Activity of mecillinam against carbapenem-resistant Enterobacterales.

BACKGROUND: Despite the fact that carbapenem-resistant Enterobacterales (CRE) mostly cause urinary tract infections (UTIs), only few studies have focused on the efficacity of mecillinam against these CRE. OBJECTIVES: To evaluate the mecillinam susceptibility of a huge collection of CRE, including carbapenemase-producing Enterobacterales (CPE) and non-CPE (ESBL and AmpC producers with decreased permeability of the outer membrane). METHODS: A total of 8310 non-duplicate clinical CRE, including 4042 OXA-48-like producers, 1094 NDM producers, 411 VIM producers, 174 KPC producers, 42 IMI producers, 153 multiple-carbapenemase producers and 45 isolates producing other types of carbapenemases (such as IMP-like enzymes or GES-5), were included in the study. WGS was performed on all CPE using Illumina technology. Categorization of susceptibility to mecillinam was performed using disc diffusion (mecillinam discs at 10 µg; I2A, France) according to EUCAST recommendations. The results were interpreted according to EUCAST guidelines (S ≥15 mm). RESULTS: Significantly higher susceptibility rates were observed for carbapenem-resistant Proteus spp. (85%) and carbapenem-resistant Escherichia coli (84%), which are the two most common species responsible for UTIs, than for Klebsiella pneumoniae (67%), Enterobacter cloacae complex (75%), Citrobacter spp. (65%), Serratia spp. (34%) and Morganella morganii (12%). Susceptibility rates were 84%, 71% and 91% for OXA-48-like, NDM and IMI producers and 70% for non-CPE CRE. Mecillinam was less active against VIM and KPC producers (14% and 0%, respectively). CONCLUSIONS: Mecillinam might be an alternative for the treatment of infections due to CRE, particularly UTIs, except for VIM and KPC producers and for M. morganii and Serratia spp species.

Pivmecillinam, the paradigm of an antibiotic with low resistance rates in Escherichia coli urine isolates despite high consumption.

OBJECTIVES: Pivmecillinam, the oral version of mecillinam, represents one of the major recommended and used antibiotics for empiric and targeted treatment of urinary tract infections in primary care in Denmark, Norway and Sweden. Mecillinam resistant mutants in Escherichia coli develop easily in vitro, but their fitness cost has been shown to be high. METHODS: We revisited the resistance and consumption data from the monitoring programmes in the three countries and compared pivmecillinam with ciprofloxacin from 2010 to 2020. RESULTS: Mecillinam resistance rates in Escherichia coli remained around 6% in Denmark and Norway relative to a constant consumption in Norway of 1.6-1.8 DID (defined daily doses per 1000 inhabitants per day), and even increasing in Denmark from 1.6 to 2.3 DID. In Sweden resistance was significantly lower at 4% related to the lower consumption of 0.5 DID. For ciprofloxacin, resistance rates fluctuated around 6%-12%, highest in Sweden with the highest consumption (0.8-0.6 DID) and lowest in Denmark (0.55-0.35 DID) and Norway (0.7-0.3 DID), although consumption declined significantly in all three countries. CONCLUSIONS: Pivmecillinam is an example of an antibiotic, which easily develops resistance in vitro, but apparently can be used broadly in primary care without increase in resistance rates.

A combination of mecillinam and amoxicillin/clavulanate can restore susceptibility of high-level TEM-1-producing Escherichia coli to mecillinam.

Objectives: Mecillinam is recommended in France as a first-line treatment for lower urinary tract infections, due to the large increase in resistance of Escherichia coli to other oral treatments, such as co-trimoxazole or fluoroquinolones, its limited impact on faecal microbiota and its stability in the presence of numerous ß-lactamases. However, we recently identified several mecillinam-resistant E. coli isolates with a high-level expression penicillinase (HEP) phenotype that merit further study. Patients and methods: We studied two isogenic clinical isolates from one patient (one susceptible to mecillinam and one resistant to mecillinam) by WGS to determine the mechanism of mecillinam resistance and compared it with other mecillinam-resistant E. coli . We evaluated the synergistic combination of amoxicillin/clavulanate and mecillinam using a simple test, suitable for daily laboratory practice, to determine the MIC of this combination. Results: We showed that the presence of an SNP in the promoter of the plasmidic TEM-1 ß-lactamase gene is sufficient to confer resistance to mecillinam. This mechanism was present in 67% of HEP-phenotype E. coli tested. Combining mecillinam with amoxicillin/clavulanate abolished resistance, with an MIC compatible with clinical use. This association was not sensitive to the inoculum effect, in contrast to mecillinam alone. Conclusions: An HEP phenotype can confer mecillinam resistance in vitro . This resistance is abolished, regardless of the inoculum, by combining mecillinam with amoxicillin/clavulanate, and can be easily tested in the laboratory. This combination may be used as an oral relay treatment of non-complicated pyelonephritis due to multiresistant E. coli strains.

Characteristics of gram-negative urinary tract infections caused by extended spectrum beta lactamases: pivmecillinam as a treatment option within South Dublin, Ireland.

BACKGROUND: The prevalence of urinary tract infections (UTIs) caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae is increasing and the therapeutic options are limited, especially in primary care. Recent indications have suggested pivmecillinam to be a suitable option. This pilot study aimed to assess the viability of pivmecillinam as a therapeutic option in a Dublin cohort of mixed community and healthcare origin. METHODS: A prospective measurement of mean and fractional inhibitory concentrations of antibiotic use in 95 patients diagnosed with UTI caused by ESBL-producing Enterobacteriaceae was carried out. 36 % patients were from general practice, 40 % were admitted to hospital within south Dublin, and 25 % samples arose from nursing homes. EUCAST breakpoints were used to determine if an isolate was sensitive or resistant to antibiotic agents. RESULTS: Sixty-nine percent of patients (N = 66) with urinary ESBL isolates were female. The mean age of females was 66 years compared with a mean age of 74 years for males. Thirty-six percent of isolates originated from primary care, hospital inpatients (26 %), and nursing homes (24 %). The vast majority of ESBL isolates were E. coli (80 %). The E tests for mecillinam and co-amoxiclav had concentration ranges from 0.16 mg/L up to 256 mg/L. The mean inhibitory concentration (MIC) of mecillinam ranged from 0.25 to 256 mg/L, while co-amoxiclav MICs ranged from 6 to 256 mg/L. The percentage of isolates resistant to mecillinam and co-amoxiclav was found to be 5.26 and 94.74 % respectively. CONCLUSIONS: This is the first study exploring the use of pivmecillinam in an Irish cohort and has demonstrated that its use in conjunction with or without co-amoxiclav is an appropriate and useful treatment for urinary tract infections caused by ESBL-producing organisms.

Ibuprofen versus mecillinam for uncomplicated cystitis--a randomized controlled trial study protocol.

BACKGROUND: Although uncomplicated cystitis is often self-limiting, most such patients will be prescribed antibiotic treatment. We are investigating whether treatment of cystitis with an NSAID is as effective as an antibiotic in achieving symptomatic resolution. METHODS/DESIGN: This is a randomized, controlled, double blind trial following the principles of Good Clinical Practice. Women between the ages of 18 to 60 presenting with symptoms of uncomplicated cystitis are screened for eligibility. 500 women from four sites in Norway, Sweden and Denmark are allocated to treatment with 600 mg ibuprofen three times a day or 200 mg mecillinam three times a day for three days. Allocation is conducted using block randomization. The primary outcome is the number of patients who feel cured by day four as recorded in a diary. Adverse events will be handled and reported in accordance with Good Clinical Practice. DISCUSSION: If treatment of uncomplicated cystitis with ibuprofen is as effective as mecillinam for symptom relief, we can potentially reduce the use of antibiotics on a global scale. TRIAL REGISTRATION: EudraCTnr: 2012-002776-14. ClinicalTrials.gov: NCT01849926.

A simple intervention to reduce inappropriate ciprofloxacin prescribing in the emergency department.

BACKGROUND: According to Norwegian guidelines for antibiotic use in primary care, ciprofloxacin is reserved for complicated urinary tract infections (UTI). Despite these recommendations, ciprofloxacin use has increased in Norway in recent years. We aimed to reduce inappropriate ciprofloxacin prescribing in the emergency department. METHODS: An intervention study was performed by removing ciprofloxacin from the local antibiotic formulary and including a suggestion list for antibiotic use with all point of care urine dipstick testing in an emergency department. An emergency department in the neighbouring county served as the control. Prescriptions for UTI were registered 1 y prior to and 1 y after the intervention. RESULTS: In the targeted emergency department, there was a significant (p < 0.0001) reduction in ciprofloxacin prescribing for cystitis, while the use of mecillinam increased (p = 0.042). In the control department, prescribing of ciprofloxacin doubled (p < 0.0001). CONCLUSIONS: An intervention based on a therapy suggestion list and on limiting the availability of ciprofloxacin in the local formulary, resulted in treatment more in line with national guidelines by reducing ciprofloxacin and increasing mecillinam prescribing.

Mecillinam/clavulanate combination: a possible option for the treatment of community-acquired uncomplicated urinary tract infections caused by extended-spectrum ß-lactamase-producing Escherichia coli.

BACKGROUND: Extended-spectrum ß-lactamases (ESBLs) have emerged as an important mechanism of ß-lactam resistance among community uropathogens. We characterized the ESBLs of a collection of Escherichia coli isolates recovered from outpatients with urinary tract infection during nationwide surveillance conducted from 2005 to 2006 in Greece, and evaluated the in vitro activity of mecillinam and mecillinam/clavulanate against them. MATERIALS AND METHODS: ESBLs were characterized with PCR and sequencing. In vitro interactions were evaluated with agar dilution with and without clavulanate (4 mg/L) using an inoculum of 10(4) or 10(6) cfu/spot as well as with time-kill methodology. RESULTS: Among 48 ESBL producers, 47 (97.9%) were susceptible to mecillinam. CTX-M-type enzymes were produced by 87.2%, with CTX-M-3 being the most prevalent. SHV enzymes were found in 10.6%, VEB enzymes in 2.1%, TEM enzymes in 19.2% and OXA-type enzymes in 12.8%. Synergy with clavulanate was detected in 60.4% using the agar dilution method and in 43.8% using the time-kill methodology. An inoculum effect was detected in 64.6% of isolates, but this phenomenon was inverted and synergy was evidenced for 85.4% with clavulanate. When a high inoculum was used, 60.4% (29/48) were resistant to mecillinam, but 97.9% (47/48) were susceptible in the presence of clavulanate. CONCLUSIONS: CTX-M-type enzymes were the most prevalent among ESBL-producing E. coli uropathogens in Greece. Mecillinam may be useful in uncomplicated cystitis caused by ESBL producers with low MICs. The addition of the inhibitor could improve and extend the activity of mecillinam, even in the setting of infection with a high bacterial inoculum, and merits clinical evaluation.

[Do general practitioners follow the national guidelines for treating urinary tract infections with antibiotics?]. / Følges retningslinjene ved antibiotikaforskrivning mot urinveisinfeksjon?

BACKGROUND: Incorrect use of antibiotics is a major public health concern both nationally and globally due to the development of antibiotic resistance. The goal of this study was to see if prescription of antibiotics for urinary tract infections in general practice was in accordance with national guidelines. MATERIAL AND METHODS: We combined two sets of data from February and March 2003: prescriptions of antibiotics redeemed in pharmacies, and electronic billing cards collected from the National Insurance Agency from 145 general practitioners in Vestfold county. We analysed all consultations related to urinary tract problems, and we found which antibiotics had been prescribed and for how long. The treatment was then compared with the national guidelines. A logistic regression analysis identified factors associated with adequate treatment length. RESULTS: Trimetoprime and mecillinam were most frequently prescribed to both genders. Sixty-nine (6 %) of the total 1,102 prescriptions were quinolones. A total of 271 (32 %) of 847 patients who were prescribed antibiotics for cystitis did not get treatment of sufficient length. Female and young patients were more often given the correct duration of treatment. Doctors with 1,000-1,500 patients more frequently prescribed sufficiently long treatment compared to other physicians. Six patients (0.5 %) were prescribed another antibiotic between two and 14 days after the first prescription. CONCLUSION: The choice of antibiotics conformed well with national guidelines, but the duration of the treatment was often too short. In spite of this, only 0.5 % showed signs of relapse. A number of factors associated with adequate treatment length were identified. The empirical use of furadantin can be increased.

Efficacy of mecillinam against clinical multidrug-resistant Escherichia coli in a murine urinary tract infection model.

Pivmecillinam, a pro-drug of mecillinam, has been used extensively in Scandinavia for the treatment of acute lower urinary tract infections (UTIs) caused by Enterobacterales. It is still an attractive first-line drug for the empirical treatment of UTIs owing to the low prevalence of resistance as well as its favourable impact on the intestinal microbiota as a pro-drug and good in vitro efficacy against extended-spectrum ß-lactamase (ESBL)- and plasmid-mediated AmpC ß-lactamase-producing Escherichia coli. However, optimal dosing of pivmecillinam as well as its in vivo efficacy against UTIs caused by multidrug-resistant (MDR) broad-spectrum ß-lactamase-producing E. coli has not been thoroughly studied. In this study, the efficacy of two mimicked human dosing regimens of pivmecillinam (200 mg and 400 mg three times daily) against clinical E. coli strains, including isolates producing ESBLs (CTX-M-14 and CTX-M-15), plasmid-mediated AmpCs (CMY-4 and CMY-6) and carbapenemases (NDM-1 and VIM-29), in a murine UTI model was compared. Both dosing regimens reduced the number of CFU/mL in urine for all strains, including mecillinam-resistant strains. Combining the effect for all six strains showed no significant differences in effect between doses for all three fluids/organs, but for each dose there was a highly significant effect in urine, kidney and bladder compared with vehicle-treated mice. Overall, this highlights the need for further studies to elucidate the role of mecillinam in the treatment of infections caused by MDR E. coli producing broad-spectrum ß-lactamases, including specific carbapenemases.

Secondary syphilis with exclusive peno-scrotal localization.

Syphilis is a sexually transmitted disease, caused by Treponema pallidum subspecies pallidum, its incidence, in the last decade, has significantly increased both in Western World and in developing countries. It represents a global health problem: it is estimated that each year the new cases of syphilis account for about 12 millions. The diagnosis is not always easy, especially in secondary syphilis in which the cutaneous manifestations are quite variable and should be considered in the differential diagnosis. A 26-year-old homosexual man had from some days papular lesions in the scrotum and penis. Four months before he had consulted a surgeon for the presence of an ulcerated nodular lesion in the perianal area, which advised to remove it in the suspicion of cancer. The patient declined surgery while observing in the following weeks a gradual and complete disappearance of the lesion. On the basis of clinical history, clinical features and laboratory results, a diagnosis of secondary syphilis with an exclusive peno-scrotal localization was made and systemic therapy with diaminocillin was started that led to complete resolution of skin lesions and to significant reduction of sierologic values.

[In-vitro activity of mecillinam against urine isolates of Escherichia coli from outpatient departments in Germany]. / In-vitro-Aktivität von Mecillinam gegen Escherichia coli: Urinisolate von Patienten im niedergelassenen Versorgungsbereich in Deutschland.

National and international guidelines recommend fosfomycin trometamol, nitrofurantoin, nitroxoline, and pivmecillinam as first-line agents for the treatment of acute uncomplicated cystitis. Escherichia coli is by far the leading cause of community-acquired urinary tract infections. Pivmecillinam (X-SYSTO®) is an oral prodrug of mecillinam, a penicillin derivative that was reintroduced to the German market in March 2016. This study aimed to investigate the proportion of mecillinam-resistant strains among E. coli isolates prior to the introduction of X-SYSTO® in Germany.An in-vitro study was carried out to determine the minimal inhibitory concentrations (MICs) of mecillinam against 494 urine isolates of E. coli (including multidrug-resistant strains). Isolates were obtained from outpatients and collected in 25 laboratories between October and December 2013. MIC breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were applied for classifying the bacterial isolates as mecillinam-susceptible (MIC ≤ 8 mg/l) or resistant (MIC > 8 mg/l).The concentrations of mecillinam needed to inhibit 50 % and 90 % of the test isolates were 1 and 4 mg/l, respectively, for isolates displaying the extended spectrum ß-lactamase phenotype, and 0.25 and 4 mg/l, respectively, for the remaining isolates. Overall, 98 % of the isolates were found to be mecillinam-susceptible (MIC ≤ 8 mg/l), and 2 % were found to be resistant (MIC > 8 mg/l).These findings support the recommendation to regard pivmecillinam as a first-line option for the treatment of acute uncomplicated cystitis.

Revival of old antibiotics: needs, the state of evidence and expectations.

The gap between the emergence of antibiotic resistance and new antibiotic development has drawn attention to old antibiotics whose spectrum of coverage frequently comprises highly resistant bacteria. However, these antibiotics have frequently not undergone the structured process of antibiotic development of modern antibiotics, from pharmacokinetic/pharmacodynamic (PK/PD) studies establishing safe and effective dosing, establishment of susceptibility breakpoints, to clinical trials establishing clinical safety and effectiveness. In this review, we highlight the gaps for which we need old antibiotics in community- and hospital-acquired infections. Reviewing recently published and ongoing randomised controlled trials (RCTs) shows advances in our understanding of the efficacy and effectiveness of oral fosfomycin, mecillinam and nitrofurantoin for cystitis, and of trimethoprim/sulfamethoxazole for complicated skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in the community. Summarising older evidence shows the inferiority of chloramphenicol versus modern antibiotics for severe infections. We lack studies on severe infections caused by carbapenem-resistant Gram-negative bacteria and other multidrug-resistant (MDR) bacteria in hospitalised and critically ill patients; ongoing studies assessing colistin and intravenous fosfomycin might fill in some gaps. In the re-development process of old antibiotics, we mandate modern PK/PD studies comprising special populations as well as RCTs addressing the target population of patients in need of these antibiotics powered to examine patient-relevant outcomes. Structured antibiotic re-development from the laboratory to evidence-based treatment recommendations requires public funding, multidisciplinary collaboration, international co-ordination, and methods to streamline the recruitment of critically ill patients infected by MDR bacteria.

Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine.

Mecillinam (amdinocillin) is a ß-lactam antibiotic used to treat uncomplicated urinary tract infections (UTIs). We have previously shown that inactivation of the Escherichia coli cysB gene is the major cause of mecillinam resistance (MecR) in clinical isolates. In this study, we used different E. coli strains (laboratory and clinical isolates) that were MecR due to cysB mutations to determine how mecillinam susceptibility was affected during growth in urine compared to growth in the commonly used growth medium Mueller Hinton (MHB). We also examined mecillinam susceptibility when bacteria were grown in urine obtained from 48 different healthy volunteers. Metabolome analysis was done on the urine samples and the association between the mecillinam susceptibility patterns of the bacteria and urine metabolite levels was studied. Two major findings with clinical significance are reported. First, MecRE. coli cysB mutant strains (both laboratory and clinical isolates) were always more susceptible to mecillinam when grown in urine as compared to laboratory medium, with many strains showing complete phenotypic susceptibility in urine. Second, the degree of reversion to susceptibility varied between urine samples obtained from different individuals. This difference was correlated with osmolality such that in urine with low osmolality the MecR mutants were more susceptible to mecillinam than in urine with high osmolality. This is the first example describing conditional resistance where a genetically stable antibiotic resistance can be phenotypically reverted to susceptibility by metabolites present in urine. These findings have several important clinical implications regarding the use of mecillinam to treat UTIs. First, they suggest that mecillinam can be used to treat also those clinical strains that are identified as MecR in standard laboratory tests. Second, the results suggest that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant susceptibility testing results. Third, these findings imply that changes in patient behavior, such as increased water intake or use of diuretics to reduce urine osmolality and increased intake of cysteine, might induce antibiotic susceptibility in an infecting MecRE. coli strain and thereby increase treatment efficiency.

Efficacy, pharmacology, and safety of amdinocillin in treatment of neonates.

One hundred and nine neonates with complications conducive to lethal infections were investigated to determine the efficacy, pharmacokinetics, and safety of amdinocillin. Of these 109 neonates, 70 were participants in the clinical study and 39 in the pharmacokinetic study. Amdinocillin (40 mg/kg per day) and penicillin (60,000 units/kg per day) were administered separately in divided doses by intramuscular injection at six-hourly intervals for five days. Amdinocillin/penicillin proved to be a safe and effective alternative to gentamicin/penicillin; no adverse reactions were noted nor did the regimen adversely affect renal or hepatic function. Throughout the treatment period, amdinocillin maintained high therapeutic serum levels. Resistance to amdinocillin did not develop during treatment.

Amdinocillin therapy of experimental animal infections.

Amdinocillin has been shown to have broad coverage in vitro against many strains of Enterobacteriaceae. Synergy has been demonstrated in vitro with several other beta-lactam antibiotics. The rabbit model of meningitis was used to study the in vivo effectiveness of amdinocillin when combined with other beta-lactams for serious infections. Organisms that showed an enhanced in vitro bactericidal effect from the combination of amdinocillin and another beta-lactam showed more rapid elimination of the organisms in vivo.

Management of enteric fever with amdinocillin.

Twenty-six patients with enteric fever treated with amdinocillin and/or its pivaloyloxymethyl ester in 1975 to 1978 were compared with 21 patients with enteric fever treated with trimethoprim-sulfamethoxazole in 1972 to 1974. Diagnosis was based on clinical illness and isolation of Salmonella typhi or S. paratyphi A/B from blood cultures or stool cultures. The dosage of pivamdinocillin in adults was 400 to 800 mg, every 6 hours, for 10 to 16 days; dosage in children was half this amount for 11 to 15 days. Of the 21 patients treated with trimethoprim-sulfamethoxazole, 18 (86 percent) showed a satisfactory clinical response; 13 of these 18 had negative stools immediately after therapy, and two more were negative at the time of discharge (total: 83 percent). Mean hospital stay of these patients was 34.5 days. Of the 26 patients treated with amdinocillin, 23 showed a satisfactory clinical response; 20 of those responding clinically were still excreting the causative organism at the end of therapy; seven of the group remained as convalescent patients who continued to excrete the causative organism in feces at the time of discharge. Mean hospital stay was 43 days. The results of initial trials of amdinocillin and ampicillin in combination suggest that such therapy may be preferable to use of amdinocillin alone, although the excretion of the causative organism during convalescence has not been adequately assessed.

Review of clinical experience with amdinocillin monotherapy and comparative studies.

Activity against gram-negative bacilli and frequent synergism with other beta-lactam antibiotics were demonstrated by amdinocillin in urinary tract infections, urosepsis, and in a variety of other infections. In a prospective study, 299 patients were assigned at random to receive amdinocillin or another antibiotic considered standard treatment for the infection. The majority of infections were of the urinary tract, and 58 of 59 patients treated with amdinocillin responded clinically, with cures in 49. Of the 52 patients treated with tobramycin or other comparative agents, 49 responded, and 42 were cured. Escherichia coli and other Enterobacteriaceae were the usual pathogens. Immediately after treatment, 90 percent of urine samples were negative in both treatment groups. At four to six weeks follow-up, relapse or reinfection rates were about 20 percent in either group. Miscellaneous infections were treated with either amdinocillin or a comparative agent. Eleven of 15 infections responded favorably to amdinocillin, and seven were cured. Adverse effects were usually mild and characteristic of the penicillins.

Changes during travel in the composition and antibiotic resistance pattern of the intestinal Enterobacteriaceae flora: results from a study of mecillinam prophylaxis against travellers' diarrhoea.

A randomized double-blind study was carried out in a group of Danish students visiting Mexico for 2 weeks to investigate the efficacy of mecillinam when given orally in preventing travellers' diarrhoea. The subjects took either 200 mg mecillinam daily as a single dose or placebo for 14 days. Nine (56%) out of 16 taking placebo and 3 (19%) out of 16 taking mecillinam developed travellers' diarrhoea (p less than 0.05). The pathogenic aetiology was not ascertained. A complete change in the Enterobacteriaceae flora took place during travel. A highly antibiotic-resistant Enterobacteriaceae flora was acquired in Mexico in subjects on mecillinam prophylaxis as well as on placebo. Selection of mecillinam-resistant bacteria was minimal.

Preliminary experience with parenteral mecillinam.

Case reports are reviewed of 26 patients, mainly with severe Gram-negative infections, treatment with parenteral mecillinam. Twenty-three patients received other antibiotics in addition to mecillinam. In 19 patients, potentially synergistic antimicrobial therapy was given. Overall, a beneficial clinical effect was recorded in 17 (68%) of the 25 patients assessed. A better response was observed in those patients who had not received other antibiotics before treatment with mecillinam was instituted. It is concluded that parenteral mecillinam may have an important role in the treatment of severe Gram-negative infections.