Clinical Microbiology and Infection 26 (2020) 871e879

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Clinical Microbiology and Infection

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Narrative review

Oral amoxicillin and amoxicillineclavulanic acid: properties,

indications and usage
A. Huttner 1, *, J. Bielicki 2, 3, M.N. Clements 4, N. Frimodt-Møller 5, A.E. Muller 6, 7,
J.-P. Paccaud 8, J.W. Mouton 6
1)
Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland
2)
University of Basel Children's Hospital, Paediatric Infectious Diseases, Basel, Switzerland
3)
Paediatric Infectious Diseases Research Group, St. George's University of London, London, UK
4)
MRC Clinical Trials Unit at UCL, UCL, London, UK
5)
Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
6)
Department of Medical Microbiology, Haaglanden Medical Centre, The Hague, the Netherlands
7)
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, Rotterdam, the Netherlands
8)
Global Antibiotic Research and Development Partnership, Geneva, Switzerland

a r t i c l e i n f o a b s t r a c t

Article history: Background: Amoxicillin has been in use since the 1970s; it is the most widely used penicillin both alone
Received 7 September 2019 and in combination with the b-lactamase clavulanic acid.
Received in revised form Objectives: In this narrative review, we re-examine the properties of oral amoxicillin and clavulanic acid
22 November 2019
and provide guidance on their use, with emphasis on the preferred use of amoxicillin alone.
Accepted 25 November 2019
Available online 4 December 2019
Sources: Published medical literature (MEDLINE database via Pubmed).
Content: While amoxicillin and clavulanic acid have similar half-lives, clavulanic acid is more protein
Editor: L Leibovici bound and even less heat stable than amoxicillin, with primarily hepatic metabolism. It is also more
strongly associated with gastrointestinal side effects, including Clostridium difficile infection, and, thus, in
Keywords: oral combination formulations, limits the maximum daily dose of amoxicillin that can be given. The first
Appropriate therapy ratio for an amoxicillineclavulanic acid combination was set at 4:1 due to clavulanic acid's high affinity
Clavulanic acid for b-lactamases; ratios of 2:1, 7:1, 14:1 and 16:1 are currently available in various regions. Comparative
Indications effectiveness data for the different ratios are scarce. Amoxicillineclavulanic acid is often used as empiric
Oral amoxicillin
therapy for many of the World Health Organization's Priority Infectious Syndromes in adults and chil-
Pharmacokinetics
dren, leading to extensive consumption, when some of these syndromes could be handled with a delayed
Stewardship
antibiotic prescription approach or amoxicillin alone.
Implications: Using available epidemiological and pharmacokinetic data, we provide guidance on in-
dications for amoxicillin versus amoxicillineclavulanic acid and on optimal oral administration,
including choice of combination ratio. More data are needed, particularly on heat stability, pharmaco-
dynamic effects and emergence of resistance in ‘real-world’ clinical settings. A. Huttner, Clin Microbiol
Infect 2020;26:871
© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction designated ‘core access antibiotic’ [2]. This document outlines the
key properties of amoxicillin and clavulanic acid, describes current
Amoxicillin is a semisynthetic penicillin in use since the 1970s. oral formulations and clinical experience with them, and provides
Alone and in combination with the b-lactamase inhibitor (BLI) recommendations for appropriate use of oral amoxicillin alone
clavulanic acid, it is the most widely used penicillin in Europe [1] versus amoxicillin with clavulanic acid.
and elsewhere, and is a World Health Organization (WHO)-
History of amoxicillin and clavulanic acid

* Corresponding author. A. Huttner, Geneva University Hospitals, Rue Gabrielle-

Penicillin's narrow spectrum led to a search for derivative agents
Perret-Gentil 4, Geneva, 1205, Switzerland. with bactericidal activity against both Gram-positive and Gram-
E-mail address: angela.huttner@hcuge.ch (A. Huttner). negative organisms. The first clinically relevant derivative was

https://doi.org/10.1016/j.cmi.2019.11.028
1198-743X/© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
872 A. Huttner et al. / Clinical Microbiology and Infection 26 (2020) 871e879

ampicillin, discovered by Beecham Laboratory scientists in the More information on stability is available for intravenous solu-
United Kingdom and released in 1961. Amoxicillin was then built tions of amoxicillin than for oral preparations. The recommended
from ampicillin: in 1972, Beecham released the novel, semi- storage temperature for amoxicillin sodium solution is 2e8
C. It is
synthetic penicillin, which differs structurally from ampicillin only stable at higher temperatures for only short periods of time and
by the addition of a hydroxyl group on the benzene ring [3]. dependent on several conditions (container, solvent, light exposure);
Clavulanic acid, sometimes referred to as clavulanate, its salt in sodium chloride or water for injection, stability at 25
C may reach
form in solution, was also developed by Beecham scientists who 8 or 3 hr, respectively [17]. There are few data (with robust reporting
isolated this BLI from Streptomyces clavuligerus [4] in 1974. Despite allowing for reproducibility) on stability at higher temperatures.
also possessing a b-lactam ring, clavulanic acid has little efficacy by While an early report indicated strong stability of reconstituted
itself as an antibiotic [5]; it works as a ‘suicide inhibitor’, irrevers- oral amoxicillin at 25
C and even 40
C, with conservation of at least
ibly binding to and thus preventing bacterial b-lactamase enzymes 90% in prepared unit dose syringes for 78 and 10 days, respectively
from hydrolysing amoxicillin and other penicillins. Currently, [18], recent studies have demonstrated more rapid degradation in
clavulanic acid is commercially available only in combination with similar conditions. Mehta et al. observed 90% conservation of
either amoxicillin or ticarcillin. reconstituted oral amoxicillin at 20
C for only 7 days [19], while
Peace et al. report only 79% conservation at 7 days at a temperature
of 27e29
C [20]. Currently there are few data on the stability of oral
Properties of amoxicillin and clavulanic acid alone and in
amoxicillin tablets.
combination

Amoxicillin Clavulanic acid

Amoxicillin binds to penicillin-binding protein (PBP) 1A, an Clavulanic acid achieves its effect as a suicide inhibitor by
enzyme essential for bacterial cell wall synthesis. Amoxicillin's b- covalently binding to a serine residue in the active site of the b-
lactam ring opens to acylate the transpeptidase C-terminal domain lactamase, which results in its own restructuring. Clavulanic acid
of PBP 1A. This irreversible binding inactivates PBP 1A, without then becomes more active, attacking another amino acid at the b-
which peptidoglycan, an integral bacterial cell wall component, lactamase active site, permanently inactivating it.
cannot be synthesized; cell wall elongation and permeability While clavulanic acid and amoxicillin have similar distribution
follow, leading ultimately to cell lysis and death [6]. patterns and a half-life of roughly 1 hr, the BLI differs with respect to
The hydroxyl group creating amoxicillin from ampicillin results other pharmacokinetic properties [21]. Its metabolism is primarily
in a drug that is more lipid soluble and thus has increased hepatic, with only 30e40% excreted unchanged in the urine, and up
bioavailability and duration of action and, in some pharmacody- to 30% is bound to serum proteins. A recent study confirms that the
namic studies, heightened bactericidal activity [3,7]. In healthy absorption of clavulanic acid in healthy volunteers is highly variable
volunteers, amoxicillin's half-life is roughly 1 hr, its volume of and suggests that it decreases through the course of the day [22].
distribution approximately 20 L, and its protein binding up to 20% Importantly, oral clavulanic acid appears to cause increased
in serum [8]. Most amoxicillin is excreted unchanged in urine; gastrointestinal side effects, particularly diarrhoea compared with
hepatic metabolism accounts for little of the biotransformation of those experienced in relation to amoxicillin alone. Thus the addition
most penicillins. of the BLI significantly limits the maximal daily dose of amoxicillin
Amoxicillin is rapidly absorbed after oral administration; early that can be given orally [23,24], as the maximum recommended
studies in young, healthy male volunteers reported bioavailability daily dose of clavulanic acid is 500 mg [14].
of 77e93% [8,9]. While bioavailability appears to be improved Importantly, clavulanic acid is even less heat stable than
when amoxicillin is taken fasting [10], clinical trials in which oral amoxicillin in either intravenous or reconstituted oral suspension
amoxicillin was administered without regard to meals have form. Its stability in aqueous solutions has been poorly character-
demonstrated efficacy [11]. Data on penetration into various tissues ized, though one recent study noted that in sodium chloride, sta-
are somewhat complex, as many studies were performed with bility was maintained for 8 hr at 4
C and for only 4 hr at 20
C.
outdated techniques rather than microdialysis. It is traditionally Reconstituted oral suspensions appear to be somewhat more sta-
reported that amoxicillin distributes well into liver, lungs, prostate, ble; at 8
C, clavulanic acid maintains at least 90% of its initial
muscle, middle ear effusions, maxillary sinus secretions, bone, concentration for 7 days, though at 20
C only 60% is maintained in
gallbladder, bile, and into ascitic and synovial fluids [12] but has the same time period [19], and at 27e29
C, only 55% [20].
poor penetration into cerebrospinal fluid [13]. Yet effective distri-
bution depends, of course, on the targeted microorganism's mini- Amoxicillineclavulanic acid combinations
mal inhibitory concentration (MIC), e.g., penetration may be
sufficient for a streptococcus but insufficient for an enterococcus. The first ratio for an amoxicillineclavulanic acid combination
Meanwhile, bioavailability of oral amoxicillin, which appears to was set by Beecham pharmacists at 4:1; relatively little clavulanic
have high interindividual variability, will greatly affect the medi- acid was needed to inhibit b-lactamases because of its high affinity
cine's distribution. Bioavailability in healthy volunteers is reported for them [4]. Later, a 7:1 ratio was introduced, largely to avoid
to be roughly 70% [14,15]; recent data on bioavailability in ill, co- clavulanic acid-related toxicity. Currently ratios of up to 14:1 and
morbid or elderly patients are lacking. A recent study shows that 16:1 are available in some areas.
amoxicillin's absorption rate appears to be saturable, with more Data on both clinical and microbiological comparative effec-
frequent doses increasing the probability of pharmacokinetic/ tiveness of the varying ratios are scarce. One US trial compared a
pharmacodynamic (PK/PD) target attainment [16]. In this study, no 16:1 formulation of amoxicillin (2 g, extended release) combined
beneficial effect of doses higher than 750 mg per administration with 125 mg of clavulanic acid (traditional formulation) to the 7:1
was observed. The drug is often administered to pregnant women; formulation of 875/125 mg for clinical efficacy in a randomized trial
no teratogenic effects have been observed in non-human studies of nearly 900 patients with chronic bronchitis exacerbations [25];
(US FDA category B). clinical non-inferiority was demonstrated at 14e21 days. Bacterial
 A. Huttner et al. / Clinical Microbiology and Infection 26 (2020) 871e879 873

Table 1
Clinical syndromes that may precipitate use of oral amoxicillin or amoxicillineclavulanic acid, the organisms that are most often causative of these syndromes, and the
approximate fraction of amoxicillineclavulanic acid-susceptible strains by geographic region that are susceptible to amoxicillin alone

Clinical syndrome Most common causative bacterial pathogens

Organism Geographic region Approximate fraction of amoxicillineclavulanic

acid susceptible strains that are susceptible
to amoxicillin alone, %

Community-acquired pneumonia [36] Streptococcus pneumoniaea All regions 100

Haemophilus influenzae North America 70 [37]
South America 82 [37]
Europe 86 [37]
Asia 60e98 [37e39]
Africa 94 [37]
Staphylococcus aureusb North America 13e50 [40]
South America 12e50 [40]
Europe 20e50 [40,41]
Asia 1e50 [40,42]
Africa 3e50 [43,44]
Mycoplasma pneumoniae NA NA
Legionella pneumophila NA NA
Pharyngitis [45] Streptococcus pyogenesa All 100
S. pneumoniae As above 100
Corynebacterium diphtheriae North America >99 [46]
South America 100 [46]
Europe 100 [47]
Asia 100 [48]
Africa 100 [49]
Fusobacterium spp.c North America 23e60 [50]
South America 33 [51]
Europe 50 [52]
Asia 100 [51]
Africa No data
Moraxella catarrhalis North America <5 [53]
South America 5e10 [37]
Europe 5e10 [37]
Asia 5e10 [37]
Africa 5e10 [37]
M. pneumoniae NA NA
Chlamydophila pneumoniae NA NA
Bordetella pertussis NA NA
Neisseria gonorrhoeae NA NA
Sinusitis [54] S. pneumoniae All regions 100
H. influenzae As above As above
Moraxella catarrhalis As above As above
S. aureus As above As above
S. pyogenes All regions 100
Otitis media [55] S. pneumoniae All regions 100
H. influenzae As above As above
M. catarrhalis As above As above
S. aureus As above As above
S. pyogenes All regions 100
Urinary tract infectiond [56] Escherichia coli North America 55e71 [57,58]
South America 50 [59]
Europe 68 [60]
Asia 0e47 [61e63]
Africa 30e70 [64,65]
Klebsiella spp. All regions 0
Proteus spp.c North America 32 [66]
South America 5e70 [67,68]
Europe 33 [69]
Asia 46 [70]
Africa 34e90 [65]
Group B streptococcia All 100
Enterobacter spp. NA NA
Enterococcus faecalisa All regions 100
Complicated intra-abdominal infections [71] E. coli As above As above
Bacteroides spp.c North America 0e35 [50]
South America 2 [72]
Europe 1e2 [73]
Asia 2e30 [70,74,75]
Africa <30 [76]
Enterobacter spp. NA NA
Klebsiella spp. As above 0
Enterococcus faecalis All regions 100
Clostridium spp.c North America <10 [77]
South America <2 [78]
(continued on next page)
874 A. Huttner et al. / Clinical Microbiology and Infection 26 (2020) 871e879

Table 1 (continued )

Clinical syndrome Most common causative bacterial pathogens

Organism Geographic region Approximate fraction of amoxicillineclavulanic

acid susceptible strains that are susceptible
to amoxicillin alone, %

Europe 2 [79]
Asia 10e30 [75]
Africa No recent comparative data
Wound, skin and soft-tissue infections, S. aureus As above As above
including erysipelase [80] Coagulase-negative Staphylococcic North America 30e75 [81]
South America 30e75 [81]
Europe 30e75 [81]
Asia 37 [82]
Africa 28 [83]
S. pyogenes All regions 100
Streptococcus agalactiaea All regions 100
E. coli As above As above
Surgical site infections [84] S. aureus As above As above
Coagulase-negative Staphylococci As above As above
Enterococcus faecalis All regions 100
E. coli 55
Cellulitis [85] S. aureus As above As above
Streptococcus dysgalactiaea All regions 100
S. pyogenes All regions 100
S. agalactiaea All regions 100
Acute infectious diarrhoea [86] E. coli As above As above
Campylobacter spp.c North America 0e50 [87,88]
South America 88 [89]
Europef 0e98 [90]
Asiaf 20 [91]
Africa 20 [92]
Salmonella spp.c North Americaf 0e70 [93]
South America No recent comparative data
Europe 70 [94]
Asia 0 [95]
Africa 40 [96]
Shigella spp. North America 27 [97]
Asia 30 [98]
Africa 37e40 [96,99]
Other regions No recent comparative data
Yersinia enterocolitica NA NA
Vibrio cholera NA NA
Exacerbations of chronic obstructive H. influenzae As above As above
pulmonary disease [100] M. catarrhalis As above As above
S. pneumoniae All regions 100
P. aeruginosa NA NA
Haemophilus parainfluenzae North America 30 [101]
Europe 70 [101]
Other regions No recent data
S. aureus As above As above
Bone and joint infections [102] S. aureus As above As above
Coagulase-negative Staphylococci As above As above
S. pyogenes All regions 100
Enterococcus faecalis All regions 100
Enterobacter spp. NA NA

Neither the list of syndromes nor that of causative pathogens is exhaustive, and proportions presented here cannot be considered fully representative: recent data allowing
comparisons between these two compounds are scarce and may come from relatively small datasets. Numbers in square brackets are reference numbers.
a
These organisms are not known to possess b-lactam enzymes and thus are essentially always susceptible to amoxicillin alone.
b
Efficacy of amoxicillin in oral formulations remains uncertain (refer to EUCAST breakpoints; www.eucast.org).
c
There is considerable variability in resistance among different species of this genus; local patterns should be reviewed.
d
Amoxicillin and amoxicillineclavulanic acid are not first-line agents for urinary tract infection.
e
Erysipelas is most commonly caused by streptococci and can be treated with amoxicillin alone.
f
Isolates are from poultry on dairy farms; no recent comparative data from human clinical specimens identified.

infections were few, however, with only 30% of sputum samples Microbiological spectra and indications for the addition of
positive for potential bacterial pathogens; bacteriological success clavulanic acid
rates for b-lactamase-positive organismsdeven fewer in this large
studydwere similar in both groups (22/24, 92% versus 21/25, 84%). Classification of b-lactamases
Further, recent evidence that the absorption of oral-tablet amoxi-
cillin is saturable [16] might also contribute to the lack of difference b-Lactamases have been classified via different systems; the
in clinical outcomes, given the limited uptake of the 2-g dose. The best known is that of Ambler [26], which currently categorizes the
adverse event profiles of both formulations were similar, with enzymes into four classes, A through D, based upon their amino
diarrhoea reported by 14% and 17% of patients in the 16:1 and 7:1 acid sequences. Initially there were only classes A and B, composed
arms, respectively. of active-site serine b-lactamases and metallo-b-lactamases,
 A. Huttner et al. / Clinical Microbiology and Infection 26 (2020) 871e879 875

respectively. Thereafter a new class of serine b-lactamases was here. For some syndromes, intravenous antibiotics may be more
identified; this group of cephalosporinases had little sequence appropriate, at least during the initial treatment phase. We have
similarity to class A enzymes and was thus designated class C; its included them here, however, for settings in which access to
members are also known as AmpC b-lactamases [27]. Finally, intravenous antibiotics is limited. Also of note, the prevalences
another group of serine b-lactamases, familiarly known as the OXA cited here are general and not necessarily population-specific, and
b-lactamases, was identified and given its own class D [28]. Though though we list bacterial pathogens only, some of these syndromes
differences in sequence structure are significant enough to warrant are more commonly caused by viruses (e.g. pneumonia, otitis me-
separate classes, the three serine classes are descendants of a dia, etc.).
common ancestor [29].
The penicillinases responsible for inactivating amoxicillin Testing for susceptibility to amoxicillineclavulanic acid
belong to class A. Some organisms express these b-lactamases
intrinsically: they carry chromosomal genes coding for the en- To test susceptibility to amoxicillineclavulanic acid, most labo-
zymes. For example, all Klebsiella species and Citrobacter koseri are ratories follow guidelines and breakpoints from the European
intrinsically resistant to amoxicillin given their chromosomal cod- Committee on Antimicrobial Susceptibility Testing (EUCAST), the
ing for class A penicillinases. United States Committee on Antimicrobial Susceptibility Testing
Organisms may also acquire the ability to express b-lacta- (USCAST) or the Clinical & Laboratory Standards Institute (CLSI).
mases, either through chromosomal mutations or through Current testing is not always an exact science: disc contents vary
horizontal transfers of mobile genetic elements, most notably among different committees and bacterial species, and for many
via plasmids. Unfortunately plasmids often carry multiple species, such as viridans and Groups A, B, C and G streptococci,
resistance determinants, so that a single conjugation event may amoxicillin susceptibility is inferred from the susceptibility of other
confer multidrug resistance to a bacterial strain [30]. The antibiotics such as benzylpenicillin or ampicillin.
expression of penicillinases leading to amoxicillin resistance is The concentration of clavulanic acid used varies by testing
both intrinsic and acquired. Clavulanic acid effectively ‘blocks’ method. The EUCAST method uses a fixed concentration of 2 mg/L
only class A b-lactamases. Most extended-spectrum b-lacta- of clavulanic acid, whereas USCAST recommends the use of a fixed
mases (ESBLs) derive from this class, however, indicating that ratio between the amoxicillin and clavulanic acid concentrations of
clavulanic acid is stable against these enzymes, which is why it 2:1 mg/L. These different strategies provide different test results,
is commonly used for in vitro detection of ESBL-producing and there is no consensus among committees as to which strategy
bacteria. should be used. Nonetheless, there is evidence that inhibitor-
resistant TEM b-lactamases, which represent a potential threat to
Susceptibility to amoxicillin versus amoxicillineclavulanic acid: a the use of amoxicillineclavulanic acid, are more likely detected
rough overview of organisms and their resistance prevalence when fixed concentrations of clavulanic acid are used [31].

In Table 1, we list clinical syndromes that may precipitate use of Current post-market use
amoxicillin or amoxicillineclavulanic acid, the organisms that are
most often causative of these syndromes, and their respective re- Despite the plethora of bacterial strains listed above that are not
sistances by geographic region. The clinical syndromes align with b-lactamase producers, amoxicillineclavulanic acid use far out-
World Health Organization's ‘priority infectious syndromes’ in strips that of amoxicillin alone in some regions and populations.
adults and children; syndromes for which empiric therapy with Fig. 1 shows the comparative use in various countries of amino-
amoxicillin alone or in combination with clavulanic acid is either penicillins, chiefly amoxicillin, and penicillin-b-lactamase-inhibitor
inappropriate or unlikely to be effective have not been included combinations, chiefly amoxicillineclavulanic acid. Many countries

Fig. 1. Consumption of aminopenicillins (chiefly amoxicillin) and penicillin-b-lactamase-inhibitor combinations (chiefly amoxicillineclavulanic-acid) in various European countries
in 2017. Data are from the European Centres for Disease Prevention and Control (www.ecdc.eu). J01CR ¼ The Anatomical Therapeutic Chemical Classification System (ATC) code for
medicines that are combinations of penicillins, including beta-lactamase inhibitors. J01CA ¼ ATC code for penicillins with extended spectrum.
876 A. Huttner et al. / Clinical Microbiology and Infection 26 (2020) 871e879

increase in consumption of amoxicillineclavulanic acid will further

select for organisms resistant to both the b-lactam and its BLI, and
by extension for increased consumption of ‘downstream’ antibi-
otics such as cephalosporins, fluoroquinolones and carbapenems.
The other disadvantages of adding clavulanic acid are very im-
mediate: clavulanic acid is associated with more side effects,
particularly diarrhoea that can be disabling [24]; Clostridium difficile
infection is more associated with amoxicillineclavulanic acid than
with amoxicillin alone [32]. In turn, the addition of clavulanic acid
significantly limits the maximal daily dose of amoxicillin that can
be given orally [23,24].

Recommendations for use of oral amoxicillin versus

amoxicillineclavulanic acid

Because amoxicillin with or without clavulanic acid is often used

empirically when, by definition, pathogen identity and resistance
Fig. 2. Increasing use over time of amoxicillineclavulanic acid in Germany (www.ecdc.
profiles are not available, we provide recommendations that are
eu).
syndrome-based rather than pathogen based. The severity of illness
at the time of presentation should also play a role in clinical
consume twice as much of the latter. In some countries, con- decision-making: patients with mild disease do not need imme-
sumption of the combination amoxicillineclavulanic acid is diate coverage for all possible scenarios, no matter how unlikely. In
increasing steadily and not entirely within proportion to the in- addition, the level of access to healthcare should be considered: the
crease in b-lactamase-producing strains (Fig. 2). consequences of missing a b-lactam-resistant strain with initial
therapy are unlikely to be serious in a patient with mild symptoms
Recommendations and conclusions and an ability to return easily for re-evaluation in case of non-
improvement or worsening. Finally, certain clinical syndromes do
Advantage and disadvantages of amoxicillin combined with not warrant any antibiotic therapy given that their aetiologies are
clavulanic acid likely to be viral or even non-infectious. In Table 2, we thus list four
possible therapeutic approaches to the clinical syndromes for
The advantage of prescribing the amoxicillineclavulanic acid which amoxicillin with or without clavulanic acid may be relevant
combination has been clear for decades: with little effort and as empiric therapy:
minimal reflection, the physician's patient is better ‘covered’ for all
clinical eventualities. Yet this short-term, non-collective approach 1. ‘Delayed antibiotic therapy’ with amoxicillin alone only after
has quicklydin the space of just decadesdbrought this and all symptomatic therapy and the passage of time have failed to
patients to a new reality in which adequate antibiotic options for improve clinical symptoms.
the next infection are increasingly jeopardized. 2. Delayed therapy with amoxicillineclavulanic acid as the delayed
The major disadvantage of using the combination instead of antibiotic.
amoxicillin alone is thus the unavoidable fact that antibiotic over- 3. Treatment with amoxicillin alone.
use is the main accelerator of emergence of resistance. The current 4. Treatment with amoxicillineclavulanic acid.

Table 2
Recommended approaches to empiric therapy for clinical syndromes for which amoxicillin with or without clavulanic acid may be warranted, and only where oral therapy is
considered sufficient, or intravenous antibiotic therapy cannot be accessed

Empiric therapeutic approach Clinical syndrome Comments

Delayed prescription, with Pharyngitis Usually of viral origin

amoxicillin alone as the Sinusitis
delayed therapy Otitis media
Mild COPD exacerbation Often no pathogen detected or of viral origin
Delayed prescription, with Lower, uncomplicated UTI Nitrofurantoin and fosfomycin should be used as first-line
amoxicillineclavulanic acid agents and amoxicillineclavulanic acid only second line
as the delayed therapy Acute infectious diarrhoea Antibiotics are generally not recommended
Wound, skin and soft-tissue infections Try to avoid any antibiotic therapy, with local wound care,
debridement and drainage as first-line strategies
Amoxicillin alone Mild or moderate community-acquired pneumonia in patients Other aetiologies (viral, atypical bacteria) should be ruled out
with good/rapid access to healthcare structures according to the clinical presentation and corresponding
therapy considered
Amoxicillineclavulanic acid Severe community-acquired pneumonia In all cases, narrow the spectrum once microbiological data
Community-acquired pneumonia of any severity in patients available
with little/no access to healthcare structures
Severe COPD exacerbation
Surgical site infection
Complicated intra-abdominal infection
Cellulitis
Bone and joint infections

UTI, urinary tract infection; COPD, chronic obstructive pulmonary disease.

 A. Huttner et al. / Clinical Microbiology and Infection 26 (2020) 871e879 877

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