Table 1.

Characteristics of 26 Included Studies (Primary and/or Secondary Outcomes) According to Infection

Study	Country	Setting	Infection type	Study design	Participants	Potential pathogen being studied	Total no. recruited	Total no. with potential pathogen being studied	No. of potential pathogens being studied with evidence of antibiotic resistance	No. of patients where resistance and outcome data available	Primary outcome time pointa, b	Secondary outcomesc	Treatment antibiotic/ antibiotic classd	Antibiotic to which resistance measured
Urinary-tract infection
Brown et al (2002) [35]	United States	OP/ PHC	UTI	Obs (R)	Women	E	NR	601 isolatese	44	104	…	Recc	TMP-SMX	TMP-SMX
Butler et al (2006) [8]	United Kingdom	PHC	UTI	CC Obs (P)	Aduluts	E	932	922	94	797 [1] 862 (Rec) [2] 816 (Fab) [2] 420 (Sdur) [2]	Within 30 days	Recc Fabc Sdurc	Not specified	To prescribed antibiotic [1] To at least 1 antibiotic [2]
Gupta et al (2007) [37]	United States	PHC	UTI	RCT	Women	E	338	276	34	308f	Day 3b	…	TMP-SMX Nitrofurantoin	TMP-SMX Nitrofurantoin
Little et al (2010) [50]	United Kingdom	PHC	UTI	Obs (P)	Women	NRg	843	NR	NR	264 (Sdur) 264 (Ssev)	-	Sdurc Ssevc	Not specified	To >1 antibiotics
McNulty et al (2006) [32]	United Kingdom	PHC	UTI	Obs (P)	Women	E	497	298h	44	207 (Sdur)f 317 (Rec)	Day 7b	Sdurc Recc	Trimethoprim	Trimethoprim
Noskin et al (2001) [33]	United States	OP	UTI	Obs (P)	Women	E	156	89	42	71	NRb	…	Not specified	To >1 antibiotics
Raz et al (2002) [36]	Israel	OP	UTI	Obs (P)	Women	E	618	425	30	484f	Days 5–9b	…	TMP-SMX	TMP-SMX
Soraas et al (2014) [34]	Norway	Other	UTI	Obs (P)	Adults	ESBL-E	343	343i	81 (ESBL-E)	343	Within 14 daysb	Fabc	Mecillinam Nonmecillinam	Mecillinam and ESBL status
Vallano et al (2006) [39]	Spain	PHC	UTI	Obs (P)	Women	E	220	88	15f	108f	Within 14 daysb	…	Not specified	To >1 antibiotics
Van Merode et al (2005) [38]	Netherlands	PHC	UTI	RCT	Women	E	324	80	17	114f	Days 6–8b	…	Trimethoprim	Trimethoprim
Community-acquired pneumonia
Cao et al (2010) [49]	China	OP	RTI (CAP)	Obs (P)	Adults; adolescents	MP	356	67	46	59	…	Fabc Sdurc	Not specified	Erythromycin
Hagberg et al (2003) [29]	Multiple	IP/OP	RTI (CAP)	Pooled data from 6 phase III trials	Adults	SP	1373	174	23j	174	Days 3–5b	…	Telithromycin	Penicillin or erythromycin
Kawai et al (2012) [51]	Japan	OP	RTI (CAP)	Obs (P)	Children; adolescents	MP	476	50	21	30	…	Fabc	Not specified	To >1 macrolide
O’Doherty et al (1997) [40]	United Kingdom; Ireland	OP	RTI (CAP)	RCT	Adults	SP	264	30k	6	30	Days 3–5b	…	Grepafloxacin Amoxicillin	Amoxicillin
Van Rensburg et al (2005) [30]	Multiple	OP	RTI (CAP)	Pooled RCT (8 phase III trials and 1 phase II study)	Adults	SP	2339	418	61	327	Days 17–24b	…	Telithromycin	To erythromycin and penicillin
Yanagihara et al (2004) [41]	Japan	OP	RTI (CAP)	Obs (R)	Adults	SP	306	306	129	306	NRb	…	Not specified	Penicillin
Zhanel et al (2014) [31]	Multiple	Other	RTI (AMS) RTI (CAP) RTI (AOM)	Pooled RCT (11 RCTs; 2 phase III trials)	Adults; children	SP	872l 309 CAP	CAP 79	CAP 27	CAP 79	NRb	…	Azithromycin	Azithromycin
Acute otitis media
Barry et al (1994) [27]	France	OP	RTI (AOM)	Pooled data from 3 RCTs	Children	SP	1092	236	54m	219	Day 10	…	B-lactams (combined)	Penicillin; B-lactams
Dagan et al (1996) [42]	Israel	ER	RTI (AOM)	RCT	Children	SP	266	98	18	77	Day 10	…	Cefuroxime Cefaclor	Cefuroxime Cefaclor
Hoberman et al (1996) [47]	Multiple	IP/OP	RTI (AOM)	Obs (P)	Children	SP	917	298	82	260	Days 12–14b	…	Co-amoxiclav	Penicillin
Hoberman et al (2005) [45]	Multiple	OP	RTI (AOM)	RCT	Children	SP	730	229	158	188	Days 12–14b	…	Co-amoxiclav Azithromycin	Penicillin Azithromycin
Zhanel et al (2014) [31]	Multiple	Other	RTI (AMS) RTI (CAP) RTI (AOM)	Pooled RCT (11 RCTs; 2 phase III trials)	Adults; children	SP	872l AOM 402	AOM 177	AOM 41	AOM 177	NR	…	Azithromycin	Azithromycin
Acute sore throat
Quinn et al (2003) [46]	United States; Canada	OP	RTI (sore throat)	RCT	Adults; adolescents	Spy	526	360n	9	285	Days 16–23b	…	Telithromycin Clarithromycin	Erythromycin
Seppala et al (2002) [48]	Finland	OP	RTI (sore throat)	Obs (R)	NR	Spy	NR	529	76	273	NR	…	Erythromycin Penicillin	Erythromycin
Acute maxillary sinusitis
Buchanan et al (2005) [28]	Sweden	Other	RTI (AMS)	Pooled data from 3 RCTs	Adults; adolescents	SP	1298	126	1	78	Days 17–24b	…	Telithromycin	Telithromycin
Zhanel et al (2014) [31]	Multiple	Other	RTI (AMS) RTI (CAP) RTI (AOM)	Pooled RCT (11 RCTs; 2 phase III trials)	Adults; children	SP	872l AMS 161	AMS 57	AMS 19	AMS 57	NR	…	Azithromycin	Azithromycin
Skin and soft-tissue infection
Dagan et al (1992) [43]	Israel	OP	Skin (Imp)	RCT	Children	SA	102	90	27	89	Days 3–8	…	Erythromycin Mupirocin	Erythromycin, Mupirocin
Giordano et al (2006) [44]	United States	Other	Skin (USSSI)	RCT	Adults; adolescents	SA	392	171	79	151	Days 17–24b	…	Cefdinir Cephalexin	Methicillin
Overall							15580			5659 [3]

Abbreviations: AMS, acute maxillary sinusitis; AOM, acute otitis media; CAP, community-acquired pneumonia; CC, case control; E, Escherichia coli; ER, Emergency room; ESBL-E, extended spectrum β-lactamase Escherichia coli; Imp, impetigo; IP, hospital inpatients; MP, Mycoplasma pneumoniae; NR, not reported; Obs (P), prospective observational; Obs (R), retrospective observational; OP, hospital outpatients; Other, community setting (not specified); PHC, primary care clinic/general practice; RCT, randomized controlled trial; RTI, respiratory-tract infection; SA, Staphylococcus aureus; SP, Streptococcus pneumoniae; Spy, Streptococcus pyogenes; TMP-SMX, trimethoprim-sulfamethoxazole; USSSI, uncomplicated skin and skin structure infections (eg, cellulitis, erysipelas, impetigo, simple abscess, wound infection, furunculosis, folliculitis); UTI, urinary-tract infection.

^aPrimary outcome: “response failure” defined as the persistence of symptoms after completion of antibiotic treatment. Where the outcome was reported as “clinical cure” in the study, we calculated the proportion of patients that had failed to respond to antibiotic treatment within the designated timescale (ie, 1 − proportion of patients with clinical cure).

^bData on clinical cure, rather than clinical response failure, were reported by 10 randomized controlled trials [28–31, 37, 38, 40, 44–46] and 7 observational studies [32–34, 36, 39, 41, 47]. Overall, clinical response failure was assessed 3–5 days from baseline in 3 studies [29, 37, 40], 6–10 days from baseline in 6 studies [27, 32, 36, 38, 42, 43], 11–14 days from baseline in 4 studies [34, 39, 45, 47], 20–30 days from baseline in 5 studies [8, 28, 30, 44, 46], and not reported in 4 studies [31, 33, 41, 48].

^cSecondary outcomes: reconsultation (Rec), further antibiotic prescriptions (Fab), symptom duration (Sdur), and symptom severity (Ssev).

^dMultiple antibiotics prescribed in separate study arms.

^eWe assumed 1 isolate per participant.

^fAll combined pathogens.

^gSpecific organism not reported.

^hColiforms; 242 single isolates were sent to HPA Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL) of which Escherichia coli accounted for 90% (n = 219/242).

ⁱESBL E. coli and non-ESBL E. coli only.

^jPenicillin- or erythromycin-resistant (all Streptococcus pneumoniae isolates were susceptible to telithromycin).

^kOnly 81 were evaluated microbiologically.

^lExcluded acute exacerbations of chronic bronchitis.

^mOne child in the SpRP group did not complete the treatment course because of adverse events and was not evaluable for clinical response.

ⁿPositive screening for group A ß-haemolytic streptococcus.

…not applicable [1].: Resistance measured to prescribed antibiotic [2];: Resistance measured to at least one antibiotic [3];: where more than one outcome data available, the lowest number was taken.