Table 1.
Prospective studies of mecillinam for the treatment of pyelonephritis and Enterobacteriaceae bacteremia
| Pyelonephritis
| ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | Design | Intervention | Patients (N) | Age (mean) (years) | Temperature (°C) | Male: female | Bacteremia (N) | Complicating factors (N) | Estimated AUP (N) | Pathogens (S to mecillinam) (N) | Clinical success | Bacteriological
|
Comment | |
| Success | Without relapse/ reinfection | |||||||||||||
| Trollfors et al (1982)38 | Randomized, open label, comparative | IV: mecillinam 800 mg tid 5 days Oral: P-MEC 400 mg tid 5 days Duration: 10 days |
25 | 19–76 (48) | ≥38.5 | 6:19 | 7 | 8 | ≤17 |
E. coli (S) (22) K. pneumoniae (S) (1) P. mirabilis (S) (2) |
15/25 | 24/25 | 18/23 (2 lower UTI) | The clinical outcome was significantly poorer (P<0.05) in patients with mecillinam. The study excluded resistant strains and negative culture |
| IV: cephaloridine 1 g tid 5 days Oral: cephalexin 500 mg tid 5 days Duration: 10 days |
26 | 18–83 (55) | 6:20 | 10 | 10 | ≤16 |
E. coli (S) (24) K. pneumoniae (S) (2) P. mirabilis (S) (1) |
25/26 | 26/26 | 18/24 (3 lower UTI) | ||||
| Ode et al (1983)39 | Randomized, open label, comparative | IV: mecillinam 1.2 g qid ≥3 days Oral: P-MEC 400 mg tid Duration: 28 days |
20 | 19–88 (56) | >37.5 | 4:16 | 4 | 6 | 14 |
E. coli (S) (17) E. coli (R) (1) P. mirabilis (S) (1) K. pneumoniae (R) (1) |
17/20 AUP: 12/14 |
12/18 AUP: 11/13 |
The resistant isolates were not evaluable for bacteriological evaluation because of change in therapy | |
| IV: trimetoprim 160 mg bid ≥3 days Oral: trimetoprim 160 mg bid Duration: 28 days |
22 | 32–86 (56) | 8:14 | 5 | 10 | 12 |
E. coli (17) P. mirabilis (1) K. pneumoniae (1) Others (3) |
18/22 | 12/21 | |||||
| IV: AMP 2 g qid ≥3 days Oral: P-AMP 600 mg tid Duration: 28 days |
21 | 20–86 (58) | 2:19 | 6 | 5 | 15 |
E. coli (18) K. pneumoniae (1) Others (2) |
16/21 | 13/20 | |||||
| Helin (1983)33 | Open label, noncomparative (pediatric) | Oral: P-MEC 25–40 mg/kg/day bid or tid Duration: 10 days |
20 | 0.5–14 (4) | >38.5 | 4:16 | – | 1 | – |
E. coli (S) (16) K. pneumoniae (S) (2) S. saphropyticus (R) (1) Others (R) (1) |
nd | 19/20 | 18/19 | Failure was seen in the patient with mixed Gram-positive bacteriuria. Relapse was seen in the patient with ureteral stenosis (K. pneumoniae) |
| Rotstein and Farrar (1983)37 | Open label, comparative | IV: mecillinam 10 mg/kg + AMP nd qid Duration: 4–10 days |
11 | 18–80 (39)a | nd | ~1/3 male | 4 | – | – |
E. coli (S) (16) E. coli (R) (5) |
11/11 | 11/11 | nd | 3/10 had clinical relapse (intervention group nd). In vitro synergism between mecillinam and other beta-lactam (P<0.025) |
| IV: mecillinam 10 mg/kg + CCC nd qid Duration: 4–10 days |
9 | 3 | 2 | – | K. pneumoniae (S) (5) | 8/9 | 9/9 | |||||||
| King et al (1983)35 | Open label, comparative | IV: mecillinam 10 mg/kg + AMP nd qid Duration: nd |
14 | nd | nd | ~50% male | nd | nd | nd | Gram-negative bacteria (31) |
26/28 | 21/31 | Low bacteriological cure rate in subgroup with complicated UTI | |
| IV: mecillinam 10 mg/kg + CCC nd qid Duration: nd |
14 | |||||||||||||
| Eriksson et al (1986)31 | Randomized, open label, comparative | IV: mecillinam 400 mg/AMP 500 mg tid (N=15) ~4 days Oral: P-MEC 200 mg/P-AMP 250 mg tid Duration: 14 days |
27 (IV: 15) | 15–86 (55) | ≥38 | 6:21 | 5 | 7 | 20 |
E. coli (25) S. saphropyticus (1) Others (2) |
25/27 (including no relapse) | 27/27 | 15/27 (only two clinical relapses) | Better clinical outcome in the combination group (P=0.002). With only S strains (P=0.06). Better bacteriological outcome in the combination group (P=0.007). Males |
| IV: AMP 1.4 g or tid ~4 days Oral: P-AMP 700 mg bid Duration: 14 days |
30 (IV: 17) | 16–82 (57) | 8:22 | 9 | 9 | 21 |
E. coli (24) K. pneumoniae (4) P. mirabilis (3) Others (2) |
16/30 (including no relapse) | 22/30 | 10/21 (only two clinical relapses) | and complicated infections (P=0.06) and high age (P<0.01) were more common in the unsuccessful treatment group | |||
| Jernelius et al (1988)34 | Randomized, double blinded, placebo controlled | Oral: P-MEC /P-AMP 400/500 mg tid 7 days + placebo tid 14 days Duration: 7 days |
32 | 18–81 (59) | ≥38 | 12:20 | 5 | 14 | 18 |
E. coli (S) (28) K. pneumoniae (S) (2) P. mirabilis (S) (1) S. saphropyticus (R) (2) Others (R) (1) Others (S) (2) |
29/32 Relapse: 3/32 |
9/32 | 14/32 | Significantly better bacteriological success (P=0.004) and lower relapse rate in the 3-week group, (P=0.02). Of the nine patients without bacteriological success in the 3-week group, seven had complicating factors. All bacteria had clinical success |
| Oral: P-MEC /P-AMP 400/500 mg tid 7 days + 200/250 mg tid 14 days Duration: 21 days |
29 | 16–78 (61) | 7:22 | 4 | 13 | 16 |
E. coli (S) (29) S. saphropyticus (R) (1) Others (R) (2) |
28/29 Relapse: 1/29 |
20/29 | 23/29 | ||||
| Cronberg et al (1995)29 | Randomized, double blinded, comparative | IV: mecillinam 600 mg/AMP 1.2 g bid ~3 days Oral: P-MEC 400 mg/P-AMP 500 mg bid Duration: 14 days |
65 | (61) | ≥38.5 | Estimated <50% male | 12 | nd | nd |
E. coli (49) K. pneumoniae (5) P. mirabilis (2) Others (12) |
41/60 | 44/60 | Therapeutic outcomes, parameters adherence rate, and adverse effects were similar in both groups. More severe adverse reactions in cephalosporin group (ie, diarrhea, Clostridium | |
| IV: cefotaxime 2 g bid ~3 days Oral: cefadroxil 800 mg bid Duration: 14 days |
71 | (61) | Estimated <50% male | 20 | nd | nd |
E. coli (58) K. pneumoniae (3) P. mirabilis (6) Others (16) |
45/70 | 50/70 | difficile. and fungal superinfection). The study used ITT analyses, however, since the majority of the studies used PP analysis we decided to use that | ||||
| Nicolle and Mulvey (2007)36 | Case report | Oral: P-MEC 400 mg bid Duration: 2 years |
1 | 47 | nd | 0:1 | – | 1 | 0 | ESBL – E. coli (S) (1) | Bacteriological and clinical success was seen over the following weeks after initiating the therapy, no relapse of ESBL producing E. coli over following 2 years | |||
| Jansåker et al (2015)40 | Observational noncomparative | Oral: P-MEC 400 mg tid Duration: 14 days |
6 | 23–78 (47) | nd | 0:6 | – | 0 | 6 |
E. coli (S) (6) K. pneumoniae (S) (1) |
6/6 | 6/6 | 4/5 (relapse: asymptomatic) | Including retrospective cases: bacteriological and clinical success 17/22 (77%). Bacteriological relapse 7/22 (32%). One ESBL producing E. coli infection with treatment success |
| Enterobacteriaceae bacteremia
| ||||||||
|---|---|---|---|---|---|---|---|---|
| Study | Design | Intervention | Number of patients | Age (median) (years) | Male:female | Complicating factors | Pathogens | Results and comments |
| Frimodt-Møller and Ravn (1979)32 | Observational noncomparative | IV: mecillinam 10 mg/kg qid with/without one other antibiotics Duration: 4–10 days (median 7) |
5 | 47–85 (78) | 1:4 | All patients had serious comorbidities and impaired renal function |
E. coli (S) (2) K. pneumoniae (S) (2) K. oxytoca (S) (1) |
2/2 with monotherapy had clinical and bacteriological success 3/3 with concomitant therapy had clinical and bacteriological success |
| Ekwall et al (1980)30 | Randomized, open label, comparative | IV: mecillinam 10 mg/kg qid 7–14 days Oral: P-MEC 400 mg tid Duration: 21 days |
3 | 56–86 (57) | 1:2 | nd |
E. coli (S) Citrobacter sp (S) K. pneumoniae (S) |
2/3 had clinical and bacteriological success 1/3 had clinical and bacteriological failure (female with K. pneumoniae ) |
| IV: mecillinam 5 mg/kg + AMP 15 mg/kg qid 7–14 days Oral: P-MEC 200 mg + P-AMP 350 mg tid Duration: 21 days |
5 | 21–73 (45) | 3:2 | nd |
E. coli (S) (4) K. pneumoniae (S) E. coli (S) (3) |
4/5 had clinical and bacteriological success 1/5 had clinical and bacteriological failure (male with E. coli) 4/5 had clinical and bacteriological success |
||
| Nonrandomized | IV: mecillinam 10 mg/kg + AMP 30 mg/kg qid 7–14 days Oral: P-MEC 400 mg + P-AMP 700 mg tid Duration: 21 days |
5 | 52–87 (65) | 3:2 | Patients with serious comorbidities |
Citrobacter sp (S) P. mirabilis (S) (2) |
1/5 had clinical and bacteriological failure (male with Ec and Citrobacter sp) | |
| King et al (1983)35 | Open-label comparative (stratified cases) | IV: mecillinam 10 mg/kg + AMP nd qid Duration: nd |
11 | b | ~50% male | b | Gram-negative bacteria | 11/11 had clinical and bacteriological success |
| IV: mecillinam 10 mg/kg + CCC nd qid Duration: nd |
14 | 13/14 had clinical and bacteriological success | ||||||
Notes:
a
Including five cases with other infections.
b
Stratified cases of bacteremia caused by pyelonephritis (for detailed data refer Table 2).
Abbreviations: AMP, ampicillin; AUP, acute uncomplicated pyelonephritis; bid, two times daily; CCC, cephalosporin or carbenicillin; E. coli, Escherichia coli; ESBL, extended spectrum beta-lactamase; GI, gastrointestinal; ITT, intention to treat; IV, intravenous; K. oxytoca, Klebsiella oxytoca; K. pneumoniae, Klebsiella pneumoniae; nd, no data/not described; P. mirabilis, Proteus mirabilis; P-AMP, pivampicillin; P-MEC, pivmecillinam; PP, per protocol; qid, four times daily; SAR, severe adverse reaction; S, sensitive; S. saphropyticus, Staphylococcus saphropyticus; tid, three times daily; UTI, urinary tract infections.