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CONSULTANTS' PAPERS
THE APPENDIXES
The following papers, Appendixes A through K, were commis-
sioned by the Committee to Study the Human Health Effects of
Subtherapeutic Antibiotic Use in Animal Feeds. They were used by
the committee as working papers and are attached to the committee's
report for information only. They do not constitute part of the
foregoing report prepared by the committee. All references to
these papers should be attributed to the authors, not to the cam-
mittee.
A transcription of the public meeting held August 23, 1979
also formed part of the working papers used by the committee.
These records may be obtained on loan from Dr. Enriqueta C. Bond,
National Academy of Sciences, 2101 Constitution Ave., N.W., Room
347, Washington, D.C. 20418.
65
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APPENDIX A
THE CLINICAL USE OF ANT IMICROBIALS AND THE DEVELOP1dE:NT
OF RESISTANCE
John P. Utz
Infectious diseases are the most common cause of absence
from school or work, are the most frequent of the known causes
of birth defects, and, as pneumonia and influenza, are the fourth
most c ammo n cause of death in the United States.
CONTROL OF DISEASE
.
Immunization with vaccines is the major technique used in
the United States to prevent infectious diseases. The oral
polio vaccine, as the ultimate example, is clearly responsible
for the world-wide control of poliomyelitis, despite an outbreak
of the disease, which spread from the Netherlands to Canada and
the United States in 1979 (Center for Disease Control, 1979a).
Similarly, the tetanus vaccine is solely responsible for the
elimination of tetanus, as observed in the Armed Forces during
World War II and the conflicts in Korea and Vietnam. Other live
virus vaccines are used primarily in children to prevent rubella,
rubeola, and mumps. Vaccination with killed bacteria (pertussis)
or their toxic products (diphtheria toxoid) is also an effective
preventive measure.
Antimicrobials are used to prevent approximately a dozen
categories of infection. Some of these uses are described below.
Between 1960 and 1976 there were 131 published studies of
the prophylactic use of antimicrobials to reduce the possibility
of infection after surgical procedures. Although only 24 of
these studies describe controlled, prospective, double-blind
studies, they report striking statistically significant reductions
in various types of wound infections when antimicrobials were
administered in conjunction with repair after hip fracture, hip
prosthesis, vaginal hysterectomy, and colon, biliary, and gastro-
intestinal surgery (Chodak and Plaut, 1977~. These procedures are
regarded as clean in contrast to compound fractures and gunshot or
stab wounds of the abdomen, which are considered already infected.
Thus, antimicrobial use in these instances is therapeutic, rather
than prophylactic.
School of Medicine, Georgetown University, Washington, D.C.
67
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68
A second category of antimicrobial prophylaxis was first
demonstrated in San Francisco where isoniazid was used to pre-
vent overt tuberculosis in populations with delayed cutaneous
hypersensitivity to tuberculin (American Thoracic Society, 1974;
Ferebee, 1970~. The continuing protection demonstrated in the
treated group led to the wide use of this drug in patients with
a known positive test. The enthusiasm engendered by these suc-
cesses continued until the recognition in the Washington, D.C.
area of the hepatotoxicity of isoniazid (Garibaldi et al., 1972~.
Antimicrobials administered prophylactically to immunode-
ficient patients lacking the benefit of a protected environment
have produced variable results. Immunodeficiency may result
from a disease state or from the use of drugs. Immunosuppres-
sion may be desired, e.g., when drugs are administered to trans-
plant recipients to prevent host-versus graft rejection, or may
be an undesired consequence of cancer chemotherapy. Protection
afforded by antimicrobial prophylaxis is enhanced by a protected
environment.
Studies conducted over many years, beginning early in the
antimicrobial era, have shown that oral sulfonamides and peni-
cillin G or intramuscular benzathine penicillin G protect against
recurrence of rheumatic fever by preventing infection by Group A
Streptococcus pyogenes. Failure of such prophylaxis is not
usually related to the development of resistance, but instead to
a lack of compliance on the part of patient or parents. Hence,
benzathine penicillin G injected by a medical professional is the
most successful drug and route, since patient cooperation--except
for travel to a doctor's office or clinic--is not required.
An even earlier practice was the prevention of ophthalmia
neonatorum by the routine use of silver nitrate and, later, peni-
cillin G. in all newborn infants.
Scrub typhus (tsutsugamushi disease) occurs rarely in this
country, and then only in people who have once spent time near or
in northern Australia, Pakistan, or Japan. This disease can be
prevented by 1 g of chloramphenicol every other day for a month
after exposure, but because the disease is infrequent, this pro-
phylactic application of chloramphenicol is little known.
At various times and during different epidemics, sulfonamides,
rifampin, or minocycline given to family members or other groups
have prevented the spread of meningococcal infections from patients
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69
or carriers of Neisseria meningitidis.
-
frequently a commensal of humans, it has virtually always re-
sulted in later recolonization and the carrier state following
prophylaxis.
Since this species is
Chemoprophylaxis is probably effective in the prevention
of syphilis and shigellosis, but is rarely used for this purpose.
More commonly it is practiced in the hope of preventing bacterial
endocarditis, but there are no data demonstrating the efficacy of
this use.
Controlled trials indicate that either a tetracycline or ampi-
cillin is effective in preventing febrile disease and loss of time
from work for patients with chronic obstructive pulmonary disease
(Batten, 1976~. However, the magnitude of that population and the
cost-benefit ratio are so great that this method of preventing
recurrent infection has not been widespread.
The elimination of smallpox (variola) by the use of vaccina-
tion (cowpox or vaccinia) has overshadowed the demonstration of
methisazone as a chemoprophylactic agent. Field trials in Madras,
India showed that the use of methisezone in 1,101 exposed persons
resulted in only three cases of mild smallpox, in contrast to 78
cases (with 12 deaths) among 1,126 controls who did not receive
the drug (Bauer et al., 1963~.
Enthusiasm for amantadine in the prevention of influenzas has
been tempered by the limited spectrum of its antiviral activity--
type A2 (Asian) influenza only--and by the limited period of effec-
tiveness (immediately before or after the exposure, the time of
which is always uncertain).
Since World War II chemoprophylaxis has been an accepted prac-
tice in malarial areas. The development of chloroquine-resistant
strains in Southeast Asia and Africa has lessened the effectiveness
of that antimalarial drug and has led to the requirement for other
drugs (Anonymous, 1978a).
Specific Agents
With the exception of the arsenicals and bismuth, the anti-
microbial era began in the mid-1930's with the use of the sulfo-
namides. Even today members of this family are the first choice
in the treatment of uncomplicated urinary tract infections,
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70
nocardiosis, some Chlamydia trachomatis infections, and chan-
croid. Resistance of N. meningitidis to the sulfonamides has
been encountered principally in prophylaxis of family members
or in active treatment of meningitis. The more recent combina-
tion of a sulfonamide, sulfamethoxazole, with trimethoprim has
resulted in an oral preparation that is useful in the treatment
of an even wider range of infections, e.g., pneumonia caused by
Pneumocystis carinii.
The antibiotic era began in the mid-1940's with the redis-
covery of the activity of penicillin G and its use in severe
human disease. This drug remains the first choice in the treat-
ment of infection by Group A S. pyogenes (e.g., rheumatic fever),
S. pneumonias (pneumonia), N. meningitidis (meningococcal dis-
eases), Pasteurella multocida (e.g., skin ulcer, osteomyelitis,
pleuritis, sinusitis, leptomeningitis), Treponema pallidum
(syphilis), Actinomyces Israelis (actinomycosis), Leptospira
spp. (leptospirosis), Bacillus anthracis (anthrax), and Strep-
tobacillus moniliformis (streptobacillary rat-bite fever).
However, by 1947 Weinstein had reported superinfection by
Haemophilus influenzas, which produced septicemia in a patient
treated with penicillin G for pneumonia. This first report is
the prototype of the truism that the use of any antimicrobial
agent ultimately results in the appearance of, or colonization
by, microorganisms that are resistant to or not susceptible to
that agent. However, this is not always detrimental if the
pathogenicity of the new microorganism is less or nonexistent.
Indeed, were this not usually the case, antimicrobial therapy
could rarely, if ever, be justified.
Streptomycin, first used in 1945, remains as a single drug
treatment for one infection by Francisella tularensis (tularemia).
In combination with penicillin G it is optimal therapy for Entero-
coccus (Group D streptococcal infections), with a tetracycline for
Malleomyces mallet ("landers) and Yersinia pestis (plague), with
ampicillin for more resistant Listeria monocytogenes (listeriosis),
and with other antituberculous drugs for tuberculosis.
The tetracyclines and chloramphenicol became available almost
simultaneously in 1948. The former are active against many of the
Gram-negative Enterobacteriaceae that are resistant to streptomycin
and are optimal therapy for Calymmatobacterium granulomatis (granu-
loma inguinale), Brucella spp. (brucellosis), Vibrio cholera e
(cholera), and Borrelia recurrentis (relapsing fever). Tetracy-
clines are also the first choice in the treatment of another group
of infections caused by Rickettsia. Infections caused by Chlamydia,
both _. psittaci and C. trachomatis, are similarly treated._
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71
Despite the rare, but commonly fatal, idiosyncratic pancyto-
penic reactions, chloramphenicol is indicated for H. influenzee
(meningitis) and Salmonella typhi (typhoid). Decisions on whether
to use antimicrobials for salmonellosis, often acquired from meats
and eggs, should be based upon the studies of Woodward and Smadel
(1964~. These authors defined the precise benefits of such therapy
as well as the unaffected factors, e.g., metastases, carrier state,
and bowel perforations, and its ill effects, e.g., enhanced relapse
rate.
Tricarcillin, usually in combination with an aminoglycoside,
is used to treat Pseudomonas aeruginosa infections. Among the
aminoglycoside antibiotics, tobramycin appears to have both greater
efficacy and less toxicity than gentamicin, kanamycin, or amikacin.
The development of the penicillinase-resistant penicillins
methicillin, oxacillin, cloxacillin, dicloxacillin, and nafcillin
has resulted in the preferential use of the last two for any
Staphyloccus aureus infection when the sensitivity to penicillin G
is unknown.
In addition to streptomycin, the most active and best toler-
ated among the antituberculous drugs are rifampin, ethambutol, and
isoniazid. The latter three drugs are generally preferred because
they can be administered orally, which is more convenient than the
intramuscular route for both long-term use and therapy administered
in the home or to ambulatory patients. A study by Phillipon et al.
(1977) indicates that rifampin may be preferable to tetracycline in
the treatment of brucellos~s, especially in its ability to reduce
residual infections. But further confirmatory studies are needed
before its widespread use can be recommended.
Erythromycin is indicated for the Corynebacterium diphtheriae
carrier state (but is not adequate for active diphtheria, which re-
quires antitoxin) and for Mycoplasma spp. and Legionella pneumophila
infections because the drug lacks serious side-effects.
For the anaerobic infections, which commonly cause intracere-
bral, pulmonary, peritoneal, or pelvic infections (usually with
abscesses), one has a choice of four drugs: chloramphenicol, clin-
damycin, metronidazole, or cefoxitin, depending upon which side-
effect is less disturbing to the physician, e.g., enterocolitis
from clindamycin or the idiosyncratic pancytopenic reactions from
chloramphenicol.
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72
Although the activity of amoxicillin or ampicillin is similar
to that of penicillin G. the drugs are especially effective in the
treatment of infection from Proteus mirabilis, Salmonella (except
typhi), Shigella spp., and Listeria monocytogenes.
When none of the preceding microorganisms is the pathogen, or
occasionally, when one after another has been progressively selected,
fungal infection or superinfection may occur. Agents for these are
amphotericin B. flucytosine, or miconazole, depending on the species
or occasionally on the sensitivity of the isolated strain.
Other useful agents include vancomycin, which is enjoying a
resurgence of interest because it is so helpful in patients on
dialysis, with Clostridium difficile in necrotizing, pseudomem-
branous enterocolitis and in Gram-positive coccal infections that
are resistant to penicillin. A special mention must be made of
the cephalosporins because there are so many of them, because they
are remarkably active against many Gram-negative and Gram-positive
bacteria, and because minute chemical changes have resulted in such
great activity against previously unsusceptible organisms, e.g.,
Enterococcus and Pseudomonas aeruginosa.
BACTERIAL RESISTANCE TO ANTIMICROBIALS
Failure of antimicrobial therapy can be attributed to a number
of causes: untreatable infections (e.g., pneumonia due to measles
virus), improper dosage (e.g., overdosage increasing risk of super-
infection or too low a dose resulting in failure to achieve bacter-
icidal concentrations, as might occur in bacterial meningitis where
the level in cerebrospinal fluid may be much lower than that in the
blood), improper duration (e.g., failure to treat a Group A strepto-
coccal infection for 10 days), omission of surgical drainage of an
intraabdominal or pelvic abscess, or the emergence of microorganisms
that are resistant to the antimicrobial.
The development of S. aureus that is resistant to penicillin G
by means of a penicillinase is of historical importance. From 1955
to 1960 severe disease was caused by such bacteria. These outbreaks
were ended by the development of penicillinase-resistant penicillins.
The second instance of resistance to antimicrobial agents that
was of major importance was the development of Streptococcus pneumon-
iae, which became resistant to tetracyclines, drugs that were useful
at that time for treating pneumonias of uncertain origin, i.e., those
now known to to be caused by Mycoplasma pneumonias, Cox~ella burnetii,
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73
and Legionella pneumophila. In their studies of Australian
aborigines and New Guineans, Hansman et al. (1971) found the
first isolates of Streptococcus pneumonias with resistance to
penicillin. Although strains with intermediate resistance were
first reported in New Guinea and Australia and highly resistant
ones first in South Africa, resistant organisms were soon there-
after identified in Europe and the United States. Curiously,
the highly resistant strains have not been further reported in
states other than Minnesota (Center for Disease Control, 1979b).
Fortunately, alternative chemotherapy exists for those
bacteria with resistance to both tetracyclines and penicillin.
Examples of alternatives to the first-choice drugs usually used
for various diseases will be found in the literature (Anonymous,
1978b). The disadvantages in having to use alternatives vary
from case to case and are related to the organisms to be com-
batted, the alternative doughs), and the patient to be treated.
An additional aspect of importance is the 10% to 15% frequency of
patients with alleged sensitivity to penicillin and to whom the
drug cannot be given. An examination of alternative drugs to
combat penicillin- and tetracycline-resistant pneumococci reveals
problems in therapy caused by antibiotic resistance quite well.
In order of decreasing desirability, alternatives include the
cephalosporins, which can be administered orally or parenterally,
but are less active; chloramphenicol, which has the danger of
fatal aplastic anemia in approximately 1 in 30,000 individuals;
vanc~mycin, which is the most active but can only be administered
intravenously and is ototoxic; and erythromycin, which, while
being the least toxic, is also the least active.
Resistance to the tetracyclines and penicillins has not
been a recognized problem in those patients more prone to infec-
tion or more severe disease, e.g., those who have congenital or
acquired impairment of antibody- (hypogammaglobulinemia) or
cellular- (Hodgkin's disease, sarcoidosis) mediated immunity, or
both (chronic lymphatic leukemia). Other patients are susceptible
because their defenses are deliberately compromised by azathio-
prine or prednisone to prevent host-versus-graft reaction, as in
kidney or heart transplant patients. Lastly, there are other
patients, e.g., those with malignancy, whose antineoplastic ther-
apy, e.g., chemotherapy or radiologic therapy, has the undesired
and unpreventable side-effect of such compromise.
Although infants and the elderly are considered fragile and
susceptible, one can contend that either group has an advantage
over populations of less extreme ages: the infants because they
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74
handle stressful procedures well and possess transplacental
material antibody, and the elderly because of their past expo-
sure over many years to infectious agents and their development
of an imposing immune globulin or other nonantibody defenses.
However, one would not question the assertion that there is a
distinctive pattern of susceptibility to infections in each
group: the infant to the Gram-negative Enterobacteriaceae,
Haemophilus influenzas, and the Group B S. pyogenes, and the
elderly, notably those hospitalized, to S. pneumonias and the
Gram-negative Enterobacteriaceae.
Increased frequency of infection, especially in those
colonized with resistant bacteria, had been anticipated. There
have been many studies of two groups of patients that have re-
ceived antimicrobials daily for many years in doses considered
suboptimal for treatment of active disease. One group consists
of cystic fibrotic patients in whom duration and quality of life
have been improved with such drugs as a tetracycline or chloram-
phenicol (Batten, 1976~. Recurrent infection with P. aeruginosa,
especially the highly mucous variant, is an acknowledged problem,
but it is difficult to attribute this directly to chemotherapy
(Mearns _ al., 1972~. The second group is composed of patients
taking tetracycline for either acne vulgaris (adolescents) or
acne rosacea (middle-aged and elderly patients). Although tetra-
cycline-resistant organisms can be isolated readily from these
patients, more frequent or more resistant disease has not been
documented (Schmidt et al., 1973~.
Resistance in microorganisms occurs in four patterns, which
may overlap:
· Bacteria are unaltered in their pathogenicity or other
characteristics (e.g., resistance to streptomycin or sulfonamide)
· Some bacteria lose special enzymes (e.g., catalase and
peroxidase) and pathogenicity (e.g., resistance to isoniazid).
~ Plasmid-mediated (nonchromosomal) antibiotic resistance
may be acquired by and transferred among many Enterobacteriaceae.
This is the most recently observed pattern and the most alarming
one.
· Development of a specific enzyme (beta-lactamase) by
Enterobacteriaceae and S. aureus that inactivates penicillin.
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75
Resistant strains become more prevalent when antibiotics
are used frequently and/or in high doses (Finland, 1979~.
Often a resistant strain may develop during the course of anti-
biotic treatment given to a patient originally infected with a
sensitive strain. It is well known that a patient entering a
hospital with a urinary tract infection usually has sensitive E.
colt, whereas the patient hospitalized for only 3 or 4 days who
develops such an infection has a much more resistant isolate,
presumably acquired from the hospital flora which has been sub-
jected to selection pressure by the use of antimicrobials. To a
considerable degree this is a reflection of in-hospital therapy.
Surprising, however, is the fact that extensive out-of-hospital
use of a drug, e.g., for acne, has not resulted in noticeable
increases in diseases from the emergence of resistant organisms.
Primary or emergent resistance has not been attributable to
antibiotic use in animal feeds. Nor does it seem possible to
attribute a hospital outbreak to therapeutic or subtherapeutic
use in those feeds.
Lack of response to an antimicrobial may be the result of
an inappropriate choice of agent. This is most likely when the
causative organism for a disease has not been fully characterized.
A number of examples of such diseases whose cause has only recently
or has not been recognized come to mind. They include Legionnaires
disease (Legionella pneumophila), nongonococcal urethritis (Chlamy-
dia sppe ~ ~ infantile pneumonia (Chlamydia trachomatis), Lassa fever
(Lassa virus), Marburg disease (Hamburg virus), infantile botulism
(Clostridium botulinum), hepatitis (non-A/non-B hepatitis viruses),
Norwalk gastroenteritis (Norwalk virus), and enterocolitis caused
by Yersinia enterocolitica, Clostridium difficile, or Campylobacter
fetus. To choose the optimal therapeutic agent, one must know the
cause of a disease or infection and its antibiotic susceptibility.
For these new diseases as well as the older diseases, the
selection of antimicrobial agents must be continually reviewed;
the pattern of sensitivities of isolates in the hospital or com-
munity microbiological laboratory must be evaluated at least yearly,
laboratory by laboratory; and the practice of chemotherapy must be
monitored, adjusted, and changed continuously. Since the discovery
of antimicrobials approximately 40 years ago, the changes in antimi-
crobial use have been far too numerous to list, but some examples
can be cited: the drift toward tetracycline from penicillin to
treat N. gonhorrheae; the increased use of chloramphenicol and the
decreased use of penicillin for acute otitis media owing to the
frequency of resistant H. influenza; the resurgence of vancomycin
after a hiatus of almost 20 years because of newer uses and more
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76
resistant microorganisms; and the changing pattern in the
immediate treatment of meningitis (i.e., treatment before the
causative species are identified). Sulfonamide was the first
agent of choice, but it was replaced by penicillin G which was
itself replaced by a combination of penicillin, sulfonamide, and
chloramphenicol. This combination gave way to ampicillin, then
to a combination of ampicillin and chloramphenicol, which is
commonly used today.
In many instances the reason for change has been develop-
ment of a more efficacious and/or less toxic drug by industry.
Two examples of such improved drugs are the aminoglycosides
and the cephalosporins. The development of the former spans
almost 35 years, beginning with streptomycin, neomycin, and
dihydrostreptomycin, progressing to kanamycin, then to amika-
cin, gentamicin, tobramycin, and sisomicin. The history of the
cephalosporins covers about half as many years, but the number
of new agents is far greater. The two earliest agents, e.g.,
~ ~ ~ ~ ~ But other
drugs, e.g., novobiocin, paromomycin, paraminosalicylic acid,
colist~methate, bacitracin, and ristocetin, have disappeared
from systemic formularies. But who could predict that they will
never reemerge?
streptomycin and cephalothin, retain some usefulness.
There is no reason to anticipate a radical departure from
the past in the development of emergent and primary resistant
organisms, of new and challenging diseases, of better and better
drugs, and of ebbs and flows in drug selection and usage. Thus,
we can expect a continuing production of newer vaccines, most
imminently for hepatitis B antigen. Most likely vaccines will
not replace the need for antimicrobial therapy of overt disease.
Rather, both the prophylaxis against and treatment of infectious
diseases will continue to be employed, neither replacing the
other.
r
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77
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Anonymous. 1978a. Malaria (plasmodia). The Medical Letter 20~1)
(Issue 496~:20-21.
Anonymous. 1978b. The choice of antimicrobial drugs. The Medical
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Batten, J. 1976. Chemoprophylaxis of respiratory infections.
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Garibaldi, R. A., R. E. Drusin, S. H. Ferebee, and M. B. Gregg.
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Schmidt, H., E. From, and G. Heydenreich. 1973. Bacteriological
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Representative terms from entire chapter:
antimicrobial therapy
