Ampicillin/Sulbactam - Springer

Drugs 2007; 67 (13): 1829-1849REVIEW ARTICLE 0012-6667/07/0013-1829/$49.95/0

© 2007 Adis Data Information BV. All rights reserved.

Ampicillin/SulbactamCurrent Status in Severe Bacterial Infections

Petros I. Rafailidis,1,2 Eleni N. Ioannidou1 and Matthew E. Falagas1,3,2

1 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece2 Department of Medicine, Henry Dunant Hospital, Athens, Greece3 Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18291. Overview of Antibacterial Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1830

1.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18301.2 Spectrum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18301.3 Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1832

2. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18333. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18334. Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18335. Therapeutic Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1834

5.1 Lower Respiratory Tract Infections (LRTIs) and Aspiration Pneumonia . . . . . . . . . . . . . . . . . . . . . 18345.1.1 LRTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18345.1.2 Aspiration Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1834

5.2 Gynaecological/Obstetrical Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18365.3 Intra-Abdominal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18385.4 Diabetic Foot Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18395.5 Skin and Soft Tissue Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18415.6 Sepsis in the Paediatric Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18425.7 Infections in the Intensive Care Unit Setting Due to Acinetobacter baumannii . . . . . . . . . . . . 1843

6. Place of Ampicillin/Sulbactam in the Treatment of Severe Infections . . . . . . . . . . . . . . . . . . . . . . . . . 18447. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845

Ampicillin/sulbactam is a β-lactam/β-lactamase inhibitor combination with aAbstractbroad spectrum of antibacterial activity against Gram-positive, Gram-negativeand anaerobic bacteria. Data from comparative studies justify the use of ampi-cillin/sulbactam in a 2 : 1 ratio in various severe bacterial infections. In compara-tive clinical trials, ampicillin/sulbactam has proved to be a significant drug in thetherapeutic armamentarium for lower respiratory tract infections and aspirationpneumonia, gynaecological/obstetrical infections, intra-abdominal infections,paediatric infections such as acute epiglottitis and periorbital cellulitis, diabeticfoot infections, and skin and soft tissue infections. Of particular interest duringthis era of increasing antimicrobial resistance in various settings and populationsis the effectiveness of sulbactam against a considerable proportion of infectionsdue to Acinetobacter baumannii.

1830 Rafailidis et al.

Ampicillin/sulbactam is a β-lactam/β-lactamase tive therapeutic option for this nosocomial patho-inhibitor combination that was first developed and gen.marketed in the US in 1987. Since then, several

1.1 Mechanism of Actionclinical studies have been conducted to examine itseffectiveness in various types of infections. More-

Ampicillin inhibits bacterial cell wall synthesisover, in the era of emerging resistance, there has

by binding to penicillin binding proteins (PBPs),been an effort to evaluate ampicillin/sulbactam as a

which are the enzymes responsible for the formationdrug against multidrug-resistant (MDR) Acineto-

of the cell wall structure. Ampicillin, like all penicil-bacter spp. This review updates information con-

lins, acts as a structural analogue of acyl-D-alanyl-Dcerning the use of ampicillin/sulbactam in severe

alanine and acylates the transpeptidase enzyme re-infections.

sponsible for the final stage of the formation of theA literature search was performed in order to peptidoglycan, which is the main component of the

retrieve comparative studies concerning the clinical cell wall.[2] Sulbactam, a β-lactamase inhibitor ob-effectiveness of ampicillin/sulbactam. Studies were tained by oxidation of the thiazolidine sulfur ofidentified in the Scopus and PubMed databases. Key penicillanic acid, lacks significant antibacterial ac-words used were ‘ampicillin/sulbactam AND severe tivity (except for Neisseria and Acinetobacterinfection’ as well as combinations of ampicillin/ spp.)[3-7] but increases the activity of ampicillin as itsulbactam with specific infections or pathogens protects it from hydrolysis by β-lactamases.[8] The(lower respiratory tract, pneumonia, gynaecological exact mechanism is complicated, but there is generalinfections, obstetrical infections, pelvic inflammato- agreement that sulbactam is initially recognised byry disease, endometritis, salpingitis, intra-abdominal the β-lactamases as the normal substrate and formsinfections, appendicitis, sepsis, diabetic foot infec- an acyl enzyme by reacting with the active sitetions, skin or soft tissue infections, Acinetobacter). serine hydroxyl group. This intermediate can thenKey terms used to retrieve studies concerning undergo (i) a deacylation and hydrolysis of theampicillin/sulbactam spectrum were ‘ampicillin/ enamine liberated, which leads to the formation ofsulbactam AND Gram-negative OR anaerobes’ or smaller products; (ii) a tautomerisation to enaminespecific pathogens (pneumococcus, Staphylococcus, leading to a transiently inhibited form of the en-Haemophilus influenzae, Enterobacteriaceae, Es- zyme; and (iii) a transamination reaction or reactioncherichia coli, Bacteroides fragilis). with serine 130 that leads to an irreversibly inhibited

enzyme form.[9]

1. Overview of Antibacterial Activity1.2 Spectrum

β-Lactamase production is of critical importanceTable I presents an overview of the antibacterialfor the emergence of resistant bacterial mutants.

activity of ampicillin/sulbactam.Combinations of β-lactams with β-lactamase inhibi-Streptococcus pneumoniae, H. influenzae andtors, such as ampicillin/sulbactam, extend the spec-

Moraxella catarrhalis are pathogens that exhibittrum of β-lactams by preventing the hydrolysis byhigh susceptibility rates to ampicillin/sulbactam ac-β-lactamases. Additionally, the fact that β-lactam/cording to data obtained from a multicentre study inβ-lactamase inhibitor combinations are less potentGermany[16] (331 S. pneumoniae isolates, 300 H.β-lactamase inducers than cephalosporins makeinfluenzae isolates and 308 M. catarrhalis isolates),them a useful weapon in controlling resistance.[1]

and from a study in Argentina[10] (30 S. pneumoniaeThe cumulating data about the intrinsic antimicrobi-isolates).al activity of sulbactam against Acinetobacter spe-

cies and the synergistic effect it may exhibit in Among Enterobacteriaceae, the genera Mor-combination with other antimicrobial agents (see ganella, Enterobacter and Serratia have the highestsection 1.1), make ampicillin/sulbactam an alterna- resistance rates to ampicillin/sulbactam. For other

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (13)

Ampicillin/Sulbactam in Severe Bacterial Infections 1831

Table I. Susceptibilities of Gram-positive and Gram-negative pathogens, and anaerobes to ampicillin/sulbactam

Pathogen No. of isolates in the reviewed Susceptibility (%) Commentstudies

Streptococcus pneumoniae 331[10] 100 Ampicillin/sulbactam has satisfactory activityagainst Gram-positive pathogens. However, datafrom large multicentre studies are missing

Haemophilus influenzae 300[10] 100

Moraxella catarrhalis 30[11] 100

Escherichia coli 108,[10] 1403,[11] 52,[12] 21–60 The lowest susceptibility rates were observed in86 569[13] Latin America and Asia/Pacific, and the highest in

the US[11]

E. coli (ESBL) 37,[10] 102[11] 5–12 Susceptibility of ESBL strains is lower than non-ESBL strains

Klebsiella pneumoniae 44,[10] 526,[11] 49,[12] 36 456[13] 73–86 The lowest susceptibility rates were observed inLatin America and Asia/Pacific, and the highest inEurope[11]

K. pneumoniae (ESBL) 56,[10] 67,[11] 50[12] 4–7 Susceptibility of ESBL strains is notably lowerthan non-ESBL strains

Citrobacter spp. 129,[11] 6015[13] 46–54

Proteus spp. 144,[11] 16 462[13] 81–92

Morganella spp. 66,[11] 3767[13] 8–31

Enterobacter spp. 230,[11] 15 587[13] 18–25

Serratia spp. 39,[11] 51,[12] 9514[13] 2–10

Acinetobacter baumannii 1248a 32–97 The lowest susceptibility rates were observed inArgentina and the highest in Hong Kong

Bacteroides fragilis group 158,[14] 2673[15] 85–98 Non-Bacteroides fragilis spp. have higherresistance rates than B. fragilis

a Data from relevant studies are presented in detail in table II.

ESBL = extended-spectrum β-lactamase.

members of the Enterobacteriaceae family (E. coli, were retrieved from the SENTRY AntimicrobialKlebsiella pneumoniae, Citrobacter spp. and Pro- Surveillance Program on three continents[17] andteus spp.), susceptibility rates are higher despite the from studies conducted in Esthonia,[18] Germany,[19]

fact that ampicillin/sulbactam is less active when Spain,[20] Hong Kong,[20] China,[21] the US,[22] Tai-compared with carbapenems, third or fourth genera- wan,[12] Argentina[10] and Turkey.[23] It should betion cephalosporins, aminoglycosides and piperacil- noted that existing methods to determinelin/tazobactam.[11] It should be noted that ampicillin/ A. baumannii susceptibilities (disc diffusion andsulbactam is not active against Pseudomonas aerug- broth microdilution) might not be reliable in predict-inosa[11] and Enterobacteriaceae that produce ex- ing susceptibility to sulbactam, which is the activetended-spectrum β-lactamases (ESBLs).[10-12] The drug against this pathogen. Additionally, thererelevant data presented in table I were obtained from might be discrepancies in minimum inhibitory con-a multicentre study conducted in 17 countries (Study centrations (MICs) depending on whether a fixedfor Monitoring Antimicrobial Resistance Trends ratio of ampicillin/sulbactam or a fixed concentra-[SMART]),[11] and from three studies conducted in tion of sulbactam was used.[24]

Argentina, Taiwan and the US.[10,12,13] B. fragilis isolates exhibit high susceptibilityAcinetobacter baumannii exhibits variable sensi- rates to ampicillin/sulbactam. The relevant data

tivity rates to ampicillin/sulbactam according to the presented in table I were collected from two multi-sensitivity rates presented in table II. Relevant data centre studies conducted in the US.[14,15]



1.3 Resistance

The principal mechanism of resistance againstampicillin involves inactivation by β-lactamases,which are the hydrolytic enzymes responsible forthe formation of an acidic derivative of β-lactamsdeprived of antibacterial activity. Resistance to β-lactams can also arise from a reduced number ofporin channels, which are the proteins that regulatethe permeability of the outer membrane of Gram-negative bacteria for antibacterials and the interac-tion with their environment.[2,25] Mutations to genesthat encode PBPs is another mechanism of resis-tance, as alterations in the structure of PBPs maysignificantly reduce their affinity with β-lactams.There may be more than one resistance mechanismpresent in a bacterium, i.e. methicillin-resistantStaphylococcus aureus (MRSA) exhibits resistanceby mecA gene expression, which encodes for thealtered PBP2, and by increased production of β-lactamases.[26]

The first mechanisms of resistance to the β-lactam/β-lactamase inhibitors described were hyper-production of wild-type TEM-1 and TEM-2 penicil-linases, and alteration of the permeability of theouter membrane due to mutations in the genes en-coding porin channels.[27] β-Lactamase hyper-production is caused by point mutation at position162 in the promoter region of the blaTEM gene,which encodes β-lactamases.[28] In the 1990s, thefirst inhibitor-resistant TEM (IRT) β-lactamaseswere described.[29] These mutated β-lactamasesarise from amino acid substitutions, which are dif-ferent from those responsible for ESBL production,in the genes encoding TEM-1 and TEM-2 β-lactamases, and up to 29 December 2006 there hadbeen 25 IRTs identified.[30] They are found mainlyin E. coli, K. pneumoniae and K. oxytoca, Proteusmirabilis and Citrobacter freundii.[31]

In the era of evolving resistance, the effective-ness of ampicillin/sulbactam against ESBL-produc-ing species would be a matter of great interest.However, existing data suggest that ampicillin/sulbactam should not be used in ESBL-producingbacteria as even when in vitro susceptibility isdemonstrated, clinical failures may be noticed.[32,33]


Tab

le I

I. S

usce

ptib

ilitie

s of

Aci

neto

bact

er b

aum

anni

i iso

late

s to

am

pici

llin/

sulb

acta

m

Par

amet

erE

ston

ia 2

006

Ger

man

yS

pain

Hon

g K

ong

Nor

thC

hina

200

4U

SA

200

4T

aiw

an 2

003

Arg

entin

aT

urke

y(L

oivu

kene

et

2005

2004

– 520

04– 5

Am

eric

a,(H

uang

et

(Sw

enso

n et

(Wan

g et

al.[1

2])

2001

– 219

94– 2

000

al.[1

8])

(Bra

uers

et

(Gar

cia-

(Gar

cia-

Sou

thal

.[21])

al.[2

2])

(Cas

ella

s et

(Tat

man

-al

.[19])

Pen

uela

et

Pen

uela

et

Am

eric

a,al

.[10])

Otk

un e

tal

.[20])

al.[2

0])

Eur

ope

2004

al.[2

3])

(Fed

ler

etal

.[17])

No.

of

isol

ates

5039

574

3064

132

195

68a

30b

6015

0

Sus

cept

ible

6092

5496

.675

76.5

63.6

76.5

7032

73

(%)

aIm

ipen

em-s

ensi

tive

A.

baum

anni

i.

bIm

ipen

em-r

esis

tant

A.

baum

anni

i.


Inoculum effect and loss of porin channels are someof the factors contributing to in vivo failures. Themainstay of antibacterial treatment for infectionsdue to ESBL-producing strains are the carbapen-ems.[34]

2. Pharmacodynamics

Sulbactam exhibits a synergistic effect withampicillin as it inhibits hydrolysis of the latter by β-lactamases.[35] As a result, the antimicrobial activityof ampicillin when combined with sulbactam in-

Table III. Pharmacokinetics of ampicillin/sulbactam administeredintravenously in healthy middle-aged volunteers.[46]

Parameter Ampicillin (2g) Sulbactam (1g)

Cmax (μg/mL) 82 ± 15 42 ± 7

Vdss (L/kg) 31 ± 9 30 ± 10

t1/2 1 ± 0.2 1 ± 0.2

AUC∞ (μg • h/mL) 120 ± 16 72 ± 9

Clearance (mL/min) 281 ± 34 236 ± 27

Renal clearance 144 ± 64 136 ± 58(mL/min)

AUC∞ = area under the serum concentration-time curve from zeroto infinity; Cmax = serum maximum concentration; t1/2 = eliminationhalf-life; Vdss = volume of distribution at steady state.

creases by 4- to 32-fold.[2] Sulbactam is more activeagainst class A β-lactamases (mainly plasma medi- are presented in table III.[46] Comparative pharma-ated, highly active against penicillins) than class C cokinetic data for ampicillin/sulbactam in youngβ-lactamases (mainly chromosomally encoded, and elderly individuals suggest that there is prolon-highly active against cephalosporins). However, in gation of ampicillin/sulbactam antimicrobial activi-comparison with clavulanic acid and tazobactam, ty as age increases that is due to the area under thesulbactam is a less potent inhibitor of class A β- serum concentration-time curve, half-life (t1/2), se-lactamases and a more potent inhibitor than clavu- rum maximum concentration and decreased totallanic for class C β-lactamases. Inhibitory potency of clearance in older age groups.[46] Given that ampicil-sulbactam against class D enzymes is weaker than lin/sulbactam is primarily eliminated by renal excre-against class A β-lactamases.[2] Although sulbactam tion, the t1/2 and serum concentrations in patientshas the ability to induce β-lactamases, it is a less with impaired renal function are increased.[47]

potent inducer than clavulanic acid and a more po- Pharmacokinetic properties of ampicillin/sulbactamtent inducer than tazobactam.[36] in children and adults do not differ significantly.[48]

However, ampicillin/sulbactam should be adminis-Ampicillin/sulbactam may exhibit the inoculumtered with caution to infants aged <1 week and toeffect only at high concentrations of bacteria.[37]

premature neonates as t1/2 is significantly increasedThere are a number of in vitro studies that investi-for both ampicillin and sulbactam because of thegate the combination of ampicillin/sulbactam withunderdevelopment of the urinary system in neo-other antimicrobial agents and their effect on MDRnates.[48,49] The t1/2 of ampicillin/sulbactam is de-Gram-positive cocci. An in vitro synergistic effectcreased in women during labour, which suggests theof ampicillin/sulbactam has been noticed againstappropriateness of a more frequent administrationMRSA with daptomycin[38] and fosfomycin[39,40]

schedule.[49] The protein binding of ampicillin andagainst some strains of vancomycin intermediate S.sulbactam in serum is moderate (38% for sulbactamaureus with trovafloxacin,[41] and againstand 28% for ampicillin). Data on sulbactam penetra-A. baumannii with tobramycin,[23,42] amikacin,[42]

tion into tissues/fluids include: intraperitoneal fluidcefepime,[43] meropenem and imipenem.[44,45]

(60%), sputum (12–14%), cerebrospinal fluid (CSF)3. Pharmacokinetic Properties [11–34%], intestinal mucosa (0.7–0.8%) and my-

ometrium (64%).[2]

Ampicillin/sulbactam is not well absorbed afteroral administration. Sultamicillin, the double ester 4. Adverse Effectsprodrug of ampicillin/sulbactam, has increased ab-sorption after oral administration that reaches 80%. Ampicillin/sulbactam is generally well tolerated.The pharmacokinetic properties of ampicillin/ The most prominent adverse reaction is site painsulbactam after intravenous administration in adults after intramuscular injection and this can be avoided



by diluting the preparation with lidocaine before imipenem/cilastatin[60] as comparators. In all theadministration. Other adverse reactions reported are: identified studies, the cure rates achieved withdiarrhoea (1.9%), phlebitis (1.2%) and rash (<2%). ampicillin/sulbactam were higher than the compara-Laboratory changes most commonly reported in- tors (though not significantly higher) and rangedvolve elevated hepatic enzymes (AST, ALT, alka- from 83% to 100%. An exception to this was noticedline phosphatase, lactate dehydrogenase). Haemato- in one study,[59] where patients who receivedlogical abnormalities (decreased haematocrit/ ampicillin/sulbactam 3g had lower cure rates thanhaemoglobin, leukopenia, lymphopenia, thrombo- those treated with ticarcillin/clavulanic acid. Thecytopenia or increased lymphocytes, monocytes, ba- authors of this study do not further discuss thissophils, eosinophils and platelets), decreased albu- finding as it was not statistically significant. Bacteri-min and total proteins, increased creatinine, and the ological eradication rates with ampicillin/sulbactampresence of red blood cells and hyaline casts in the range from 58% to 100% and are higher than thoseurine are less frequent.[47,50] achieved by the comparators in half of the studies

providing relevant data.[53,56,57,60] However, the dif-ferences between regimens were not statistically5. Therapeutic Effectivenesssignificant.

The efficacy and cost of ampicillin/sulbactam5.1 Lower Respiratory Tract Infections (LRTIs)

versus ticarcillin/clavulanic acid was compared ret-and Aspiration Pneumonia

rospectively in patients with lower respiratory tractinfections (LRTIs) by McKinnon and Neuhauser.[59]

Pneumonia is the seventh leading cause of deathAlthough differences in clinical and bacteriologicalin the US. Causative agents are S. pneumoniae, H.efficacy between ampicillin/sulbactam and ticarcil-influenzae, Mycoplasma pneumoniae, Chlamy-lin/clavulanic acid were not statistically significant,dophila (Chlamydia) pneumoniae, S. aureus, S. py-the length of stay was significantly smaller in pa-ogenes, M. catarrhalis, K. pneumoniae, Legionellatients who received half-dose ampicillin/sulbactam.spp., and the influenza virus.[51] According to theAdditionally, ticarcillin/clavulanic acid was a lessInfectious Diseases Society of America (IDSA) andexpensive treatment option than ampicillin/sulbac-the American Thoracic Society (ATS) guidelinestam (3g) and more expensive than ampicillin/(2007), ampicillin/sulbactam can be used in inten-sulbactam (1.5g). Differences between groups weresive care unit (ICU) patients with community-ac-statistically significant. A meta-analysis[63] of thequired pneumonia who are not at risk forefficacy and safety of ampicillin/sulbactam versus aPseudomonas infection, in combination with aset of cephalosporins (cefoxitin, cefotaxime, ce-macrolide or fluoroquinolone.[51] IDSA/ATS guide-furoxime and cefamandole) showed that rates oflines (2005) for hospital-acquired pneumonia (HAP)clinical cure were higher with ampicillin/sulbactamsuggest that ampicillin/sulbactam may be adminis-by 9.56% (p = 0.055), whereas rates of clinical curetered to patients without risk factors for multidrugor improvement were significantly higher withresistance pathogens and in early-onset HAP.[52]

ampicillin/sulbactam (p = 0.019). Adverse effects5.1.1 LRTIs were comparable in both groups.The eight identified comparable studies[53-60] con-

5.1.2 Aspiration Pneumoniacern pneumonia, acute exacerbation of chronicbronchitis and bronchitis (table IV). The majority of In the management of aspiration pneumonia,the studies compare the effectiveness of ampicillin/ ampicillin/sulbactam has been compared withsulbactam with second- and third-generation antimicrobials with antianaerobic activity such ascephalosporins (cefuroxime,[53,55,56] cefotaxime,[54] clindamycin and imipenem/cilastatin. Cure ratesand cefoxitin[58]), except for three studies that used with ampicillin/sulbactam in aspiration pneumoniamezlocillin,[57] ticarcillin/clavulanic acid[59] and were relatively low in comparison with the cure/




Tab

le I

V.

Sum

mar

y of

the

stu

dies

exa

min

ing

effic

acy

of a

mpi

cilli

n/su

lbac

tam

in p

atie

nts

with

low

er r

espi

rato

ry t

ract

infe

ctio

ns (

LRT

Is)

Stu

dyN

o. o

fIn

fect

ion

Ant

ibac

teria

l (do

sage

)C

ure

and/

or im

prov

emen

tB

acte

riolo

gica

l era

dica

tion

(yea

r)ev

alua

ble

ampi

cilli

n/co

mpa

rato

ram

pici

llin/

com

para

tor

p-va

lue

ampi

cilli

n/co

mpa

rato

rp-

valu

epa

tient

ssu

lbac

tam

sulb

acta

m (

%)

(%)

sulb

acta

m (

%)

(%)

Gec

kler

[53]

37P

neum

onia

: 32

1.5–

3g q

idC

efur

oxim

e10

095

0.57

100

940.

49

(199

4)A

EC

B:

5(7

50m

g–1g

q8h

)

Jaur

egui

et

al.[5

4]48

LRT

I3g

q6h

Cef

otax

ime

85.3

81.3

0.82

Tot

al:

55.9

Tot

al:

62.5

0.65

(199

5)(2

g q6

h)P

artia

l: 20

.6P

artia

l: 12

.5

Ros

soff

et a

l.[55]

47P

neum

onia

: 41

3g q

6hC

efur

oxim

e88

810.

4764

680.

24

(199

5)B

ronc

hitis

: 6

(1.5

g q8

h)

Sch

wig

on e

t al

. [5

6]73

Pne

umon

ia:

463g

tid

Cef

urox

ime

8980

ND

8482

ND

(199

6)A

cute

pur

ulen

t(1

.5g

tid)

bron

chiti

s: 2

7

Sch

wig

on e

t al

.[57]

96P

neum

onia

: 65

3g q

8hM

ezlo

cilli

n84

82.6

ND

90.2

88.9

ND

(199

6)A

EC

B:

31(4

g q8

h)

Cas

tella

no a

nd75

Pne

umon

ia3g

q6h

Cef

oxiti

n92

87N

D67

78N

D

Man

iatis

[58] (

1998

)A

EC

B(2

g q6

h)

McK

inno

n an

d20

0LR

TI

G1:

1.5

g q6

hG

3: t

icar

cilli

n/G

1: 8

378

0.39

G1:

62

G3:

71

0.42

Neu

haus

er[5

9]G

2: 3

g q6

hcl

avul

anic

aci

dG

2: 7

0G

2: 5

8

(199

9)(3

.1g

q6h)

Alle

wel

t et

al.[6

1]70

Asp

iratio

n pn

eum

onia

3g t

idC

linda

myc

in73

66.7

ND

ND

ND

(200

4)(6

00m

g tid

)

Kad

owak

i et

al.[6

2]10

0A

spira

tion

pneu

mon

iaG

1: 1

.5g

bid

G3:

clin

dam

ycin

G1:

76

G3:

76

0.62

ND

ND

(200

5)(d

istr

ibut

edG

2: 3

g bi

d(6

00m

g bi

d)G

2: 8

4G

4: 8

8

equa

llyG

4: im

ipen

em/

into

4ci

last

atin

(0.

5g b

id)

grou

ps)

Yan

agih

ara

et67

Com

mun

ity-a

cqui

red

3g b

idIm

ipen

em/c

ilast

atin

91.4

87.5

NS

8480

ND

al.[6

0] (

2006

)pn

eum

onia

(0.5

g bi

d)

AE

CB

= a

cute

exa

cerb

atio

n of

chr

onic

bro

nchi

tis;

bid

= t

wic

e da

ily;

G =

gro

up;

ND

= n

o da

ta;

NS

= n

ot s

igni

fican

t; q

xh =

eve

ry x

hou

rs;

qid

= f

our

times

dai

ly;

tid

= t

hree

tim

es

daily

.


improvement rates of ampicillin/sulbactam in clini- stetrical infections, i.e. post-caesarean and post-par-cal trials of LRTIs without aspiration (i.e. 73% and tum endometritis (table V). In five studies,[67-71]

76%, respectively) in two identified studies (table ampicillin/sulbactam is compared with cefoxitin. InIV).[61,62] Kadowaki et al.[62] examined the cost ef- four studies,[65,69,74,75] the comparator is clindamycinfectiveness of ampicillin/sulbactam, clindamycin alone or with gentamicin. In two studies,[66,73]

and imipenem/cilastatin in 100 elderly patients with ampicillin/sulbactam is compared with me-mild to moderate aspiration pneumonia. Ampicillin/ tronidazole ± gentamicin. One study[72] usessulbactam was administered in two different dosage cefotetan as a comparator and one study[59] exam-protocols: 3g twice daily and 1.5g twice daily. Cure ines ampicillin/sulbactam versus ticarcillin/clavu-rates in the patients who received ampicillin/ lanic acid. Cure and/or improvement rates rangedsulbactam 3g were higher (84%) than the respective

from 82% to 100%. Clinical efficacy with ampicil-rates in patients treated with the half dose and com-

lin/sulbactam was higher than[66,68,70] or equal to[67]parable with those in the imipenem/cilastatin group

cefoxitin except in one study,[69] but was inferior(88%), which seemed to be the most effective regi-than clindamycin plus gentamicin in all relevantmen. However, it is noticeable that this study wasstudies. Cefotetan and metronidazole plusinterrupted early because of the appearance ofgentamicin were found to have equal clinical effica-MRSA in all patient groups except those who re-cy with ampicillin/sulbactam in two studies.[72,73]

ceived clindamycin. The highest rate of MRSA wasHowever, it should be noted that differences be-noticed in the carbapenem group. Clindamycin wastween therapeutic regimens in cure/improvementalso found to be significantly less expensive than therates were not statistically significant except in oneother three regimens.study conducted by Bruhat et al.,[76] which, in con-trast with the studies included in table V, examined5.2 Gynaecological/Obstetrical Infectionsthe effectiveness of comparative regimens

Pelvic inflammatory disease (PID) is a broad laparoscopically. In this study,[76] ampicillin/term that includes endometritis, salpingitis, tubo- sulbactam was compared with cefoxitin in 40 pa-ovarian abscess and pelvic peritonitis. Pathogens tients with acute salpingitis and achieved 95% curecommonly responsible for PID are sexually trans- rates established laparoscopically versus 70% in themitted, such as N. gonorrhoeae and Chlamydia cefoxitin arm. Bacteriological eradication wastrachomatis, or they belong to the vaginal flora, i.e. higher in the ampicillin/sulbactam arm in all theanaerobes, Gardnerella vaginalis, H. influenzae, studies[59,65,67,70,71,75] providing relevant data (dataGram-negative bacteria and S. agalactiae.[64] First-

not available in 6 of 12 studies). In most of theline treatment options consist of cefotetan or cefoxi-

studies, differences in bacteriological efficacy aretin plus doxycycline or clindamycin with gentam-not significant.[59,65,67,71,75] However, Stiglmayer eticin plus doxycycline (Centers for Disease Controlal.,[70] who compared ampicillin/sulbactam withand Prevention 2006).[64] A dosage of ampicillin/cefoxitin in 76 patients with PID, found that despitesulbactam 3g every 6 hours is recommended as anthe fact that cure rates in both regimens were compa-alternative treatment for PID, with clinical efficacyrable (cure 87%, improvement 10.5% in the ampicil-comparable with the first-line regimens according tolin/sulbactam group vs cure 79%, improvementexisting data.10.5% in the cefoxitin group), eradication rates Eight of 12 identified studies[59,65-71] examine thereached 91% in the ampicillin/sulbactam arm versuseffectiveness of ampicillin/sulbactam in PID/only 59% in the cefoxitin arm. Thus, the ampicillin/gynaecological infections in general or focus onsulbactam regimen was significantly superior totubo-ovarian abscess, endomyometritis, pelvic cel-cefoxitin in terms of bacteriological eradication, al-lulitis, salpingitis or pelvic peritonitis. The remain-

ing four studies[72-75] examine gynaecological/ob- though not in terms of clinical efficacy.




Tab

le V

. S

umm

ary

of s

tudi

es e

xam

inin

g th

e ef

ficac

y of

am

pici

llin/

sulb

acta

m v

ersu

s co

mpa

rato

r in

gyn

aeco

logi

cal a

nd o

bste

tric

al in

fect

ions

Stu

dyN

o. o

fIn

fect

ion

Ant

ibac

teria

l (do

sage

)C

ure

and/

or im

prov

emen

tB

acte

riolo

gica

l era

dica

tion

(yea

r)ev

alua

ble

ampi

cilli

n/co

mpa

rato

ram

pici

llin/

com

para

tor

p-va

lue

ampi

cilli

n/co

mpa

rato

rp-

valu

epa

tient

ssu

lbac

tam

sulb

acta

m (

%)

(%)

sulb

acta

m (

%)

(%)

Gun

ning

[65] (

1986

)60

PID

3g q

6hC

linda

myc

in85

.794

.4N

D10

097

.1N

D(6

00m

g q6

h) +

gent

amic

in (

1.5

mg/

kg q

8h)

Cro

mbl

ehol

me

et41

Sev

ere

PID

, tu

bo-

3g q

6hM

etro

nida

zole

(15

9586

ND

ND

ND

al.[6

6]ov

aria

n ab

sces

s,m

g/kg

load

ing,

7.5

(198

7)en

dom

yom

etrit

is,

pelv

icm

g/kg

q6h

cellu

litis

mai

nten

ance

) +

gent

amic

in (

1.5

mg/

kg q

8h)

Hem

sell

et a

l.[67]

22C

ompl

icat

ed/

3g q

6hC

efox

itin

(2g

q6h)

100

100

ND

9894

ND

(198

8)un

com

plic

ated

PID

Sca

lam

brin

o et

95gy

naec

olog

ical

/3g

q6h

Cef

otet

an (

2g89

89N

DN

DN

Dal

.[72]

obst

etric

al in

fect

ions

q12h

)(1

989)

Mar

tens

et

al.[7

3]67

Pos

tcae

sare

an3g

q6h

Met

roni

dazo

le 9

1 9

1N

DN

DN

D(1

989)

endo

met

ritis

(500

mg

q6h)

+ge

ntam

icin

(100

–120

mg

load

ing,

80m

g q8

hm

aint

enan

ce)

Mar

tens

et

al.[7

4]68

Pos

tpar

tum

3g q

6hC

linda

myc

in83

88N

DN

DN

D(1

990)

endo

myo

met

ritis

(900

mh

q8h)

Hem

sell

et a

l.[68]

54A

cute

sal

ping

itis

3g q

6hC

efox

itin

(2g

q6h)

9489

ND

ND

ND

(199

0)

McG

rego

r et

al.[6

9]30

4E

ndom

etrit

is3g

q6h

Clin

dam

ycin

88.7

90.8

0.7

ND

ND

(199

4)(9

00m

g q8

h) +

gent

amic

in (

1.5m

g/kg

q8h

)

McG

rego

r et

al.[6

9]10

3P

ID3g

q6h

Cef

oxiti

n (2

g q6

h)85

.589

.60.

76N

DN

D(1

994)

Con

tinue

d ne

xt p

age


A retrospective pharmacoeconomic study[77] wasconducted to assess the cost effectiveness of ampi-cillin/sulbactam versus cefoxitin in PID. Seventy-six women were treated with ampicillin/sulbactam(3g every 6 hours) and 41 women were treated withcefoxitin (2g every 6 hours). Ampicillin/sulbactamwas more effective (p = 0.05) and less costly (p <0.001) than cefoxitin. In a prospective trial,[78] 76patients with postpartum endometritis were treatedwith ampicillin/sulbactam (1.5g every 6 hours) orclindamycin (900mg intravenously every 8 hours)plus gentamicin (1 mg/kg every 8 hours after aloading dose of 1.5 mg/kg). Failure rates, days oftherapy and cost of treatment for ampicillin/sulbactam were 17.6%, 3.3 ± 1.3 and $US139.49,respectively, compared with 9.5%, 3.6 ± 1.8 and$US355.32, respectively, for clindamycin/gentam-icin. The authors suggest that ampicillin/sulbactamhas comparable cost effectiveness to clindamycinplus gentamicin in early postpartum endometritis.McKinnon and Neuhauser[59] examined ampicillin/sulbactam (1.5g in 24 patients in group 1; 3g in 38patients in group 2) versus ticarcillin/clavulanic acid(5 patients in group 3) in patients with gynaecologi-cal infections. Although clinical and bacteriologicalefficacy rates were not significantly different amonggroups, costs for preparation and delivery were sig-nificantly lower in the ampicillin/sulbactam groupthan in the ticarcillin/clavulanic acid group.

5.3 Intra-Abdominal Infections

The mainstay of treatment of intra-abdominalinfections is surgical debridement in combinationwith antimicrobial cover against the anticipatedpolymicrobial flora. Common aetiological agents ofintra-abdominal infections are facultative and aero-bic Gram-negative organisms and anaerobes.[79] TheIDSA guidelines regarding complicated intra-ab-dominal infections recommend that ampicillin/sulbactam should be used in mild to moderate com-munity-acquired infections; patients with more se-vere infections might benefit from regimens with abroader spectrum against facultative and Gram-neg-ative aerobic bacteria. Health care associated withcomplicated intra-abdominal infections necessitates


Tab

le V

. C

ontd

Stu

dyN

o. o

fIn

fect

ion

Ant

ibac

teria

l (do

sage

)C

ure

and/

or im

prov

emen

tB

acte

riolo

gica

l era

dica

tion

(yea

r)ev

alua

ble

ampi

cilli

n/co

mpa

rato

ram

pici

llin/

com

para

tor

p-va

lue

ampi

cilli

n/co

mpa

rato

rp-

valu

epa

tient

ssu

lbac

tam

sulb

acta

m (

%)

(%)

sulb

acta

m (

%)

(%)

Gal

l and

Kou

kol[7

5]10

7P

ostp

artu

m3g

q6h

Clin

dam

ycin

8284

NS

8684

NS

(199

6)en

dom

etrit

is(9

00m

g q8

h) +

gent

amic

in (

1.5

mg/

kg q

8h)

Stig

lmay

er e

t al

.[70]

76E

ndom

etrit

is,

3g q

8hC

efox

itin

(2g

q8h)

97.5

89.5

ND

9159

0.03

(199

6)sa

lpin

gitis

, tu

bo-o

varia

nab

sces

s, p

elvi

cpe

riton

itis

Jem

sek

and

93P

ID3g

q6h

Cef

oxiti

n (2

g q6

h)97

920.

6770

560.

64H

arris

on,[7

1] (

1997

)

McK

inno

n an

d67

gyna

ecol

ogic

alG

1: 1

.5g

q6h

G3:

tic

arci

llin/

G1:

96

G3:

100

0.68

G1:

80

G3:

29

ND

Neu

haus

er[5

9]in

fect

ions

G2:

3g

q6h

clav

ulan

ic a

cid

G2:

91

G 2

: 52

(199

9)(4

.1g

q6h)

G =

gro

up;

ND

= n

o da

ta;

NS

= n

o si

gnifi

canc

e; P

ID =

pel

vic

infla

mm

ator

y di

seas

e; q

xh =

eve

ry x

hou

rs.


the use of multidrug combinations (such as a car- antimicrobials (ampicillin/sulbactam, ceftriaxone,ertapenem, levofloxacin or piperacillin/tazobac-bapenem in combination with vancomycin).[79]

tam). Ampicillin/sulbactam and ertapenem were as-In four identified studies[59,80-82] examining pa-sociated with shorter hospital days, but this findingtients with intra-abdominal infections (table VI),could be attributed to the fact that surgeons mayampicillin/sulbactam is tested versus clindamycinprefer the previously mentioned regimens for lessplus gentamicin, cefoxitin, ampicillin plus clin-severe infections. In a retrospective pharmacoeco-damycin and ticarcillin/clavulanic acid. The differ-nomic study[85] ampicillin/sulbactam was comparedences between the cure rates achieved with eachwith cefoxitin in the treatment of intra-abdominalregimen were comparable except for the ones re-infections. Ninety-six patients had received ampicil-ported in the study conducted by Yellin et al.[80]

lin/sulbactam and 101 patients had received cefoxi-(significantly lower for ampicillin/sulbactam vstin. Cefoxitin had a 9% higher frequency of failureclindamycin plus gentamicin). Bacteriological erad-than ampicillin/sulbactam and when all outcomes ofication rates were comparable in all studies provid-interest were considered (i.e. cure/failure rates, de-ing relevant data except for one,[59] where the eradi-velopment of new infection, adverse effects),cation rates achieved with ticarcillin/clavulanic acidampicillin/sulbactam was less costly than cefoxitin.were significantly inferior to those achieved by

ampicillin/sulbactam.5.4 Diabetic Foot Infections

Many efforts have been made to assess the costeffectiveness of ampicillin/sulbactam versus other Diabetic foot infections are a significant cause oftreatment regimens for intra-abdominal infections. morbidity and mortality.[86] A randomised, double-Chin et al.[83] compared ampicillin/sulbactam (ampi- blind study comparing imipenem/cilastatin (0.5gcillin 2g/sulbactam 1g four times daily) with every 6 hours) and ampicillin/sulbactam (3g every 6clindamycin (900mg three times daily) plus gentam- hours) in limb-threatening infections in diabetic pa-icin (1.5 mg/kg three times daily) administered to tients showed comparable outcomes. After 5 days ofpatients with perforated appendicitis in a retrospec- empirical treatment, improvement was achieved intive pharmacoeconomic study. Costs incurring from 94% of the 48 ampicillin/sulbactam-treated infec-intravenous supplies, nursing administration, phar- tions and in 98% of the 48 imipenem/cilastatin-macist and technician preparation, laboratory fees, treated infections. Cure rates were 81% for theand pharmacokinetic monitoring were considered. ampicillin/sulbactam group versus 85% for theNo statistically significant difference in total costs imipenem/cilastatin group, failure rates were 17%was noticed. McKinnon and Neuhauser[59] examined for ampicillin/sulbactam versus 13% for imipenem/ampicillin/sulbactam (1.5g every 6 hours in 112 cilastatin, and bacterial eradication was 67% andpatients in group 1; 3g every 6 hours in 107 patients 75% for ampicillin/sulbactam and imipenem/cilasta-in group 2) versus ticarcillin/clavulanic acid (38 tin, respectively. The episodes of treatment failurespatients in group 3; 3.1g every 6 hours) in patients were associated with resistant pathogens acquisitionwith intra-abdominal infections. Although clinical of nosocomial pathogens.[87] Parenteral treatmenteffectiveness was comparable in all groups, bacteri- with ampicillin/sulbactam (2/1g) has been evaluatedological efficacy rates were significantly higher in against piperacillin/tazobactam (4/0.5g) in a ran-patients treated with ampicillin/sulbactam. The low- domised, open-label study comparing efficacy anddose ampicillin/sulbactam regimen was significant- safety for infected moderate to severe diabetic footly less costly than the full-dose ampicillin/sulbactam ulcers in 314 patients. Patients with polymicrobialand ticarcillin/clavulanic acid regimens. A retro- infections including MRSA received additionalspective analysis[84] was conducted to analyse the vancomycin intravenously. Clinical efficacy waslength of stay in 2150 patients with intra-abdominal comparable (83.1% for ampicillin/sulbactam vsinfections who had received one of five first-line 81% for piperacillin/tazobactam). A higher bacterio-




Tab

le V

I. S

umm

ary

of t

he s

tudi

es e

xam

inin

g th

e ef

ficac

y of

am

pici

llin/

sulb

acta

m v

ersu

s co

mpa

rato

r in

intr

a-ab

dom

inal

infe

ctio

ns

Stu

dyN

o. o

fIn

fect

ion

Ant

ibac

teria

l (do

sage

)C

ure

and/

or im

prov

emen

tB

acte

riolo

gica

l era

dica

tion

(yea

r)ev

alua

ble

ampi

cilli

n/co

mpa

rato

ram

pici

llin/

com

para

tor

p-va

lue

ampi

cilli

n/co

mpa

rato

rp-

valu

epa

tient

ssu

lbac

tam

sulb

acta

m (

%)

(%)

sulb

acta

m (

%)

(%)

Yel

lin e

t al

.[80]

105

Per

fora

ted

or3g

q6h

Clin

dam

ycin

8810

00.

03N

DN

D

(198

5)ga

ngre

nous

(600

mg

q6h

) +

appe

ndic

itis

gent

amic

in

(1.5

mg/

kg q

8h)

Wal

ker

et a

l.[81]

197

Sev

ere

intr

a-3g

q6h

Cef

oxiti

n86

78N

D85

83N

D

(199

3)ab

dom

inal

infe

ctio

n(2

g ev

ery

q8h)

Col

lins

et a

l.[82]

114

Intr

a-ab

dom

inal

150–

300

mg/

kg/d

Am

pici

llin

(200

mg/

97.3

97.4

ND

8992

ND

(199

8)in

fect

ions

(pr

imar

ilyq6

h ±

gent

amic

inkg

/d q

6h o

r q8

h) +

perf

orat

edor

tob

ram

ycin

clin

dam

ycin

appe

ndic

itis)

(6–7

.5 m

g/kg

/d)

(20–

40 m

g/kg

/d

q6h

or q

8h)

±

gent

amic

in o

r

tobr

amyc

in (

6–7.

5

mg/

kg/d

)

McK

inno

n an

d25

7A

ppen

dici

tis,

G1:

am

pici

llin

(1g)

/G

3: t

icar

cilli

n (3

g)/

G1:

89

G3:

73

ND

G1:

68

G3:

29

0.00

11

Neu

haus

er[5

9]ch

olec

ystit

is,

sulb

acta

m (

0.5g

)cl

avul

anic

aci

dG

2: 8

7G

2: 7

1

(199

9)pe

riton

itis,

intr

a-q6

h(0

.1g)

q6h

abdo

min

al a

bsce

ssG

2: a

mpi

cilli

n (2

g)/

sulb

acta

m (

1g)

q6h

G =

gro

up;

ND

= n

o da

ta;

qxh

= e

very

x h

ours

.


logical success rate was achieved by piperacillin/ obic infection was encountered frequently in bothtazobactam as the most common Gram-negative treatment groups. Patients with a history of injectionbacterium in this study was P. aeruginosa.[88] drug abuse were significantly more likely to have

streptococci isolated than those without a history ofIn a pharmacoeconomic study regarding limb-drug abuse (37% vs 19%, respectively). Bacterialthreatening infections in 90 diabetic patients, treat-

ment with ampicillin/sulbactam was $US2924 less eradication was achieved in 100% of patients receiv-than treatment with imipenem/cilastatin.[89] In a ing ampicillin/sulbactam, whereas the eradicationnon-comparative study, 74 patients with severe dia- rate with cefoxitin was 97.9%.[92]

betic foot infections were treated with parenteral A randomised, double-blind study in 58 hospital-ampicillin/sulbactam (1.5g four times daily). The ised patients compared intravenous administrationmean duration (± standard deviation) of treatment in of ampicillin/sulbactam (1g/0.5g every 6 hours)patients with osteomyelitis (n = 49) and soft tissue with cefazolin 0.5g (every 6 hours) in the treatmentinfections (n = 25) was 41 ± 5 and 14 ± 3 days, of cellulitis and with cefoxitin 1g (every 6 hours) inrespectively. Infected limbs were amputated at vari- other skin and skin-structure infections; no statisti-ous levels in 14 patients (19%). Clinical cure rates cally significant differences in efficacy or safetywere 86% and 100% in patients with osteomyelitis were detected. More specifically, in patients withand soft tissue infection, respectively.[90]

cellulitis, ampicillin/sulbactam and cefazolin pro-In a comparison of ampicillin/sulbactam versus duced a clinical cure or improvement in 100% and

linezolid in a randomised, open-label trial, the com- 91.7% of patients, respectively, and duration of hos-parators were statistically equivalent overall for in- pitalisation was 7.7 and 7.2 days, respectively. Inpatients and outpatients. Higher cure rates were other skin and skin-structure infections, results forachieved in the linezolid treatment arm (plus aztre- ampicillin/sulbactam and cefoxitin, respectively,onam in 5% of the 241 patients) than in the ampicil- were clinical cure or improvement 80% and 64.7%;lin/sulbactam treatment arm (plus vancomycin in treatment failures 0% and 11.8%; bacterial eradica-9.6% of the 120 patients or aztreonam in 3 [2.5%] of tion 40% and 53%; and duration of hospitalisationthe patients) in patients with infected ulcers (81% vs 7.7 and 9.4 days.[93]

68%; p = 0.018) and in patients without osteomyeli-Similar results were shown in a study of 76tis (87% vs 72%; p = 0.003).[91]

hospitalised patients with complicated skin and softtissue infections in a randomised, prospective, third-5.5 Skin and Soft Tissue Infectionsparty blinded, comparative study of the effective-ness and safety of intravenous or intramuscular ad-In a randomised, double-blind trial, the clinicalministration of ampicillin/sulbactam (1.0–2.0g/and bacteriological efficacy of ampicillin/sulbactam0.5–1.0g every 6 hours) and cefoxitin (1.0–2.0g(2/1g) and cefoxitin (2g) administered intravenouslyevery 6 hours). Twenty-five of the 36 patients whoevery 6 hours was compared in patients with orreceived ampicillin/sulbactam and 33 of 39 patientswithout a history of injection drug abuse whowho received cefoxitin were evaluable. Neitherpresented with cutaneous or other soft tissue infec-clinical and bacteriological effectiveness nor dura-tions. These two agents were equally effective fortion of hospitalisation differed significantly betweenthe empirical treatment of cutaneous or other softthe two treatment groups. Twenty-one (84%) pa-tissue infections in injection drug abusers and pa-tients receiving ampicillin/sulbactam were cured,tients who did not inject drugs. Cure or improve-two (8%) improved and treatment failed in twoment occurred in 89.8% of ampicillin/sulbactam-(8%). Twenty-eight (85%) patients receiving cefoxi-treated patients compared with 93.6% of cefoxitin-tin were cured, four (12%) improved and treatmenttreated patients. The median time to resolution of allfailed in one (3%). All primary pathogens weresymptoms was 10.5 days with ampicillin/sulbactam

and 15.5 days with cefoxitin. Mixed aerobic-anaer- eradicated in six (24%) and partial eradication oc-



curred in nine (36%) ampicillin/sulbactam recipi- aureus was isolated from 14 (74%) of 19 cultures.ents, while eradication occurred in 15 (47%) and The duration of treatment with these two combina-partial eradication in eight (25%) cefoxitin recipi- tion regimens was generally between 7 and 10 days.ents.[94] No statistical difference was found between the two

regimens in cure and recurrence rates, but fiveIn a randomised, open-label, comparative study,(17%) patients receiving penicillin plus chloram-23 patients with bone, joint or soft tissue infectionsphenicol, and one (3%) receiving ampicillin/sulbac-were treated with ampicillin/sulbactam (2/1g) threetam with or without ornidazole had recurrent peri-times daily or cefotaxime (2g) three times daily asorbital cellulitis.[98]an initial 2-week therapy. Monomicrobial infections

due to S. aureus were the most common bone or Thirty-one infants and children with documentedjoint infections. Clinical cure or improvement 2 acute epiglottitis received intravenous ampicillin/weeks after the end of therapy was observed in all 13 sulbactam (200/30 mg/kg/day). Of the 31 patients,patients treated with ampicillin/sulbactam and in 7 26 (84%) had H. influenzae type B isolated fromof the 8 patients evaluated for efficacy after treat- blood cultures; seven (27%) of these 26 strains werement with cefotaxime. Treatment failed to eradicate positive for production of β-lactamases. A highS. aureus in one patient from each group. In addi- (96%) cure rate was achieved with the use of ampi-tion, S. aureus infection recurred in two patients in cillin/sulbactam. In view of the decreased use ofthe cefotaxime group within 2 weeks after the end of chloramphenicol, ampicillin/sulbactam is probablytherapy.[95]

now the first choice in cases of acute epiglottitis dueSixty patients with documented soft tissue infec- to H. influenzae type B.[99]

tions were prospectively randomised to receive ei-In a randomised comparative study, 41 and 40

ther ampicillin/sulbactam (2/1g; n = 30) every 6children with bacterial meningitis, received intrave-

hours or clindamycin (600mg) every 6 hours plusnous ampicillin/sulbactam or ampicillin plus chlor-

tobramycin (1.5 mg/kg) every 8 hours (n = 30). Theamphenicol, respectively. One of 29 (3.4%) treated

age and sex of the patients were similar betweenwith ampicillin/sulbactam and 6 of 34 (18%) treated

groups, as were co-morbidity and bacterial isolateswith ampicillin plus chloramphenicol died. Neuro-

of wounds. A 93% cure or improvement rate waslogical sequelae were also more common in ampicil-

seen with ampicillin/sulbactam compared with 81%lin plus chloramphenicol recipients (18% vs

in the clindamycin plus tobramycin group. Eradica-12%).[100] According to MIC and time-kill studies of

tion of organisms was greater in the ampicillin/45 H. influenzae β-lactamase strains, an initial de-

sulbactam group (67% vs 35%). The antibacterialcrease in H. influenzae type B CSF isolates was

activity of ampicillin against 223 total bacteriologi-observed with ampicillin/sulbactam treatment, but

cal isolates was significantly augmented by the addi-eventually bacteriological eradication was not

tion of sulbactam from 38% to 70%.[96]

achieved.[101] Additionally, although ampicillin/sul-bactam penetrates into the CSF, concentrations de-

5.6 Sepsis in the Paediatric Populationcrease quickly to only one-sixth of what is achievedin serum.[102]

Ampicillin/sulbactam has proved effective in va-Ampicillin/sulbactam has also been evaluated inrious severe paediatric infections, such as periorbital

the treatment of skin, soft tissues and skeletal infec-infections, acute epiglottitis, bacterial meningitistions in a randomised, prospective study of 125and acute fulminant meningococcaemia.[97] In a ret-children (105 with skin and soft tissue infections androspective cohort study of patients with periorbital20 with suppurative arthritis or osteomyelitis). Ainfections, two antibacterial combinations, penicil-total of 84 children received ampicillin/sulbactamlin plus chloramphenicol and ampicillin/sulbactam(100–200/15–30 mg/kg/day in four divided doses)with or without ornidazole, were administered in 30and 41 children received ceftriaxone (50–75 mg/kg/(43%) and 39 (57%) of 69 children, respectively. S.



day in two divided doses). Ampicillin/sulbactam cause the patients died within the first 48 hours ofand ceftriaxone showed a similar clinical and bacte- treatment. Two patients with meningitis were treat-riological response rate of 100% and 93%, respec- ed and did not respond. No adverse effects weretively.[103] A randomised, open-label, multicentre observed.[105]

study of serious paediatric skin and skin structure Wood et al.[106] conducted a retrospective studyinfections compared ampicillin/sulbactam (150–300 to compare the efficacy of ampicillin/sulbactam andmg/kg/day in four divided doses) with cefuroxime

imipenem/cilastatin. Fourteen patients received(50–100 mg/kg/day in three or four divided doses).

ampicillin/sulbactam and 63 patients were treatedIn the ampicillin/sulbactam treatment arm, 46 of the

with the comparator regimen. Mortality, duration of59 evaluable patients (78%) were cured and 13mechanical ventilation and length of stay in the ICUpatients (22%) were improved. Thirty patientsor the hospital, were comparable between treatment(76.9%) were cured and nine patients (23.1%) im-groups. In a retrospective study,[107] forty-eight pa-proved in the cefuroxime comparator arm. Bacterio-tients with A. baumannii bacteraemia were treatedlogical eradication was achieved in 93.2% andwith either ampicillin/sulbactam or imipenem/cilas-100%, respectively, in the ampicillin/sulbactam andtatin. There were no differences between days ofcefuroxime treatment arms. No statistically signifi-bacteraemia (4 vs 2 days; p = 0.05), days to resolu-cant differences in clinical or bacteriological effica-tion of temperature or white blood cell count, suc-cy were observed between the treatment arms.[104]

cess or failure during or at the end of treatment, orICU total or antibacterial-related length of stay (135.7 Infections in the Intensive Care Unitvs 10 days; p = 0.05). However, treatment withSetting Due to Acinetobacter baumanniiampicillin/sulbactam saved $US1000 dollars per pa-tient treated (p = 0.004).[107] In an observationalAmpicillin/sulbactam may be an effective and

safely used therapeutic option to treat severe prospective study of 79 adult inpatients with A.nosocomial infections caused by MDR A. bauman- baumannii bacteraemia, ampicillin/sulbactam andnii. Corbella et al.[6] showed that the active drug imipenem/cilastatin were the most effective agents.against A. baumannii in the ampicillin/sulbactam A total of 35 patients (83%) of 42 who receivedcombination is sulbactam. In a non-comparative imipenem/cilastatin and 7 (87.5%) of 8 patients whostudy,[105] forty consecutive patients with nosocomi- received ampicillin/sulbactam were cured.[108]

al infections caused by MDR A. baumannii wereIn a study of 94 patients with nosocomial

treated with intravenous ampicillin/sulbactam.A. baumannii bloodstream infections, 54% involved

MDR A. baumannii were resistant to penicillins,MDR strains, 81% of which were genetically relat-cephalosporins, aminoglycosides, fluoroquinolones,ed. Of the 51 patients with MDR A. baumannii, 65%imipenem and aztreonam in vitro. The median dailyreceived ampicillin/sulbactam and 35% received in-dose of ampicillin/sulbactam was 6/3g and six pa-adequate antibacterial therapy, whereas of 43 pa-tients received 12/6g. Of the infections, 72.5% oc-tients with non-MDR A. baumannii, 86% were treat-curred in the ICU setting. The infections were pri-ed according to susceptibility and 14% were treatedmary bacteraemia (32.5%), pneumonia (30%), uri-inappropriately with antibacterials to which thesenary tract (15%), peritonitis (7.5%), surgical siteorganisms were resistant. Crude mortality was com-(7.5%), meningitis (5%) and sinusitis (2.5%). Mostparable in the adequately treated groups. Respectivewere severe infections with underlying conditionsmortalities among patients treated adequately and(median Acute Physiologic and Chronic Healthinadequately were 41.4% and 91.7% (p < 0.001),Evaluation [APACHE] II score: 14.5). A total of 27respectively. Among severely ill patients, ampicil-patients (67.5%) were improved/cured, 7 (17.5%)lin/sulbactam therapy significantly decreased theexperienced treatment failure and 6 (15%) wererisk of death (p = 0.02; odds ratio = 7.64).[109]considered to have an indeterminate outcome be-



Ampicillin/sulbactam was evaluated in a study of especially aspiration pneumonia, and intra-abdomi-eight patients with nosocomial A. baumannii menin- nal, gynaecological, skin and soft tissue, and diabet-gitis (seven treated with 2/lg every 6 hours and one ic foot infections, infections due to MDR A.with 2/lg every 8 hours). All A. baumannii isolates baumannii, and paediatric infections, such as acutewere resistant to cefotaxime, ceftriaxone, cef- epiglottitis and periorbital cellulitis.tazidime, ureidopenicillins, ciprofloxacin and gen- Ampicillin/sulbactam is comparable to second-tamicin. Seven isolates were resistant to imipenem. and third-generation cephalosporins in the treatmentFor all CSF isolates of A. baumannii, the MIC of of LRTIs. The role of ampicillin/sulbactam in theampicillin/sulbactam was ≤8/4 mg/mL. The MIC treatment of aspiration pneumonia, when anaerobesvalues for sulbactam by microdilution in two cases are a key component of the infection, has beenwere 4 mg/mL. Six patients were cured and two proved comparable to clindamycin and imipenem/patients died of meningitis.[6]

cilastatin. P. aeruginosa is not among the pathogensHowever, according to data from a non-compara- that are effectively targeted by ampicillin/sulbac-

tive study and a comparative study with imipenem- tam. In addition, the intracellular bacteria that com-cilastatin, lower doses of ampicillin/sulbactam can monly are aetiological pathogens necessitate the usebe effective against MDR A. baumannii as we- of a macrolide, respiratory fluoroquinolone or all.[105,107] Betrosian et al.[110] conducted a randomis- tetracycline. Ampicillin/sulbactam can be used ined, non-comparative, prospective trial to assess the ICU patients with community-acquired pneumoniaefficiency of two high-dose regimens of ampicillin/ who are not at risk for pseudomonas infection, insulbactam in patients with ventilator associated combination with a macrolide or a fluoroquinolonepneumonia due to MDR A. baumannii. Patients according to IDSA/ATS guidelines (2007). IDSA/received either ampicillin/sulbactam 18/9g daily ATS guidelines (2004) suggest that ampicillin/(group A) or 24/12g daily (group B). Clinical im- sulbactam may be administered to patients withoutprovement and bacteriological success rates were risk factors for MDR pathogens and in early-onset64.3% and 84.7% for group A, respectively, where- HAP.as equivalent figures for group B were 69.2% and

In many comparative trials in patients with intra-69.2%, respectively. Therefore, despite the reportedabdominal infections, ampicillin/sulbactam hasin vitro resistance, high-dose regimens of ampicil-been found to have the same favourable responses aslin/sulbactam were both clinically and bacteriologi-clindamycin plus gentamicin and cefoxitin. Accord-cally effective in this patient group.ing to a recent meta-analysis, β-lactams have highercure rates than clindamycin-aminoglycoside combi-6. Place of Ampicillin/Sulbactam in thenations, although mortality is not different.[111]

Treatment of Severe InfectionsAmpicillin/sulbactam has also has proved itself val-uable in the treatment of gynaecological and obstet-It was approximately two decades ago when therical infections. In a significant number of compara-production by bacteria of enzymes (lactamases) de-tive studies, it shows comparable favourable infec-stroying β-lactams unfortunately narrowed the spec-tion outcome to cefoxitin.trum of many of these useful medications. The obvi-

Ampicillin/sulbactam has been shown to be non-ous need to put a halt to this inexorable decline wasinferior in direct comparisons with imipenem/cilas-met by the development of β-lactamase inhibitors.tatin as well as piperacillin/tazobactam in the treat-Sulbactam significantly restored the lost part of thement of diabetic foot infections. In a comparativespectrum. The ampicillin/sulbactam combinationstudy of ampicillin/sulbactam versus linezolid, therecovers a broad array of Gram-positive, Gram-nega-was no statistical difference overall between the twotive and anaerobic pathogens. Ample clinical evi-regimens, although linezolid achieved higher curedence exists regarding the value of ampicillin/sul-rates in patients with infected ulcers and in patientsbactam in various severe respiratory tract infections,



without osteomyelitis.[92] Limitations in the manage- tidrug resistance is a common characteristic; com-bined intravenous and intrathecal administration ofment of diabetic foot infection are posed when thepolymyxins is frequently necessary.[112] Microbio-disease is due to P. aeruginosa, in which case anlogical data show that A. baumannii is more suscep-antipseudomonal penicillin should probably be em-tible to polymyxins than ampicillin/sulbactam.[113]ployed. It is interesting though that in the compara-

The value of the ampicillin/sulbactam combina-tive study of linezolid and ampicillin/sulbactam, thetion has also been proved in various severe pediatrictreatment against P. aeruginosa (with aztreonam)infections such as acute epiglottitis and periorbitaldid not alter the outcome of the infection when thecellulitis. The impact of immunisation against inva-patient population was examined as a whole. Wheresive H. influenzae type B infections is beyond anyMRSA is deemed a culprit, vancomycin, or linezoliddoubt. Nevertheless, in the clinical cases of acuteor daptomycin, should be added according to theepiglottitis that a physician will encounter, the use ofIDSA guidelines. As severe diabetic foot infectionsa β-lactam/β-lactamase inhibitor is mandatory be-are frequently polymicrobial, ampicillin/sulbactamcause of the high level of resistance of H. influenzaeis a valid initial approach to their treatment. Theto β-lactams. Although ampicillin/sulbactam hassame principles apply in the treatment of skin andbeen assessed in bacterial meningitis and was foundsoft tissue infections in non-diabetic patients. Manyeffective, it is not regarded as first-line treatment instudies in non-diabetic patients with skin and softthe IDSA guidelines. The CSF concentration of thetissue infections have shown that ampicillin/drug falls fast to only one-sixth of serum concentra-sulbactam is as effective as cefoxitin in the treat-tion in a matter of days.[102]

ment of these infections.

MDR A. baumannii poses a new challenge for 7. Conclusionphysicians world wide, especially when managingcritically ill patients. As resistance to carbapenems Ampicillin/sulbactam remains a valuable andis a particular problem in many countries, possible safely used antibacterial in the physician’s arma-options include polymyxins [colistin], ampicillin/ mentarium when treating monomicrobial as well assulbactam and tigecycline. Although experimental polymicrobial infections in the paediatric and adultdata suggest that sulbactam is the key player in the patient population. Ampicillin/sulbactam has high

success rates and a particular role in severe infec-treatment of infections due to MDR A. baumannii,tions such as respiratory tract infections (especiallyclinical data do not support monotherapy withaspiration pneumonia), gynaecological and obstetri-sulbactam in these severe infections.[6] In addition,cal infections, intra-abdominal infections, paediatricthe majority of the clinical data come from studiesinfections such as acute epiglottitis and periorbitalexamining the ampicillin/sulbactam combination. Acellulitis, diabetic foot infections, skin and soft tis-higher dose of ampicillin/sulbactam than that usedsue infections, and infections due to MDR A.in other infections is usually employed in the treat-baumannii.ment of A. baumannii.[110] Similar effectiveness be-

tween imipenem/cilastatin and ampicillin/sulbactamAcknowledgementswas also shown also in the treatment of A. bauman-

nii bacteraemia in a prospective observational No sources of funding were used in the preparation of thisstudy.[87] Ampicillin/sulbactam has also been suc- review. The authors have no conflicts of interest that are

directly relevant to the content of this review.cessfully employed in the treatment of A. baumanniimeningitis. The potential limitation concerningmeningitis treatment stems from the fact that the References

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