2. • Microorganisms of medical importance fall
into four categories: bacteria, viruses, fungi,
and parasites.
• The first broad classification of antibiotics
follows this classification closely, so that we
have (1) antibacterial, (2) antiviral, (3)
antifungal, and (4) antiparasitic agents.
3. • Chemotherapy is the term originally used to
describe the use of drugs that are 'selectively
toxic' to invading microorganisms while having
minimal effects on the host. The term also
embraces the use of drugs that target tumours.
• The term chemotherapy was coined by Ehrlich
himself at the beginning of the 20th century to
describe the use of synthetic chemicals to destroy
infective agents.
4. • Antibiotics are the substances produced by some
microorganisms (or by pharmaceutical chemists)
that kill (bactericidal) or inhibit (bactriostatic) the
growth of other microorganisms. It also includes
agents that kill or inhibit the growth of cancer
cells.
• An ideal antimicrobial agent exhibits selective
toxicity meaning that the drug is harmful to the
parasite without causing any harmful effect to the
host.
5. Classification of an antibiotic is based on:
• the class and spectrum of microorganisms it
kills
• the biochemical pathway it interferes with
• the chemical structure of its pharmacophore
6. Bacteria
• Bacteria cause most infectious diseases. Surrounding
the cell is the cell wall, which characteristically contains
peptidoglycan in all forms of bacteria except
Mycoplasma. Peptidoglycan is unique to prokaryotic
cells and has no counterpart in eukaryotes. Within the
cell wall is the plasma membrane, which, like that of
eukaryotic cells, consists of a phospholipid bilayer and
proteins. It functions as a selectively permeable
membrane with specific transport mechanisms for
various nutrients. However, in bacteria the plasma
membrane does not contain any sterols, and this may
alter the penetration of some chemicals.
7. • The function of the cell wall is to support the
underlying plasma membrane, which is
subject to an internal osmotic pressure of
about 5 atmospheres in Gram-negative
organisms, and about 20 atmospheres in
Gram-positive organisms. The plasma
membrane and cell wall together comprise
the bacterial envelope
8. • Bounded by the plasma membrane is the cytoplasm.
The cytoplasm contains soluble enzymes and other
proteins, the ribosomes involved in protein synthesis,
the small-molecule intermediates involved in
metabolism as well as inorganic ions. The bacterial cell
has no nucleus; instead, the genetic material, in the
form of a single chromosome containing all the genetic
information, lies in the cytoplasm with no surrounding
nuclear membrane. In further contrast to eukaryotic
cells, there are no mitochondria-cellular energy is
generated by enzyme systems located in the plasma
membrane.
9. • Some bacteria have additional components such as a
capsule and/or flagella, but the only additional
structure with relevance for chemotherapy is the outer
membrane outside the cell wall. The nature of this
membrane enables bacteria to be classified according
to whether they take up Gram's stain ('Gram-positive')
or not ('Gram-negative). In Gram-negative bacteria, this
membrane may prevent penetration of antibacterial
agents, and it also prevents easy access of lysozyme (a
microbiocidal enzyme found in white blood cells, tears
and other tissue fluids that breaks down
peptidoglycan).
10.
11. • The cell wall of Gram-positive organisms is a
relatively simple structure, 15-50 nm thick. It
comprises about 50% peptidoglycan, 40-45%
acidic polymer (which results in the cell surface
being highly polar and carrying a negative charge)
and 5-10% proteins and polysaccharides. The
strongly polar polymer layer influences the
penetration of ionised molecules and favours the
penetration into the cell of positively charged
compounds such as streptomycin.
12. The cell wall of Gram-negative organisms is much
more complex. From the plasma membrane
outwards, it consists of the following:
• A periplasmic space containing enzymes and
other components.
• A peptidoglycan layer 2 nm in thickness, forming
5% of the cell wall mass, that is often linked to
outwardly projecting lipoprotein molecules.
13. • An outer membrane consisting of a lipid
bilayer, similar in some respects to the plasma
membrane, that contains protein molecules
and (on its inner aspect) lipoproteins linked to
the peptidoglycan. Other proteins form
transmembrane water-filled channels, termed
porins, through which hydrophilic antibiotics
can move freely.
14. • Complex polysaccharides forming important
components of the outer surface. These differ
between strains of bacteria and are the main
determinants of their antigenicity. They are
the source of endotoxin, which, in vivo,
triggers various aspects of the inflammatory
reaction by activating complement, causing
fever, etc
15. Acid fast bacteria
• Mycobacterium have unusual cell wall
resulting in the inability of the bacteria to be
gram stained. These are called acid fast
because they resist decolourization with acid
alcohol after being stained with carbofuschin.
This property is related to presence of mycolic
acid (high concentration of lipids) in the cell
wall.
16.
17. • Difficulty in penetrating this complex outer
layer is probably the reason why some
antibiotics are less active against Gram-
negative than Gram-positive bacteria. This is
one reason for the extraordinary antibiotic
resistance exhibited by Pseudomonas
aeruginosa, a pathogen that can cause life-
threatening infections in neutropenic patients
and those with burns and wounds.
18. • The cell wall lipopolysaccharide is also a major
barrier to penetration. Antibiotics affected
include benzylpenicillin (penicillin G),
meticillin, the macrolides, rifampicin
(rifampin), fusidic acid, vancomycin,
bacitracin and novobiocin.
19.
20.
21. MIC
• Testing bacterial pathogens in vitro for their
susceptibility to antimicrobial agents is extremely
valuable in confirming susceptibility, ideally to a
narrow-spectrum nontoxic antimicrobial drug.
Tests measure the concentration of drug required
to inhibit growth of the organism (minimal
inhibitory concentration [MIC]) or to kill the
organism (minimal bactericidal concentration
[MBC]). The lowest concentration of the agent
that prevents visible growth after 18-24 hours of
incubation is known as the minimum inhibitory
concentration (MIC).
22. • The results of these tests can then be
correlated with known drug concentrations in
various body compartments. Only MICs are
routinely measured in most infections,
whereas in infections in which bactericidal
therapy is required for eradication of infection
(e.g, meningitis, endocarditis, sepsis in the
granulocytopenic host), MBC measurements
occasionally may be useful.
23. Post antibiotic effect (PAE)
• This effect refers to persistent suppression of
bacterial growth after limited exposure to an
anti-microbial agent. The PAE in fact reflects the
time required to return to logarithmic growth.
Most antimicrobials have significant in-vitro PAE
against susceptible gram positive cocci. A few
antimicrobials (carbapenems, chloramphenicol,
aminoglycosides, quinolones and tetracyclines)
possess PAE against susceptible gram negative
bacilli.
24. • The PAE can be expressed mathematically as follows:
• PAE= T - C
• where T is the time required for the viable count in the
test (in vitro) culture to increase tenfold above the
count observed immediately before drug removal and
C is the time required for the count in an untreated
culture to increase tenfold above the count observed
immediately after completion of the same procedure
used on the test culture. The PAE reflects the time
required for bacteria to return to logarithmic growth.
25. • The in-vivo PAE is usually longer than in-vitro. This is
thought to be due to post antibiotic leucocyte
enhancement (PALE). The PALE reflects increased
susceptibility of bacteria to phagocytic and bactericidal
actions of neutrophils. The subinhibitory drug
concentrations result in changed bacterial morphology and
decreased rate of growth.
• Aminoglycosides and quinolones possess concentration-
dependent PAEs; thus, high doses of aminoglycosides given
once daily result in enhanced bactericidal activity and
extended PAEs. This combination of pharmacodynamic
effects allows aminoglycoside serum concentrations that
are below the MICs of target organisms to remain effective
for extended periods of time.
26. • Bactericidal drugs can be divided into two groups
1. Concentration dependent killing
The drugs with concentration dependent killing,
the rate and extent of killing increases with increasing
concentration of drug above minimum bactericidal
concentration (MBC). Maximizing peak concentration of
such drugs result in increased efficacy and decreased
emergence of resistant bacteria. Concentration
dependant killing is one of the pharmacodynamic factors
responsible for efficacy of once daily dosing of
aminoglycosides. The aminoglycoside possess significant
post-antibiotic effect.
27. 2. Time dependent killing
Drugs with bactericidal action that is dependant on
time donot exhibit increased killing with increasing
concentrations above MBC. The bactericidal activity
of the drug continues as long as the serum drug
concentrations are greater than MBC. So the
bactericidal activity is directly related to the time
above MBC and becomes independent of
concentration once MBC is achieved. For example,
beta-lactam antibiotics and vancomycin
28. Growth Cycle
• Bacteria reproduce by binary fission. In binary fission
the parent cell divides to form two progeny or
daughter cells. As one cell gives rise to two daughter
cells, the bacteria are said to undergo logarithmic
(exponential) growth. The doubling time of bacteria
ranges from as less as 20 minutes (E. coli) to more than
24 hours (Mycobacterium tuberculosis). E. coli after 7
hrs produce one million bacteria. The doubling time
varies not only with species but also with amount of
nutrient, pH, temperature and so many other factors.
The growth cycle of bacteria has four phases.
29. • The standard growth curve has 4 phases
1. Lag Phase: In this phase vigorous metabolic activity
occurs but no division takes place
2. Logarithmic Phase: In this phase rapid cell division
takes place.
3. Stationary Phase: In this phase depletion of nutrients
or production of toxic metabolites cause growth to
slow until the number of new cells produced balances
the number of cells that die.
4. Death Phase: There is marked death of bacteria and
the number of viable cells decline till it reaches zero.
30. Methods for testing Microbial
susceptibility
• Automated systems also use a broth-dilution
method. The optical density of a broth culture
of the clinical isolate incubated in the
presence of drug is determined. If the density
of the culture exceeds a threshold optical
density, then growth has occurred at that
concentration of drug. The MIC is the
concentration at which the optical density
remains below the threshold.
31. • The disk-diffusion technique provides only
qualitative or semi-quantitative information on
antimicrobial susceptibility. The test is performed
by applying commercially available filter-paper
disks impregnated with a specific amount of the
drug onto an agar surface, over which a culture of
the microorganism has been streaked. After 18-
24 hours of incubation, the size of the clear zone
of inhibition around the disk is measured. The
diameter of the zone depends on the activity of
the drug against the test strain.
32. • Standardized values for zone sizes for each
bacterial species and antibiotic permit
classification of the clinical isolate as either
resistant or susceptible. A variant of the disk
diffusion tests is the Epsilometer test, or E-
test. A rectangular test strip impregnated with
changing concentrations of antimicrobial
agent, usually across 15 dilutions, is placed on
an agar plate that has a heavy inoculum of
test organism.
33. • The drug concentrations are printed along this long
test strip. The cultures are then incubated under
favorable conditions for 24 hours, 48 hours, or 5 days,
depending on the test organism. There is no growth
with higher concentrations and heavy microbial growth
where there is lower drug concentration, so that a
clear elliptical zone is formed that bisects the test strip
at the MIC. This test has the virtue of determining an
actual MIC value, rather than the dichotomous
categorization of "susceptible" or "resistant." There are
test strips for hundreds of antibacterial agents as well
as for some antifungal agents active against Candida
species.
34. Types of Antimicrobial Therapy
• A useful way to organize the types and goals
of antimicrobial therapy is to consider where
along the disease progression timetable
therapy is initiated; therapy can be
prophylactic, pre-emptive, empirical,
definitive, or suppressive.
35. • Prophylactic Therapy
• Prophylaxis involves treating patients who are not yet
infected or have not yet developed disease. The goal of
prophylaxis is to prevent infection in some patients or
to prevent development of a potentially dangerous
disease in those who already have evidence of
infection. Ideally, a single, effective, nontoxic drug is
successful in preventing infection by a specific
microorganism or eradicating an early infection. The
main principle behind prophylaxis is targeted therapy.
However, prophylaxis to prevent colonization or
infection by any or all microorganisms present in the
environment of a patient often fails.
36. Chemoprophylaxis
• Chemoprophylaxis is also used to prevent wound infections
after various surgical procedures. Wound infection results
when a critical number of bacteria are present in the
wound at the time of closure. Antimicrobial agents directed
against the invading microorganisms may reduce the
number of viable bacteria below the critical level and thus
prevent infection. Several factors are important for the
effective and judicious use of antibiotics for surgical
prophylaxis. First, antimicrobial activity must be present at
the wound site at the time of its closure. Thus, infusion of
the first antimicrobial dose should begin within 60 minutes
before surgical incision and should be discontinued within
24 hours of the end of surgery
37. • The antibiotic must be active against the most
likely contaminating microorganisms for that type
of surgery. A number of studies indicate that
chemoprophylaxis can be justified in dirty or
contaminated surgical procedures (e.g., resection
of the colon), where the incidence of wound
infections is high. These include <10% of all
surgical procedures. In clean surgical procedures,
which account for ~75% of the total, the expected
incidence of wound infection is <5%, and
antibiotics should not be used routinely.
38. • The National Research Council (NRC) Wound
Classification Criteria have served as the basis
for recommending antimicrobial prophylaxis.
NRC criteria consist of four classes
• Clean: Elective, primarily closed procedure;
respiratory, gastrointestinal, biliary,
genitourinary, or oropharyngeal tract not
entered; no acute inflammation and no break
in technique; expected infection rate ≤ 2%.
39. • Clean contaminated: Urgent or emergency case
that is otherwise clean; elective, controlled
opening of respiratory, gastrointestinal, biliary, or
oropharyngeal tract; minimal spillage or minor
break in technique; expected infection rate ≤
10%.
• Contaminated: Acute nonpurulent inflammation;
major technique break or major spill from hollow
organ; penetrating trauma less than 4 hours old;
chronic open wounds to be grafted or covered;
expected infection rate about 20%.
40. • Dirty: Purulence or abscess; preoperative
perforation of respiratory, gastrointestinal,
biliary, or oropharyngeal tract; penetrating
trauma more than 4 hours old; expected
infection rate about 40%.
Surgical procedures that necessitate the use of
antimicrobial prophylaxis include contaminated
and clean-contaminated operations
41. Some successful examples of chemoprophylaxis are
• When the surgery involves insertion of a prosthetic implant
(e.g., prosthetic valve, vascular graft, prosthetic joint),
cardiac surgery, or neurosurgical procedures, the
complications of infection are so drastic that most
authorities currently agree to chemoprophylaxis for these
indications.
• Penicillin G is used to prevent the infection caused by
streptococci and sexually transmitted diseases (syphilis and
gonorrhoea)
• Prophylaxis is also reasonable for procedures that will
involve infected skin and soft tissues as well as infected
respiratory tract
42. Patients at the highest risk for infective endocarditis for
which prophylaxis is recommended fall into four groups
• those with a prosthetic material used for heart valve
repair or replacement
• previous infective endocarditis
• congenital heart disease such as unrepaired cyanotic
heart disease, or within 6 months of repair of the heart
disease with prosthetic material, or those with residual
defects adjacent to prosthetic material
• postcardiac transplant patients with heart valve defects
43. • Chemoprophylaxis is reasonable in patients undergoing
dental procedures if there is manipulation of gingival
tissue or periapical region of teeth, or perforation of
oral mucosa, but not for other dental procedures.
• Recommended therapy is a single dose of oral
amoxicillin 30 minutes to 1 hour before the procedure
or intravenous ampicillin or ceftriaxone in those unable
to take oral medication. A macrolide or clindamycin
may be administered for patients who are allergic to
beta- lactam agents. Therapy may be administered no
more than 2 hours after the procedure for patients
who failed to receive the prophylaxis prior to the
procedure
44. • Prophylaxis may be used to protect healthy persons
from acquisition of or invasion by specific
microorganisms to which they are exposed. This is
termed post-exposure prophylaxis. Successful
examples of this practice include rifampin
administration to prevent meningococcal meningitis in
people who are in close contact with a case, prevention
of gonorrhea or syphilis after contact with an infected
person, and macrolides after contact with confirmed
cases of pertussis. Post-exposure prophylaxis is
recommended in those patients inadvertently exposed
to HIV infection.
45. Pre-Emptive Therapy
• Pre-emptive therapy is used as a substitute for
universal prophylaxis and as early targeted
therapy in high-risk patients who already have a
laboratory or other test indicating that an
asymptomatic patient has become infected. The
principle is that delivery of therapy prior to
development of symptoms (presymptomatic)
aborts impending disease, and the therapy is for
a short and defined duration.
46. • This has been applied in the clinic to therapy
for cytomegalovirus (CMV) after both
hematopoietic stem cell transplants and after
solid organ transplantation. It is unclear
whether this method is superior to keeping all
at-risk patients on ganciclovir. Recent evidence
in liver transplant patients suggest this
approach may be as efficacious as universal
prophylaxis while using far less antiviral
medications
47. Empirical Therapy in the Symptomatic Patient
• Once a patient is symptomatic, should the
patient be treated immediately? The first
consideration in selecting an antimicrobial is
to determine if the drug is indicated. The
reflex action to associate fever with treatable
infections and prescribe antimicrobial therapy
without further evaluation is irrational and
potentially dangerous.
48. • The diagnosis may be masked if therapy is started
and appropriate cultures are not obtained.
Antimicrobial agents are potentially toxic and
may promote selection of resistant
microorganisms. For some diseases, the cost of
waiting a few days is low. These patients can wait
for microbiological evidence of infection without
empirical treatment. In a second group of
patients, the risks of waiting are high, based
either on the patient's immune status or other
known risk factors for poor outcome with therapy
delay.
49. • Initiation of optimal empirical antimicrobial
therapy should rely on the clinical
presentation, which may suggest the specific
microorganism, and knowledge of the
microorganisms most likely to cause specific
infections in a given host. In addition, simple
and rapid laboratory techniques are available
for the examination of infected tissues.
50. • The most valuable and time-tested method for
immediate identification of bacteria is
examination of the infected secretion or body
fluid with Gram stain. In malaria-endemic areas,
or in travelers returning from such an area, a
simple thick and thin blood smear may mean the
difference between a patient's receiving
appropriate therapy and surviving or death while
on wrong therapy for presumed bacterial
infection.
51. • Such tests help to narrow the list of potential
pathogens and permit more rational selection of
initial antibiotic therapy. Similarly, neutropenic
patients with fever have high risks of mortality,
and, when febrile, they are presumed to have
either a bacterial or fungal infection; thus a
broad-spectrum combination of antibacterial and
antifungal agents that cover common infections
encountered in granulocytopenic patients are
given. Performance of cultures is still mandatory
with a view to modify antimicrobial therapy with
culture results.
52. Definitive Therapy with Known Pathogen
• Once a pathogen has been isolated and susceptibilities
results are available, therapy should be streamlined to a
narrow targeted antibiotic. Monotherapy is preferred to
decrease the risk of antimicrobial toxicity and selection of
antimicrobial-resistant pathogens. Proper antimicrobial
doses and dose schedules are crucial to maximizing efficacy
and minimizing toxicity. In addition, the duration of therapy
should be as short as is necessary. The practice of keeping a
patient indefinitely on antimicrobial therapy without a
particular reason is discouraged. In fact, both experimental
and clinical evidence have shown that unnecessarily
prolonged therapies lead to the emergence of resistance.
53. • Combination therapy is an exception, rather than a
rule. Once a pathogen has been isolated, there should
be no reason to use multiple antibiotics. Using two
antimicrobial agents where one is required leads to
increased toxicity and unnecessary damage to the
patient's otherwise protective fungal and bacterial
flora. For example, there was increased nephrotoxicity
of low-dose gentamicin administered only for 4 days as
"synergistic therapy" with vancomycin or an
antistaphylococcal penicillin for S. aureus bacteremia
and endocarditis, without improving efficacy
54. However, there are special circumstances where evidence
is unequivocal in favour of combination therapy. The
principles behind such antimicrobial use include:
• preventing resistance to monotherapy
• accelerating the rapidity of microbial kill
• enhancing therapeutic efficacy by use of synergistic
interactions or enhancing kill by a drug based on a
mutation generated by resistance to another drug
• paradoxically, reducing toxicity (i.e., when full efficacy
of a standard antibacterial agent can only be achieved
at doses that are toxic to the patient, and a second
drug is co-administered to exert additive effects)
55. Post-Treatment Suppressive Therapy
• In some patients, after the initial disease is controlled
by the antimicrobial agent, therapy is continued at a
lower dose. This is because in these patients the
infection is not completely eradicated and the
immunological or anatomical defect that led to the
original infection is still present. This is common in
AIDS patients and post-transplant patients, for
example. The goal is more as secondary prophylaxis.
Nevertheless, risks of toxicity from long durations of
the therapy are still real. In this group of patients, the
suppressive therapy is eventually discontinued if the
patient's immune system improves.
56. Types of resistance
CHROMOSOMAL DETERMINANTS: MUTATIONS
• The spontaneous mutation rate in bacterial
populations for any particular gene is very low,
and the probability is that approximately only 1
cell in 10 million will, on division, give rise to a
daughter cell containing a mutation in that gene.
The probability of a mutation causing a change
from drug sensitivity to drug resistance can be
quite high with some species of bacteria and with
some drugs.
57. • Fortunately, the presence of a few mutants is not
generally sufficient to produce resistance: despite
the selective advantage that the resistant
mutants possess, the drastic reduction of the
population by the antibiotic usually enables the
host's natural defences
• Resistance resulting from chromosomal mutation
is important in some instances, notably infections
with methicillin-resistant S. aureus, and in
tuberculosis
58. GENE AMPLIFICATION
• Gene duplication and amplification are
important mechanisms for resistance in some
organisms. According to this idea, treatment
with antibiotics can induce an increased
number of copies for pre-existing resistance
genes such as antibiotic-destroying enzymes
and efflux pumps.
59. Spread of resistance to bacteria
Antibiotic resistance in bacteria spreads in three
ways:
• by transfer of resistance genes between
bacteria (usually on plasmids)
• by transfer of resistance genes between
genetic elements within bacteria, on
transposons.
60. EXTRACHROMOSOMAL
DETERMINANTS: PLASMIDS
• Many species of bacteria contain extrachromosomal
genetic elements called plasmids that exist free in the
cytoplasm. These are also genetic elements that can
replicate independently. Structurally, they are closed
loops of DNA that may comprise a single gene or as
many as 500 or even more. Only a few plasmid copies
may exist in the cell but often multiple copies are
present, and there may also be more than one type of
plasmid in each bacterial cell. Plasmids that carry genes
for resistance to antibiotics (r genes) are referred to as
R plasmids. Much of the drug resistance encountered
in clinical medicine is plasmid determined.
61. • The whole process can occur with frightening
speed. S. aureus, for example, is a past master
of the art of antibiotic resistance.
62. TRANSFER OF RESISTANCE GENES
BETWEEN GENETIC ELEMENTS WITHIN
THE BACTERIUM
Transposons
• Some stretches of DNA are readily transferred
(transposed) from one plasmid to another and also
from plasmid to chromosome or vice versa. This is
because integration of these segments of DNA, which
are called transposons, into the acceptor DNA can
occur independently of the normal mechanism of
homologous genetic recombination. Unlike plasmids,
transposons are not able to replicate independently,
although some may replicate during the process of
integration resulting in a copy in both the donor and
the acceptor DNA molecules.
63. TRANSFER OF RESISTANCE GENES
BETWEEN BACTERIA
• The transfer of resistance genes between
bacteria of the same and indeed of different
species is of fundamental importance in the
spread of antibiotic resistance. The most
important mechanism in this context is
conjugation. Other gene transfer mechanisms,
transduction and transformation, are of little
importance in spreading resistance genes.
64. Conjugation
• Conjugation involves cell-to-cell contact during
which chromosomal or extrachromosomal DNA is
transferred from one bacterium to another, and is
the main mechanism for the spread of resistance.
The ability to conjugate is encoded in conjugative
plasmids; these are plasmids that contain transfer
genes that, in coliform bacteria, code for the
production by the host bacterium of
proteinaceous surface tubules, termed sex pili,
which connect the two cells.
65. • The conjugative plasmid then passes across from one
bacterial cell to another (generally of the same
species). Many Gram-negative and some Gram-positive
bacteria can conjugate. Some promiscuous plasmids
can cross the species barrier, accepting one host as
readily as another. Many R plasmids are conjugative.
Non-conjugative plasmids, if they co-exist in a 'donor'
cell with conjugative plasmids, can hitch-hike from one
bacterium to the other with the conjugative plasmids.
The transfer of resistance by conjugation is significant
in populations of bacteria that are normally found at
high densities, as in the gut.
66. Transduction
• Transduction is a process by which plasmid
DNA is enclosed in a bacterial virus (or phage)
and transferred to another bacterium of the
same species. It is a relatively ineffective
means of transfer of genetic material but is
clinically important in the transmission of
resistance genes between strains of
staphylococci and of streptococci.
67. • Transposons may carry one or more resistance
genes and can 'hitch-hike' on a plasmid to a new
species of bacterium. Even if the plasmid is
unable to replicate in the new host, the
transposon may integrate into the new host's
chromosome or into its indigenous plasmids. This
probably accounts for the widespread
distribution of certain of the resistance genes on
different R plasmids and among unrelated
bacteria.
68. Mechanisms of resistance
• Two major factors are associated with emergence of
antibiotic resistance: evolution and clinical/ environmental
practices.
• A species that is subjected to pressure, chemical or
otherwise, that threatens its extinction often evolves
mechanisms to survive under that stress. Pathogens will
evolve to develop resistance to the chemical warfare to
which they are subjected. This evolution is mostly aided by
poor therapeutic practices by healthcare workers, as well
as indiscriminant use of antibiotics for agricultural and
animal husbandry purposes. Poor clinical practices that fail
to incorporate the pharmacological properties of
antimicrobials amplify the speed of development of drug
resistance.
69. Antimicrobial resistance can develop at any one
or more of steps in the processes by which a
drug reaches and combines with its target. Thus,
resistance development may develop due to:
• reduced entry of antibiotic into pathogen
• enhanced export of antibiotic by efflux pumps
• release of microbial enzymes that destroy the
antibiotic
70. • alteration of microbial proteins that transform
pro-drugs to the effective moieties
• alteration of target proteins
• development of alternative pathways to those
inhibited by the antibiotic
• Mechanisms by which such resistance develops
can include acquisition of genetic elements that
code for the resistant mechanism, mutations that
develop under antibiotic pressure, or constitutive
induction.
71. Resistance Due to Drug Efflux
Microorganisms can overexpress efflux pumps and then
expel antibiotics to which the microbes would otherwise
be susceptible. There are five major systems of efflux
pumps that are relevant to antimicrobial agents:
• the multidrug and toxic compound extruder (MATE)
• the major facilitator superfamily (MFS) transporters
• the small multidrug resistance (SMR) system
• the resistance nodulation division (RND) exporters
• ATP binding cassette (ABC) transporters
72. • Drug resistance to most antimalarial drugs,
specifically chloroquine, quinine, mefloquine,
halofantrine, lumefantrine, and the artemether-
lumefantrine combination is mediated by an ABC
transporter encoded by Plasmodium falciparum
multidrug resistance gene 1 (Pfmdr1).
• Drug efflux sometimes occurs with chromosomal
resistance, as is seen in Streptococcus
pneumoniae.
73. Resistance Due to Destruction of
Antibiotic
• Drug inactivation is a common mechanism of
drug resistance. Bacterial resistance to
aminoglycosides and to –beta lactam
antibiotics usually is due to production of an
aminoglycoside-modifying enzyme or beta
lactamase, respectively.
74. Resistance Due to Reduced Affinity of
Drug to Altered Target Structure
• A change in amino acid composition and
conformation of target protein leads to a
reduced affinity of drug for its target, or of a
prodrug for the enzyme that converts the
prodrug to active drug.
75. • Such alterations may be due to mutation of
the natural target (e.g., fluoroquinolone
resistance), target modification (e.g.,
ribosomal protection type of resistance to
macrolides and tetracyclines), or acquisition of
a resistant form of the native, susceptible
target (e.g., staphylococcal methicillin
resistance caused by production of a low-
affinity penicillin-binding protein)
76. Incorporation of Drug
• An uncommon situation occurs when an
organism not only becomes resistant to an
antimicrobial agent but subsequently starts
requiring it for growth. Enterococcus, which
easily develops vancomycin resistance, can,
after prolonged exposure to the antibiotic,
develop vancomycin-requiring strains.
77. Resistance Due to Enhanced Excision
of Incorporated Drug
• Nucleoside reverse transcriptase inhibitors such
as zidovudine are 2'-deoxyribonucleoside analogs
that are converted to their 5'-triphosphate form
and compete with natural nucleotides. These
drugs are incorporated into the viral DNA chain
and cause chain termination. When resistance
emerges via mutations at a variety of points in
the reverse transcriptase gene, phosphorolytic
excision of the incorporated chain-terminating
nucleoside analog is enhanced
78. Superinfection
• Many Different organisms live commensally in man,
each competing with the other so that a harmless
balance is maintained. When antimicrobial drugs, some
members of the natural flora, as well as the pathogenic
organism, from competition; consequently they may
multiply to cause what is called a superinfection, which
may give rise to a secondary disease and even be fatal.
It has been estimated that about 2% of the patients
develop superinfections. Common organisms include,
Staphlococci, Proteus vulgaris, Pseudomonas and yeast
like organisms.
79. • Unnecessary prolonged treatment with
antimocrobial drugs is one of the major factors
contributing to the development of
superinfections. The frequency of hepatitis C
virus (HCV) superinfection with a divergent viral
strain was determined in a cohort of recently
infected young injection drug users (IDUs) with an
HCV incidence rate of 25%. 2 IDUs were
superinfected with different HCV genotypes, and
3 were superinfected with divergent strains of the
same genotype.
81. • The cell walls of bacteria are essential for their normal
growth and development. Peptidoglycan is a
heteropolymeric component of the cell wall that
provides rigid mechanical stability by virtue of its highly
cross-linked latticework structure. In gram-positive
microorganisms, the cell wall is 50-100 molecules thick,
but it is only 1 or 2 molecules thick in gram-negative
bacteria. The peptidoglycan is composed of glycan
chains, which are linear strands of two alternating
amino sugars (N-acetylglucosamine and N-
acetylmuramic acid) that are cross-linked by peptide
chains.
82. • The biosynthesis of the peptidoglycan involves ~30
bacterial enzymes and may be considered in three
stages. The first stage, precursor formation, takes place
in the cytoplasm.
• During reactions of the second stage, UDP-
acetylmuramyl-pentapeptide and UDP-
acetylglucosamine are linked (with the release of the
uridine nucleotides) to form a long polymer. The third
and final stage involves completion of the cross-link.
This is accomplished by peptidoglycan
glycosyltransferases outside the cell membrane of
gram-positive and within the periplasmic space of
gram-negative bacteria
83. • The terminal glycine residue of the
pentaglycine bridge is linked to the fourth
residue of the pentapeptide (D-alanine),
releasing the fifth residue (also D-alanine). It is
this last step in peptidoglycan synthesis that is
inhibited by the beta-lactam antibiotics
84. Chemistry
• The basic structure of the penicillins consists of a
thiazolidine ring (A) connected to a -lactam ring (B) to
which is attached a side chain (R). The penicillin nucleus
itself is the chief structural requirement for biological
activity; metabolic transformation or chemical alteration of
this portion of the molecule causes loss of all significant
antibacterial activity. The side chain determines many of
the antibacterial and pharmacological characteristics of a
particular type of penicillin. Several natural penicillins can
be produced depending on the chemical composition of
the fermentation medium used to culture Penicillium.
Penicillin G (benzylpenicillin) has the greatest antimicrobial
activity of these and is the only natural penicillin used
clinically.
85. Classification
• Penicillin G and its Congeners
• The close congener of Penicillin G is Penicillin V.
Penicillin G is benzylpenicillin and penicillin V is
phenoxymethylpenicillin. These have greatest activity
against gram-positive organisms, gram-negative cocci,
and non–-lactamase producing anaerobes. However,
they have little activity against gram-negative rods, and
they are susceptible to hydrolysis by lactamases. They
are readily hydrolysed by beta-lactamases and
penicillinases. Penicillin G is acid labile so cannot be
given orally whereas Penicillin V is acid resistant.
86. • Antistaphylococcal Penicillins
• These penicillins for example nafcillin, flucloxicillin,
dicloxicillin are resistant to staphylococcal lactamases. They
are active against staphylococci and streptococci but not
against enterococci, anaerobic bacteria, and gram-negative
cocci and rods. These penicillinase-resistant penicillins
(methicillin, discontinued in U.S.), nafcillin, oxacillin,
cloxacillin (not currently marketed in the United States),
and dicloxacillin have less potent antimicrobial activity
against microorganisms that are sensitive to penicillin G,
but they are the agents of first choice for treatment of
penicillinase-producing S. aureus and S. epidermidis that
are not methicillin resistant.
87. Broad Spectrum Penicillins
• Ampicillin, amoxicillin, and others make up a
group of penicillins whose antimicrobial activity is
extended to include such gram-negative
microorganisms as Haemophilus influenzae, E.
coli, and Proteus mirabilis. Frequently these drugs
are administered with a -lactamase inhibitor such
as clavulanate or sulbactam to prevent hydrolysis
by class A -lactamases.
88. Extended-Spectrum Penicillins (Ampicillin and the
Antipseudomonal Penicillins)
• These drugs retain the antibacterial spectrum of penicillin
and have improved activity against gram-negative
organisms. Like penicillin, however, they are relatively
susceptible to hydrolysis by lactamases. The antimicrobial
activity of carbenicillin (discontinued in the U.S.), its indanyl
ester (carbenicillin indanyl), and ticarcillin (marketed only in
combination with clavulanate in the U.S.) is extended to
include Pseudomonas, Enterobacter, and Proteus spp.
These agents are inferior to ampicillin against gram-positive
cocci and Listeria monocytogenes and are less active than
piperacillin against Pseudomonas.
89. • Other extended spectrum Penicillins include
mezlocillin, azlocillin and piperacillin (both
discontinued in the U.S.). These are not given
orally and are active against Pseudomonas
Klebsiella and Bacteroides species and certain
other gram-negative microorganisms. However,
the emergence of broad-spectrum beta-
lactamases is threatening the utility of these
agents. Piperacillin retains the activity of
ampicillin against gram-positive cocci and L.
monocytogenes.
90. Penicillin Units and Formulations
• The activity of penicillin G was originally
defined in units. Crystalline sodium penicillin
G contains approximately 1600 units per mg (1
unit = 0.6 mcg; 1 million units of penicillin =
0.6 g). Semisynthetic penicillins are prescribed
by weight rather than units. The minimum
inhibitory concentration (MIC) of any
penicillin (or other antimicrobial) is usually
given in mcg/mL.
91. • Most penicillins are dispensed as the sodium or
potassium salt of the free acid. Potassium
penicillin G contains about 1.7 mEq of K+ per
million units of penicillin (2.8 mEq/g). Nafcillin
contains Na+, 2.8 mEq/g. Procaine salts and
benzathine salts of penicillin G provide repository
forms for intramuscular injection. In dry
crystalline form, penicillin salts are stable for
years at 4°C. Solutions lose their activity rapidly
(eg, 24 hours at 20°C) and must be prepared
fresh for administration.
92. Pharmacokinetics
• About one-third of an orally administered
dose of penicillin G is absorbed from the
intestinal tract under favorable conditions.
Gastric juice at pH 2 rapidly destroys the
antibiotic. The decrease in gastric acid
production with aging accounts for better
absorption of penicillin G from the
gastrointestinal (GI) tract of older individuals.
93. • The virtue of penicillin V in comparison with
penicillin G is that it is more stable in an acidic
medium and therefore is better absorbed from
the GI tract. On an equivalent oral-dose basis,
penicillin V (K+ salt) yields plasma concentrations
two to five times greater than those provided by
penicillin G.
• Penicillin G benzathine is absorbed very slowly
from intramuscular depots and produces the
longest duration of detectable antibiotic of all the
available repository penicillins.
94. • Penicillin G is distributed widely throughout
the body, but the concentrations in various
fluids and tissues differ widely. Its apparent
volume of distribution is ~0.35 L/kg.
Approximately 60% of the penicillin G in
plasma is reversibly bound to albumin.
Significant amounts appear in liver, bile,
kidney, semen, joint fluid, lymph, and
intestine.
95. • Penicillin does not readily enter the CSF when
the meninges are normal. However, when the
meninges are acutely inflamed, penicillin
penetrates into the CSF more easily. Although
the concentrations attained vary and are
unpredictable, they are usually in the range of
5% of the value in plasma and are
therapeutically effective against susceptible
microorganisms.
96. • Under normal conditions, penicillin G is eliminated
rapidly from the body mainly by the kidney but in small
part in the bile and by other routes. Approximately 60-
90% of an intramuscular dose of penicillin G in aqueous
solution is eliminated in the urine, largely within the
first hour after injection. The remainder is metabolized
to penicilloic acid. The t1/2 for elimination of penicillin
G is ~30 minutes in normal adults. Approximately 10%
of the drug is eliminated by glomerular filtration and
90% by tubular secretion. Renal clearance
approximates the total renal plasma flow.
97. • Anuria increases the t1/2 of penicillin G from a
normal value of 0.5 hour to ~10 hours. When
renal function is impaired, 7-10% of the
antibiotic may be inactivated each hour by the
liver. Patients with renal shutdown who
require high-dose therapy with penicillin can
be treated adequately with 3 million units of
aqueous penicillin G followed by 1.5 million
units every 8-12 hours.
98. Therapeutic Uses
Pneumococcal Infections
• Penicillin G remains the agent of choice for
the management of infections caused by
sensitive strains of S. pneumoniae. However,
strains of pneumococci resistant to usual
doses of penicillin G are being isolated more
frequently in several countries, including the
U.S.
99. Pneumococcal Pneumonia
• However Pneumococcus is penicillin-sensitive,
pneumococcal pneumonia should be treated
with a third-generation cephalosporin or with
20-24 million units of penicillin G daily by
constant intravenous infusion. If the organism
is sensitive to penicillin, then the dose can be
reduced.
100. • Although oral treatment with 500 mg
penicillin V given every 6 hours for treatment
of pneumonia owing to penicillin-sensitive
isolates has been used with success in this
disease, it cannot be recommended for
routine initial use because of the existence of
resistance. Therapy should be continued for 7-
10 days, including 3-5 days after the patient's
temperature has returned to normal.
101. • Pneumococcal Meningitis
• Until it is established that the infecting pneumococcus is
sensitive to penicillin, pneumococcal meningitis should be
treated with a combination of vancomycin and a third-
generation cephalosporin
• Dexamethasone given at the same time as antibiotics was
associated with an improved outcome. Prior to the
appearance of penicillin resistance, penicillin treatment
reduced the death rate in this disease from nearly 100% to
~25%. The recommended therapy is 20-24 million units of
penicillin G daily by constant intravenous infusion or
divided into boluses given every 2-3 hours. The usual
duration of therapy is 14 days.
102. • Streptococcal Infections
• Streptococcal Pharyngitis (Including Scarlet Fever)
• This is the most common disease produced by S. pyogenes
(group A -hemolytic streptococcus). Penicillin-resistant
isolates have yet to be observed for S. pyogenes. The
preferred oral therapy is with penicillin V, 500 mg every 6
hours for 10 days. Penicillin therapy of streptococcal
pharyngitis reduces the risk of subsequent acute rheumatic
fever; however, current evidence suggests that the
incidence of glomerulonephritis that follows streptococcal
infections is not reduced to a significant degree by
treatment with penicillin.
103. • Streptococcal Toxic Shock and Necrotizing
Fasciitis
• These are life-threatening infections
associated with toxin production and are
treated optimally with penicillin plus
clindamycin (to decrease toxin synthesis)
104. Streptococcal Pneumonia, Arthritis, Meningitis,
and Endocarditis
• Although uncommon, these conditions should
be treated with penicillin G when they are
caused by S. pyogenes; daily doses of 12-20
million units are administered intravenously
for 2-4 weeks. Such treatment of endocarditis
should be continued for a full 4 weeks.
105. • Infections Caused by Other Streptococci
• The viridans group of streptococci are the
most common cause of infectious
endocarditis. These are nongroupable -
hemolytic microorganisms that are
increasingly resistant to penicillin G.
106. • Because enterococci also may be alpha-
hemolytic, and certain other α-hemolytic strains
may be relatively resistant to penicillin, it is
important to determine quantitative microbial
sensitivities to penicillin G in patients with
endocarditis. Patients with penicillin-sensitive
VIRIDANS group streptococcal endocarditis can
be treated successfully with daily doses of 12-20
million units of intravenous penicillin G for 2
weeks in combination with gentamicin 1 mg/kg
every 8 hours. Some physicians prefer a 4-week
course of treatment with penicillin G alone.
107. • Enterococcal endocarditis is one of the few
diseases treated optimally with two antibiotics.
The recommended therapy for penicillin- and
aminoglycoside-sensitive enterococcal
endocarditis is 20 million units of penicillin G or
12 g ampicillin daily administered intravenously in
combination with a low dose of gentamicin.
Therapy usually should be continued for 6 weeks,
but selected patients with a short duration of
illness (<3 months) have been treated
successfully in 4 weeks
108. • Infections with Anaerobes
• Many anaerobic infections are caused by mixtures of
microorganisms. Most are sensitive to penicillin G.
• Pulmonary and periodontal infections (with the
exception of beta-lactamase-producing Prevotella
melaninogenica) usually respond well to penicillin G.
• Mild-to-moderate infections at these sites may be
treated with oral medication (either penicillin G or
penicillin V 400,000 units [250 mg] four times daily).
More severe infections should be treated with 12-20
million units of penicillin G intravenously.
109. • Brain abscesses also frequently contain
several species of anaerobes, and such
diseases are treated with high doses of
penicillin G (20 million units per day) plus
metronidazole or chloramphenicol.
110. • Staphylococcal Infections
• The vast majority of staphylococcal infections are
caused by microorganisms that produce
penicillinase. Hospital-acquired methicillin-
resistant staphylococci are resistant to penicillin
G, all the penicillinase-resistant penicillins, and
the cephalosporins. Isolates occasionally may
appear to be sensitive to various cephalosporins
in vitro, but resistant populations arise during
therapy and lead to failure.
111. • Vancomycin, linezolid, quinupristin-
dalfopristin, and daptomycin are active for
infections caused by these bacteria, although
reduced susceptibility to vancomycin has been
observed. Community-acquired methicillin-
resistant S. aureus (MRSA) in many cases
retains susceptibility to trimethoprim-
sulfamethoxazole, doxycycline, and
clindamycin
112. • Meningococcal Infections
• Penicillin G remains the drug of choice for
meningococcal disease. Patients should be treated with
high doses of penicillin given intravenously, as
described for pneumococcal meningitis. Penicillin-
resistant strains of N. meningitides have been reported
in Britain and Spain but are infrequent at present. The
occurrence of penicillin-resistant strains should be
considered in patients who are slow to respond to
treatment. Penicillin G does not eliminate the
meningococcal carrier state, and its administration thus
is ineffective as a prophylactic measure.
113. • Gonococcal Infections
• Gonococci gradually have become more resistant to
penicillin G, and penicillins are no longer the therapy of
choice, unless it is known that gonococcal strains in a
particular geographic area are susceptible. Uncomplicated
gonococcal urethritis is the most common infection, and a
single intramuscular injection of 250 mg ceftriaxone is the
recommended treatment.
• Gonococcal arthritis, disseminated gonococcal infections
with skin lesions, and gonococcemia should be treated with
ceftriaxone 1 g daily given either intramuscularly or
intravenously for 7-10 days. Ophthalmia neonatorum also
should be treated with ceftriaxone for 7-10 days (25-50
mg/kg per day intramuscularly or intravenously).
114. • Syphilis
• Therapy of syphilis with penicillin G is highly
effective. Primary, secondary, and latent syphilis
of <1-year duration may be treated with penicillin
G procaine (2.4 million units per day
intramuscularly) plus probenecid (1.0 g/day
orally) for 10 days or with 1-3 weekly
intramuscular doses of 2.4 million units of
penicillin G benzathine (three doses in patients
with HIV infection).
115. • Actinomycosis
• Penicillin G is the agent of choice for the
treatment of all forms of actinomycosis. The
dose should be 10-20 million units of penicillin
G intravenously per day for 6 weeks.
116. • Diphtheria
• Penicillin G eliminates the carrier state. The
parenteral administration of 2-3 million units
per day in divided doses for 10-12 days
eliminates the diphtheria bacilli from the
pharynx and other sites in practically 100% of
patients.
117. • Anthrax
• Strains of Bacillus anthracis resistant to penicillin
have been recovered from human infections.
When penicillin G is used, the dose should be 12-
20 million units per day.
• Clostridial Infections
• Penicillin G is the agent of choice for gas
gangrene; the dose is in the range of 12-20
million units per day given parenterally as an
adjunct to the antitoxin. Adequate debridement
of the infected areas is essential.
118. • Fusospirochetal Infections
• Gingivostomatitis, produced by the synergistic
action of Leptotrichia buccalis and spirochetes
that are present in the mouth, is readily
treatable with penicillin.
119. • Rat-Bite Fever
• The two microorganisms responsible for this infection,
Spirillum minor in the Far East and Streptobacillus
moniliformis in America and Europe, are sensitive to
penicillin G, the therapeutic agent of choice. Because
most cases due to Streptobacillus are complicated by
bacteremia and, in many instances, by metastatic
infections, especially of the synovia and endocardium,
the dose should be large; a daily dose of 12-15 million
units given parenterally for 3-4 weeks has been
recommended.
120. • Listeria Infections
• Ampicillin (with gentamicin for
immunosuppressed patients with meningitis) and
penicillin G are the drugs of choice in the
management of infections owing to L.
monocytogenes. The recommended dose of
ampicillin is 1-2 g intravenously every 4 hours.
The recommended dose of penicillin G is 15-20
million units parenterally per day for at least 2
weeks.
121. • Lyme Disease
• Although a tetracycline is the usual drug of
choice for early disease, amoxicillin is
effective; the dose is 500 mg three times daily
for 21 days. Severe disease is treated with a
third-generation cephalosporin or up to 20
million units of intravenous penicillin G daily
for 10-14 days.
122. • Erysipeloid
• The causative agent of this disease,
Erysipelothrix rhusiopathiae, is sensitive to
penicillin. The uncomplicated infection
responds well to a single injection of 1.2
million units of penicillin G benzathine.
123. • Pasteurella Multocida
• Pasteurella multocida is the cause of wound
infections after a cat or dog bite. It is
uniformly susceptible to penicillin G and
ampicillin and resistant to penicillinase-
resistant penicillins and first-generation
cephalosporins
124. Side effects
• Hypersensitivity reactions may occur with any
dosage form of penicillin; allergy to one penicillin
exposes the patient to a greater risk of reaction if
another is given.
• Allergic reactions include anaphylactic shock
(very rare—0.05% of recipients); serum sickness-
type reactions (now rare—urticaria, fever, joint
swelling, angioneurotic edema, intense pruritus,
and rapid shallow breathing occurring 7–12 days
after exposure); and a variety of skin rashes.
125. • Oral lesions, fever, interstitial nephritis (an
autoimmune reaction to a penicillin-protein
complex), eosinophilia, hemolytic anemia and
other hematologic disturbances, and vasculitis
may also occur. Most patients allergic to
penicillins can be treated with alternative drugs.
However, if necessary (eg, treatment of
enterococcal endocarditis or neurosyphilis in a
highly penicillin-allergic patient), desensitization
can be accomplished with gradually increasing
doses of penicillin.
126. • Mechanisms of resistance
• 1. reduction in the permeability of the outer
membrane
• 2. Development of modified penicillin binding
proteins
• 3. lack of activation of autolytic enzymes
• 4. beta lactamases
127. Cephalosporins
• Cephalosporium acremonium, the first source
of the cephalosporins, was isolated in 1948 by
Brotzu from the sea near a sewer outlet off
the Sardinian coast. Crude filtrates from
cultures of this fungus were found to inhibit
the in vitro growth of S. aureus and to cure
staphylococcal infections and typhoid fever in
humans.
128. • Chemistry
• Cephalosporin C contains a side chain derived
from D--aminoadipic acid, which is condensed
with a dihydrothiazine -lactam ring system (7-
aminocephalosporanic acid). Compounds
containing 7-aminocephalosporanic acid are
relatively stable in dilute acid and highly resistant
to penicillinase regardless of the nature of their
side chains and their affinity for the enzyme.
129. • Modifications at position 7 of the beta-lactam
ring are associated with alteration in
antibacterial activity and that substitutions at
position 3 of the dihydrothiazine ring are
associated with changes in the metabolism
and pharmacokinetic properties of the drugs.
130. Classification
• Classification by generations is based on general
features of antimicrobial activity
First generation Cphalosporins
First-generation cephalosporins include
1. Cefazolin
2. Cefadroxil
3. Cephalexin
4. Cephalothin
5. Cephapirin
6. Cephradine.
131. • These drugs are very active against gram-
positive cocci, such as pneumococci,
streptococci, and staphylococci with the
exception of enterococci, methicillin-resistant
S. aureus, and S. epidermidis. Most oral cavity
anaerobes are sensitive, but the B. fragilis
group is resistant.
132. • Pharmacokinetics
• Cephalexin, cephradine, and cefadroxil are
absorbed from the gut to a variable extent.
• Cephalexin and cephradine are given orally in
dosages of 0.25–0.5 g four times daily (15–30
mg/kg/d) and cefadroxil in dosages of 0.5–1 g
twice daily. Excretion is mainly by glomerular
filtration and tubular secretion into the urine.
133. • Cefazolin is the first-generation parenteral
cephalosporin. The usual intravenous dosage of
cefazolin for adults is 0.5–2 g intravenously every 8
hours. Cefazolin can also be administered
intramuscularly. Excretion is via the kidney, and dose
adjustments must be made for impaired renal function.
• Cephradine is similar in structure to cephalexin, and its
activity in vitro is almost identical. Cephradine is not
metabolized and, after rapid absorption from the GI
tract, is excreted unchanged in the urine. Cephradine
can be administered orally, intramuscularly, or
intravenously.
134. • Clinical Uses
• Although the first-generation cephalosporins are
broad spectrum and relatively nontoxic, they are
rarely the drug of choice for any infection. Oral
drugs may be used for the treatment of urinary
tract infections, for staphylococcal, or for
streptococcal infections including cellulitis or soft
tissue abscess. However, oral cephalosporins
should not be relied on in serious systemic
infections.
135. • Cefazolin penetrates well into most tissues. It is a
drug of choice for surgical prophylaxis. Cefazolin
may be a choice in infections for which it is the
least toxic drug (eg, penicillinase-producing E coli
or K pneumoniae) and in persons with
staphylococcal or streptococcal infections who
have a history of penicillin allergy other than
immediate hypersensitivity. Cefazolin does not
penetrate the central nervous system and cannot
be used to treat meningitis.
136. Second Generation Cephalosporins
• The second-generation cephalosporins include
1. Cefaclor
2. Cefamandole
3. Cefonicid
4. Cefuroxime
5. Cefprozil
6. Loracarbef
7. Ceforanide
8. The structurally related cephamycins cefoxitin,
cefmetazole, and cefotetan, which have activity against
anaerobes.
137. • They are active against organisms inhibited by
first-generation drugs, but in addition they have
extended gram-negative coverage. Klebsiellae
(including those resistant to cephalothin) are
usually sensitive. Cefamandole, cefuroxime,
cefonicid, ceforanide, and cefaclor are active
against H influenzae but not against serratia or B
fragilis. In contrast, cefoxitin, cefmetazole, and
cefotetan are active against B fragilis and some
serratia strains but are less active against H
influenzae. As with first-generation agents, none
is active against enterococci or P aeruginosa.
138. Pharmacokinetics
• Cefaclor, cefuroxime axetil, cefprozil, and
loracarbef can be given orally. Except for
cefuroxime, these drugs are not predictably
active against penicillin-resistant pneumococci
and should be used cautiously, if at all, to treat
suspected or proved pneumococcal infections.
Cefaclor is more susceptible to beta-lactamase
hydrolysis compared with the other agents, and
its usefulness is correspondingly diminished.
139. • Ceforandine, Cefotetan and cefoxitin are
administered intravenously. After a 1-g
intravenous infusion, serum levels are 75–125
mcg/mL for most second-generation
cephalosporins. Intramuscular administration
is painful and should be avoided. Cefuroxime
can be administered orally as well as I/V
depending upon the clinical situation of the
patient.
140. • Clinical Uses
• The oral second-generation cephalosporins
are active against -lactamase-producing H
influenzae or Moraxella catarrhalis and have
been primarily used to treat sinusitis, otitis,
and lower respiratory tract infections.
141. • Because of their activity against anaerobes
(including B fragilis), cefoxitin, cefotetan, or
cefmetazole can be used to treat mixed
anaerobic infections such as peritonitis or
diverticulitis. Cefuroxime is used to treat
community-acquired pneumonia because it is
active against -lactamase-producing H
influenzae or K pneumoniae and penicillin-
resistant pneumococci.
143. • Compared with second-generation agents, these
drugs have expanded gram-negative coverage,
and some are able to cross the blood-brain
barrier. Third-generation drugs are active against
citrobacter, S marcescens, and providencia
(although resistance can emerge during
treatment of infections caused by these species
due to selection of mutants that constitutively
produce cephalosporinase). They are also
effective against -lactamase-producing strains of
haemophilus and neisseria.
144. • Cefotaxime has been used effectively for
meningitis caused by H. influenzae, penicillin-
sensitive S. pneumoniae, and N. meningitides.
Cefotaxime has a t1/2 in plasma of ~1 hour and
should be administered every 4–8 hours for
serious infections. The drug is metabolized in
vivo to desacetylcefotaxime, which is less
active against most microorganisms than is
the parent compound.
145. • Ceftizoxime has a spectrum of activity in vitro
that is very similar to that of cefotaxime,
except that it is less active against S.
pneumoniae and more active against B.
fragilis. The t1/2 is somewhat longer, 1.8 hours,
and the drug thus can be administered every
8-12 hours for serious infections. Ceftizoxime
is not metabolized, and 90% is recovered in
urine.
146. • Ceftriaxone has activity in vitro very similar to
that of ceftizoxime and cefotaxime. A t1/2 of ~8
hours is the outstanding feature. Administration
of the drug once or twice daily has been effective
for patients with meningitis, whereas dosage
once a day has been effective for other infections.
About half the drug can be recovered from the
urine; the remainder appears to be eliminated by
biliary secretion. A single dose of ceftriaxone
(125-250 mg) is effective in the treatment of
urethral, cervical, rectal, or pharyngeal gonorrhea
147. • Cefpodoxime proxetil is an orally administered
third-generation agent that is very similar in
activity to the fourth-generation agent
cefepime except that it is not more active
against Enterobacter or Pseudomonas spp. It
has a serum t1/2 of 2.2 hours.
148. • Cefditoren pivoxil is a prodrug that is hydrolyzed
by esterases during absorption to the active drug,
cefditoren. The drug is active against methicillin-
susceptible strains of S. aureus, penicillin-
susceptible strains of S. pneumoniae, S. pyogenes,
H. influenzae, H. parainfluenzae, and Moraxella
catarrhalis. Cefditoren pivoxil is only indicated for
the treatment of mild-to-moderate pharyngitis,
tonsillitis, uncomplicated skin and skin structure
infections, and acute exacerbations of chronic
bronchitis. Cefditoren has a t1/2 of ~1.6 hours and
is eliminated unchanged in the urine.
149. • Cefixime is an oral third-generation
cephalosporin with clinical efficacy against
urinary tract infections caused by E. coli and P.
mirabilis, otitis media caused by H. influenza and
S. pyogenes, pharyngitis due to S. pyogenes, and
uncomplicated gonorrhea. Cefixime has a plasma
t1/2 of 3–4 hours and is both excreted in the urine
and eliminated in the bile. The standard dose for
adults is 400 mg/day for 5-7 days, and for a
longer interval in patients with S. pyogenes.
Doses must be reduced in patients with renal
impairment
150. • Ceftibuten is an orally effective cephalosporin
with a t1/2 of 2.4 hours. It is less active against
gram-positive and gram-negative organisms
than cefixime, with activity limited to S.
pneumonia and S. pyogenes, H. influenzae,
and M. catarrhalis. Ceftibuten is only
indicated for acute bacterial exacerbations of
chronic bronchitis, acute bacterial otitis
media, pharyngitis, and tonsillitis. It lacks
useful activity against S. aureus.
151. • Cefdinir is effective orally, with a t1/2 of about
1.7 hours; it is eliminated primarily unchanged
in the urine. Cefdinir has greater activity than
the second-generation agents for facultative
gram-negative bacteria but lacks anaerobic
activity. It is also inactive against
Pseudomonas and Enterobacter spp.
152. • Ceftazidime is active against the
Enterobacteriaceae, but its major
distinguishing feature is excellent activity
against Pseudomonas and other gram-
negative bacteria. Ceftazidime has poor
activity against B. fragilis. Its t1/2 in plasma is
~1.5 hours, and the drug is not metabolized.
Ceftazidime is more active in vitro against
Pseudomonas than piperacillin is
153. • Clinical uses
• Ceftriaxone and cefotaxime are approved for
treatment of meningitis, including meningitis
caused by pneumococci, meningococci, H
influenzae, and susceptible enteric gram-negative
rods, but not by L monocytogenes. Ceftriaxone
and cefotaxime are the most active
cephalosporins against penicillin-resistant strains
of pneumococci and are recommended for
empirical therapy of serious infections that may
be caused by these strains.
154. • Fourth generation cephalosporins
• Cefepime and cefpirome are fourth-generation
cephalosporins. Cefepime is stable to hydrolysis
by many of the previously identified plasmid-
encoded beta-lactamases.
• It is active against many Enterobacteriaceae that
are resistant to other cephalosporins via
induction of type I beta-lactamases but remains
susceptible to many bacteria expressing
extended-spectrum plasmid-mediated –beta
lactamases
155. • Cefepime has comparable or greater in vitro
activity than cefotaxime Against the fastidious
gram-negative bacteria (H. influenzae, N.
gonorrhoeae, and N. meningitidis).
• Cefepime has higher activity than ceftazidime
and comparable activity to cefotaxime for
streptococci and methicillin-sensitive S.
aureus.
156. • It is not active against methicillin-resistant S.
aureus, penicillin-resistant pneumococci,
enterococci, B. fragilis, L. monocytogenes,
Mycobacterium avium complex, or M.
tuberculosis.
• Cefepime is excreted almost 100% renally, and
doses should be adjusted for renal failure.
Cefepime has excellent penetration into the
CSF in animal models of meningitis
157. • Adverse effects
• Hypersensitivity reactions to the cephalosporins
are the most common side effects, and there is
no evidence that any single cephalosporin is
more or less likely to cause such sensitization.
• Immediate reactions such as anaphylaxis,
bronchospasm, and urticaria are observed. More
commonly, maculopapular rash develops, usually
after several days of therapy; this may or may not
be accompanied by fever and eosinophilia.
158. • Because of the similar structures of the
penicillins and cephalosporins, patients who
are allergic to one class of agents may
manifest cross-reactivity to a member of the
other class. Immunological studies have
demonstrated cross-reactivity in as many as
20% of patients who are allergic to penicillin,
but clinical studies indicate a much lower
frequency (~1%) of such reactions.
159. • The cephalosporins have been implicated as
potentially nephrotoxic agents, although they
are not nearly as toxic to the kidney as the
aminoglycosides or the polymyxins.
160. Mechanism of resistance in
cephalosporins
• Resistance to the cephalosporins may be related to the
inability of the antibiotic to reach its sites of action
• Alterations in the penicillin-binding proteins (PBPs) that
are targets of the cephalosporins
• The antibiotics bind to bacterial enzymes (beta-
lactamases) that can hydrolyze the beta-lactam ring
and inactivate the cephalosporin. The most prevalent
mechanism of resistance to cephalosporins is
destruction of the cephalosporins by hydrolysis of the
beta-lactam ring.
161. • The cephalosporins have variable
susceptibility to beta-lactamase. For example,
of the first-generation agents, cefazolin is
more susceptible to hydrolysis by beta-
lactamase from S. aureus than is cephalothin.
162. • Cefoxitin, cefuroxime, and the third-generation
cephalosporins are more resistant to hydrolysis by the -
lactamases produced by gram-negative bacteria than
first-generation cephalosporins. Third-generation
cephalosporins are susceptible to hydrolysis by
inducible, chromosomally encoded (type I) -
lactamases. Induction of type I beta-lactamases by
treatment of infections owing to aerobic gram-negative
bacilli (especially Enterobacter spp., Citrobacter
freundii, Morganella, Serratia, Providencia, and P.
aeruginosa) with second- or third-generation
cephalosporins and/or imipenem may result in
resistance to all third-generation cephalosporins.
163. • Beta-Lactamases are grouped into four classes: A
through D. Class A β-lactamases include the extended-
spectrum β-lactamases (ESBLs) that degrade penicillins,
some cephalosporins, and, in some instances,
carbapenems. Perhaps most worrisome of the class A
enzymes is the KPC carbapenemase that is rapidly
emerging in the Enterobacteriaceae. This enzyme
confers resistance to carbapenems, penicillins, and all
of the extended-spectrum cephalosporins. Some class
A and D enzymes are inhibited by the commercially
available β-lactamase inhibitors, such as clavulanate
and tazobactam.
164. Carbapenems
• Carbapenems are -lactams that contain a
fused -lactam ring and a five-member ring
system that differs from the penicillins
because it is unsaturated and contains a
carbon atom instead of the sulfur atom. This
class of antibiotics has a broader spectrum of
activity than most other beta-lactam
antibiotics.
165. • Imipenem
• Imipenem is marketed in combination with
cilastatin, a drug that inhibits the degradation
of imipenem by a renal tubular dipeptidase.
• Imipenem is derived from a compound
produced by Streptomyces cattleya.
166. • Imipenem, like other β-lactam antibiotics,
binds to penicillin-binding proteins, disrupts
bacterial cell wall synthesis, and causes death
of susceptible microorganisms. It is very
resistant to hydrolysis by most β-lactamases.
167. • Imipenem–cilastatin is effective for a wide variety
of infections, including urinary tract and lower
respiratory infections; intra-abdominal and
gynecological infections; and skin, soft tissue,
bone, and joint infections. The drug combination
appears to be especially useful for the treatment
of infections caused by cephalosporin-resistant
nosocomial bacteria, such as Citrobacter freundii
and Enterobacter spp. (with the exception of the
increasingly common KPC, Klebsiella pneumoniae
carbapenemase-producing strains).
168. • Meropenem
• It does not require co-administration with
cilastatin because it is not sensitive to renal
dipeptidase. Its toxicity is similar to that of
imipenem except that it may be less likely to
cause seizures (0.5% for meropenem; 1.5% for
imipenem). Its in vitro activity is similar to that of
imipenem, with activity against some imipenem-
resistant P. aeruginosa but less activity against
gram-positive cocci.
169. • Doripenem
• Ertapenem
• Ertapenem differs from imipenem and
meropenem by having a longer t1/2 that allows
once-daily dosing and by having inferior activity
against P. aeruginosa and Acinetobacter spp. Its
spectrum of activity against gram-positive
organisms, Enterobacteriaceae, and anaerobes
makes it attractive for use in intra-abdominal and
pelvic infections
170. Glycopeptide Antibiotics
• Vancomycin
• Vancomycin is an antibiotic produced by Streptococcus
orientalis and Amycolatopsis orientalis.
• Vancomycin inhibits cell wall synthesis by binding
firmly to the D-Ala-D-Ala terminus of nascent
peptidoglycan pentapeptide. This inhibits the
transglycosylase, preventing further elongation of
peptidoglycan and cross-linking. The peptidoglycan is
thus weakened, and the cell becomes susceptible to
lysis. The cell membrane is also damaged, which
contributes to the antibacterial effect.
171. • Resistance to vancomycin in enterococci is due
to modification of the D -Ala-D -Ala binding
site of the peptidoglycan building block in
which the terminal D -Ala is replaced by D -
lactate. This results in the loss of a critical
hydrogen bond that facilitates high-affinity
binding of vancomycin to its target and loss of
activity. This mechanism is also present in
vancomycin-resistant S aureus strains
172. • Vancomycin is poorly absorbed from the intestinal tract
and is administered orally only for the treatment of
antibiotic-associated enterocolitis caused by C difficile.
Parenteral doses must be administered intravenously.
• The main indication for parenteral vancomycin is sepsis
or endocarditis caused by methicillin-resistant
staphylococci. However, vancomycin is not as effective
as an antistaphylococcal penicillin for treatment of
serious infections such as endocarditis caused by
methicillin-susceptible strains. Vancomycin in
combination with gentamicin is an alternative regimen
for treatment of enterococcal endocarditis in a patient
with serious penicillin allergy.
173. • Vancomycin (in combination with cefotaxime,
ceftriaxone, or rifampin) is also recommended
for treatment of meningitis suspected or
known to be caused by a highly penicillin-
resistant strain of pneumococcus
174. • Vancomycin is irritating to tissue, resulting in phlebitis
at the site of injection. Chills and fever may occur.
Ototoxicity is rare and nephrotoxicity uncommon with
current preparations. However, administration with
another ototoxic or nephrotoxic drug, such as an
aminoglycoside, increases the risk of these toxicities.
Ototoxicity can be minimized by maintaining peak
serum concentrations below 60 mcg/mL. Among the
more common reactions is the so-called "red man" or
"red neck" syndrome. This infusion-related flushing is
caused by release of histamine. It can be largely
prevented by prolonging the infusion period to 1–2
hours.
176. Monobactam
• The antimicrobial activity of aztreonam differs
from those of other -lactam antibiotics and
more closely resembles that of an
aminoglycoside. Aztreonam has activity only
against gram-negative bacteria; it has no
activity against gram-positive bacteria and
anaerobic organisms. However, activity against
Enterobacteriaceae is excellent, as is that
against P. aeruginosa.
177. • Aztreonam is administered either
intramuscularly or intravenously.
• Aztreonam generally is well tolerated.
Interestingly, patients who are allergic to
penicillins or cephalosporins appear not to
react to aztreonam
• The usual dose of aztreonam for severe
infections is 2 g every 6-8 hours. This should
be reduced in patients with renal insufficiency.
178. Beta lactamase inhibitors
• Certain molecules can inactivate β-lactamases,
thereby preventing the destruction of -lactam
antibiotics that are substrates for these enzymes.
β-Lactamase inhibitors are most active against
plasmid-encoded -lactamases (including the
enzymes that hydrolyze ceftazidime and
cefotaxime), but they are inactive at clinically
achievable concentrations against the type I
chromosomal β -lactamases induced in gram-
negative bacilli (such as Enterobacter,
Acinetobacter, and Citrobacter) by treatment with
second- and third-generation cephalosporins.
179. • Amoxicillin plus clavulanate is effective in vitro
and in vivo for -lactamase-producing strains of
staphylococci, H. influenzae, gonococci, and E.
coli.
• Sulbactam is another -lactamase inhibitor
similar in structure to clavulanic acid. It may
be given orally or parenterally along with a -
lactam antibiotic. It is available for intravenous
or intramuscular use combined with ampicillin
180. • Tazobactam is a penicillanic acid sulfone -
lactamase inhibitor. In comparison with the
other available inhibitors, it has poor activity
against the inducible chromosomal -
lactamases of Enterobacteriaceae but has
good activity against many of the plasmid -
lactamases, including some of the extended-
spectrum class. It has been combined with
piperacillin as a parenteral preparation
