80 JOURNAL OF COSMETIC SCIENCE
FRONTIERS OF SCIENCE AWARD LECTURE SPONSORED
BV COSMETICS AND TOILETRIES®
ANTIBIOTIC RESISTANCE ..A GATHERING STORM
James J. Leyden, M.D.
University of Pennsylvania School of Medicine
Throughout history, man has been in continual battle with microbes and witil relatively recently could
only depend on the innate and acquired immwie systems as defense systems. Malaria, tuberculosis, polio,
measles, syphilis and bubonic plaque are examples of infections that plagued mankind and resulted in
significant morbidity and mortality. It is relatively recently that the development of vaccines and
antibiotics has made an impact on viral and bacterial infections.
The development of penicillin in the early 1940' s was the start of the antibiotic era. Almost immediately,
bacteria developed mechanisms of resistance. The pharmaceutical industry responded by developing newer
agents and for the most part we have stayed ahead of bacteria and their ability to develop resistance. The
cost and time to developing new antibiotics and maneuvering through the labyrinth of the F.D.A. approval
process is limiting the delivery of new agents. The practice of using antibiotics even when bacterial
infection has not necessarily been demonstrated and pressure exerted on physicians by their patients for
antibiotic treatment has influenced the emergence of resistance. All of have come to view antibiotics as
"cure alls".
Antibiotic Mechanism ofAction
Interference with cell wall synthesis
Interference with protein synthesis
Interference with nucleic acid thesis
Interference of metabolism
P-lactams -penicillin, cephalosporins,
tides -vancom cin
Macrolides, chloramphenicol, linezolid,
amino · · irocin
sulfon
Mechanism of Resistance
Bacteria become resistant through mutation and selection or by acquiring from other bacteria the genetic
information encoding resistance.
1) innate resistance
2) acquisition of genes encoding enzymes that destroy the antibiotic e.g. P-lactamases that destroy
penicillins and cephalosporins
3) Efflux pumps e.g. fluoroquinolones in S. aureus
4) acquisition of genes for a metabolic pathway or mutations that limit access to the intracellular site.
Antibiotic Resistance in Gram-Positive Bacteria
Gram positive bacteria such as Staphylococcus aureus and Enterococcus species particularly E. faecium
are important pathogens in hospital environments.
V ancomycin resistant enterococci (VRE) occurred :first in intensive care units and then throughout
hospitals in the 1990' s and now nearly 30% of all isolates from patients infected in ICU' s are resistant to
vancomycin. This resistance is caused by 2 classes of related gene clusters which alter the cell wall target
by changing D-alanine-D-alanine to D-alanine-D-lactate.
The development of VRE appears to have been influenced by the use of antibiotics which enhanced
colonization and persistence of colonization already established.

2006 ANNUAL SCIENTIFIC MEETING 81
S. aureus is a major pathogen for both cutaneous and systemic infections. The initial euphoria following
development of penicillin was dampened by the evolution of P-lactamase production. These resistant
strains first appeared in hospital settings but over time spread to the community and today virtually all
strains of S. aureus are resistant to natural penicillins, aminopenicillins and antipseudomonal penicillins.
Methicillin came along just in time, 1959 in Emope and 1961 in America. Almost immediately scattered
resistant isolates were reported, followed by periodic outbreaks of :tvm..SA in the 1970' s and by the 1980' s,
MRSA became a significant problem in hospitals. By 200 I, more than half of S. aureus infections in
hospital settings were MRSA. Nosocomial MRSA has been shown to be clonal in nature and infection
control lapses by healthcare workers have helped the spread of these strains. In general, these strains are
multi-drug resistant and contain gene encoding for a low affinity penicillin-binding protein. For many
years vancomycin was the only effective treatment of MRSA. In recent years, 4 new agents have been
introduced just as vancomycin resistance is emerging. These resistant strains are associated with cell wall
thickening limiting access to the cytoplasmic membranes where the functional targets of vancomycin are
located. Horizontal transfer of genes from VRE have been shown to play a role particularly in high level
resistance.
As is the case in other examples of resistance, :tvm..SA has now spread to the community. CA-MRSA was
first described in illegal drug users or those with serious underlying disease or previous hospitalization. It
is now apparent that CA-MRSA occurs in those without risk factors and is becoming more prevalent
particularly in children. Skin and soft tissue infections (particularly furuncles) are the most common
manifestation of CA-MRSA. A high percentage of CA-:tvm..SA carry genes for a leukocidin that causes
destruction ofleucocytes and also causes tissue destruction. CA-MR.SA contains different genetic material
conferring resistance than HA-MR.SA. As a consequence, CA-MR.SA does not show multiple drug
resistance. CA-MRSA strains are more susceptible to other antibiotics than HA-MR.SA and tend to be
susceptible to sulfonamides and tetracycline.
P. acnes Resistance
Propionibacterium acnes is a gram positive anaerobic bacterium which proliferates in sebaceous follicles
of acne patients. Antibiotic therapy has been a major factor in treating the multi-factored pathophysiology
of acne and antibiotics work primarily by suppressing P. acnes viability although there is evidence for non-
antimicrobial, anti-inflammatory effects as well.
P. acnes wild strains are very sensitive to a wide range of antibiotic classes with tetracyclines, macrolides
such as erythromycin, the chemically related clindamycin, the agents most widely used. P. acnes
sensitivity remained wichanged despite widespread use of systemic antibiotics until the early 1980' s.
Following the introduction of topical erythromycin and clindamycin, less sensitive strains of P. acnes were
found and patients carrying these strains had poorer clinical outcomes. In the past 20 years, decreasing
sensitivity particularly to erythromycin and clindamycin has been found worldwide and is associated with
poor clinical response. Specific point mutations in genes encoding 23S (erythromycin and clindamycin)
and 16S rRNA (tetracycline) have been identified worldwide. In addition, resistant strams have been
isolated in which mutations could not be identified suggesting as yet uncharacterized resistance mechanism
have evolved.
Antibiotic Resistance in Gram-Negative Bacteria
Gram-negative bacteria of the Enterobacteriaceae family are important causes of urinary tract infections,
blood stream infections, pneumonia and intra-abdominal infections. Resistance related to production of
extended spectrum P-lactamase (ESBLs) is a major cause of resistance although other mechanisms are
emerging leading to multidrug resistance. The genes that encode ESBLs are frequently found on the same
plasmids as genes that encode resistance to aminoglycosides, sulfonamides and quinolones.
To date, the vast majority of Enterbacteriaceae remain susceptible to carbapenems although resistance to
these agents is beginning to occm due to carbapenemases.