N-
acetylglucosamine (NAGA) & N-acetylmuramic acid
(NAMA)
- a chain of 4 amino acid that extend down from the
backbone (stem peptides)
- peptide bridge that cross-link the peptide chain
• Chemotherapeutic agent directed at any stage of the
synthesis, export, assembly, or cross-linking of
peptidoglycan lead to inhibition of bacterial cell growth.
• Bacitracin – a cyclic peptide antibiotic, which inhibits the
conversion of the active form of the lipid carrier that
moves the water soluble cytoplasmic peptidoglycan
subunitthrough the cell membrane to the exterior.
• Glycopeptides (vancomycin & teicoplanin – high
molecular weight antibiotic that bind to the terminal D-
alanine-D-alanine component of stem peptide while the
subunits are external to the cell membrane but still linked
to the lipid layer causing sterical inhibition of the addition
of subunit to the peptidoglycan backbone
• B-lactam Antibiotics (penicillins, cephalosporins,
carbapenem & monobactam) – a four-membered B-
lactam ring which prevent the cross-linking reaction
called transpeptidation by binding to transpeptidases
and enzymes invoveld in cross-linking (Penicillin
binding proteins[PBP])
B. Inhibition of Protein Synthesis – interacts with bacterial
ribosomes.
• Aminoglycosides (gentamycin, kanamycin, tobramycin,
streptomycin, netilmycin, neomycin & amikacin) – group
of structurally related compounds containing 3 linked
hexose sugars that exert it’s bactericidal effect by binding
irreversibly to the 30S subunit of the bacterial ribosome
and blocking the initiation of protein synthesis.
• Macrolide Antibiotics (erythromycin, clarithromycin &
azithromycin) – consist of large lactone ring to which
sugars are attached which bind specifically to the 50S
portion of the bacterial ribosomal subunit inhibiting it to
join t the 30S component to form to the 70S subunit
complex responsible for further protein chain elongation
(so walang protein chain elongation). Although,
structurally unrelated to macrolides: lincosamides
(clindamycin & lincomycin) bind also to the site of 50S
similar to macrolides.
• Chloramphenicol – consist of a single aromatic ring & a
short side chain which bind irreversibly to the 50S portion
of the bacterial ribosome at the site close but not
identical with the binding site ofmacrolides &
linconamides.
• Linezolid – (first new synthetic class of antibiotics ex.
Oxazolidones) – also binds to the 50S ribosomal subunit.
• Tetracyclines – (tetracycline, doxycycline, minocycline) –
consist of 4 aromatic rings with various substituent
groups which interact reversibly with the bacterial 30S
ribosomal subunit, blocking the binding of aminoacyl
tRNA to the mRNA-ribosome complex.
• Mupirocin (pseudomonic acid) – produced by bacterium
Pseudomonas flourescens. It inhibits isoleucine tRNA
synthetase by its binding site on the enzyme depleting
the cellular store of isoleucin-charged tRNA leading to
cessation of protein synthesis.
C. Inhibition of Bacterial Metabolism (Antimetabolite –
synthetic compound that interfere with bacterial synthesis of
folic acid which lead to the cessation of bacterial cell growth
and to bacterial cell death).
• Sulfonamides – are structural analogues of p-
aminobenzoic acid (PABA), one of the three structural
component of folic acid (the two are pteridine &
glutamate), which competes with PABA for the enzyme
dihydropteroic acid synthetase which is responsible for
the first step of folic acid synthesis.
• Trimethoprim – is a diaminopyrimidine, a structural
analogue of the pteridine moiety of folic acid, which serve
as a competitive inhibitor of dihydrofolate reductase, an
enzyme responsible for the reduction of dihydrofolic acid
to tetrafolic acid – the essential final component of folic
acid synthesis.
D. Inhibition of Nucleic Acid Synthesis or Activity – cause
disparate effect to nucleic acid
• Quinolones (including Nalidixic acid & its fluorinated
derivatives [ciprofloxacin, levofloxacin, gatifloxacin &
moxifloxacin]) – synthetic compounds that inhibit the
activity of the A subunit of the bacterial enzyme DNA
gyrase & topoisomerase IV, an enzyme responsible for
negative supercoiling of the DNA – an essential
conformation for DNA replication in the intact cell (so
walang DNA replication).
• Novobiocin – also interfere with the activity of DNA
gyrase, but it interferes with the B subunit.
• Rifampicin – used primarily in M. tuberculosis. It binds
tightly to the B subunit of bacterial DNA-dependent RNA
polymerase, thus inhibiting transcription of DNA to RNA.
• Nitrofurantoin – synthetic compound containing a single
five-membered ring & it is reduced by bacterial enzyme
to highly reactive, short lived intermediates that are
thought to cause DNA strand breakage.
• Metronidazole –a synthetic imidazole which is active
against a wide range of anaerobic bacteria & protozoa, .
Its activity is totally dependent on its anaerobic electron-
transport system for energy production, wherein the nitro
group of metronidazole is reduced to series of transiently
 produced, reactive intermediates that are thought to
cause DNA damage (maybe mutagenic & radiosensitizer
of hypoxic mammalian cell).
E. Alteration of Cell-Membrane Permeability
• Polymixins (Polymixin B & colistin, or Polymixin E) – are
cyclic, basic polypeptide that behave as cationic, surface-
active compound that disrupt the permeability of both the
outer & the cytoplasmic membrane of gram-negative
bacteria.
• Gramicidin A – a polypeptide of 15 amino acids that act
as an ionophore, forming pores or channels in lipid
bilayers
II. Mechanism of Resistance
• Intrinsic Resistance (resistant na noon pa, ex. Gram-
negative bacteria resistant to vancomycin)
• Acquired Resistance – bacteria which is ordinarily
susceptible to antimicrobial agents acquire resistance
due to mutation of resident gene or by acquisition of new
genes.
Major Mechanisms used by bacteria to resist the action of
antimicrobial agent:
• Inactivation of the compound
• Alteration or overproduction of the antibacterial target
through mutation of the target protein gene
• Acquisition of new gene that encodes a drug insensitive
target
• Decrease permeability of the cell wall envelope to the
agent
• Active efflux of the compound from the periplasm or
interior of the cell
A. Beta-lactam Resistance
• Destruction of drug by B-lactamase of gram-negative
bacteria, which is confined in its periplasm , between the
inner & outer membranes, while in gram-positive bacteria
secrete their B-lactamase into the surrounding medium.
 Strategy: combine B-lactam with an inhibitor
(clvulanic acid, sulbactam & tazobactam) that avidly
binds the inactivating enzyme , preventing the
attack on the antibiotics.
• Alteration of PBP targets so that the PBP’s have a
markedly reduced affinity to the drug.
• Coupling, in gram-negative bacteria, of a decrease in
outer-membrane permeability with rapid efflux of the
antibiotic from the periplasm to the cell exterior there is a
mutation of gene encoding outer-membrane protein
channels called porins which decrease the entry of B-
lactam into the cell, while additional protein form
channels that actively pump B-lactams out of the cell.
B. Vancomycin Resistance – the gene encoding resistance
are carried on plasmids that can transfer themselves from cell
to cell and from transposons that could jump from plasmid to
chromosomes. Resistance is mediated by enzymes that
substitute D-lactate for D-alanine on the peptidoglycan stem
peptide so that there are no longer an appropriate target for
vancomycin binding.
C. Aminoglycoside Resistance
• Inactivation of the antibiotics by aminoglycoside
modifying enzyme
• Decrease antibiotic uptake is some clinical isolate of P.
aeruginosa presumably due to alterations in the bacterial
outer membrane
D. Macrolides, Ketolides, Lincosamides & Streptogrammins
• Resistance of gram-positive bacteria due to the
production of enzyme – most commonly plasmid
encoded – that methylates ribosomal RNA, interfering
with binding of the antibiotics to their target
• Resistance to streptogrammin B convert
quinupristin/dalfopristin from bactericidal to bacteriostatic
• Streptococci can actively cause the efflux of macrolides,
while Staphylococci can cause the efflux of clindamycin
• Staphylococci can inactivate streptogrammin by
acetylation & hydrolysis
• Mutation of 23S ribosomal RNA alter macrolides binding
to their targets have been found in Streptococci &
Staphylococci
E. Chloramphenicol Resistance – due to plasmid encoded
enzyme, chloramphenicol acetyltransferase, that inactivates
the compound by acetylation.
F. Tetracycline Resistance – due to plasmid encoded active-
efflux pump that is inserted into the cytoplasmic membrane &
extrude antibiotic from the cell.
G. Topical Mupirocin Resistance – due to mutation of the
target isoleucine tRNA synthetase so that it is no longer
inhibited by antibiotic or plasmid-encoded production of a
form of the target enzyme that bind to mupirocin poorly.
H. Trimethoprim & Sulfonamides Resistance -due to the
acquisition of plasmid encoded genes to produce a new, drug-
insensitive target – insensitive dihydrofolate reductase for
trimethoprim & an altered dihydropteroate synthetase for
sulfonamide.
I. Quinolones Resistance – due to the development of one or
more mutations in target DNA gyrases and topoisomerasesIV
that prevent antibacterial agent from interfering with the
activity of the enzyme.
J. Rifampin Resistance– due to developing mutation in the B
subunit of RNA polymerase that render the enzyme unable to
bind the antibiotic.
K. Linezolid Resistance – due to mutation of the 23S rRNA
binding site
L. Multiple Antibiotic Resistance
• Acquisition of the multiple unrelated resistance genes
• Development of the mutations in a single gene or gene
complex that mediates resistance to a series of unrelated
compounds
III. Pharmacokinetics of Antibiotics – refers to concentrations
in serum & tissue versus time & reflects the process of
absorption, distribution, metabolism & excretion.
Key terms: Peak & through serum concentration, half-life,
clearance & distribution volume (alam nyo nay un from
pharma)
Pharmacodynamic Profile of Antibiotic – refers to the
relationship between serum & tissue concentrations of the
antibiotic & its Minimal inhibitory concentration (MICs) for
bacteria
A. Absorption – refer to the rate & extent of a drug’s systemic
bioavailability after oral, IM & IV administration,
1. Oral administration – it is usually used for patient with
relatively mild infections in whom absorption is not thought to
be compromised by the preceeding conditions with varying
bioavailability and has the advantage of low cost, fewer
adverse effect & greater acceptance to patient, however
therapeutic efficacy may be compromised when absorption is
reduced as a result of physiologic or pathologicconditions,
drug interactions or noncompliance.
2. Intramuscular Administration – although route of
administration result in 100%bioavailability, it is not widely use
due to pain of injection & the relative ease of IV access.
3. Intravenous Administration – appropriate whenoral
antibacterial agents are not effective against a particular
pathogen, when bioavailability is uncertain,or when larger
doses are required than are feasible with the oral route.
B. Distribution – antibacterial agent must exceed the
pathogen MICs & must distribute to the site of infection to be
effective. Hard to distribute areas are in the CSF, the eye, the
prostate & infected cardiac vegetationwhich require either high
dose or local aministration for prolonged periods.
C. Metabolism & Elimination – by hepatic elimination & renal
excretionof the unchanged or metabolized form, or by a
combination of the two processes.
Adustment of dosage of drug should be done when
elimination capability is impaired as to prevent toxicity.
IV. Principles of Antibacterial Chemotheraphy
• When appropriate, material containing the infecting
organism(s) should be obtained before the start of
treatment so that presumptive identification can be made
by microscopic exam, culture & susceptibility testing
• Once the organism is identified & its susceptibility to
antibacterial agents is determined, the regimen with the
narrowest effective spectrum should be chosen.
• The choice of antibiotic is guided by the pharmacokinetic
& adverse reaction profile of active compounds, the site
of infection, the immune status of the host & evidence of
efficacy from well performed clinical trials.
A. Susceptibility of Bacteria to Antimicrobial Drugs In
Vitro – essential first step in devising a chemotherapeutic
agent (ito yung Kirby-bauer na ginawa natin noon sa micro
wherein we list the drug na pwede mag-inhibit ng growth &
from dun ibabase yung drug of choice)
B. Pharmacodynamics: relationship of Pharmacokinetics & In
Vitro Susceptibility to Clinical Response – the breakpoint is the
concentration of the antibiotics that separates susceptible
from resistant bacteria.
• Phamacodynamic profile of Antibiotic – the
quantitative relationships between the time course of
antibiotic concentrations in serum & tissue, in vitro
susceptibility & microbial response.
• 3 pharmacodynamic parameter: the ratio of the area
under the curved for the plasma concentration vs time
curve to MIC (AUC/MIC), the ratio of the maximal serum
concentration to the MIC (Cmax/MIC) & the time during a
dosing interval that plasma concentration exceed the
MIC (t>MIC)
• Concentration dependent (fluoroquinones,
aminoglycoside) increase antibiotic concentration leads
to a more rapid rate of bacterial death
• Time-dependent – (B-lactam) – reduction in bacterial
density is proportional to the time of that concentration
exceed the MIC.
C. Status of the Host
• Patient’s age, sex, racial heritage, genetic background &
excretory status – determine the incidence & type of side
effect that can be expected with certain antibacterial
agents.
• Host’s antibacterial Immune function – relates to the
opsonophaghocytic function, since the major host
defense against acute, overwhelming bacterial infection
is the PMN leukocyte, patients with neutropenia & have
deficient immunity must be treated aggressively &
empirically with bactericidal (instead of bacteriostatic)
drugs for suspected infection.
• Pregnancy – icreases the risk of toxicity of certain
antibacterial drugs for the mother, affect drug desposition
& because of the risk of fetal toxicity – severely limits the
choice of agents for treating infections (Refer to Table
118-5, page 797 for antibiotics presenting toxicity during
pregnancy)
• Patient with Concomitant Viral Infection – incidience of
adverse reaction to antibacterial drugs may be unusually
high.
D. Site of Infection
• Meningitis – should received drugs that can cross the
blood-CSF barrier & the agent must be bactericidal due o
the relative paucity of phagocytes & opsonins at the site
of infection ex. Chloramphenicol
• Bacterial endocarditis vegetation – needs bactericidal,
with the selected agent administered parentally over a
long period and at a dose that produces serum levels at
least 8x higher than the minimal bactericidal
concentration (MBC)
• Osteomyolysis – site that is somewhat resistant to
opsonophagocytic removal of infecting bacteria
• Chronic prostitis – difficut to cure because most
antibiotics does not penetrate through the capillaries
serving the prostrate.
• Intraocular Infection (sp. endopthalmitis) – difficult to treat
because retinal capillaries lacking fenestration hinder
drug penetration into the vitreous from blood.
• Abcess – poor penetration of antibiotics.
• Urinary Tract Infection (sp. in the bladder) – easy to cure
because of higher concentration of antibiotics to urine
than in blood. (Nitrofurantoin & methenamnie salt)
E. Combination Therapy
Use of single agent therapy with a narrow spectrum of activity
against the pathogen diminished the alteration of the normal
flora thus limiting the overgrowth of resistant nosocomial
organism, avoids potential toxicity of multiple-drug regimens &
reduce the cost.
Circumstances for the Use of Multiple–drug regimen
1. Prevention of Emergence of resistant mutants – a
second antibacterial agent with a mechnismof action different
from that of the first is added to prevent the emergence of
resistant mutants.
2. Synergistic or Additive activity – involves the lowering of
the MIC & MBC of each drugs tested in combination against a
specific bacterium. (Synergy – each agentis more active when
combined with a second drug than would be alone; Additive –
combined activity of the drugs is equal to the sum of their
individual activities). Ex. B-lactam/Aminoglycoside &
Trimethoprim/Sulfamethoxazole.
3. Therapy directed against multiple potential pathogens
(ex. Intraabdominal or brain abcesses)
F. Empirical Theraphy
Antibacterial therapy is begun before a specific bacterial
pathogens has been identified. Situations in which empirical
therapy is appropriate include the following:
1. Life threatening infection
2. Treatment of Community-acquired infections
V. Choice of Antibacterial Therapy
A. B-lactam – Penicillins (except for the semisynthetic &
penicillinase-resistant antistaphylococcal agents) are
ineffective against isolates procing B-lactamase enzymes.
• Penicillin G – spectrum including spirochete,
streptococci, E. faecalis, most Neisseria sp., a few
staphylococcus, many fastidious oral bacteria,
clostridium sp., Pasteurella multocida, Erysipelothrix
rhusiopathiae & Streptobacillus moniliformis.
• Ampicillin – extends the spectrum of penicillin G to some
gram-negative rods active against some isolates of E.
coli, Proteus mirabilis, Salmonella, Shigella & H.
influenzae.
• Penicillinase-Resistant Penicillins (ex. Methicillin) – use
solely for the treatment of Staphylococcal infection.
• Antipseudomonal Penicillin (ex. Piperacillin) – spectrum
include bacteria covered by ampicillin as well as some
nonpseudomonal enteric gram-negative bacilli
• First-Generation Cephalosporin – spectrum including
penicillinase-producing, methicillin-susceptible
staphylococci & streptococci but not a drug of choice of
such infection. They have excellent activity against many
isolates of E. coli, Klebsiella pneumoniae & P. mirabilis &
are among the drug of choice in presumptive theraphy for
community acquired pneumoniae.
• Parenteral Second-generation Cephalosporin (ex.
Cefuroxime, Cefoxitin & cefotetan) – extends the gram-
negative spectrum of first generation compound with
good activity against B. fragilis.
• Oral second- & third-generation Cephalosporin – have
fair activities against gram-positive cocci & H. influenzae
& are widely used in patient with otitis media, sinusitis &
lower respiratory tract infection.
• Third-generation parenteral cephalosporins (ex.
Ceftaxidime & Cefepime) – all have broad spectrum of
activity against enteric gram-negative rods & are useful
for treatment of hospital-acquired infection caused by
multiple resistant organism.
• Carbapenems (Imepenem, Meropenem, Ertapenem) –
have excellent activity in vitro with virtually all bacterial
pathogens except Stenotrophomonas, MR Staphylococci
& E. faecium. They are usually in combination with renal
dipeptidase inhibito cilastin to prevent renal inactivation.
• Monobactam (Aztreonam) – spectrum limited to gram-
negative enteric bacilli.
B. Vancomycin – spectrum limited to gram-positive cocci,
especially enterococci, streptococci & staphycocci which
serve as a second-line therapy for most gram-positve bacterial
infection; drug of choice for pseudomembranous colitis
caused by C. deficille not responsive to metronidazole.
C. Aminoglycosides (Gentamicin & Tobramycin)– rapidly
bactericidal in vitro at low concentrations, with activity limited
to gram-negative bacteria & staphylococci; drug of choice for
any suspected gram-negative bacteremia infection & for
severe infection of the upper urinary tract. Streptomycin is the
drug of choice in initial therapy for tularemia, plague, glanders
& brucellosis.
D. Macrolides (Erythromycin) & Ketolides – has a broad-
spectrum activity against gram-positive bacteria with the
additional activity against (drug of choice)Legionella,
Mycoplasma, Camphylobacter, Bordetella pertusis and some
Chlamydia isolates. Drug of choice to communit acquired
pneumococcal pneumoniae & group A streptococcal
pharyngitis to penicillin-allergic patient. Clarithroymycin, in
combination of proton pump inhibitor has been the drug of
choice for the treatment of gastric infection by H. pylori.
E. Lincosamides (Clindamycin) – shares gram-positve coccal
spectrum of erythromycin but is more active against
susceptible staphylococci. Drug of choice for treatment of
severe invasive group A streptococcal infection.
F. Chloramphenicol – broad spectrum of activity against
gram-positive & gram-negative bacteria, although plasmid
mediated resistance has diminished its effective spectrum.
Remains the drug of choice for the treatment of typhoid fever
& plague & still useful for the treatment of brucellosis & both
pneumococcal & meningococcal meningitis in patient with
severe penicillin allergy.
G. Tetracycline (Doxycycline & Minocycline) – has broad
spectrum of bacteriostatic activity against gram-positive &
gram-negative bacteria & are widely used in a variety of
community acquired infection. Drug of choice for acute
bacterial exacerbations of chronic bronchitis, granuloma
inguinale, brucellosis, tularemia, glanders, meliodosis,
spirochetal infections caused by Borrelia, infectiondue to
Vibrio vulnificus, some Aeromonas infections due to
Stenotrophomonas, plague, ehrlichiosis & due to
Mycobacterium marinum.
H. Sulfonamides & Trimethoprim – has a broad spectrum of
bacteriostatic activity individually & in combination against
facultative gram-negative bacteria & Staphylococci. Drug of
choice for the treatment of Nocardia Infections, Leprosy
(dapsone) & toxoplasmosis (sulfadiazine), and uncomplicated
urinary tract infection.
I. Fluoroquinolones – excellent activity against most
facultative gram-negative rods & variable activity against
gram-positive cocci. Oral agents with greatest activity to p.
aeruginosa (Ciprofloxacon). Drug of choice for urinary tract
infection, bacterial gastroenteritis, community acquired
pneumoniae & enteric fever & useful for serious hospital-
acquired infections caused by gram negative organism.
J. Rifampin – used for combination treatment of serious
infection due to methicillin resistant staphylococci & for
chemoprophylaxis in persons at risk of meningococcemia
meningitis & for treatment of Legionella pneumonia.
K. Metronidazole – spectrum limited to anaerobic bacteria,
specially gram-negative species (ex. Bacteroides spp.). Drug
of choice for the treatment of abscess in which the
involvement of obligate anaerobes is suspected., treatment of
bacteria vaginosis & antibiotic associated pseudomembranous
colitis.
L. Linezolid – bacteriosttic spectrum limited to gram-positive
bacteria & is indicated for the treatment of infections caused
by staphylococci, streptococci & enterococci.
M. Polymixins – broad spectrum of activity that includes
virtually all gram-negative bacteria used commonly as topical
agent (ex. colistin).
N. Streptogramins – combination of Streptogramins B
(quinupristin) & streptogramin A (dalfopristin) has spectrum
limited to gram-positive bacteria & is indicated for the
treatment of staphylococci, streptococci & E. faecium.
O. Urinary Tract Antiseptics (Nitrofurantoin & Methenamine
salt) – are active only in the lower urinary tract & cannot be
used as treatment for upper urinary tract or systemic
infections, are most active against susceptible gram-negative
bacteria.
P. Topical Antibacterial Agents – mupuricin is available only as
topical preparation for use against staphylococci &
streptococci, which has major application for impetigo &
eradication of staphylococcal carrier state.
VI. Adverse Reaction – mechanism of either dose-related
(“toxic”) effects of unpredictable reactions which is either
idiosyncratic or allergic.

A. B-Lactam – generally concerned with all type allergic
reaction
Type 1 – immediate-hypersensitivity ex. Anaphylaxis
Type 2 – cytotoxic reaction ex. Nephritis & coombs-positive
hemolytic anemia
Type 3 – immune-complex formation ex. Serum sickness
Type 4 – cell-mediated effect ex. Contact dermatitis
Type 5 – idiopathic reaction ex. Macvulopapular eruption
Micellaneous reaction includes gastrointestinal side effect
ranging from mild diarrhea to severe form of membranous
colitis
In high dose, penicillin can cause bleeding from impaired
platelet aggregation
B. Vancomycin – most common side effect is the red man
syndrome, characterized by pruritus,flushing & erythema of
the head & upper torso often mislabeled as allergy.
• Can rarely cause nephrotoxicity, ototoxicity, leucopenia,
skin rashes & true allergy
C. Aminoglycoside – the two most common adverse reaction
is nephrotoxicity (result from the accumulation of
aminoglycoside in the peritubular space, with damage to the
proximal tubule & a corresponding reduction in GFR) &
Ototoxicity (auditory or vestibular damage since
aminoglycoside can destroy hair cells in the inner ear)
• Neuromuscular depression from aminoglycosides is
caused by reduced acetylcholine activity at postsynaptic
membranes that can result in rare but severe respiratory
depression.
D. Macrolides – Gastrointestinal effect such as burning,
nausea & vomiting are the most common since macrolides
bind to motilin receptor, increasing gastrointestinal motility.
Less common side effect is hepatotoxicity & ototoxicity, and
allergic cutaneous reaction.
E. Lincosamides – most common adverse effect is
gastrointestinal distress ranging from diarrhea to
pseudomembranous colitis. Allergic reaction, hepatotoxicity &
neutropenia are observed in only rarely.
F. Chloramphenicol – causes two types of bone marrow
suppression: a dose-related, reversible suppression of all
elements which occur commonly during therapy at the
maximal recommended dose, & an idiosyncratic, irreversible
aplastic anemia.
• In premature neonates & infants, it can cause dose-
related “gray syndrome” characterized by cyanosis,
hypotension & death that results from an inability of the
newborn to metabolize the drug.
G. Tetracyclines – GI effects (most common) which may be
related to a direct irritant effect, since it could also cause
esophageal ulcerations when they dissolve before reaching
the stomach..
• Hepatotoxicity has been reported after administration of
tetracycline intravenously at a lower doses during
pregnancy, hence it is contraindicated in pregnant
woman,
• Tetracyclines are contraindicated in children <8y/o
because of mottling of the permanent teeth.
H. Sulfonamides & Trimethoprim – generally safe but may
occasionally cause a number of allergic reactions, from
relative minor skin rashes to severe life threatening reactions
such as erythma multiforme, steven Johnson syndrome &
toxic epidermal necrosis.
• Both can also cause severe hematologic complications,
including agranulocytosis, hemolytic & megaloblastic
anemia & thrombocytopenia.
• Renal insufficiency, caused by crystals of the relatively
insoluble acetyl metabolites, is observed primarily with
the long-acting sulfonamides.
• It is recommended that sulfonamides not be administered
in the newborns because of concerns that bilirubin may
be displaced from protein-binding sites, with subsequent
jaundice & kernicterus.
• Occasionaly could cause drug fever with serum sickness,
hepatic toxicity & systemic lupus erythematosus.
I. Fluoroqunolones – are relatively safe but adverse reaction
discontinuation of therapy which includes GI distress, central
nervous system effect including insomnia & dizziness.
Phototoxiciy is occasionally severe . Rarely hepatic & renal
dysfunction & anaphylactoid & allergic reaction are observed.
J. Rifampin – is generally well-tolerated but has several
important side effect such as transient rise in hepatic
aminotransferases although rifampin hepatitis is rare. Patient
should also be warned that rifampin & its metabolites cause
secretions such as urine, tears, sweat & saliva to turn orange
& that contact lens may be stained.
K. Metronidazole – GI side effect such as nausea are most
frequent but rarely necessitate discontinuation of theraphy. A
metallic taste is relatively common, & stomitis & glositis are
occasionally reported
• Concerns about mutagenecity & carcinogenicity from
metronidazole have led to recommendations that it not
be used in pregnancy when alternative agents are
available.
L. Linezolid – GI upset (nausea, vomiting & diarrhea) &
headache. Of most concern is a reversible myelosuppresion
that is directly related to the duration of theraphy.
M. Quinupristin/Dalfopristin –venous irritation is frequent &
potential adverse effect when the drug is given by peripheral
intravenous infusion. In addition, arthralgia & myalgia are
substantially more common among patient treated with
quinupristin/dalfopristin.
VII. Drug Interaction (Refer to Table 118-7, page 803)
A. Macrolides & Ketolides – erythromycin, clarithromycin &
telithromycin inhibit the p450 enzyme CYP3A4 & thus
metabolism of other drugs, including cyclosporine, certain
statins, theophylline, carbamazepine, warfarin, certain
antineoplastic agents & ergot alkaloids.
B. Quinupristin/Dalfopristin – also inhibitor of CYP3A4 similar
to those of erythromycin
C. Linezolid – are monoamine oxidase inhibitor & its
concomitant administration with sympathomimetics, with SSRI
& with food with high concentration of tyramine should be
avoided
D. tetracycline – reduction in absorption when these drugs
are coadministerd with divalent & trivalent cations such as
antacids, iron compounds or dairy products.
E. Sulfonamides – including sulfomethoxazole, increase the
hypothrombinemic effect of warfarin by inhibition of its
metabolism & possibly protein binding displacement.
F. Fluoroquinolones – like tetracycline, are also chelated by
divalent & trivalent cations. Certain fluroquinolones including
ciprofloxacin, inhibit hepatic enzymes that metabolized
theophyllin, thus theophylline toxicity.

G. Rifampin – an excellent inducer of many cytochrome P450

enzymes & increases the hepatic clearance of a number of
drugs including oral contraceptive, warfarin, cyclosporine &
prednisone, & verapamil & diltiazem.

H. Metronidazole – can cause disulfaram-like syndrome

when alcohol is ingested.

VIII. Prophylaxis of Bacterial Infection (Refer to table 118-

8, page 804)
Basic tenets of antimicrobial prophylaxis:
• Risk or potential severity of infection should be greater
than the risk of side effectfrom the antibacterial agent
• The antibacterial agentshould be given for the shortest
period necessary to prevent the target infections
• The antibacterial agent should be given before the
expected period of risk (ex. Surgical prophylaxis) or as
soon as possibleafter contact with the infected individual
(ex. Prophylaxis for meningococcal meningitis)

IX. Duration of Theraphy & Treatment (Refer to table 119-

9, page 805)
• The ultimate test of cure for a bacterialinfection is the
absence of relapse (the occurrence of infection with the
identical organism that cause the first infection.
• In general, the duration of the therapy should be long
enough to prevent relapse yet not excessive that could
cause increase side effects of medication & encourage
the selection of resistant microorganism

X. Antibacterial Cost & Inappropriate Use

Guidance through the antibiotic maze
• Objective evidence regarding the merits of newer drugs
is available through publication such as “The Medical
Letter” & through online reference of John Hopkins
Website.
• Clinicians should became comfortable using a few drugs
recommended dy independent experts and professional
organizations and should resist the temptation to use a
new drug unless the merit is clear.
• Clinicians should be familiar with local bacterial
susceptibility profile
• Appropriate empirical treatment with one or more broad-
spectrum agents may often be simplified, with the use of
narrower spectrum agent or even an oral drug, once the
results of cultures and susceptibility tests becomes
available.

ZPDM 2005