Treatment of Bacterial Infections - Antibiotics

Dr Andrew Fuller
Basic Principles
1. Are antibiotics needed?
2. Narrow spectrum
3. Appropriate choice
4. Least number
5. Allergies
6. Cultures prior
7. Combination therapy needed
8. Oral vs IV
9. Prophylaxis
10. Avoid topical
 Mechanisms of antibiotic action
Classification of Antibiotics by Target Site of Activity
Target site Drugs Usual activity

1. Inhibitors of cell wall synthesis

Beta-lactams: penicillins Bactericidal
cephalosporins
carbapenems
monobactams
Glycopeptides: vancomycin Bactericidal
teicoplanin
Others: cycloserine Bactericidal
bacitracin
2. Inhibitors of protein synthesis
30S ribosomal sub-unit: Aminoglycosides Bactericidal
Tetracyclines Bacteriostatic
50S ribosomal sub-unit: Chloramphenicol Bacteriostatic
Clindamycin Bacteriostatic
Macrolides (e.g. erythromycin) Bacteriostatic
Fusidic acid. Bacteriostatic
 Mechanisms of antibiotic action
Classification of Antibiotics by Target Site of Activity

Target site Drugs Usual activity

3. Inhibitors of nucleic acid synthesis

Block folic acid synthesis: Trimethoprim ? Bacteriostatic
Sulphonamides
(E.g. sulfamethoxazole)
DNA gyrase inhibition: Fluoroquinolones Bactericidal
(e.g. ciprofloxacin, norfloxacin)
RNA polymerase inhibition: Rifamycins ? Bacteriostatic
(e.g. rifampicin)
4. Inhibitors of cell membrane function
Colistin Bacteriostatic
Polyene antifungal drugs
(e.g. Amphotericin B, nystatin)
 Mechanisms of antibiotic resistance
Antibiotic resistance acquired by:
Chromosomal mutation
Plasmids.
Transposons (free DNA)
Bacteriophage (virus)
 Mechanisms of antibiotic resistance
Four broad categories of resistance mechanisms:
1. Antibiotic inactivation
2. Alteration of antibiotic target sites
3. Decreased antibiotic permeability of the cell wall preventing drug access to its target
4. Active antibiotic efflux from the bacteria

3. 1.

2.
4.
 1. Antibiotic inactivation

(a) b-lactamases: Some b-lactamases can be inhibited by the b-lactamase -inhibitors

clavulanic acid, tazobactam and sulbactam.
b-lactamases produced by Gram-positive organisms are often excreted into the
milieu surrounding the organism and are therefore termed exoenzymes. Eg
Staphylococcus aureus, which are plasmid-mediated and responsible for the
organism's widespread resistance to penicillin. These enzymes are inhibited by
clavulanic acid.

In Gram-negative pathogens, however, b-lactamases are generally found in

the periplasmic space rather than excreted extracellularly. Plasmid-mediated
ampicillin-hydrolysing enzymes are now common among Gram-negative pathogens
such as E. coli, H. influenzae and Neisseria gonorrhoea.
Staph aureus
Staph aureus
1. Antibiotic inactivation
 1. Antibiotic inactivation
(b) Inducible chromosomally mediated b-lactamase production.

Inactivate third-generation cephalosporins.

In particular, organisms which demonstrate this important form of b-
lactamase production are summarised by the term "ESCAPPM":

E Enterobacter species
S Serratia species
C Citrobacter species
A Acinetobacter species
P Pseudomonas aeruginosa
P Proteus vulgaris (ie. indole-positive Proteus species; not P. mirabilis)
M Morganella morganii
 1. Antibiotic inactivation
(c) Aminoglycoside modifying enzymes:

(d) Others: ESBL

Extended spectrum b-lactamases are now becoming common in

large hospitals.

These enzymes are encoded by a plasmid which can be

transmitted between bacteria.

They inactivate all cephalosporins.

Klebsiella pneumoniae and E.Coli are the usual organisms to

harbour ESBLs.

Treatment is with meropenem or cotrimoxazole.

 Mechanisms of antibiotic resistance
3.
1.

2.
4.
 2. Alteration of target sites

Penicillin-binding proteins (PBPs) are associated with the bacterial

cytoplasmic membrane.

These are associated with enzymatic functions essential for cell wall
synthesis and remodelling, and vary in number and size depending on the
bacterial species.

Individual b-lactams vary in their binding of specific PBPS, but such

interactions result in growth inhibition, with eventual cell death.

Alterations in PBP target sites resulting in resistance to penicillin have

been noted among
- penicillin-resistant strains of Streptococcus pneumoniae
- and are responsible for the methicillin resistance in both S. aureus
and coagulase negative staphylococci.
 2. Alteration of target sites

Resistance to fluoroquinolones (e.g. ciprofloxacin and norfloxacin) is being

increasingly noted among some Gram-negative pathogens.
Fluoroquinolones act by inhibition of bacterial DNA gyrase, an enzyme that
acts to introduce superhelical twists in bacterial DNA and is vital for normal
cell replication. Alterations to this gyrase target means that it is no longer
blocked by fluoroquinolones, therefore allowing such bacteria to multiply
uninhibited.

Alteration in ribosomal target sites accounts for resistance to a number of

antibiotics including streptomycin (30s ribosomal sub-unit), erythromycin
(50s sub-unit) and tetracycline.
 2. Alteration of target sites

Rifampicin acts by binding the b-sub-unit RNA polymerase. However, single-

step mutations resulting in altered affinity of rifampicin for this polymerase
result in rapid emergence of resistance when this drug is used alone for
treating bacterial infections. Such resistance has been noted among strains of
Neisseria meningitidis, S. aureus, Mycobacteria spp., Pseudomonas aeruginosa
and Enterobacteriaceae.

Trimethoprim and sulphonamide resistance can be the result of changes in

cell permeability or alterations in, or over production of dihydrofolate
reductase that is resistant to inhibition by trimethoprim.
 Mechanisms of antibiotic resistance
3.
1.

2.
4.
3. Decreased antibiotic permeability

Gram-positive bacteria have a relatively simple cell wall structure

consisting of a peptidoglycan layer surrounding the cytoplasmic
membrane.

Gram-negative bacteria have a more complex cell envelope with an

outer layer consisting mainly of lipopolysaccarides and an inner
layer of phospholipids. Therefore, many drugs penetrate the simple
cell wall of Gram-positive bacteria, but to penetrate Gram-negatives
bacteria, drugs frequently need to travel through small protein
channels called porins.
3. Decreased antibiotic permeability

Porins vary in size and hydrophobicity so that the rate of antibiotic

penetration through these channels depends on the physical
characteristics of each drug.

Thus, changes in porins may result in diminished penetration by a

number of structurally unrelated antibiotics and therefore increased
bacterial resistance to these agents (e.g. b -lactams, aminoglycosides
and chloramphenicol). This mechanism is especially important in
resistance among Enterobacteriaceae and Pseudomonas aeruginosa
to trimethoprim and some fluoroquinolones.
 Mechanisms of antibiotic resistance
3.
1.

2.
4.
 4. Active Efflux

A less well recognised mechanism of resistance is

the active efflux of antibiotics from within bacteria -
thereby diminishing intra-cellular drug
concentrations below a level sufficient for
antimicrobial activity.
 Antibiotic Classes

Antibiotics can be classified as follows:

1. Beta-lactams

1.1 Penicillins
Anti-staphylococcal penicillins
Moderate-spectrum penicillins
Broad-spectrum (anti-Pseudomonas aeruginosa) penicillins
1.2 Penicillin + b -lactamase inhibitor combinations
1.3 Cephalosporins
1.4 Carbapenems
1.5 Monobactams
 Antibiotic Classes

2. Glycopeptides
3. Aminoglycosides
4. Macrolides
5. Tetracyclines
6. Antifolate agents
7. Fluoroquinolones
8. Rifamycins
9. Nitroimidazoles
10. Others- Chloramphenicol, clindamycin, fusidic acid,
nitrofurantoin and spectinomycin. Linezolid. Daptomycin.
Ceftaroline.
 1. Beta-lactams
b -Lactams are structurally related, in that they all have a b -lactam
ring; all primarily act by binding with PBPs to inhibit cell wall synthesis
and/or repair and in most cases all classes are bactericidal.

Hypersensitivity to penicillins occurs in up to 10% of patients and

includes either type 1 (anaphylaxis) and type 3 allergic reactions (rash
and fever). Hypersensitivity to any one member of this Class implies
sensitisation to all penicillins.

Notably, among patients who are hypersensitive to penicillin, only 3-6%

will also exhibit cross-reactivity with cephalosporins. Thus, if a patient
has not had an episode of anaphylaxis to penicillin, cephalosporins may
be considered a reasonable alternative.

However, if anaphylaxis has occurred then all b -lactams should

generally be avoided.
 1. Beta-lactams
There are four classes of b -lactams:
 1.1 Penicillins
Narrow spectrum penicillins:

Phenoxymethylpenicillin (penicillin V): This is given orally

Benzylpenicillin (penicillin G): This is administered parenterally (IM or IV)

and is the treatment of choice for many infections.
Procaine penicillin: This preparation has an extended half-life compared to
benzylpenicillin and is administered by intramuscular
injection, not IV.
Benzathine penicillin: This is given IM and provides low levels of
benzylpenicillin for up to 4 weeks.

Penicillin is mainly used for the treatment of Gram-positive pathogens such as

streptococci, enterococci and anaerobes such as Clostridium spp. Due to
increasing penicillin resistance among S. pneumoniae, its role as first-line
monotherapy for meningitis in many regions is now under review.
 1.1 Penicillins
Anti-staphylococcal penicillins:
Members include: flucloxacillin, dicloxacillin. These drugs are stable to b-
lactamase produced by staphylococci and are therefore particularly useful
against most strains of S. aureus. In Australia flucloxacillin and
dicloxacillin are the two agents most frequently used, since oral
preparations are reliably absorbed and both are also available in IV
preparations.

Methicillin-resistant S. aureus (MRSA) is resistant to this class of

penicillins due to the presence of altered PBPs - hence none of these drugs
are effective against this pathogen. Appropriate treatment for MRSA
includes the use of a glycopeptide, or the use of a combination of
rifampicin plus fusidic acid .
 1.1 Penicillins
Moderate-spectrum penicillins:
These agents, the aminopenicillins (amoxycillin and ampicillin), have
greater activity than benzylpenicillin against common Gram-negative
pathogens such as E. coli and H.influenzae.

Nevertheless, resistance among many strains because they produce b-

lactamase now appears to be increasing and the role of these drugs is
changing. Since amoxycillin is better orally absorbed than ampicillin, it is
preferred; but both drugs are otherwise equivalent in terms of their dosing
regimens and their efficacy when administered parenterally.

Among patients with acute Epstein Barr virus infection (glandular fever),
both drugs are similarly associated with the production of a prominent
erythematous rash - however this does not indicate true allergy.
 1.1 Penicillins

Broad-spectrum penicillins

Piperacillin and ticarcillin are active against Pseudomonas aeruginosa, but are
generally administered in combination with a second anti-pseudomonal drug
such an aminoglycoside.

Both drugs are available only in parenteral form. Both agents have been
combined with a b-lactamase inhibitor (see below) to broaden their spectrum:
piperacillin/tazobactam and ticarcillin/clavulanate.

Ticarcillin is generally inferior to piperacillin in its coverage of Klebsiella

species, as well as enterococci. Both drugs are reasonably expensive, especially
piperacillin.
 1.1 Penicillins

1.2 Penicillin/ b-lactamase inhibitor combinations

amoxycillin (amoxycillin + clavulanate; Augmentin®)

ticarcillin (ticarcillin + clavulanate; Timentin®)
piperacillin (piperacillin + tazobactam; Tazocin®)

has extended the spectrum of these drugs to include activity against S.

aureus, anaerobes (e.g. B. fragilis) and strains of Gram-negative
pathogens such as E. coli, Neisseria gonorrhoea and H. influenzae that
are resistant to each of these penicillins alone.
b -lactamase inhibitors produce little inherent antibacterial activity, but
greatly broaden the activity of these penicillins when administered in
combination
 1. Beta-lactams
There are four classes of b -lactams:
 1.3 Cephalosporins
First-generation cephalosporins:
Cephalothin and cephazolin
Cephalexin
Second-generation cephalosporins:
Cefaclor and cefuroxime.
Cefoxitin and cefotetan
Third-generation cephalosporins:
Cefotaxime and ceftriaxone.

Ceftazidime.
Fourth-generation cephalosporins:
cefepime and cefpirome
1.3 Cephalosporins
 1.3 Cephalosporins
Fifth-generation cephalosporins:
Ceftaroline
Ceftaroline is a cephalosporin with activity against Gram positive and
Gram negative bacteria. C
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Ceftaroline is also active against methicillin resistant Staphylococcus

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aureus (MRSA) and penicillin nonsusceptible Streptococcus

pneumoniae (PNSP) due to its affinity for the altered PBPs found in
these organisms.
 1. Beta-lactams
There are four classes of b -lactams:
1.4 Carbapenems

Imipenem and meropenem.

The two agents in this class are imipenem and meropenem. They have an
extremely broad range of activity including staphylococci and streptococci,
the majority of Gram-negative pathogens (including Pseudomonas
aeruginosa) and almost all anaerobes.
They are, however, inactive against MRSA and the important nosocomial
pathogens Burkholderia cepacia and Stenotrophomonas maltophilia.

Imipenem may cause seizures in predisposed individuals, especially if they

have renal impairment - when serum concentrations may become elevated.

Meropenem has the advantage of fewer side-effects and 8-hourly dosing (cf 6
hourly dosing for imipenem), but is cheaper. Both agents may be associated
with antibiotic-associated diarrhoea, presumably due to their impact on the
natural bowel flora. Meropenem attains better CSF levels than imipenem and
is preferred if CSF penetration is important.
1.4 Carbapenems

Doripenem

? Better than meropenem for pseudomonas. Not available now

Ertapenem

No activity against pseudomonas

1 gm IV daily – useful for HITH eg for ESBL E.Coli infections
 1.5 Monobactams

Aztreonam is the only drug in this class. It is notable since it has good
activity against Gram- negative pathogens, but is inactive against Gram-
positive organisms and anaerobes.

It is of limited value only against "ESCAPPM" organisms. Aztreonam's

main claim to fame is that for patients with severe penicillin allergy it
can be used with minimal 'risk of cross-reactivity. Overall, however,
there is little role for aztreonam therapeutically
 2. Glycopeptides
Vancomycin and teicoplanin
Glycopeptides include vancomycin and teicoplanin, both of which are active against
a wide range of Gram-positive organisms including MRSA and methicillin-resistant
S. epidermidis (MRSE).
Both drugs are useful for the b lactam-allergic patient. Teicoplanin is heavily
protein-bound and has the advantage of long half-life and once-daily dosing.
However, some questions remain regarding its efficacy in serious staphylococcal
infections.
Overall, vancomycin is preferred due to the greater clinical experience with this
agent and the ability to monitor serum concentrations readily.
Vancomycin and teicoplanin are alternatives to ampicillin or penicillin for the
treatment of serious enterococcal infections where they are usually combined with
an aminoglycoside to obtain antibacterial synergy.
 3. Aminoglycosides

Aminoglycosides (gentamicin, tobramycin, netilmicin,

amikacin, streptomycin, neomycin and framycetin) are
active against most Gram-negative pathogens including
Pseudomonas aeruginosa, but have no substantive Gram-
positive activity as monotherapy.
3. Aminoglycosides
 3. Aminoglycosides

• Gentamicin
• Tobramycin
• Netilmicin
• Amikacin.
• Streptomycin
• Framycetin
• Neomycin
 4. Macrolides
Macrolides include erythromycin, roxithromycin, azithromycin and
clarithromycin.
They have a wide spectrum of activity including Gram-positive cocci such
as streptococci and staphylococci, as well as so-called "atypical" pathogens
such as Legionella, Mycoplasma and Chlamydia spp.
They are also active against Bordetella pertussis (whooping cough),
Corynebacteria and some strains of H. influenzae. Notably, they have no
activity against enteric Gram-negative bacilli and resistance among S.
pneumoniae and S. aureus is increasing.
Erythromycin has a number of oral formulations which have variable
absorption and are frequently associated with gastrointestinal side effects,
particularly nausea. Rarely, hepatotoxicity may occur. Parenteral
erythromycin is frequently associated with painful phlebitis at the injection
site and therefore needs to be given slowly or even through a central
venous catheter.
 4. Macrolides
Roxithromycin is an alternative to oral erythromycin as it has good oral
availability, but less gastrointestinal side effects.
The newer macrolides, clarithromycin and azithromycin, are more reliably
absorbed and have longer half-lives than erythromycin, allowing less
frequent dosing. They attain high intracellular concentrations and therefore
may be more effective for intracellular pathogens.
Azithromycin has good in vitro activity against a wide range of organisms
including H. influenzae. It is notable for its once-daily dosing which is
particularly useful for the treatment of chlamydial sexually transmitted
diseases, as well as trachoma and donovanosis.
Clarithromycin has similar activity to azithromycin, but in addition, is
active against Mycobacterium avium complex in patients with HIV
infection. For this indication it has proven effective for both prophylaxis
and treatment.
 5. Tetracyclines

Tetracyclines have a broad range of activity against many Gram-positive

and Gram-negative bacteria, mycoplasma, chlamydia, rickettsia and some
spirochaetes. Although usually bacteriostatic, the efficacy of tetracyclines
against intra-cellular pathogens is notable. Emergence of resistance has
limited the role of tetracyclines for treating some infections.
Tetracycline and doxycycline have a similar range of activity, however the
once or twice-daily dosing of doxycycline has led to it being the preferred
agent, although it may be more expensive.
All tetracyclines are contra-indicated in pregnancy, during lactation and in
children under the age of 8 years due to the potential for causing dental
staining.

Tetracyclines may also be associated with a photosensitive skin rash. Unless

taken with food nausea is a common side effect.
 5. Tetracyclines

Tigecycline
50mg bd IV
is a tetracycline class antibiotic in the glycylcycline subcategory for
intravenous infusion.
Used for MRSA, VRE, resistant mycobacteria eg m.abscessus
Activity against atypicals, anaerobes.
Not pseudomonas and some other gram negatives
Blood levels poor – not for septicaemia
Nausea
 6. Antifolate agents
Trimethoprim and sulfamethoxazole both have anti-folate activity that impairs
satisfactory DNA production. Except in combination with trimethoprim as
cotrimoxazole, sulphonamides have little place in clinical practice (apart from their
use in the treatment of cerebral toxoplasmosis). For many of the indications
previously considered to require cotrimoxazole, trimethoprim alone has now been
found to be as effective, especially for the treatment of urinary tract infections.

Cotrimoxazole is a useful antibiotic for a broad range of indications, but especially

for the treatment and prophylaxis of Pneumocystis carinii, the treatment of Listeria
monocytogenes, Nocardia spp. and Stenotrophomonas maltophilia infections, and as
an alternative for the treatment of infections due to "ESCAPPM" organisms.
Allergic reactions to either the sulpha or trimethoprim components of cotrimoxazole
are notable. Stevens-Johnson syndrome is one extreme of this allergic spectra, with
marked muco-cutaneous desquamation and potentially fatal outcome. Patients with a
history of sulpha allergy should not be given cotrimoxazole.
 7. Fluoroquinolones
Fluoroquinolones (ciprofloxacin, norfloxacin, ofloxacin and enoxacin)
have significant advantages over previous quinolones (naladixic acid) in
that they have extremely broad range of activity against most Gram-
negative bacteria (including Pseudomonas aeruginosa).
In many respects, fluoroquinolones can be considered to have a similar
spectrum of activity as aminoglycosides.
In addition, however, ciprofloxacin has excellent intra- cellular penetration
and good oral availability, such that oral ciprofloxacin provides similar
serum concentrations to intravenous ciprofloxacin. Ciprofloxacin can
currently be considered the "gold standard" of this class.
Norfloxacin provides adequate drug concentrations in the gastrointestinal
and urinary tracts and is useful for infections in these areas. However,
norfloxacin does not achieve reliable serum concentrations for infections in
other sites.
 7. Fluoroquinolones
Fluoroquinolones should be reserved for the treatment of infections resistant
to cheaper agents, or for situations when an oral agent with extended Gram-
negative spectrum is essential. Limiting the widespread use of these drugs
should reduce the emergence of resistance to this valuable class.
Newer fluoroquinolones with extended Gram-positive spectrum to include
activity against S. pneumoniae have recently been developed. However, this
extended spectrum is at the cost of reduced activity against difficult-to-treat
Gram-negative pathogens such as Pseudomonas aeruginosa. These newer
agents include gatifloxacin and moxifloxacin. Most of these agents also
have broad anti-anaerobic activity, and good activity against staph aureus
and "atypical" respiratory pathogens.
Side effects to fluoroquinolones include photosensitive skin rash, CNS
toxicity (e.g. nightmares) and some agents interact with theophylline and
caffeine. Fluoroquinolones have been shown to damage the joints of
immature animals and are therefore recommended to be used with caution in
children under the age of 14 years.
 8. Rifamycins

Rifamycins (rifampicin, rifabutin) are active against Gram-positive pathogens

including staphylococci and many mycobacterial species.

They generally need to be used in combination with other agents to avoid the rapid
emergence of resistance.

Both agents are potent inducers of hepatic P450 activity and therefore interactions
with other drugs need to be noted.

Rifampicin is one of the few orally available agents active against MRSA - in this
situation it should be used in combination with either fusidic acid or ciprofloxacin.

Rifabutin is used mainly for treatment of Mycobacterium avium complex. Both

drugs cause marked orange-pink discolouration of the urine, causing some patients
to believe they have haematuria unless they have been alerted to this feature.
 9. Nitroimidazoles

Metronidazole and tinidazole are nitroimidazoles - both are notable for their extremely
broad activity against Gram-positive and Gram-negative anaerobes (e.g. Clostridia
species, Bacteroides fragilis) and anaerobic protozoa including Trichomonas
vaginalis, Giardia lamblia and Entamoeba histolytica.
Metronidazole is the drug of choice for the treatment of Clostridium difficile
diarrhoea. Metronidazole is available in both oral and intravenous preparations as well
as suppositories.
Metronidazole is commonly combined with ampicillin and gentamicin for the
treatment of serious intra-abdominal sepsis, or wherever substantive anaerobic activity
is required.
Tinidazole is only available as an oral preparation and but its long half-life allows
once-daily dosing. Both drugs may cause a disulfiram (antabuse-like) reaction if
alcohol is consumed concurrently.
 10. Others
Clindamycin is a lincosamide with activity against Gram-positive aerobes and
most anaerobes. It also has activity against Toxoplasma gondii. It is useful since it
is available in both intravenous and oral preparations, but is expensive and may be
associated with antibiotic-associated diarrhoea.

Chloramphenicol has a broad range of activity against Gram-positive and Gram-

negative bacteria as well as rickettsia and chlamydia. Previously it was considered
to be one of the key drugs in the treatment of Salmonella typhi, but the emergence
of resistance has now limited its role.
An important advantage of chloramphenicol is that, similar to ciprofloxacin, oral
chloramphenicol achieves similar, or higher, serum concentrations than
intravenously administered drug. A crucial toxicity, however, is irreversible dose-
independent (idiosyncratic) aplastic anaemia which occurs approximately once
every 30,000 courses. Chloramphenicol has also been noted to cause reversible
dose-dependent bone marrow hypoplasia and so-called "grey baby syndrome"
when administered to neonates. Although inexpensive, chloramphenicol should
only be used when there are no suitable alternative therapies.
 10. Others

Fusidic acid is highly active against S. aureus, when it is usually

given in combination with oral rifampicin. In higher doses it may
be associated with nausea, but these symptoms usually resolve with
minor dose reductions.

Nitrofurantoin is used for the treatment and prophylaxis of lower

urinary tract infections. Toxicities include polyneuropathy, acute or
chronic pulmonary hypersensitivity, haemolysis and chronic active
hepatitis. Nitrofurantoin has no role outside the urinary tract.
 10. Others
LINEZOLID is an oxazolidinone, which is a new class of drug that is active against
resistant gram positive bacteria. Linezolid binds to the 23S ribosomal RNA of the 50S
subunit of the bacterial ribosome and prevents the formation of a functional 70S
initiation complex which is an essential component of the bacterial translation process.

Its main indication is treatment of methicillin-resistant Staph aureus, vancomycin-

resistant Staph aureus and vancomycin-resistant Enterococcus. Adverse reactions
include: myelo-suppression, taste perversion and abnormal liver function.

It is available in injection and tablet form. Doses are equivalent as the drug is highly
bio-available. Eg 600mg orally BD.

For MRSA infections, its cure rate compared to vancomycin is equivalent. At present it
is not indicated for use more than 28 days. Its current price @ $125.00 per tablet makes
it the most expensive oral antibiotic.
 10. Others
SYNERCID (Dalfopristin, Quinupristin)
This drug is now not available for treating methicillin-resistant Staph aureus,
vancomycin- resistant Enterococcus faecium. It is not active against Enterococcus
faecalis. It is only available in intravenous formulation, which is extremely expensive.
Dose: 7.5 mgs per kilogram 8-hourly. Synercid i.v. is given through a peripherally
inserted central catheter because of its ability to cause severe venous irritation.
Major side effects include: Local effects; raised LFTs; arthralgia, myalgia;
superinfection; rash; GI upset
Drug interactions: Drugs metabolised by CYP3A4 eg cyclosporin A, midazolam,
nifedipine, esp. drugs which prolong QT interval eg terfenadine, astemizole, cisapride,
disopyramide, quinidine, lignocaine (avoid concurrent use)
The two components (called streptogramins) are bacteriostatic drugs that act on
the bacterial ribosome; however, when combined, these drugs work in a bactericidal
fashion by inhibiting early and late phases of bacterial protein synthesis. It is extremely
expensive.

PRISTINOMYCIN Oral capsule, SAS availability.

 10. Others
DAPTOMYCIN
Daptomycin is an antibacterial agent of a new class of antibiotics, the cyclic
lipopeptides.

Daptomycin retains potency against antibiotic resistant Gram positive bacteria,

including isolates resistant to methicillin, vancomycin and linezolid.
Mechanism of action. Daptomycin binds to bacterial membranes and causes a
rapid depolarisation of membrane potential in both growing and stationary phase
cells. This loss of membrane potential causes inhibition of protein, DNA and
RNA synthesis. This results in bacterial cell death with negligible cell lysis.
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Endocarditis

Empiric therapy benzylpenicillin vancomycin

(pending culture results) + flucloxacillin + gentamicin
+ gentamicin
Streptococcal benzylpenicillin ceftriaxone/cefotaxime
+ gentamicin + gentamicin

Enterococcal benzylpenicillin or ampicillin vancomycin

+ gentamicin + gentamicin
Methicillin-sensitive flu(di)cloxacillin vancomycin
Staphylococcus aureus (MSSA) + gentamicin (first week only)
Methicillin-resistant vancomycin teicoplanin
Staphylococcus aureus (MRSA)

Culture negative benzylpenicillin or ampicillin vancomycin

+ gentamicin + ceftriaxone/cefotaxime

Prosthetic valve vancomycin 1

+ gentamicin
 Commonly recommended antibiotic regimens for various conditions
Clinical condition Commonly-used regimen Alternative regimen

Meningitis
Empiric therapy benzylpenicillin ceftriaxone
+ ceftriaxone/cefotaxime or chloramphenicol

S. pneumoniae Sensitive 2 benzylpenicillin ceftriaxone/cefotaxime

Intermediate 2 ceftriaxone/cefotaxime
Resistant 2 vancomycin meropenem
N. meningitidis benzylpenicillin ceftriaxone/cefotaxime

H. influenzae Sensitive benzylpenicillin ceftriaxone/cefotaxime

Resistant ceftriaxone/cefotaxime
Listeria monocytogenes benzylpenicillin or ampicillin cotrimoxazole

Brain abscess
Empiric therapy benzylpenicillin
+ metronidazole
+ ceftriaxone/cefotaxime
Post-operative vancomycin
+ ceftriaxone/cefotaxime
Toxoplasmosis sulfadiazine clindamycin
+ pyrimethamine (+ folinic acid) + pyrimethamine
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Gastrointestinal infectious
Enteric fever (typhoid, paratyphoid) ciprofloxacin ceftriaxone/cefotaxime
cotrimoxazole 4
amoxycillin 4
chloramphenicol 4

Clostridium difficile metronidazole vancomycin

or bacitracin
Giardia lamblia tinidazole or metronidazole
Salmonellosis (not enteric fever) No treatment generally required
Shigellosis norfloxacin or ciprofloxacin ampicillin 4
cotrimoxazole 4

Traveller's diarrhoea norfloxacin 5 cotrimoxazole

(Enterotoxigenic E. coli)
Cholera Rehydration amoxycillin
+ doxycycline
 Commonly recommended antibiotic regimens for various conditions
Clinical condition Commonly-used regimen Alternative regimen
Gastrointestinal infectious
Intestinal amoebiasis metronidazole
+ diloxanide
Cyclospora cayetanensis cotrimoxazole
Microsporidia albendazole 6
Helicobacter pylori 7 bismuth omeprazole
+ metronidazole + clarithromycin
+ either tetracycline + either amoxycillin
or amoxycillin or metronidazole
or
omeprazole
+ amoxycillin
+ metronidazole
Diverticulitis amoxycillin/clavulanate 8 metronidazole
+ cephalexin

Acute cholecystitis amoxy(ampi)cillin ceftriaxone/cefotaxime

+ gentamicin
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Acute peritonitis:
a. Secondary to perforated viscus amoxy(ampi)cillin ceftriaxone/cefotaxime
+gentamicin + metronidazole
+metronidazole
ticarcillin/clavulanate
b. Spontaneous bacterial peritonitis amoxy(ampi)cillin ceftriaxone/cefotaxime
+gentamicin

c. Complicating continuous ambulatory

peritoneal dialysis
Gram +ves: cephazolin IP 9 vancomycin IP 9
Gram -ves: gentamicin IP ceftriaxone/cefotaxime
No organisms seen: vancomycin IP 9
+ gentamicin IP

Pancreatitis
Acute: None
Necrotising: ticarcillin/clavulanate ceftriaxone/cefotaxime
+ metronidazole
Pyogenic liver abscess Similar to acute peritonitis due to perforated viscus 10
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Urinary tract infection

Acute cystitis
Non-pregnant females: trimethoprim cephalexin
amoxycillin/clavulanate nitrofurantoin

Pregnant females: cephalexin nitrofurantoin

amoxycillin/clavulanate

Acute pyelonephritis
Mild-moderate cephalexin amoxycillin/clavulanate
trimethoprim
norfloxacin

Severe: amoxy(ampi)cillin IV ceftriaxone/cefotaxime

+ gentamicin
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Genital tract infections:

Candidiasis clotrimazole 2% cream fluconazole
or nystatin cream or pessaries or ketoconazole

Bacterial vaginosis clindamycin 2% cream clindamycin

or metronidazole
Trichomonas vaginalis tinidazole metronidazole

Prostatitis
Acute-severe: amoxy(ampi)cillin IV
+ gentamicin

Chronic ciprofloxacin or norfloxacin

± doxycycline 11
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Sexually transmitted diseases

Chlamydia or non-gonococcal doxycycline azithromycin
urethritis/cervicitis
Gonorrhoea ceftriaxone or ciprofloxacin
[+ either doxycycline or azithromycin]
Donovanosis azithromycin
(Granuloma inguinale,
Calymmatobacterium granulomatis)

Chancroid (H. ducreyi) azithromycin ceftriaxone

ciprofloxacin
Syphilis penicillin 12

Lymphogranuloma venereum doxycycline roxithromycin

(LGV, Chlamydia trachomatis) erythromycin
azithromycin
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Pelvic Inflammatory Disease (PID)

Sexually-acquired: Mild-moderate: metronidazole

+ doxycycline roxithromycin
±ceftriaxone erythromycin
Severe.- doxycycline
+ metronidazole
+ ceftriaxone/cefotaxime
Non-sexually-acquired:
Mild-moderate: amoxycillin/clavulanate
+ doxycycline roxithromycin
erythromycin
Severe: As per severe sexually acquired PID
Postpartum fever & endometritis amoxycillin/clavulanate clindamycin
±roxithromycin/erythromycin
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Respiratory tract infections (RTI)

Upper RTI..
Acute sore throat None
or penicillin/amoxycillin13
Tonsillitis penicillin/amoxycillin13

Acute otitis media & sinusitis ? None

or amoxycillin cotrimoxazole
cefaclor
Croup None
(acute laryngotracheobronchitis)

Acute epigiottitis ceftriaxone/cefotaxime chloramphenicol

Pertussis erythromycin cotrimoxazole

roxithromycin
 Commonly recommended antibiotic regimens for various conditions
Clinical condition Commonly-used regimen Alternative regimen

Lower RTI..
Exacerbations of chronic bronchitis amoxycillin doxycycline
Community-acquired pneumonia:
Mild: roxithromycin amoxycillin
doxycycline
Moderate penicillin IV 14
+ roxithromycin
Severe 15 erythromycin IV
+ ceftriaxone/cefotaxime
or penicillin IV 16

Aspiration pneumonia &

lung abscess 20 to aspiration penicillin IV clindamycin
+ metronidazole ticarcillin/clavulanate

Staphylococcal pneumonia di(flu)cloxacillin cephalothin/zolin

vancomycin
 Commonly recommended antibiotic regimens for various conditions
Clinical condition Commonly-used regimen Alternative regimen
Hospital-acquired pneumonia:
Mild. amoxycillin/clavulanate penicillin
+ gentamicin
or ceftriaxone/cefotaxime

Moderate: penicillin 17 ticarcillin/clavulanate

+gentamicin
+ metronidazole or clindamycin

Severe: gentamicin 18 imipenem/meropenem

+ either ceftazidime ciprofloxacin
or ticarcillin/clavulanate

Pneumocystis carinii pneumonia cotrimoxazole 19 dapsone

+ trimethoprim
Pulmonary tuberculosis rifampicin
+ isoniazid (+ pyridoxine)
+ pyrazinamide
+ ethambutol
 Commonly recommended antibiotic regimens for various conditions
Clinical condition Commonly-used regimen
Skin, muscle & bone infections
Impetigo penicillin
or di(flu)cloxacillin
Folliculitis, boils, carbuncles di(flu)cloxacillin
Septic arthritis di(flu)cloxacillin
Cellulitis di(flu)cloxacillin
or penicillin
Orbital cellulitis di(flu)cloxacillin
+ ceftriaxone/cefotaxime
Suppurative wound infection di(flu)cloxacillin
+ gentamicin
Bites & clenched fist injuries penicillin (IM)
then amoxycillin/clavulanate
Compound fractures di(flu)cloxacillin
± gentamicin
Alternative regimen
roxithromycin
cephalexin
cephalothin/cephazolin
clindamycin
cephalothin/cephazolin
amoxycillin/clavulanate
ticarcillin/clavulanate
ceftriaxone/cefotaxime
+ metronidazole
cephalothin/cephazolin
+gentamicin
 Commonly recommended antibiotic regimens for various conditions
Clinical condition Commonly-used regimen Alternative regimen
Diabetic foot infections
Mild.. amoxycillin/clavulanate cephalexin

Moderate (potentially limb-threatening): ticarcillin/clavulanate cephalothin/cephazolin

+ gentamicin
Severe (potentially life-threatening): di(flu)cloxacillin
+ gentamicin
+ metronidazole

Synergistic gangrene: penicillin imipenem/meropenem

(or necrotising fasciitis) + gentamicin ± vancomycin
+ metronidazole
or clindamycin
If S. aureus likely: + di(flu)cloxacillin
If S. pyogenes likely penicillin
+ clindamycin
Osteomyelitis
Children (<5 yo) di(flu)cloxacillin
±ceftriaxone/cefotaxime
Children (>5 yo) di(flu)cloxacillin
Adults di(flu)cloxacillin 20 cephalothin/cephazolin
clindamycin
vancomycin 20
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Septicaemia

Empiric (no obvious source):

Normal child di(flu)cloxacillin
+ ceftriaxone/cefotaxime
Normal adult di(flu)cloxacillin cephalothin/cephazolin
+ gentamicin
Neutropenic - low risk ceftazidime cefepime/cefpirome
high risk gentamicin gentamicin
+ ceftazidime + cefepime/cefpirome
or ticarcillin/clavulanate or piperacillin/tazobactam
± vancomycin
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Septicaemia

Empiric with predicted source:

Urinary tract amoxy(ampi)cillin ceftriaxone/cefotaxime
+ gentamicin
Biliary or GI tract amoxy(ampi)cillin vancomycin
(including ascending cholangitis) + gentamicin + ceftriaxone/cefotaxime
+ metronidazole + metronidazole
Female genital tract amoxy(ampi)cillin metronidazole
+gentamicin + cephalothin
+metronidazole or ceftriaxone/cefotaxime

clindamycin
+ gentamicin
 Commonly recommended antibiotic regimens for various conditions

Clinical condition Commonly-used regimen Alternative regimen

Septicaemia

Skin di(flu)cloxacillin cephalothin/cephazolin

(including cellulitis) or penicillin clindamycin

Periorbital cellulitis di(flu)cloxacillin clindamycin

+ ceftriaxone/cefotaxime (for children) vancomycin

Diabetic foot ulcers di(flu)cloxacillin timentin

+ gentamicin + gentamicin
+ metronidazole
cephalothin/cephazolin
+gentamicin
+metronidazole
 Commonly recommended antibiotic regimens for various conditions
Clinical condition Commonly-used regimen Alternative regimen
Septicaemia
IV line sepsis di(flu)cloxacillin 20 vancomycin 20

+ gentamicin
Pneumonia Children: di(flu)cloxacillin
+ ceftriaxone/cefotaxime
Adults: erythromycin erythromycin
+ ceftriaxone/cefotaxime + penicillin
+ gentamicin
Other Infections
Q fever (Coxiella burnetii) doxycycline chloramphenicol

Leptospirosis penicillin IV doxycycline

Brucellosis Children: cotrimoxazole
(<8 YO + either rifampicin or gentamicin
Adults &
children (>8yo) doxycycline
+ either.rifampicin or gentamicin
Meliodosis ceftazidime
+ either cotrimoxazole or doxycycline