ANTIMICROBIAL AGENTS

-LACTAMS
These antibiotics contain a -lactam ring as part of their molecular structure.
1. Penicillins
! The antibiotics listed in Table 1 under "Penicillins" are those in common use. Penicillin can
be taken by mouth (penicillin V) but should be injected when used to treat serious infections,
such as severe streptococcal infections (pneumococcal pneumonia and streptococcal
cellulitis), as well as for the treatment of syphilis.
! The majority of staphylococci isolated since the 1960s are resistant to penicillin G.
Consequently, flucloxacillin or dicloxacillin, penicillins which are not inactivated by
staphylococcal -lactamases, are used as the initial treatment for most staphylococcal
infections. Flucloxacillin and related -lactams are ineffective against methicillin-resistant
Staphylococcus aureus (MRSA).
! Amoxycillin can be administered alone or in combination with clavulanic acid. The latter is a
-lactam antibiotic with poor antibacterial activity, but with strong anti--lactamase activity. It
is used to protect amoxycillin from inactivation by certain (mainly plasmid-encoded)
-lactamases. Clavulanic acid or other -lactamase inhibitors (e.g. sulbactam) can also be
combined with other penicillins, e.g. ticarcillin, for the same purpose.
! The anti-pseudomonal penicillins are parenteral antibiotics only and are generally restricted
to hospital use.
2. Cephalosporins
! The terms 1st, 2nd, 3rd and 4th generation cephalosporins indicate:
a) Time sequence of development, i.e, the 1st generation cephalosporins were the first to
be available for clinical use.
b) Differing spectrum. The 1st generation cephalosporins have good activity against Gram
positive bacteria. The Gram positive spectrum tends to decrease and the Gram negative
spectrum and resistance to -lactamase tends to increase as one moves to 2nd, 3rd and
4th generation cephalosporins. Note: MRSA, enterococci and the Bacteroides fragilis
group are resistant to all cephalosporins.
! The third generation cephalosporins have excellent CSF penetration. Because of this, they
are used for the treatment of bacterial meningitis.
3. Other -lactams
! The antibiotics listed under this heading have become available more recently. They are
parenteral antibiotics, which generally are restricted to hospital use only.

1.

Table 1 : -Lactam antibiotics

1. Penicillins
Name

Comment

Common Targets

Penicillin G and V

Active vs. G+ bacteria

and G! cocci, but
considerable resistance

Streptococci,
G+ rods,
T. pallidum

Flucloxacillin,
dicloxacillin etc.

Anti-staphylococcal
(narrow spectrum)

Staphylococci
(except MRSA)

Amoxycillin/
ampicillin

Broad spectrum
(but susceptible to
-lactamases)

Gram negative
rods, enterococci,
Listeria

Ticarcillin,
piperacillin

Anti-pseudomonal

Pseudomonas
aeruginosa

2. Cephalosporins
Examples of:
1st generation

2nd generation

3rd generation

4th generation

Cephalothin
Cephalexin
Cephazolin

Cefoxitin

Ceftriaxone
Cefotaxime
Ceftazidime

Cefepime
Cefpirome

Spectrum
Gram +ve
Gram -ve

++
+

+
++

+
+++

++
++++

CSF penetration

++

++

2. Other -lactams
a)

Clinical tips

-lactamase inhibitors
e.g. clavulanic acid
(ampicillin+ clavulanic acid
= co-amoxyclav)

1.

b)

Monobactams
e.g. aztreonam

1.
2.
3.

Parenteral only.
Gram negative spectrum only.
Can be given to penicillin allergic patients.

c)

Carbapenems
e.g. imipenem

1.
2.

Very wide antibacterial spectrum

Mainly used in hospitals.

2.

The adverse drug reaction rate is higher with

combination than with amoxycillin alone
The spectrum of co-amoxyclav includes
flucloxacillin-sensitive staphylococci, but not MRSA.

2.

AMINOGLYCOSIDES
!

Aminoglycosides are used mainly for the treatment of Gram negative infections.

They are ineffective for infections caused by anaerobes or Salmonella species (e.g.
typhoid fever), and have reduced activity within abscess cavities.

They are potentially nephrotoxic and ototoxic.

Treatment should be monitored by blood levels to ensure adequate dosing and to minimise
the risk of toxicity.

Patients receiving treatment for more than 72 hours should have pre-dose (trough) levels
determined within 72 hours of starting therapy and at intervals thereafter depending on the
duration of therapy.

Table 2 : Aminoglycosides
Antibiotic

Use

Streptomycin

None today, except rarely for tuberculosis

Neomycin

Gastrointestinal tract decontamination

Gentamicin, tobramycin

Wide Gram negative spectrum

Amikacin

Broader spectrum, but much more expensive than gentamicin

(kept in reserve)

QUINOLONES
!

Nalidixic acid. Poor serum levels. Limited antibacterial spectrum. Used for urinary tract
infections.

Fluoroquinolones, e.g. norfloxacin and ciprofloxacin, have a wide antibacterial spectrum

which includes Enterobacteriaceae, Pseudomonas spp., staphylococci, Campylobacter,
Helicobacter, Salmonella, Shigella and Neisseria. They are not active against
streptococci, Staphylococcus saprophyticus or anaerobes.

Norfloxacin is effective in the treatment of urinary tract infections and acute bacterial
gastrointestinal infections. It is available as an oral preparation.

Ciprofloxacin has a wider clinical use than norfloxacin, and includes osteomyelitis, and
Pseudomonas chest and urinary tract infections.
It is available as an oral and an intravenous preparation.

Moxifloxacin and gatifloxacin are broad-spectrum fluoroquinolones with good activity

against anaerobes and the causative agents of atypical pneumonia. They are less active
than ciprofloxacin against Pseudomonas aeruginosa.

Quinolones should be used with caution in children, as there is evidence from animal
studies that they may damage developing joints.

3.

OTHER ANTIBACTERIAL AGENTS

Some other antimicrobial agents in use and some of their indications are listed in Table 3.
Table 3 : Other antibacterial agents
Agent
Erythromycin,
roxithromycin

Azithromycin

Clarithromycin

Uses
!

Gram positive infections in patients allergic to penicillin

Atypical pneumonia due to Mycoplasma, Legionella, Chlamydia

Pertussis prophylaxis

More active against Gram negative bacteria than erythromycin

and effective as a once daily dose. Some activity against
mycobacteria

Used for genital infections with Chlamydia

Similar to erythromycin but more active against mycobacteria

Used for infections with Mycobacterium avium complex in

combination with other drugs

Doxycycline,
tetracycline

Non gonococcal urethritis, pelvic inflammatory disease.

Infections caused by Mycoplasma, Chlamydia, Rickettsia.

Chloramphenicol

Alternative to ceftriaxone etc. for severe Haemophilus

influenzae infections and systemic salmonellosis, including
typhoid fever.

Alternative to tetracyclines for rickettsioses.

Trimethoprim

Urinary tract infections, otitis media, sinusitis.

Co-trimoxazole

Pneumocystis carinii pneumonia

Shigellosis

Nocardiasis.

IV for severe Gram positive infections in penicillin allergic

patients or with resistant organisms, e.g. MRSA.

Orally for severe pseudomembranous colitis.

Infections caused by Gram negative anaerobes.

Protozoal infections: Entamoeba, Trichomonas, Giardia.

Gardnerella vaginosis.

Effective against MRSA, vancomycin-resistant enterococci,

penicillin-resistant pneumococci, multiresistant Mycobacterium
tuberculosis. Resistance is emerging.

Vancomycin

Metronidazole

Linezolid

4.

Notes on -lactamases
-lactamases destroy penicillins and cephalosporins by opening the -lactam ring. They may be
encoded by the bacterial chromosome or by plasmids, some of which can transfer between
bacteria, thus spreading resistance. In general the chromosomal and plasmid types are distinct
from one another.
Chromosomal -lactamases occur in all bacteria but their ability to cause resistance depends on
the amount produced. Trace amounts of enzyme are unimportant but larger amounts may cause
resistance. Species where chromosomal -lactamase are produced in large amounts, and present
a resistance problem, include members of the genera Enterobacter, Serratia, Citrobacter,
Pseudomonas and Morganella (ESCaPeM).
Plasmid-mediated -lactamases were unknown before the antibiotic era, but now occur in 80-90%
of staphylococci, >50% of E. coli and in up to 50% of Haemophilus spp. and N. gonorrhoeae.
The newer generation cephalosporins, monobactams and carbapenems were developed, in part,
because of their stability to many -lactamases, and particularly to those of Gram-negative rods.
However, -lactamase-mediated resistance is now emerging to these antimicrobials. Specific
problems include :
1) the emergence of bacteria that overproduce chromosomal Class I -lactamases;
2) the evolution of new plasmid-encoded -lactamases (extended spectrum -lactamases) which
are active against newer generation cephalosporins, and
3) the occurrence of carbapenemases.

1. Chromosomal -lactamases
Chromosomal Class I -lactamases normally are inducible in Enterobacter, Serratia, Citrobacter
freundii, P. aeruginosa and Morganella. Many older -lactams, such as ampicillin and cephalothin,
induce these enzymes and are hydrolysed very rapidly. Consequently these bacteria are resistant
to these agents. Carbapenems also induce strongly, but are resistant to hydrolysis and so remain
active.
Third-generation cephalosporins and monobactams also remain active against many -lactamase
inducible species, although they are not stable to their enzymes. The reason is that they are weak
inducers of -lactamase. In many cases, this strategy is successful and the drugs remain effective,
but some bacteria with inducible -lactamases may give rise to de-repressed mutants which
manufacture Class I -lactamase continuously without induction.
When a bacterial population containing a few de-repressed mutants is challenged with a drug which
is susceptible to -lactamase, but a weak inducer, the inducible cells are killed but the de-repressed
mutants survive and over-run the population. This type of selection can occur during therapy,
causing clinical failure. Typically, the de-repressed mutants are resistant to most or all
cephalosporins, monobactams and penicillins, but remain susceptible to penems and carbapenems.
Resistance cannot be reversed with clavulanic acid, etc., which Class I enzymes bind poorly.

5.

2. Plasmid-encoded -lactamases
These pose a further threat to newer -lactams. More than 100 different plasmid mediated
-lactamases have been described in Gram-negative rods. They are designated by three-letter
codes such as TEM and SHV.
TEM-1 was first observed in Escherichia coli in 1965. It subsequently spread to other
enterobacteria, then to P. aeruginosa; by the mid-1970s to H. influenzae and N. gonorrhoeae.
TEM-1 now occurs in approximately 50% of E. coli isolates and in from 2-80% of H. influenzae and
N. gonorrhoeae. Its frequency varies considerably in different countries and populations, but
generally is increasing. SHV-1 is common in klebsiellae, but is otherwise infrequent.
TEM-1 and SHV-1 enzymes convey resistance to almost all the penicillins and to most first
generation cephalosporins. Newer cephalosporins, monobactams and carbapenems were designed
to be stable. However 'extended spectrum' mutants of TEM and SHV enzymes have emerged, with
1 to 4 amino-acid changes compared to the parent -lactamase. Such minor modifications,
representing less than 2% of the total amino-acid sequence, are sufficient to extend the enzyme's
activity. The level and spectrum of resistance varies with the particular amino-acid changes, but the
general pattern is constant: the mutants attack monobactams and all second- and third-generation
cephalosporins. Carbapenems and cephamycins remain stable and the enzymes remain
susceptible to inhibition by clavulanic acid and tazobactam.
Unknown before 1983, these extended-spectrum mutants now occur throughout the world. In
Australia, they are found mainly in nosocomial strains of K. pneumoniae. These bacteria spread
amongst patients, and their plasmids may be transferred to other species. There is little doubt that
these enzymes will continue to spread widely in future, just as TEM-1 has.

3. Zinc Carbapenemases
Carbapenems (e.g. imipenem) escape the -lactamases so far discussed, but are attacked by a few
unusual enzymes, most of which are zinc dependent. Stenotrophomonas (Xanthomonas)
maltophilia, Bacillus cereus, Aeromonas sobria, A. hydrophila and some Flavobacterium spp. have
chromosomally-mediated zinc -lactamases which can hydrolyse imipenem. None of these species
is frequent as a pathogen, but S. maltophilia is increasingly being identified as an opportunistic
pathogen. It is very resistant to most antibiotics and may be exploiting ecological niches created by
other drugs, including imipenem itself.
Carbapenemase is also found in about 1% of Bacteroides fragilis isolates. This enzyme is in
addition to the normal chromosomal cephalosporinase of this species.
Chromosomally-encoded carbapenemases which convey resistance to imipenem have been found
in a few isolates each of Serratia and Enterobacter, but are not typical of these species. More
disturbingly, plasmid-encoded carbapenemases have been identified reported in P. aeruginosa and
B. fragilis isolates from Japan, and more recently in E. coli and Klebsiella pneumoniae isolates from
India, Pakistan, China and elsewhere. This particular carbapenemase is known as the New Delhi
metallo--lactamase 1 (NDM-1) and has attracted considerable media attention world-wide.

6.

Examples of "Best Guess" Therapy for Common Clinical Conditions

which Should be Treated Before Culture Results are Known
Disease (specimen
for culture)

Likely causative
organisms

Antibiotic(s) of
choice

Route and duration

(where applicable)

Sore throat
pharyngitis

>50% viral
Strep. pyogenes

None
penicillin
(roxithromycin)

orally for 10 days

amoxycillin

orally for 5 days

amoxycillin or
doxycycline

orally for 5 days

amoxycillin
plus
doxycycline or
roxithromycin

orally 5-10 days

moderate severity index as above

+ Klebs. pneumoniae

as above
plus gentamicin
(if suspect Klebs.)

IV, then oral

high severity index

3rd-generation ceph.
(e.g. ceftriaxone) plus
erythromycin

IV, frequency, route,

dose and duration
depend on
bacteriology and
clinical response

(throat swab)

Common
Otitis media;
sinusitis
(post-nasal swab;
difficult to obtain
specimen from OM)

Acute exacerbation
of chronic bronchitis

Strep.
pneumoniae,
H. influenzae,
Moraxella
cattarhalis

Less
Common
Strep.pyogenes,
Staph.aureus,
Viral

H. influenzae
Strep. pneumoniae

(sputum)

Pneumonia: community-acquired
low severity index
Strep. pneumoniae,
Mycoplasma pneumoniae
Chlamydophila pneumoniae

Str. pneumoniae,
Staph. aureus,
Legionella spp.,
enterobacteria

(sputum, blood
culture, serology)
Hospital-acquired pneumonia: refer to Antibiotic Guidelines

7.

Disease (specimen
for culture)

Likely causative
organisms

Antibiotic(s) of
choice

Route and duration

(where applicable)

Urinary tract
infection
Cystitis

>80% E. coli

cephalexin or
co-amoxyclav or
trimethoprim

orally 3-5 days

(MSU, SPA)

Hospital acquired UTI or recurrent infections more likely to be other bacteria and multiply antibiotic resistant

Skin infection
Impetigo
(skin swab)

Staph. aureus
and/or
Str. pyogenes

penicillin
plus
mupirocin

orally 10 days

Erysipelas
(skin swab,
blood culture)

Str. pyogenes

penicillin

IM or IV until
controlled then
orally 10 days

Cellulitis:
non-clostridial

Staph. aureus,
Str. pyogenes

flu(di)cloxacillin

IM or IV

clostridial
myositis

Cl. perfringens

penicillin G

IV high dose

amoxycillin plus
gentamicin

IM or IV

(blood culture)

Enterobacteriaceae,
Enterococcus spp.,
Anaerobes
less common

Acute peritonitis,
leakage of gut
contents

Gram-negative anaerobes amoxycillin plus

Enterobacteriaceae
gentamicin plus
Enterococci
metronidazole

topically 10 days

(skin swab, blood culture)

Gastrointestinal
infections
Acute cholecystitis,
cholangitis

(blood culture,
operative specimen pus,
paracentesis fluid)

8.

IM or IV

Disease (specimen
for culture)

Likely causative
organisms

Antibiotic(s) of
choice

Route and duration

(where applicable)

CNS infections
Bacterial
meningitis
(CSF, blood
culture)

N. meningitidis
Str. pneumoniae
H. influenzae
type b

3rd-generation
cephalosporin
(e.g. ceftriaxone)

IM or IV for
7-10 days

Neonatal
meningitis

E. coli, Listeria,
group B streptococcus

ceftriaxone plus
penicillin or
amoxycillin

IM or IV
for 10 days

"Viridans" group
streptococci
Group D streptococci
and enterococci

penicillin
plus
gentamicin

CVS infections
Endocarditis
(blood culture)

IM or IV
for 4-6 weeks

Note: Penicillin/aminoglycoside combination synergistic; therefore continue both for 2 weeks even for
highly penicillin-sensitive organisms. Relatively resistant isoaltes require longer period of treatment.

Septicaemia
no obvious source

Staph. aureus
Gram-negative bacilli

flu(di)cloxacillin
plus gentamicin

IV 1-2 weeks;
longer if focal lesions

Other septicaemia
Likely source
urinary tract

Enterobacteriaceae
and other Gramnegative bacilli

amoxycillin
plus gentamicin

IV until organism and

sensitivity known; then
continue according to
severity and clinical
response

Likely source
biliary or
gastrointestinal
tract

As above plus
anaerobic Gramnegative bacilli or
Gram-positive cocci

as above
plus metronidazole

as above

Staph. aureus

flu(di)cloxacillin

IV 4-6 weeks

(blood culture)

Bone and joint

infections
Osteomyelitis,
septic arthritis
(blood culture;
joint fluid)

9.

Empirical Antimicrobial Therapy Based on Aetiological Agent

Likely or Proven Pathogen

Drug of First Choice

Alternative Drugs

Strep. pneumoniae

penicillin G (if susceptible)

cephalosporin (2/3), linezolid

Strep. pyogenes (group A)

penicillin G (?+ clindamycin)

erythromycin, cephalosporin (1)

Strep. agalactiae (group B)

penicillin G (?+ aminoglycoside)

vancomycin

Viridans streptococci

penicillin G

cephalosporin (1/3), vancomycin

Staph. aureus

flucloxacillin

cephalosporin, vancomycin

MRSA

vancomycin

linezolid, tigecycline

penicillin G aminoglycoside

vancomycin + aminoglycoside

Bacillus spp (not anthrax)

vancomycin

fluoroquinolone, clindamycin

Listeria species

ampicillin aminoglycoside

co-trimoxazole

Nocardia species

sulphonamide

micocycline, amikacin

Neisseria gonorrhoeae

ceftriaxone

spectinomycin

Neisseria meningitidis

penicillin G

ceftriaxone

Moraxella catarrhalis

cephalosporin (2/3)

azithromycin, fluoroquinolone

E. coli, Proteus

ampicillin

cephalosporin (1/2)

Klebsiella

cephalosporin (1/2)

aminoglycoside

Shigella

fluoroquinolone

ampicillin

Salmonella

fluoroquinolone, cephalosporin (3)

chloramphenicol, ampicillin

Campylobacter

erythromycin, azithromycin

fluoroquinolone, tetracycline

Helicobacter

PPI + clarithromycin + amoxycillin

PPI + metronidazole + amoxy

Pseudomonas

anti-pseudomonal penicillin

same + aminoglycoside

B. cepacia

co-trimoxazole

cephalosporin (3), fluoroquinolone

Legionella

azithromycin

doxycycline

Gram-positive

penicillin G

clindamycin

C. difficile

metronidazole

vancomycin

B. fragilis

metronidazole

co-amoxyclav

Fusobacterium, Prevotella

metronidazole

penicillin G

Mycoplasma pneumoniae

erythromycin, azithromycin

tetracycline

Chlamydia trachomatis

erythromycin, azithromycin

tetracycline

Treponema pallidum

penicillin G

tetracycline

Gram-positive cocci (aerobic)

Enterococcus species
Gram-positive rods (aerobic)

Gram-negative cocci (aerobic)

Gram-negative rods (aerobic)

Anaerobic bacteria

Some other bacteria

10.