Health and Economic Impacts of Antimicrobial Resistance

Author(s): Scott D. Holmberg, Steven L. Solomon and Paul A. Blake

Source: Reviews of Infectious Diseases , Nov. - Dec., 1987, Vol. 9, No. 6 (Nov. - Dec.,
1987), pp. 1065-1078
Published by: Oxford University Press

Stable URL: [Link]

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide
range of content in a trusted digital archive. We use information technology and tools to increase productivity and
facilitate new forms of scholarship. For more information about JSTOR, please contact support@[Link].
Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at
[Link]

Oxford University Press is collaborating with JSTOR to digitize, preserve and extend access to
Reviews of Infectious Diseases

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
REVIEWS OF INFECTIOUS DISEASES * VOL. 9, NO. 6 * NOVEMBER-DECEMBER 1987

REVIEW ARTICLES

Health and Economic Impacts of Antimicrobial Resistance

Scott D. Holmberg* Steven L. Solomon, From the Division of Bacterial Diseases and the Hospi
and Paul A. Blake Infections Program, Center for Infectious Diseases,
Centers for Disease Control, Atlanta, Georgia

For comparison of the impacts of infections due to antimicrobial-resistant bacteria with

those of infections due to antimicrobial-susceptible strains of the same bacteria, data were
evaluated from 175 published and unpublished reports of investigations of nosocomial
and community-acquired infections with selected bacteria. The evaluation of outcomes
of hospital-acquired infections with resistant organisms was often confounded by risk
factors also associated with poor outcomes. Nevertheless, for both nosocomial and
community-acquired infections, the mortality, the likelihood of hospitalization, and the
length of hospital stay were usually at least twice as great for patients infected with drug-
resistant strains as for those infected with drug-susceptible strains of the same bacteria.
Poor outcomes could be attributed both to the expected effects of ineffective antimicrobial
therapy and to the unexpected occurrence of drug-resistant infections complicated by prior
antimicrobial therapy for other medical problems. Although the adverse economic and
health effects of drug-resistant bacterial infections can only be roughly quantified, it is
concluded that antimicrobial resistance is an important health problem and an economic
burden to society.

In 1984 and 1985, a National Institutes of likely than infections with susceptible strains of the
Health/World Health Organization task force could same organism to be associated with prolonged ill-
ness, frequent hospitalization, prolonged hospital-
find virtually no information regarding the economic
costs of antimicrobial resistance. Although an- ization, and mortality? The scarcity of analyses of
this issue may reflect the difficulties in comparing
timicrobial resistance is recognized as a growing med-
ical problem [1-5], to our knowledge no one has persons infected with resistant organisms with those
reviewed and examined available data to determine infected with susceptible organisms. In hospitalized
whether antimicrobial-resistant bacteria are as- patients it may not be possible to control for all vari-
ables by which these two groups differ, e.g., age,
sociated with increased morbidity and mortality and,
thereby, with increased costs. Some have assumed
underlying disease, site of infection, and length of
hospitalization before infection. However, such
that infections with [Link] bacteria have more
adverse consequences than infections with drug- differences are much less prominent when groups of
susceptible strains of the same bacteria; yet others,
persons with resistant and susceptible community-
acquired bacterial infections are compared.
focusing on questions of in vitro virulence rather
than clinical outcome, have questioned this assump-To examine this difficult issue, we compared mor-
tion [6]. bidity and mortality associated with antimicrobial-
Are infections with resistant strains indeed more resistant and -susceptible strains of selected bacte-
ria. We reviewed published and unpublished reports
Received for publication 30 September 1985 and in revised form of investigations of bacterial infections in sporadic
6 March 1987.
cases and outbreaks in the community and in hospi-
We thank Drs. William J. Martone and James M. Hughes, Hos-
pital Infections Program, Centers for Disease Control, and Mitch-
tals. We also examined the relations among an-
timicrobial
ell L. Cohen, Assistant Director, Division of Bacterial Diseases, use, acquisition of infections, and the
outcome of infections from antimicrobial-resistant
Centers for Disease Control, for many helpful comments and criti-
cisms.
and antimicrobial-susceptible bacteria. These data
* Dr. Holmberg's present address is AIDS Program, Building
indicate that resistant bacteria are indeed associated
6-285, Centers for Disease Control, Atlanta, Georgia 30333.
Please address requests for reprints to Dr. Paul A. Blake,
with more morbidity, mortality, and cost-as mea-
CID/DBD/EDB 1-5428, Centers for Disease Control, Atlanta,sured by hospitalization and death rates-than are
Georgia 30333. their drug-susceptible counterparts.

1065

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 1066 Holmberg, Solomon, and Blake

Methods fined for Salmonella and Shigella as resistance to

one or more commonly used antimicrobial agents
Centersfor Disease Control investigations. We
and for Serratia and S. aureus as resistance to ami-
reviewed all summary reports of outbreak investi-
noglycosides or penicillinase-resistant penicillins. Be-
gations performed in the United States in the decade
cause antimicrobial testing of these bacteria was in-
between 1971 and 1980 by the Centers for Disease
frequent before 1971 and since reports after 1981 were
Control (CDC). From the more than 250 reports of
sometimes incomplete, we limited our review to
investigations of outbreaks of bacterial disease, we
reports on investigations started between January
selected for careful review only those outbreaks
1971 and December 1980. We reanalyzed data from
caused by certain organisms that had been inves-
a previous study of randomly selected, apparently
tigated and tested frequently for antimicrobial
sporadic salmonella infections in the United States
resistance; these organisms were Salmonella and
in 1979 and 1980 [7], using Thomas and Gart's adap-
Shigella in 55 community outbreaks and Serratia,
tation of Fisher's exact test [8]. Also, we reviewed
Salmonella, and Staphylococcus aureus in 43 noso-
comial outbreaks. Antimicrobial resistance was de-
the CDC reports for studies that evaluated the ef-

Table 1. Community outbreaks of salmonella infections investigated by the Centers for Disease Control in
United States, 1971-1980.

No. of ill persons

Antimicrobial Mean no.
Outbreak Date of Location/ Salmonella susceptibility Investi- Hospi- of days in
no. outbreak population serotypes pattern gated Died talized* hospital
1 6-7/71 Community S. javiana . . . 22 0 4 . . .
2 6-8/71 Community S. enteritidis . . . 15 0 12 . . .
3 8/71 Community S. thompson S:all 17 0 ... .
4 3-5/72 Community S. agona S:all 17 0 4 3-10
5 4-6/72 Community S. typhimurium R:AmCfSuStTe 151 1 29/36 2-40
6 10/72 Laboratory S. typhimurium . . . 2 0 0 ...
7 12/72-6/73 Farms S. typhimurium R:AmStSu 10 ... 7 10
8 2-3/73 Delicatessen S. virchow . . . 19 0 5 ..
9 10/73-3/74 Cruise ships S. bareilly S:all 302 0 ... ...
10 1/74-3/74 23 states S. eastborne S:all 80 0 27 ...
11 3-4/74 Community S. norwich . . . 18 0 8 ...
12 6/74 Community S. typhimurium R:StSuTe 8 0 0 0
13 8/74 Cruise ship S. enteritidis . . . 274 0 10
14 9/74 Indian S. newport . . . 3,400 0 "few" .
reservation
.15 11-12/74 Farms S. typhimurium R:KaStSuTe 14 0 0 0
16 7-8/75 Military base S. newport . . . 6 0 4 5.5
17 8/75 Community S. st. paul S:all 31 0 12/26 . . .
18 8-9/75 Community S. newport R:StSuTe 9 ... ..
19 7-8/76 Community S. heidelberg S:all 339 0 56 . . .
20 7-10/76 Community S. agona S:all 95 3 18 . . .
21 9-10/76 School S. typhimurium S:all 26 0 2 8.5
22 1979-80 Community S. dublin R:various 32 6 21 . . .
23 2-3/79 Cruise ship S. heidelberg S:all 352 0 ..
24 3-5/79 College S. enteritidis . . . 266 0 5 . . .
25 5-8/79 Community S. poona . . . 33 0 11 . . .
26 10-11/79 Restaurant S. typhimurium . . . 50 0 14 8.7
27 6-7/80 Community S. typhimurium R:AmCfKaStTe 27 ... ... ..
28 12/80-2/81 Community S. muenchen S:all 62 0 39 . .

NOTE. Abbreviations used: Am = ampicillin; Cb = carbenicillin;

mycin; St = streptomycin; Su = sulfadiazine; Te = tetracycline. R = Re
tested. Elipsis indicates unknown or not specified in report; "various" ind
organisms.
* The denominators of fractions represent the numbers of ill person

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 Impacts of Antimicrobial Resistance 1067

feet of antimicrobial organism

therapy are known for
on only
the
two of the
subseque
29 commu-
ical outcomes of infections. nity outbreaks of salmonellosis investigated by CDC;
Published data. We reviewed the literature for in those two outbreaks, the Salmonella were drug-
reports of clinical studies or investigations of out-susceptible, and the infected persons had not taken
breaks of drug-resistant and drug-susceptible organ-antimicrobial agents before onset of their illnesses.
isms. We review herein 87 published articles thatShigella. Fatality rates from Shigella sonnei in-
reported data which allowed comparisons of the clin-fection are very low; only ~0.1%-0.2%/ of infected
persons die [11]. Three deaths (0.2%) occurred in
ical outcomes of patients with antimicrobial-resistant
1,347 persons in 12 CDC-investigated outbreaks
and antimicrobial-susceptible bacterial infections.
caused by drug-resistant S. sonnei (outbreaks 2, 5,
6, 8-11, 14, 16, 17, 21, and 24; table 2), but no deaths
Results and Comment occurred among 404 persons in three outbreaks
caused by drug-susceptible S. sonnei (outbreaks 1,
Community Outbreaks
15, and 20; table 2). Admission to a hospital was
Salmonella (nontyphoidal). CDC investigated 28 more frequent for persons in outbreaks caused by
outbreaks of community-acquired salmonellosis resistant
in organisms: 190 (12.4%) of 1,531 persons in
14 outbreaks due to resistant S. sonnei (outbreaks
the United States, and both the antimicrobial resis-
2, 5, 6, 8-11, 14, 16, 17, 19, 21, 23, and 24; table 2)
tance of infecting organisms and the clinical outcome
of infected persons were known and specified for 15
were hospitalized, but fewer than 10 (<0.7%) of 1,304
outbreaks (table 1). In four outbreaks caused by persons involved in two outbreaks caused by suscep-
antimicrobial-resistant Salmonella (outbreaks 5, 12,tible S. sonnei (outbreaks 13 and 15; table 2) were
15, and 22; table 1), seven (3.4%) of 205 affected hospitalized.
persons died, whereas only three (0.2%) of 1,321 per- In the 10-year period, CDC investigated two
sons died in 10 outbreaks caused by antimicrobial- Shigellaflexneri outbreaks in United States citizens
susceptible Salmonella (outbreaks 3, 4, 9, 10, 17, in which the antimicrobial susceptibility of the in-
19-21, 23, and 28; table 1) [9]. In 12 outbreaks infecting organisms and the outcome of infection with
Shigella were determined (outbreaks 25 and 27; ta-
which hospitalization rates of infected persons were
reported, 57 (57%) of 100 persons required hospi- ble 2). More persons were hospitalized in the out-
talization in five outbreaks caused by resistant break involving the tetracycline-resistant strain (21
Salmonella (outbreaks 5, 7, 12, 15 and 22; table 1),
of 93 persons interviewed, 23%) than in the outbreak
compared with 158 (24.5%) of 645 persons in seveninvolving the susceptible strain (none of 700).
outbreaks caused by susceptible strains (outbreaksThe use of ineffective antibiotics is likely to be as-
4, 10, 17, 19-21, and 28; table 1). sociated with bad clinical outcome and greater cost.
These studies were conducted by various investi-In an outbreak of antimicrobial-sensitive Shigella
dysenteriae 1 (Shiga bacillus) dysentery in rural
gators, so data are not uniform. However, in a study
of factors leading to infection with antimicrobial-Guatemala in 1960, one of 30 infected persons died
resistant Salmonella [7], CDC collected data and iso-[12, 13]. However, in the subsequent explosive epi-
lates from 514 randomly selected sporadic cases ofdemic of multiply resistant S. dysenteriae 1 infections
salmonellosis in 1979 and 1980, representing ~1.7%in Central America, severe illnesses and a case-
fatality ratio of 7.4% were noted among the esti-
of all cases reported to CDC in that period. Three
mated 120,000 persons affected [14-16]. During that
(4.9%) of 61 persons infected with multiply resistant
Salmonella died, whereas only four (0.9%) of 453 outbreak, case-fatality ratios in hospitalized persons
were usually more than 20% and as high as 35%,
infected with susceptible strains died (Fisher's exact
test, overall odds ratio = 5.8; 95% confidence in-
which was thought to be due to inappropriate an-
terval, 1.3-26.6; P = .04, two-tailed). tiamebic and antimicrobial treatment [17]; once the
etiology and the susceptibility to ampicillin were
Published studies of sporadic cases of salmonel-
losis in the community have shown that the use ofknown, mortality rates declined sharply to 1%-2%
penicillins is a risk factor for illness caused by
[18].
Salmonella resistant to penicillins [7, 10]. The useOther bacteria. Review of the published medi-
of antimicrobial agents before salmonella infectioncal literature shows that infections with resistant
strains of other bacteria have been associated with
and the antimicrobial susceptibility of the infecting

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 1068 Holmberg, Solomon, and Blake

Table 2. Community outbreaks of shi

States, 1971-1980.

No. of ill perso

Antimicrobial N o i p Mean no.
Outbreak Date of Location/ Shigella susceptibility Investi- Hospi- of days in
no. outbreak population serotypes pattern gated Died talized* hospital

1 7/71 Summer camp S. sonnei S:Te 187 0 ... ...

2 9-10/71 Institution S. sonnei R:AmCf 9 0 1 . . .
3 10/71-2/72 Community S. sonnei . .. 49 0 5 . . .
4 5-7/72 River rafters S. sonnei R:various 115 ... ......
5 10-12/72 Community S. sonnei R:Am 169 1 23 . . .
6 11/72 School S. sonnei R:AmStSuTe 208 0 9 . . .
7 1/73 Community S. sonnei R:AmCbClTe 40 ...
8 4-5/73 Institution S. sonnei R:AmStTe 12 2 3 30
9 6-8/73 Community S. sonnei R:AmStTe 243 0 53 5
10 6-10/73 Community S. sonnei R:AmTe 47 0 31 3.5
11 7/73 Carnival S. sonnei R:Su 250 0 1 . . .
12 1/74 Hotel conference S. sonnei R:SuTe 108 ... ... ...
13 1-3/74 Community S. sonnei S:all 1,200 . . . <10 . . .
14 4-8/74 Community S. sonnei R:various 224 0 38 4.5
15 6-8/74 Institution S. sonnei S:all 104 0 0 0
16 4/75 Community S. sonnei R:various 29 0 10 ..
17 8-10/75 Day care centers S. sonnei R:Su 29 0 2 ..
18 8/77 Migrant workers S. sonnei .. 31 ... ... ...
19 1-7/78 Community S. sonnei R:AmCbTe 149 ... 10 ...
20 6-7/78 Summer camp S. sonnei S:all 113 0 ... ...
21 8/78 Community S. sonnei R:Su 8 0 0 0
22 6-7/79 River rafters S. sonnei R:AmCb 108 . .. .
23 7/80 Community S. sonnei R:AmCbCfTe 35 . . . 2 .
24 8-9/81 Day care centers S. sonnei R:AmCb 119 0 7 5.5
25 6/73 Cruise ship S. flexneri S:all 700 0 0 . .
26 2/78 Cruise ship S. flexneri S:all 267 .. ... .
27 3/78 Restaurant S. flexneri R:Te 160 1 21/93 . .

NOTE. See footnote to table 1 for abbreviations.

* See table 1.

higher mortality, more-prolonged symptoms, and three infected persons died; these persons had re-
ceived antimicrobial agents to which isolates of
more-frequent hospitalization than infections with
susceptible strains of the same bacteria. Most [Link] were later found to be resistant [22].
these increased "costs" have been related to treatment
Many authors have pointed out the difficulties in
failures. Tetracycline-resistant pneumococcal strains treating antimicrobial-resistant pneumococcal infec-
have caused serious infections and death in persons tions, including the need for antimicrobial suscepti-
treated with tetracycline [19]. In South African black bility testing of isolates, more expensive drug ther-
children with penicillin-resistant Streptococcuspneu- apy, and prolonged hospitalization [23-25].
moniae acquired both in community and in hospi- During treatment with tetracycline- the first-line
tal, death occurred in 21 (43%) of 49 children with therapy employed in most cholera outbreaks-51
bacteremia and in nine (90%) of 10 children with persons infected with Vibrio cholerae 01 resistant to
meningitis [20, 21]; in contrast, in an unspecified tetracycline and other drugs purged significantly
number of South African black children with longer and in greater volume than 102 persons in-
penicillin-susceptible pneumococcal meningitis, the with susceptible V cholerae 01 [26]. Several
fected
case-fatality ratio was 30% [21]. A recent report of have suggested that persons infected with
authors
community-acquired multi-drug-resistant pneumo- antimicrobial-resistant Haemophilus influenzae are
coccal infections in South Africa showed that all more likely to be hospitalized and have longer hos-

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 Impacts of Antimicrobial Resistance 1069

pitalization than with

those susceptible strains by
infected and if exposure to an-
susceptible
[23, 27, 28], but this timicrobial
observationagents makes patients more likely
has not to de- bee
tified. velop infections with resistant microorganisms. We
found evidence to suggest that both of these hypoth-
eses are true, particularly with reference to specific
Nosocomial Outbreaks
bacteria.
S. aureus.
Infections with antimicrobial-resistant organisms in Of the 14 nosocomial outbreaks of
hospitals appear to be occurring with increasingdisease
fre- caused by S. aureus that CDC investigate
between 1971 and 1980, seven involved strains o
quency [29, 30]. About 30%o of hospitalized patients
S. out-
receive antimicrobial drugs [31], and during aureus that were known to be resistant to methicil-
breaks, patients infected with resistant strainslin and/or aminoglycosides (usually gentamicin
are
more likely to have received prior antimicrobial(outbreaks
ther- 6-8, 10-12, and 14; table 3). In two of
apy than are patients infected or colonized withthese
sus- studies (outbreaks 11 and 12; table 3), patient
ceptible strains of the same microorganismwere
[30]. matched with controls who had positive cu
tures for nonepidemic, methicillin- and gentamicin
Some reports suggest that patients with nosocomial
susceptible S. aureus. Risk factors for colonizatio
infections are more likely than uninfected patients
to have had prior exposure to antimicrobial agents and/or infection with resistant strains included older
[32, 33]. However, to understand better the impor- age, greater severity of underlying illness, and longe
tance of antimicrobial resistance and its relation to hospital stay before infection. In both outbreaks, pa
the use of antimicrobial drugs, we need to know if tients infected with resistant strains had a signifi-
patients infected with resistant microorganisms have cantly longer (two to two and one-half times) total
poorer outcomes than do similar patients infected hospital stay than patients infected with susceptibl

Table 3. Nosocomial outbreaks of Staphylococcus aureus infections investigated by the Centers for Dis
in the United States, 1971-1980.
No. of Antimicrobial
ill persons agents administered:
Location/ Antimicrobial l p s No. of agents
Outbreak Date of hospital susceptibility Investi- days in Noninfected
no. outbreak ward pattern gated Died* hospitalt Cases controls
1 7/71-5/72 Postoperative R:CbTe 17 . . . . . . ND ND
2 1/72-9/73 Nurseries . . . 300 6 . . . ND ND
3 10/72-3/73 NICU S:all 16 0 0 4/12 18/55
4 1/74-10/76 Burn/trauma R:ErCl 69 9 + 32 69/69 ND
5 2-3/75 Surgical S:all 7 0 ... ND ND
6 2-9/75 Burn unit R:ErMeStTe 47 3 + 13 3/35 0/30
7 5/76-11/77 General R:CnErGeKaMeStToTe 48 2/26 + 30 26/26 19/26
8 8/76 NICU R:Ge 16 1 . . . 1/1 death ND
9 1/77-10/78 Surgical . . . 46 . .. .. ND ND
10 6-11/77 Surgical R:KaStTe 9 . .. ... 9/9 14/70
11 12/78 NICU
R:GeMe 78 1/24 57.2 38/78 ND
S:GeMe 49 1/24 24.0 1/49 ND
12 9/78-4/79 General R:CnErGeMeTe 25 3 27.2 19/25 ND
S:GeMe 25 . . . 15.5 8/25 ND
13 7-10/80 Cardiac S:GeMe 6 1 ... ND ND
14 11/80-5/81 General R:AmCnErGeTeTo 27 ... ... ND ND

NOTE. Abbreviations used: Am = ampicillin; Cb = carbenicillin; C

Ge = gentamicin; Ka = kanamycin; Me = methicillin; St = strep
to; S = susceptible to; "all" = all 12 antimicrobials tested (except
not specified in report; ND = not done; NICU = neonatal inten
* Deaths attributable in whole or in part to infection.
t "+" before number indicates incremental number of days spen
t Number of persons given antimicrobial agents to which organism
in "cases"). The denominator represents the total number.

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 1070 Holmberg, Solomon, and Blake

strains; however, neither report

Increased severity of illness was also notedspec
in pa-
of time patients tients infected
were in with what some describe asbefor
hospital "tolerant"
thedrug-resistant or(Tolerant
S. aureus. drug-susceptibl
staphylococci purportedly have
published CDC study [34],
a low MIC but a high five of
MBC to penicillinase-resistant
penicillins; some investigators
with bacteremia caused by gentamici feel that tolerant
S. organisms
cillin-resistant aureus should properly
(MRSA) be considered died
drug-
one of five neonates
resistant.) A studywith bactere
comparing 37 patients with toler-
ant S. aureus endocarditis and
methicillin-susceptible S. bacteremia
aureus with 67 (
Other reports in the
patients medical
with susceptible literat
S. aureus endocarditis and
bacteremia showed that
support these findings. those infected with the
Strains of toler- M
shown to have the same virulence factors as more ant organisms were more likely to have prolonged
susceptible S. aureus isolates [35] and to be as- fever (58% vs. 19%), a higher mean number of com-
sociated with severe illness, as measured by hospi-
plications (1.6 vs. 0.7), a greater frequency of inten-
sive care unit admissions (66% vs. 33%), and a
talization days, in uncontrolled series [36-40]. Al-
though some reports have found no or negligible higher mortality (25% vs. 11%o) [48]. The concept
differences in morbidity or mortality between pa-of adverse health effects specifically due to inap-
tients infected with antimicrobial-resistant vs. anti- propriate therapy was addressed in a study of 20 per-
microbial-susceptible S. aureus [41-43], most studiessons with staphylococcal infections. Four of 10 died
[44-50] have shown more adverse health and eco- who received antimicrobials not bactericidal to in-
nomic effects associated with resistant than with sus- fecting S. aureus, whereas none of 10 died who were
ceptible S. aureus infections. treated with antimicrobials to which the infecting
In the latter studies, the numbers of persons in S. aureus was susceptible in vitro [36].
case and control groups were generally small, so that Prior exposure to antimicrobial agents has been
observed differences in mortality between patients found to be a risk factor for resistant S. aureus in-
infected with resistant vs. susceptible S. aureus in any fection and colonization in controlled CDC studies
single study were usually not statistically significant (outbreaks 4, 7, 8, and 10-12; table 3) [34] and in
[45-49, 51]. For example, in one study of staphy- numerous published reports in the medical literature
lococcal infections in drug abusers, 24 MRSA-in- [33, 36, 38, 41, 43-46, 49, 51]. When exposure to spe-
fected patients were matched by age, sex, history of cific agents has been examined, semisynthetic peni-
parenteral drug abuse, site of infection, race, and un- cillins [44-46, 52], cephalosporins [44, 49, 52], and
derlying illness with 24 MSSA-infected persons [49]. aminoglycosides [45, 46, 52] have been found to be
More drug abusers with MRSA infections died than associated with acquiring resistant S. aureus.
did those with MSSA infections (two of 24 vs. none In terms of (expected) poor outcomes from in-
of 24). Among persons in the same study who did effective treatment, a relation between therapy with
not abuse drugs, the death rate was the same in an antimicrobial agent to which the infecting
MRSA and MSSA infections (three of 16 in each cat- S. aureus was resistant and subsequent morbidity
egory); however, the mean length of hospital stay was and mortality attributable to staphylococcal infec-
longer for both drug abusers (29.7 days) and other tion was noted in seven of the unpublished CDC
subjects (13.4 days) with MRSA than for drug-use- reports (outbreaks 4, 6-8, and 10-12; table 3). One
matched controls with MSSA infections (19.9 and published CDC report of treatment failures com-
5.9 days, respectively) [49]. Another study showed pared 18 survivors of multiple-drug-resistant S. au-
that patients who became infected with resistant reus infections with 17 persons who died from in-
strains had been in the hospital longer and were more fection with the same organism and found that
likely to have received antibiotics than were patients survivors had more often received antimicrobial
infected with methicillin-susceptible strains [46]. Al- agents to which the infecting S. aureus was suscep-
though the total stay for patients with resistant tible [52]; survival was more likely for patients in-
S. aureus infections was not significantly longer than fected with susceptible strains (21 of 29) than for pa-
for patients with susceptible strains, the cost of their tients infected with resistant strains (13 of 29) [52].
hospitalization was substantially greater, more than Salmonella (nontyphoidal). In nine drug-
two and one-half times that of the MSSA-infected resistant (outbreaks 1, 2, 4, 7, 9, 11, 12, 14, and 16;
matched controls ($64,370 vs. $24,280) [46]. table 4) and seven drug-susceptible (outbreaks 3, 5,

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
Table 4. Nosocomial outbreaks of nontyphoidal salmonella infections investigated by the Centers for Disease Control in

No. of ill persons a

Location/ Antimicrobial N
Outbreak Date of hospital Salmonella susceptibility Investi- day
no. outbreak ward serotype pattern gated Died* hospitalt
1 11/71-3/72 Pediatric S. heidelberg R:AmKaNeSt 57 9 . . . "
2 5-7/73 Surgical S. typhimurium R:KaNeStSuTe 4
3 9/73 General S. typhimurium S:all 35 0 ...
4 12/73-4/74 NICU S. typhimurium R:AmCbKaStTe 18
5 2/75 General S. heidelberg S:all 60 1 ... No differ
6 6/75 Nursery S. kottbus . . . 7 0 .. . No differ
7 8/75-2/76 General Not specified R:AmCbCfGeKaStSuTe 57 10
8 9/75 Nursery S. muenchen S:all 5 0 . . . No diffe
9 8/76 Nursery S. heidelberg R:ClKaNeNfStSuTe 5
10 8-9/76 General S. thompson S:all 27 0
11 3-10/76 NICU S. typhimurium R:AmCfGeKaSt 64 6 + 3
12 3-11/77 General S. typhimurium R:AmCbCfTe 29 0 .
13 12/77 Nurseries S. nienstadten S:all 12 0
14 5/78 General S. typhimurium R:AmCbCfKaTe 16
15 8-9/79 General S. enteritidis ... ... 1
16 10-11/80 General S. typhimurium R:AmCbCfKa 6
S. newport S:all 18 1 ..
17 7-8/81 Hospitals S. typhimurium S:all 45 0

NOTE. Abbreviations used: Am = ampicilli

= nitrofurantoin; St = streptomycin; Su = su
or not specified in report; ND = not done; N
* See footnote to table 3.
t See footnote to table 3.
t See footnote to table 3.

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 1072 Holmberg, Solomon, and Blake

Table 5. Nosocomial outbreaks of ser

States, 1971-1980.
No. of Antimicrobial
ill persons agents administered
Location/ Antimicrobial No. of
Outbreak Date of hospital susceptibility Investi- days in Noninfected
no. outbreak ward pattern gated Died* hospitalt Cases controls
1 8-9/71 Surgical R:various 99 ... ... 71/76 60/122
2 3-9/72 ICU R:AmCfCoNeNfTe 58 ... ... es "YesYes"
3 7/72-1/73 Several R:various 24 2 + 12.5 18/24 ND
4 5/73-10/74 General R:all 66 5 20 57/66 ND
S:all 32 0 24 4/32 ND
5 12/73 Nurseries R:GeNaTe 42 3 + 16.6 ND ND
6 1/76-11/77 Several R:Ge 236 11/35 . . . ND ND
7 7/76 ICU R:AmCbCfCoPeTe 6 0 + 7 ND ND
8 9/76-1/77 Several R:all 29 4 + 3.4 25/25 22/25
9 1977-8 General R:Ge 22 4 52.5 ND ND
S:Ge 18 0 29.2 ND ND
10 3-5/78 Physician's office R:CfPmTe 26 0 . . . 0/26 ND
11 10-11/78 Surgical R:various 15 . . . + 16 ND ND
12 6-8/80 General R:AmCICfNfTe 17 . . . + 17.9 ND ND

NOTE. Abbreviations used: Am = ampicillin; Cb = car

Ge = gentamicin; Na = nalidixic acid; Ne = neomycin;
cline; R = resistant to; S = susceptible to; "all" = all 12 antim
"various" indicates various antimicrobial resistance patte
* See footnote to table 3.
t See footnote to table 3.
1 See footnote to table 3.

8, 10, 13, 16, and 17; table 4) nontyphoidal investigations (outbreak 4; table 5), 66 persons with
salmonella nosocomial outbreaks investigated byresistant S. marcescens had a slightly shorter mean
CDC, despite appropriate initial therapy overall mor-hospital stay (20 days) -possibly because of five
deaths in this group-than did the 32 control pa-
tality was much higher in persons infected with resis-
tant strains (30 of 256, 11.7%) than in those infectedtients with susceptible S. marcescens infections (24
with susceptible strains (two of 202, 1.0%0). Data were
days). In a second study (outbreak 9; table 5), per-
insufficient to draw statistical conclusions about sons with resistant S. marcescens infections were
length of hospitalization associated with resistant hospitalized for a mean of 52.5 days, 80% longer
and susceptible salmonella infections. than those with susceptible S. marcescens infections
Although proper control groups (those with sus- (29.2 days). Few published studies reported the clin-
ceptible salmonella infections) were sometimes lack- ical outcomes of patients infected with resistant and
ing, a history of prior use of antimicrobial agents susceptible serratia infections [60, 61], but treatment
to which the infecting Salmonella was resistant was
failures leading to death have been observed more
noted many times in investigations of nosocomial frequently in persons with multiple-drug-resistant
cases of salmonellosis caused by drug-resistant S. marcescens bacteremia than in those infected with
strains in the United States [10, 53, 54] and in pub- strains resistant to fewer antimicrobial agents. In one
lished studies from South Africa [55], central Africa study, all seven survivors of S. marcescens bacter-
[56], Israel [57], Hong Kong [58], and India [59]. emia had organisms susceptible to at least one an-
Serratia marcescens. In two CDC investigations timicrobial agent used in treatment; in contrast, eight
of nosocomial S. marcescens outbreaks (outbreaks (88.9%) of nine patients who did not receive appro-
4 and 9; table 5), the clinical outcomes of infections priate antimicrobial therapy died; two of these pa-
with resistant and susceptible strains were compared: tients had strains of Serratia resistant to all com-
death occurred in nine (10%7) of 88 persons with resis- monly used antimicrobial agents [62]. Similar results
tant serratia infections, but in none of 50 persons were observed in another study in which there were
with susceptible serratia infections. In one of these three (18.8%) deaths among 16 patients treated with

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 Impacts of Antimicrobial Resistance 1073

a drug to which their organism

kanamycin-resistant was
Klebsiella and E. coli suscep
[76], and
pared with seven (46.7%)
four (40%) of 10 deaths among
infants with infection due to
tients either to whom no therapy
gentamicin-resistant was
Klebsiella type 19 [77]. giv
The numbers
had organisms resistant toof the infants investigated
drug in these
empl
In five of 12 CDC investigations
studies were small, and differencesof multip
in mortality, al-
resistant though consistently
serratia
oubreaks higher for antimicrobial-
(outbreaks 1-3,
table 5),
infections were
resistant associated
than for sensitive wit
strains, are rarely statisti-
cally significant in any one of
crobial use before development study. symptom
For example, a
tive culture in 171study(78.8%)
of gram-negativeof enteric the 217 p
bacillary infections
fected; in contrast, inonly four
neonates (usually due to (12.5%)
Klebsiella) showed ofthat 3
with drug-susceptible Serratia
death occurred (outbreak
in five (71%) of seven infants with 4
had been taking antimicrobial agents
infections due to ampicillin- befor
and gentamicin-resistant
fections. In one published CDC
strains, compared with nine (50%) of study,
18 infections
of 66 persons with drug-resistant
with drug-susceptible strains [78]. S. marc
fection had taken broad-spectrum ant
However, not all studies of infants have involved
agents before illness, compared with
too few subjects. A prophylactic trial of single-dose o
(12.5%) of 32 controls matched
penicillin by age
against group B streptococcal diseaseand
in
ing disease severity more
who than 9,000
had newborn infants was associated with
drug-suscepti
cescens infectionsan[61]. Previous
increase in infections use of
caused by penicillin-resistant
spectrum antimicrobial agents
pathogens, which, in the first 2was also
years of the ide
study, off-
a risk factor for acquisition
set by 67%o the reductionof resistant
of disease caused by peni- S
other studies [62-65]. Two
cillin-susceptible published
strains [79]. Infections with peni-rep
associations between prior
cillin-resistant use
pathogens wereof gentami
associated with a 4307o
quisition of infection with
(15 of 35) case-fatality gentamicin-
ratio, almost four times great-
S. marcescens [66, er
67].
than the case-fatality ratio associated with infec-
Other bacteria. The National Nosocomial Infec- tions with penicillin-susceptible pathogens (three of
tions Study found that infections with Escherichia27, 11%o) (P = .01, Fisher's exact test). Also, deaths
coli, Klebsiella pneumoniae, and Pseudomonas from infection with penicillin-resistant Streptococcus
aeruginosa resistant to gentamicin or tobramycin group B were much higher in infants who received
resulted in death more often than did infections with penicillin prophylaxis (1.2 deaths per 1,000 live births)
susceptible strains (1.3% vs. 0.7%); comparison than in infants who did not (0.43 deaths per 1,000
groups were matched by site of infection, but other live births). These adverse effects from penicillin-
variables could not be controlled for [68]. resistant streptococci and other pathogens were de-
Very high mortality for persons with antimi- creased but not eliminated as infants were added to
crobial-resistant klebsiella infections has been ob- the study over the subsequent 17 months [80].
served in outbreaks in England [69] and the United Some reports have shown that aminoglycoside use
States [70]. In an outbreak of gentamicin- and is a risk factor for aminoglycoside-resistant E. coli
kanamycin-susceptible K. pneumoniae septicemia ininfections [81], aminoglycoside-resistant P aeruginosa
a neonatal intensive care unit, three (20%) of 15 in-infections [82], and gentamicin-resistant gram-
fants died; these fatalities were in infants who hadnegative bacilli infections in general [83] and bac-
severe underlying disease [71]. In another outbreak teremia specifically [84]. P-Lactam drug use can
of septicemia due to kanamycin-susceptible K. pneu- complicate infection with P-lactam-tolerant organ-
moniae type 25 in six infants, none died [72]. Theseisms [45, 46, 85]. However, some reports have sug-
relatively low case-fatality ratios can be contrastedgested that use of antibiotics may not be the sole fac-
with eight (80%) deaths among 10 infants withtor in perpetuating nosocomial outbreaks of resistant
kanamycin-resistant bacteremia due to Klebsiella
bacteria [82, 86].
type 33 [73], six (50%) deaths in 12 infants with bac-
teremia due to kanamycin-resistant Klebsiella type
Discussion
26 [74], seven (70%) deaths in 10 infants with sep-
ticemia due to gentamicin- and kanamycin-resistantUnavoidable biases are inherent in the data ab-
Klebsiella type 55 [75], nine (41%) deaths in 22 in-stracted from some of the investigations reviewed
fants with bacteremia caused by gentamicin- andhere. Patients acquiring antimicrobial-resistant bac-

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 1074 Holmberg, Solomon, and Blake

terial infectionshaveduring nosocomia

been identified [95]. However, there are few or
no data to indicate
differ in important ways that resistant
- organisms
especial gener-
derlying disease -allyfrom
are more virulentthose
per se than susceptible
acquiristrains.
susceptible Thus, it seems more
bacterial likely that host factors are F
infections.
propensity of responsible
the aged for theand
adverse outcomes
the from drug-
infir
with resistant resistant bacterial infections. has
pathogens often
nosocomial aureus S. infections
Many investigators have concluded that some bad [3
85-87]. Although clinical outcomes from resistantpersons
matching bacteria probably
result from the interaction
derlying disease status, asof was
antimicrobial done
use and i
reviewed here [42, 43, or45,
the subsequent concurrent46, 48,
development 49]
of symp-
these biases, the numbers of
tomatic infections with bacteria persons
resistant to the drug
in any single study are
being taken. This phenomenon usually
is different from in- to
powerful statistical observations.
appropriate therapy in that the drugs are being given
Nonetheless, in almost every
for some reason other than outbr
to treat the (drug-resistant)
tion and published study
infecting we reviewed
organism. In investigations could here, f
with antimicrobial-resistant
drug treatment often led to the suddenorganis
appearance
ated with substantially worse
of an unsuspected bacterium resistant to the heal
drug
effects than were infections with antimicrobial-sus- used.
ceptible organisms. The adverse effects from drug- To explain this phenomenon, some have specu-
resistant organisms could not be explained entirely lated that antimicrobial use selects for organisms
by the propensity of such organisms to infect the old resistant to the drug being used and promotes their
and debilitated. Studies in which patients being com- growth at the expense of antimicrobial-susceptible
pared were matched by age and underlying disease competitors [3, 5, 83, 96, 97]. This adverse synergis-
almost always showed worse clinical outcome from tic effect from the combination of antimicrobial use
drug-resistant than from drug-susceptible organisms. and infection with an agent resistant to the drug used
Also, it is not clear that bad clinical outcomes from has been observed in infections caused by various
antimicrobial-resistant bacteria result entirely from bacteria, including Salmonella [10, 53, 54, 98, 99],
inappropriate drug therapy. For example, our review Shigella [14, 15], pneumococcus [19, 20], Strep-
of CDC investigations of community outbreaks tococcus group B [79, 80], S. aureus [36, 48], Serra-
caused by Salmonella and Shigella, involving persons tia [62], and Klebsiella [74]. We do not think that
not undergoing therapy for infections with these bac- this problem would be avoided by the empiric use
teria, shows higher rates of hospitalization and mor- of antimicrobial agents with broader spectra of ac-
tality associated with drug-resistant than with drug- tivity [100].
susceptible strains of the same bacteria. Treatment An ideal study to provide data describing incre-
failures remain unavoidable in many developing ments in costs and disability caused by antimicrobial
countries where empiric antimicrobial therapy results resistance would compare outcomes of infections
from the lack of diagnostic laboratories. Whether caused by susceptible and resistant strains of various
avoidable or not, inappropriate antimicrobial ther- organisms in persons matched for age, underlying
apy apparently does not explain all increased mor- disease status, and appropriateness of therapy-in
bidity and mortality associated with drug-resistant both the community and the hospital and in a vari-
compared with drug-susceptible organisms. ety of socioeconomic conditions [101-103]. Since no
Aside from treatment failures [88-90], why might such study has yet been performed, the rates gener-
resistant strains be associated with worse clinical out-
ated from this review may be used, along with esti-
comes than susceptible strains of the same bacteria? mated international patterns of antimicrobial resis-
Genes coding for antimicrobial resistance may be tance [104, 105] and with incidence and cost data
linked with genetic loci coding for pathogenic fac- already known for community [106-108] and noso-
tors so that selection for one results in selection for
comial [109-114] infections, to provide a first approx-
the other [18, 91-94]. This may be especially the caseimation of the increased economic costs associated
for some bacteria such as some enteroinvasive E. coli with antimicrobial resistance.
and Shigella species for which virulence plasmids

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 Impacts of Antimicrobial Resistance 1075

References terial diseases. J Antimicrob Chemother 1977;3(Suppl

C):3-6
1. WHO Scientific Working Group on Antimicrobial Resis- 19. Schaffner W, Schreiber WM, Koenig MG. Fatal pneumo-
tance. Control of antibiotic-resistant bacteria: memoran- nia due to a tetracycline-resistant pneumococcus. N Engl
dum from a WHO meeting. Bull WHO 1983;61:423-33 J Med 1966;274:451-2
2. Kunin CM. Antibiotic resistance-a world health problem 20. Ward J, Koornhof H. Antibiotic-resistant pneumococci. In:
we cannot ignore [editorial]. Ann Intern Med 1983; Remington JS, Swartz MN, eds. Current clinical topics
99:859-60 in infectious diseases. New York: McGraw-Hill, 1980:
3. Jackson GG. Antibiotic policies, practices and pressures. 265-87
J Antimicrob Chemother 1979;5:1-4 21. Ward J. Antibiotic-resistant Streptococcus pneumoniae: clin-
4. Weinstein RA, Kabins SA. Strategies for prevention and con- ical and epidemiologic aspects. Rev Infect Dis 1981;
trol of multiple drug-resistant nosocomial infection. Am 3:254-66
J Med 1981;70:449-54 22. Feldman C, Kallenbach JM, Miller SD, Thorburn JR, Koorn-
5. Levy SB. Microbial resistance to antibiotics: an evolving and hof HJ. Community-acquired pneumonia due to peni-
persistent problem. Lancet 1982;2:83-8 cillin-resistant pneumococci. N Engl J Med 1985;
6. Eickhoff TC. Antibiotics and nosocomial infections. In: Ben- 313:615-7
nett JV, Brachman PS, eds. Hospital infections. Boston:
23. Ayliffe GAJ. Trends in resistance and their significance in
Little, Brown, 1979:195-221 primary pathogenic bacteria. In: Reeves D, Geddes A,
7. Riley LW, Cohen ML, Seals JE, Blaser MJ, Birkness KA, eds. Recent advances in infection. Edinburgh; Churchill
Hargrett NT, Martin SM, Feldman RA. Importance of Livingstone, 1979:1-18
24. Dajani AS. Antibiotic-resistant pneumococci. Pediatr In-
host factors in human salmonellosis caused by multiresis-
tant strains of Salmonella. J Infect Dis 1984;149:878-83 fect Dis 1982;1:143-4
8. Thomas DG, Gart JJ. A table of exact confidence limits 25. Kalin M, Carlsson B, Karlsson I. Frequency and type dis-
for differences and ratios of two proportions and their tribution of pneumococcal strains in the Stockholm re-
odds ratios. Journal of the American Statistical Associ- gion with resistance or reduced susceptibility to antibi-
ation 1977;72:73-6 otics. Scand J Infect Dis 1984;16:73-8
9. Holmberg SD, Wells JG, Cohen ML. Animal-to-man trans- 26. Glass RI, Huq I, Alim ARMA, Yunus M. Emergence of
mission of antimicrobial-resistant Salmonella: investiga- multiply antibiotic-resistant Vibrio cholerae in Ban-
tions of U.S. outbreaks, 1971-1983. Science 1984;225:883-5 gladesh. J Infect Dis 1980;142:939-42
10. Holmberg SD, Osterholm MT, Senger KA, Cohen ML. Drug- 27. Scheifele DW. Ampicillin-resistant Hemophilus influenzae
resistant Salmonella from animals fed antimicrobials. N in Canada: nationwide survey of hospital laboratories.
Engl J Med 1984;311:617-22 Can Med Assoc J 1979;121:198-202
11. Black RE, Craun GF, Blake PA. Epidemiology of common- 28. Smith AL. Antibiotic resistance in Hemophilus influenzae.
source outbreaks of shigellosis in the United States, Pediatr Infect Dis 1983;2:352-5
1961-1975. Am J Epidemiol 1978;108:47-52 29. Finland M. Emergence of antibiotic resistance in hospitals,
12. Gordon JE, Ascoli W, Pierce V, Guzman MA, Mata LJ. 1935-1975. Rev Infect Dis 1979;1:4-21
Studies of diarrheal disease in Central America. VI. An 30. McGowan JE Jr. Antimicrobial resistance in hospital or-
epidemic of diarrhea in a Guatemalan highland village, ganisms and its relation to antibiotic use. Rev Infect Dis
with a component due to Shigella dysenteriae, type 1. Am 1983;5:1033-48
J Trop Med Hyg 1965;14:404-11 31. Shapiro M, Townsend TR, Rosner B, Kass EH. Use of an-
13. Levine MM, DuPont HL, Formal SB, Hornick RB, Takeuchi timicrobial drugs in general hospitals: patterns of pro-
A, Gangarosa EJ, Snyder MJ, Libonati JP. Pathogene- phylaxis. N Engl J Med 1979;301:351-5
sis of Shigella dysenteriae 1 (Shiga) dysentery. J Infect 32. Pollack M, Charache P, Nieman RE, Jett MP, Reinhardt
Dis 1973;127:261-70 JA, Hardy PH Jr. Factors influencing colonisation and
14. Mata LJ, Gangarosa EJ, Caceres A, Perera DR, Mejicanos antibiotic-resistance patterns of gram-negative bacteria
ML. Epidemic Shiga bacillus dysentery in Central in hospital patients. Lancet 1972;2:668-71
America. I. Etiologic investigations in Guatemala, 1969. 33. Chavigny KH, Fischer J. Competing risk factors associated
J Infect Dis 1970;122:170-80 with nosocomial infection in two university hospitals. J
15. Gangarosa EJ, Perera DR, Mata LJ, Mendizabel-Morris C, Hosp Infect 1984;5(Suppl A):57-62
Guzman G, Reller LB. Epidemic Shiga bacillus dysen- 34. Graham DR, Correa-Villasenor A, Anderson RL, Vollman
tery in Central America. II. Epidemiologic studies in 1969. JH, Baine WB. Epidemic neonatal gentamicin-methicillin-
J Infect Dis 1970;122:181-90 resistant Staphylococcus aureus infection associated with
16. Faich GA, Navarro Rivas EN, Gangarosa EJ. The rise and nonspecific topical use of gentamicin. J Pediatr 1980;
fall of Shiga dysentery in El Salvador, 1969-1973. Bull 97:972-8

Pan Am Health Organ 1973;7:20-4 35. Peacock JE Jr, Moorman DR, Wenzel RP, Mandell GL.
17. Levine MM, DuPont HL, Formal SB, Gangarosa EJ. Epi- Methicillin-resistant Staphylococcus aureus: microbiologic
demic Shiga dysentery in Central America. Lancet characteristics, antimicrobic susceptibilities, and assess-
1970;2:607-8 ment of virulence of an epidemic strain. J Infect Dis
18. Balows A. An overview of recent experiences with plasmid- 1981;144:575-82
mediated antibiotic resistance or induced virulence in bac- 36. Denny AE, Peterson LR, Gerding DN, Hall WH. Serious

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
1076 Holmberg, Solomon, and Blake

resistant Staphylococcus
staphylococcal infections with aureus: strains
introduction, transmis-
tol
ricidal antibiotics. Arch Intern
sion, and evolution Med
of nosocomial infection. 197
Ann Intern
37. Klimek JJ, Marsik MedFJ,
1982;97:317-24
Bartlett RC, W
tiliani R. Clinical,53. epidemiologic
Adler JL, Anderson RL, Boring JR III, Nahmias
and AJ. Aba
servations of an outbreakprotracted hospital-associated outbreak of salmonello-
of methicillin-r
ylococcus aureus at sis aduelarge community
to a multiple-antibiotic-resistant strain of Sal-
Med 1976;61:340-5 monella indiana. J Pediatr 1970;77:970-5
38. O'Toole RD, Drew 54. RiceWL,
PA, Craven PC, Dahlgren
Wells JG. Salmonella heidelberg BJ, en- B
break of methicillin-resistant Staphyloco
teritis and bacteremia: an epidemic on two pediatric wards.
fection: observations Am J Med in hospital and n
1976;60:509-16
JAMA 1970;213:257-63 55. Robins-Browne RM, Rowe B, Ramsaroop R, Naran AD,
39. Rountree PM, Beard MA.
Threlfall EJ, Ward LR, Hospital
Lloyd DA, Mickel RE. A strain
hospi-
cus aureus, with particular tal outbreak of multiresistant reference
Salmonella typhimurium t
resistant strains. Med belongingJ Aust
to phage type 193. J 1968;2:1163
Infect Dis 1983;147:210-6
40. Craven DE, Reed C,
56. Lepage Kollisch
P, Bogaerts J, Nsengumuremyi F, N, HitimanaDeMar
DG, Van
D, Shen K, McCabe WR. A large
Goethem C, Vandepitte J, Butzler [Link]
Severe multiresis-
caused by a strain of tantStaphylococcus
Salmonella typhimurium systemic infections in aureCen-
oxacillin and aminoglycosides. Am
tral Africa-clinical features and treatment in aJpaedi- Me
41. Thompson RL, Cabezudo I, Wenzel
atric department. J Antimicrob Chemother 1984;14(Suppl RP
nosocomial infections B):153-9 caused by methic
Staphylococcus aureus. AnnR, Berger
57. Hirsch W, Sapiro-Hirsch Intern A, Winter ST, MedMayer
42. Sorrell TC, Packham G, Merzbach DR, Shanker
D. Salmonella edinburg infection in chil-S, F
Vancomycin therapydren: for methicillin-resis
a protracted hospital epidemic due to a multiple-
coccus aureus. Ann Interm Med 1982;97:344-50 drug-resistant strain. Lancet 1965;2:828-9
43. McGowan JE Jr, Terry PM, Huang T-SR, Houk CL, Da-58. Lui WY, Chang WK, Fok TF, Teoh-Chan CH. Salmonella
vies J. Nosocomial infections with gentamicin-resistant gastroenteritis in Hong Kong - a clinical review of 200
Staphylococcus aureus: plasmid analysis as an epidemi- patients. J Trop Med Hyg 1979;82:53-8
ologic tool. J Infect Dis 1979;140:864-72 59. Sasidharan CK, Rajagopal KC, Panicker CK. Salmonella
44. Crossley K, Landesman B, Zaske D. An outbreak of infec- typhimurium epidemic in a newborn nursery. Ind J Pediatr
tions caused by strains of Staphylococcus aureus resis- 1983;50:599-605
tant to methicillin and aminoglycosides. II. Epidemio- 60. Marrie TJ, Noble MA, Haldane EV, Duncan NH, Pater-
logic studies. J Infect Dis 1979;139:280-7 son I, Carruthers RND, Barry A, West A, McCormick
45. Peacock JE Jr, Marsik FJ, Wenzel RP. Methicillin-resistant S. Serratia marcescens- a marker for an infection con-
Staphylococcus aureus: introduction and spread within trol program. Infect Control 1982;3:134-42
a hospital. Ann Intern Med 1980;93:526-32 61. Schaberg DR, Alford RH, Anderson R, Farmer JJ III, Melly
46. Boyce JM, Landry M, Deetz TR, DuPont HL. Epidemio- MA, Schaffner W. An outbreak of nosocomial infection
logic studies of an outbreak of nosocomial methicillin- due to multiply resistant Serratia marcescens: evidence
resistant Staphylococcus aureus infections. Infect Con- of interhospital spread. J Infect Dis 1976;134:181-7
trol 1981;2:110-6 62. Dodson WH. Serratia marcescens septicemia. Arch Intern
47. Grieble HG, Krause SL, Pappas SA, DiCostanzo MB. The Med 1968;121:145-50
prevalence of high-level methicillin resistance in multiply- 63. Wilfert JN, Barrett FF, Kass EH. Bacteremia due to Serra-
resistant hospital staphylococci. Medicine (Baltimore) tia marcescens. N Engl J Med 1968;279:286-9
1981;60:62-9 64. Sanders CV Jr, Luby JP, Johanson WG Jr, Barnett JA, San-
48. Rajashekaraiah KR, Rice T, Rao VS, Marsh D, Ramakrishna ford JP. Serratia marcescens infections from inhalation
B, Kallick CA. Clinical significance of tolerant strains therapy medications: nosocomial outbreak. Ann Intern
of Staphylococcus aureus in patients with endocarditis. Med 1970;73:15-21
Ann Intern Med 1980;93:796-801 65. Maki DG, Hennekens CG, Phillips CW, Shaw WV, Ben-
49. Saravolatz LD, Markowitz N, Arking L, Pohlod D, Fisher nett JV. Nosocomial urinary tract infection with Serra-
E. Methicillin-resistant Staphylococcus aureus: epidemi- tia marcescens: an epidemiologic study. J Infect Dis
ologic observations during a community-acquired out- 1973;128:579-87
break. Ann Intern Med 1982;96:11-6 66. Graham DR, Clegg HW II, Anderson RL, Chelgren GA,
50. McNeil JJ, Proudfoot AD, Tosolini FA, Morris P, Booth Mostow SR, Dixon RE. Gentamicin treatment associated
JM, Doyle AE, Louis WJ. Methicillin-resistant Staphy- with later nosocomial gentamicin-resistant Serratia mar-
lococcus aureus in an Australian teaching hospital. J Hosp cescens infections. Infect Control 1981;2:31-7
Infect 1984;5:18-28 67. Yu VL, Oakes CA, Axnick KJ, Merigan TC. Patient fac-
51. Ward TT, Winn RE, Hartstein AI, Sewell DL. Observations tors contributing to the emergence of gentamicin-resistant
relating to an inter-hospital outbreak of methicillin- Serratia marcescens. Am J Med 1979;66:468-72
resistant Staphylococcus aureus: role of antimicrobial 68. Hughes J, Munn V, Jarvis W, Culver D, Haley R. Mortality
therapy in infection control. Infect Control 1981;2:453-9 associated with nosocomial infections in the United States,
52. Locksley RM, Cohen ML, Quinn TC, Tompkins LS, Coyle 1975-81 [abstract no. 701]. In: Program and abstracts of
MB, Kirihara JM, Counts GW. Multiply antibiotic- the 22nd Interscience Conference on Antimicrobial Agents

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
Impacts of Antimicrobial Resistance 1077

and
Chemotherapy. Washington DC:In: America
of tolerance to P-lactam antibiotics? Remington JS,
for Microbiology,
1982:189Swartz MN, eds. Current clinical topics in infectious dis-
69. Curie K, Speller DCE, [Link]
New York; McGraw-Hill, RA,1983:358-77 Stephe
DI. A hospital epidemic
86. Bockcaused
BV, Pasiecznik K,by a Clinical
Meyer RD. gentamicin
and laboratory
Klebsiella aerogenes. J Hyg
studies (Camb)
of nosocomial 1978;80:1
Staphylococcus aureus resistant to
70. Smith SM, Digori JT, Eng
methicillin RHK. Infect
and aminoglycosides. Epidemiol
Control 1982;
siella antibiotic 3:224-9and
resistance serotypes. J Clin M
1982;16:868-73 87. Haley RW, Hightower AW, Khabbaz RF, Thornsberry C,
71. Pierog S, Nigam S, Lala RV,
Martone Crichlow
WJ, Allen DK, ofEv
JR, Hughes JM. The emergence
natal septicemia due tomethicillin-resistant
Klebsiella pneumoniae
Staphylococcus aureus infections in
Epidemic of unusuallyUnited low Statesvirulence.
hospitals: possible role ofNY
the houseSta
1977;77:737-41 staff-patient transfer circuit. Ann Intern Med 1982;
72. Weil AJ, Ramchand 97:297-308
S, Arias ME. Nosocomial i
Klebsiella type 25. N Engl
88. Rubens JWEMed
CE, Farrar 1966;275:1
Jr, McGee ZA, Schaffner W. Evo-
73. Hable KA, Matsen JM, lution ofWheeler DJ,
a plasmid mediating resistance Hunt
to multiple an-
Klebsiella type 33
septicemia in
timicrobial agents an
during infant
a prolonged epidemic ofinten
noso-
unit. J Pediatr 1972;80:920-4 comial infections. J Infect Dis 1981;143:170-81
74. Hill HR, Hunt CE, Matsen JM. Nosocomial colonization 89. Sugarman B, Pesanti E. Treatment failures secondary to in
with Klebsiella, type 26, in a neonatal intensive-care unit vivo development of drug resistance by microorganisms.
associated with an outbreak of sepsis, meningitis, and Rev Infect Dis 1980;2:153-68
necrotizing enterocolitis. J Pediatr 1974;85:415-9 90. Bawdon RE, Crane LR, Palchaudhuri S. Antibiotic resis-
75. Morgan ME, Hart CA, Cooke RW. Klebsiella infection in tance in anaerobic bacteria: molecular biology and clini-
a neonatal intensive care unit: role of bacteriological sur- cal aspects. Rev Infect Dis 1982;4:1075-95
veillance. J Hosp Infect 1984;5:377-85 91. Timoney JF, Linton AH. Experimental ecological studies
76. Monkus EF, MacIntyre DS, Turner J. One year's experience on H2 plasmids in the intestine and faeces of the calf.
with an outbreak of kanamycin gentamicin resistant kleb- J Appl Bacteriol 1982;52:417-24
siella bacteremia in a regional perinatal center [abstract 92. Jessen 0, Rosendal K, Bulow P, Faber V, Eriksen KR. Chang-
no. 288]. Pediatr Res 1976;10:349 ing staphylococci and staphylococcal infections: a ten-
77. Saravolatz LD, Arking L, Pohlod D, Fisher EJ, Borer R. year study of bacteria and cases of bacteremia. N Engl
An outbreak of gentamicin-resistant Klebsiella pneumo- J Med 1969;281:627-35
niae: analysis of control measures. Infect Control 1984; 93. Peluffo CA, Irino K. Virulence for mice of plasmid-bearing
5:79-84 epidemic strains of Salmonella typhimurium. In: Levy
78. White RD, Townsend TR, Stephens MA, Moxon ER. Are SB, Clowes RC, Koenig EL, eds. Molecular biology,
surveillance of resistant enteric bacilli and antimicrobial pathogenicity, and ecology of bacterial plasmids. New
usage among neonates in a newborn intensive care unit York: Plenum Press, 1981:642
useful? Pediatrics 1981;68:1-4 94. DeBoy JM II, Wachsmuth IK, Davis BR. Antibiotic resis-
79. Siegel JD, McCracken GH Jr, Threlkeld N, Milvenan B, tance in enterotoxigenic and non-enterotoxigenic Esche-
Rosenfeld CR. Single-dose penicillin prophylaxis against richia coli. J Clin Microbiol 1980;12:264-70
neonatal group B streptococcal infections. A controlled 95. Kopecko DJ, Formal SB. Plasmids and the virulence of en-
trial in 18,738 newborn infants. N Engl J Med 1980; teric and other bacterial pathogens. Ann Intern Med
303:769-75 1984;101:260-2
80. Siegel JD, McCracken GH Jr, Threlkeld N, DePasse BM,
96. van der Waaij D. Colonization pattern of the digestive tract
Rosenfeld CR. Single-dose penicillin prophylaxis of neo- by potentially pathogenic microorganisms: colonization-
natal group-B streptococcal disease. Conclusion of a 41 controlling mechanisms and consequences for antibiotic
month controlled trial. Lancet 1982;1:1426-30 treatment. Infection 1983;11(Suppl 2):S90-2
97. van der Waaij D. Colonization resistance of the digestive
81. Gaynes RP, Simpson D, Reeves SA, Noble RC, Thornsberry
C, Culver D, Allen JR, Martone WJ. A nursery outbreak tract: clinical consequences and implications. J An-
of multiple-aminoglycoside-resistant E. coli. Infect Con- timicrob Chemother 1982;10:263-70
trol 1984;5:519-24 98. Denoya CD. Nosocomial multiply resistant bacterial infec-
82. Murray SA, Snydman DR. Investigation of an epidemic of tiona: three studies in Buenos Aires. Alliance for the Pru-
multi-drug resistant Pseudomonas aeruginosa. Infect dent Use of Antibiotics Newsletter 1984;2:1-7
Control 1982;3:456-60 99. Rosenthal SL. Exacerbation of salmonella enteritis due to
83. Weinstein RA, Nathan C, Gruensfelder R, Kabins SA. En- ampicillin. N Engl J Med 1969;298:531-4
demic aminoglycoside resistance in gram-negative bacilli: 100. Sanders CC. Novel resistance selected by the new expanded-
epidemiology and mechanisms. J Infect Dis 1980; spectrum cephalosporins: a concern. J Infect Dis 1983;
141:338-45 147:585-9
101. Freeman J, McGowan JE Jr. Risk factors for nosocomial
84. Guerrant RL, Strausbaugh LJ, Wenzel RP, Hamory BH,
Sande MA. Nosocomial bloodstream infections caused infection. J Infect Dis 1978;138:811-9
by gentamicin-resistant gram-negative bacilli. Am J Med 102. Freeman J, Rosner BA, McGowan JE Jr. Adverse effects
1977;62:894-901 of nosocomial infection. J Infect Dis 1979;140:732-40
85. Sabath LD, Mokhbat JE. What is the clinical significance
103. Freeman J, McGowan JE Jr. Methodologic issues in hospi-

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]
 1078 Holmberg, Solomon, and Blake

tal epidemiology. III. Investigating the

losebekampfung. Band 131. Stuttgart, modifyi
Germany: Verlag
of time and severity of underlying
W. Kohlhammer, 1983:25-92 illness on
of cost of nosocomial infection.
109. Kereselidze Rev
T, Maglacas AM. Nosocomial infections -Infec
what
6:285-99 WHO is doing. J Hosp Infect 1984;5(Suppl A):7-11
104. O'Brien TF, Norton RA, Kent RL, Medeiros AA. Interna- 110. Daschner FD. The cost of hospital-acquired infection. J Hosp
tional surveillance of prevalence of antibiotic resistance. Infect 1984;5(Suppl A):27-33
J Antimicrob Chemother 1977;3(Suppl C):59-66 111. Dixon RE. Effect of infections on hospital care. Ann Intern
105. O'Brien TF, Acar JF, Medeiros AA, Norton RA, Goldstein Med 1978;89:749-53
F, Kent RL. International comparison of prevalence112. of Brachman PS, Dan BB, Haley RW, Hooton TM, Garner JS,
resistance to antibiotics. JAMA 1978;239:1518-23 Allen JR. Nosocomial surgical infections: incidence and
106. Cohen ML, Fontaine RE, Pollard RA, Von Allmen SD, Ver- cost. Surg Clin North Am 1980;60:15-25
non TM, Gangarosa EJ. An assessment of patient-related 113. Pinner RW, Haley RW, Blumenstein BA, Schaberg DR, Von
economic costs in an outbreak of salmonellosis. N Engl Allmen SD, McGowan JE Jr. High cost nosocomial in-
J Med 1978;299:459-60 fections. Infect Control 1982;3:143-9
107. Curtin L. Economic study of Salmonella poisoning and con- 114. Haley RW, Culver DH, White JW, Morgan WM, Emori TG.
trol measures in Canada. Ottawa, Ontario; Agriculture The nationwide nosocomial infection rate: a new need
Canada, August 1984:72-83 for vital statistics. Am J Epidemiol 1985;121:159-67
108. Krug W, Rehm N. Nutzen-Costen-Analyse der Salmonel-

This content downloaded from

[Link] on Sat, 09 Jan 2021 [Link] UTC
All use subject to [Link]