Source document: https://docs-lawep.s3.us-east-2.amazonaws.com/1697741682012.pdf (Georgia)
Review Lancet Infect Dis 2007; 7: 338–48 Department of Medicine E, Rabin Medical Center, Petah- Tiqva, Israel (D Yahav MD, M Paul MD, A Fraser MPH, N Sarid MD, L Leibovici MD); Sackler Faculty of Medicine, Tel-Aviv University, Ramat- Aviv, Tel Aviv, Israel (M Paul, L Leibovici); Department of Social Medicine, University of Bristol, Bristol, UK (A Fraser); and Department of Medicine A, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (N Sarid) Correspondence to: Dr Mical Paul, Department of Medicine E and Unit of Infectious Diseases, Rabin Medical Center, Beilinson Hospital, 49100 Petah-Tiqva, Israel.
Tel 972 3 9376501; fax 972 3 9376512; pil1pel@zahav.net.il Eﬃ cacy and safety of cefepime: a systematic review and meta-analysis Dafna Yahav, Mical Paul, Abigail Fraser, Nadav Sarid, Leonard Leibovici Cefepime is a broad-spectrum cephalosporin with enhanced coverage against Gram-positive and Gram-negative bacteria.

We did a systematic review of randomised trials that compared cefepime with another β-lactam antibiotic, alone or with the addition of a non-β-lactam antibiotic to both study groups.
We searched Central, PubMed, Embase, Lilacs, new US Food and Drug Administration drug applications, conference proceedings, and references of the included studies.

Two reviewers independently did the search and data extraction.

57 trials were included.

All-cause mortality—the primary outcome—was higher with cefepime than other β-lactams (risk ratio [RR] 1·26 [95% CI 1·08–1·49]).
Sensitivity analyses by the trials’ methodological quality revealed higher RRs for trials reporting adequate allocation-sequence generation (1·52 [1·20–1·92]) and allocation concealment (1·36 [1·09–1·70]).

Baseline risk factors for mortality were similar.

No signiﬁ cant diﬀ erences between groups in treatment failure, superinfection, or adverse events were found.
This Review provides evidence and oﬀ ers possible explanations for increased mortality among patients treated with cefepime in randomised trials.

Cefepime Introduction The cephalosporins are currently among the most widely prescribed class of antibiotics in hospitals.1 Their broad spectrum of activity both against Gram-positive and Gram-negative bacteria and a low toxicity proﬁ le contribute to their widespread use.
is a semi-synthetic, broad-spectrum cephalosporin classiﬁ ed within the fourth generation class.2,3 Compared with ceftazidime, cefepime has enhanced activity in vitro against Gram-positive bacteria, including meticillin-sensitive Staphylococcus aureus and Streptococcus pneumoniae.4 Cefepime has better activity against Gram-negative bacteria that produce extended- spectrum β-lactamase than other commercially available oxyimino-cephalosporins.4–7 Cefepime’s superior activity is attributed to more rapid penetration into bacteria, the targeting of multiple penicillin-binding proteins, or lower aﬃ nity for several β-lactamases.3 This drug may have a lower propensity for selection of resistant (derepressed) mutants, which results in a lower rate of resistant phenotypes during or after treatment,8,9 although failures have been reported.10 Cefepime is currently widely used in hospitals for its approved indications, including empirical monotherapy for febrile neutropenia, pneumonia, bacteraemia, and urinary tract, abdominal, and skin or soft-tissue infections.1,2,11 In a previous systematic review that assessed empirical monotherapy for febrile neutropenia, we found an increased rate of mortality with cefepime compared with other β-lactam antibiotics.12 The cause of the increased mortality was not clear.
Superinfections were more frequent with cefepime compared with other β-lactams, but the diﬀ erence was not statistically signiﬁ cant.

No diﬀ erences were observed within other secondary outcomes, failure.

Subgroup analyses and meta-regression did not detect an association with speciﬁ c bacteria.

treatment including We therefore did a systematic review of all randomised controlled trials that compared cefepime with other β-lactam antibiotics.

The primary outcome was all-cause mortality.


We aimed to expand our previous analysis to all cefepime trials, including patients without neutropenia, and extract patients’ baseline characteristics, adverse events, and eﬃ cacy data in the search for an explanation for the increased all-cause mortality.

systematically to Methods Inclusion criteria and outcomes We included randomised controlled trials that compared cefepime with a diﬀ erent β-lactam antibiotic.
The addition of a non-β-lactam drug (eg, aminoglycoside) was allowed as long as the same antibiotic and dose were used in both study groups.

The primary outcome assessed was 30-day all-cause mortality.

If all-cause mortality was unavailable, mortality at end of study follow-up and up to 30 days was used.
Secondary outcomes were as follows: clinical failure (deﬁ ned as non-resolved infection, treatment modiﬁ cation, or death as a result of infection); microbiological failure (deﬁ ned as failure to eradicate the causative pathogens); bacterial, fungal, and any superinfections (deﬁ ned as new, persistent, or worsening symptoms with or without signs of infection associated with the isolation of a new pathogen or the development of a new site of infection); and adverse events.
Search strategy and selection criteria We searched the Cochrane Central Register of Controlled Trials (Central), PubMed, Embase, and Lilacs databases.
The search terms “cefepim*”, “BMY-28142”, “BMY- 28142”, “maxipime”, “maxcef”, “cepimax”, “cepimex”, or “axepim” were combined with the Cochrane ﬁ lter for randomised controlled trials (except in Central).13 Unpublished trials were sought in references of all selected studies, relevant conference proceedings, trial registries and ongoing trial databases, new drug application documents of the US Food and Drug 338 http://infection.thelancet.com Vol 7 May 2007 Review 13 studies not eligible: 8 non-comparative or non-randomised 4 pseudo-randomised 1 correspondence 9 trials rejected: 6 incompatible comparisons 3 no relevant outcomes 5 full-text unavailable and inclusion criteria inapplicable 19 secondary publications of included RCTs identiﬁed 103 full-text publications retrieved from abstract search 90 RCTs assessed for inclusion 81 potentially appropriate RCTs identiﬁed 76 appropriate RCTs identiﬁed for inclusion 57 RCTs included: 41 all-cause mortality 55 clinical failure 45 microbiological failure 23 any superinfection 15 bacterial superinfection 43 any adverse event 34 discontinuation because of adverse event Figure 1: Trial proﬁ le Excluded studies and detailed reason for exclusion are shown in webtable 2.
RCT=randomised controlled trial.

outcome data for most of these subgroups were not available, meta-regression analysis was done to assess the association between the percentage of these infections and individual study eﬀ ect estimates (STATA 8).

A funnel plot was used to assess small study eﬀ ects (eg, publication bias).

Results The trial proﬁ le is shown in ﬁ gure 1.

103 publications were retrieved for full-text inspection, of which 46 were excluded.
57 randomised controlled trials that compared cefepime with a diﬀ erent β-lactam antibiotic were included in the Review15–70 (webtable 1).

One publication described two trials.50 The excluded trials and reasons for exclusion are shown in webtable 2. compared with The trials assessed cefepime for many diﬀ erent indications (webtable 1).
For febrile neutropenia, cefepime was ceftazidime,15,23,26,28,32,36,43,45,51,57,67 imipenem-cilastatin or meropenem,19,25, 29, 56,66 piperacillin- tazobactam,20,22,37,61 or ceftriaxone.30 Aminoglycosides were added to both study groups in six trials28,30,32,37,43,61 and vancomycin in one trial.15 For pneumonia or lower respiratory tract infections, cefepime was compared with ceftazidime,16,18,21,31,44,47,48,50,59,60 cefotaxime,17,27,68 ceftriaxone,38,70 cefoperazone-sulbactam,42 or imipenem-cilastatin.69 Other trials that compared cefepime with ceftazidime included patients with urinary tract infections, sepsis, bacteraemia, See Online for webtable 1 and webtable 2 Administration, and through personal contact with the investigators and sponsoring pharmaceutical companies of the included studies.
No language or date restrictions were imposed.

The last search was done in October, 2006. intention-to-treat analysis Study selection and data extraction Two reviewers (MP and DY, NS, or AF) independently did the search, applied inclusion criteria, and extracted the data.

Outcomes were extracted preferentially by intention to treat, including all individuals randomised in the outcome assessment.
If intention-to-treat data were not available, data per protocol were extracted and compared with through sensitivity analysis.

For clinical failure, a modiﬁ ed intention-to-treat analysis was done by imputing failure for all dropouts.

In all cases in which mortality data or randomisation methods were not reported in the primary reference, we requested the data from the investigators and the sponsor.
Quality assessment was done using the individual component approach, which assessed allocation-sequence generation, allocation concealment, blinding, intention-to-treat analysis, and the number of patients excluded from the outcome assessment.

Allocation concealment and generation were graded as adequate, unclear, or inadequate, by use of criteria suggested in the Cochrane handbook.13 To assess the eﬀ ect of study quality on outcomes, we did components.
sensitivity Additionally, we baseline compared characteristics that may have aﬀ ected outcomes.

For studies assessing patients with febrile neutropenia, we recorded age (in adults), neutrophil count, percentage of patients with acute leukaemia or bone-marrow transplantation, and percentage of patients with documented infections.

For the other studies, we recorded age, temperature, percentage of patients with severe infection, and percentage with septic shock.
We assigned 1 point for each risk factor to the group (cefepime vs comparator) in which it was more prevalent, and compiled the comparison between study groups for all trials.

analyses by individual patients’ Statistical analysis Risk ratios (RRs) and 95% CIs were calculated for individual studies.
Heterogeneity in the results of the trials was assessed using the chi-squared test for heterogeneity and the I2 measure of inconsistency.14 If no heterogeneity was found, meta-analysis was done using the Mantel-Haenszel ﬁ xed-eﬀ ects model (Review Manager 4.2, Nordic Cochrane Centre).

RRs of less than 1·0 favour cefepime for all comparisons.

Comparisons were subcategorised by the comparator antibiotic and main diagnosis (eg, pneumonia, febrile neutropenia).
Subgroup analyses for mortality and clinical failure were planned for Gram-negative, Gram-positive, and Pseudomonas spp infections, and pneumonia.
Because http://infection.thelancet.com Vol 7 May 2007 339 Review Cefepime (n/N) Comparator (n/N) Cefepime vs ceftazidime Bonﬁtto 199921 Kebudi 200145 Schaad 199862 Mustafa 200151 Huang 200241 Edelstein 199131 Auﬁero 199716 Schrank 199563 Chuang 200226 Ponce-de-Leon 199954 Gentry 199134 Wang 199967 Aoun 199715 McCabe 1996b50 Ramphal 199757 Leophonte 199347 Cardonnier 199728 Glauser 199736 Chandrasekar 200023 Erman 200132 McCabe 1996a50 Beaucaire 199918 Hoepelman 199339 Subtotal 0/74 0/32 0/149 2/49 2/26 3/43 3/57 1/13 3/48 1/25 1/59 0/19 5/54 4/65 6/45 7/87 13/242 8/139 22/143 8/98 17/225 29/141 32/173 167/2006 Test for heterogeneity: χ2=12·73, df=19 (p=0·85), l2=0% Test for overall eﬀect: Z=1·62 (p=0·11) Cefepime vs piperacillin-tazobactam Bohme 199820 Gomez 200137 Bow 200622 Subtotal 2/49 13/86 15/263 30/398 Test for heterogeneity: χ2=1·09, df=2 (p=0·58), l2=0% Test for overall eﬀect: Z=2·48 (p=0·01) Cefepime vs imipenem-meropenem Tamura 200266 Biron 199819 Raad 200356 Cherif 200425 Cornely 200129 Zanetti 200369 Subtotal 2/42 10/200 7/127 5/105 8/202 41/132 73/808 Test for heterogeneity: χ2=2·61, df=5 (p=0·76), l2=0% Test for overall eﬀect: Z=1·16 (p=0·24) Cefepime vs ceftriaxone-cefotaxime Newton 199352 Zervos 199870 Cornely 200230 Willis 199868 Cordero 200127 Saez-Llorens 199558 O‘Ryan 199653 Barckow 199317 Grossman 199938 Subtotal 0/159 3/59 1/100 5/54 1/84 2/43 7/103 13/41 7/76 39/719 Test for heterogeneity: χ2=4·03, df=7 (p=0·78), l2=0% Test for overall eﬀect: Z=0·88 (p=0·38) 0/66 0/31 0/150 0/55 0/26 0/22 0/29 2/15 2/48 2/25 2/53 2/22 3/57 3/34 4/45 4/44 4/111 9/142 10/133 11/97 11/111 21/134 26/175 116/1625 2/51 5/100 8/265 15/416 1/41 4/195 5/124 5/102 10/202 37/138 62/802 0/72 1/56 2/107 2/55 2/76 4/47 5/105 4/21 7/75 27/614 RR (95% CI) Not estimable Not estimable Not estimable 5·60 (0·28–113·87) 5·00 (0·25–99·34) 3·66 (0·20–67·84) 3·62 (0·19–67·82) 0·58 (0·06–5·66) 1·50 (0·26–8·58) 0·50 (0·05–5·17) 0·45 (0·04–4·81) 0·23 (0·01–4·51) 1·76 (0·44–7·01) 0·70 (0·17–2·94) 1·50 (0·45–4·96) 0·89 (0·27–2·86)
 1·49 (0·50–4·47) 0·91 (0·36–2·29) 2·05 (1·01–4·16) 0·72 (0·30–1·71) 0·76 (0·37–1·57) 1·31 (0·79–2·18) 1·25 (0·78–2·00) 1·20 (0·96–1·50) 1·04 (0·15–7·10) 3·02 (1·12–8·14) 1·89 (0·81–4·38) 2·14 (1·17–3·89) 1·95 (0·18–20·71) 2·44 (0·78–7·64) 1·37 (0·45–4·19) 0·97 (0·29–3·26) 0·80 (0·32–1·99) 1·16 (0·80–1·69) 1·20 (0·88–1·63) Not estimable 2·85 (0·31–26·57) 0·54 (0·05–5·81) 2·55 (0·52–12·56) 0·45 (0·04–4·89) 0·55 (0·11–2·83) 1·43 (0·47–4·35) 1·66 (0·62–4·48) 0·99 (0·36–2·68) 1·24 (0·77–1·99) Total 309/3931 220/3457 1·26 (1·08–1·49) Test for heterogeneity: χ2=23·74, df=36 (p=0·94), l2=0% Test for overall eﬀect: Z=2·84 (p=0·005) 0·1 0·2 0·5 2 1 RR (95% CI) 5 10 Favours cefepime Favours comparator Figure 2: All-cause mortality by comparator drug Studies are identiﬁ ed by the name of the ﬁ rst author, year of publication, and reference.
Fixed-eﬀ ects meta-analysis used for estimation of combined risk ratio (RR; 95% CI).

The comparison is subcategorised by the comparator antibiotic.
340 http://infection.thelancet.com Vol 7 May 2007 Review RR (95% CI) Not estimable 5·60 (0·28–113·87) 1·95 (0·18–20·71) 0·54 (0·05–5·81) 1·04 (0·15–7·10) 1·50 (0·26–8·58) 0·23 (0·01–4·51) 1·76 (0·44–7·01) 1·50 (0·45–4·96) 2·44 (0·78–7·64) 3·02 (1·12–8·14) 1·37 (0·45–4·19) 0·97 (0·29–3·26) 1·49 (0·50–4·47) 1·89 (0·81–4·38) 0·91 (0·36–2·29) 0·80 (0·32–1·99) 2·05 (1·01–4·16) 0·72 (0·30–1·71) 1·42 (1·09–1·84) Not estimable 3·66 (0·20–67·84) 2·85 (0·31–26·57) 2·55 (0·52–12·56) 0·45 (0·04–4·89) 0·70 (0·17–2·94) 0·99 (0·36–2·68) 0·76 (0·37–1·57) 1·31 (0·79–2·18) 1·16 (0·80–1·69) 1·15 (1·89–1·48) Not estimable Not estimable Not estimable 5·00 (0·25–99·34) 3·62 (0·19–67·82) 0·58 (0·06–5·66) 0·50 (0·05–5·17) 0·45 (0·04–4·81) 0·55 (0·11–2·83) 1·43 (0·47–4·35) 1·66 (0·62–4·48) 0·89 (0·27–2·86) 1·25 (0·78–2·00) 1·20 (0·85–1·69) Cefepime (n/N) Comparator (n/N) Neutropenic fever Kebudi 200145 Mustafa 200151 Tamura 200266 Cornely 200230 Bohme 199820 Chuang 200226 Wang 199967 Aoun 199715 Ramphal 199757 Biron 199819 Gomez 200137 Raad 200356 Cherif 200425 Cordonier 199728 Bow 200622 Glauser 199736 Cornely 200129 Chanraseker 200023 Erman 200132 Subtotal 0/32 2/49 2/42 1/100 2/49 3/48 0/19 5/54 6/45 10/200 13/86 7/127 5/105 13/242 15/263 8/139 8/202 22/143 8/98 130/2043 Test for heterogeneity: χ2=12·89, df=17 (p=0·74), l2=0% Test for overall eﬀect: Z=2·61 (p=0·009) Pneumonia Bonﬁtto 199921 Edelstein 199131 Zervos 199870 Willis 199868 Cordero 200127 McCabe 1996b50 Grossman 199938 McCabe 1996a50 Beaucaire 199918 Zanetti 200369 Subtotal 0/74 3/43 3/59 5/54 1/84 4/65 7/76 17/225 29/141 41/132 110/953 Test for heterogeneity: χ2=4·83, df=8 (p=0·78), l2=0% Test for overall eﬀect: Z=1·06 (p=0·29) Urinary tract/gynaecological infections Newton 199352 Schaad 199862 Subtotal 0/159 0/149 0/308 Test for heterogeneity: not applicable Test for overall eﬀect: not applicable Other/mixed infections Huang 200241 Auﬁero 199716 Schrank 199563 Ponce-de-Leon 199954 Gentry 199134 Saez-Llorens 199558 O‘Ryan 199653 Barckow 199317 Leophonte 199347 Hoepelman
 199339 Subtotal 2/26 3/57 1/13 1/25 1/59 2/43 7/103 13/41 7/87 32/173 69/627 Test for heterogeneity: χ2=4·69, df=9 (p=0·86), l2=0% Test for overall eﬀect: Z=1·03 (p=0·30) 0/31 0/55 1/41 2/107 2/51 2/48 2/22 3/57 4/45 4/195 5/100 5/124 5/102 4/111 8/265 9/142 10/202 10/133 11/97 87/1928 0/66 0/22 1/56 2/55 2/76 3/34 7/75 11/111 21/134 37/138 84/767 0/72 0/150 0/222 0/26 0/29 2/15 2/25 2/53 4/47 5/105 4/21 4/44 26/175 49/540 Total 309/3931 220/3457 1·26 (1·08–1·49) Test for heterogeneity: χ2=23·74, df=36 (p=0·94), l2=0% Test for overall eﬀect: Z=2·84 (p=0·005) 0·1 0·2 0·5 1 2 5 10 RR (95% CI) Favours cefepime Favours comparator Figure 3: All-cause mortality by indication Studies are identiﬁ ed by the name of the ﬁ rst author, year of publication, and reference.
Fixed-eﬀ ects meta-analysis used for estimation of combined risk ratio (RR; 95% CI).

The comparison is subcategorised by the main infectious diagnosis that deﬁ ned patients for inclusion in the trial.
http://infection.thelancet.com Vol 7 May 2007 341 Review 0·0 0·4 0·8 1·2 1·6 ) R R g o l ( E S See Online for webtable 3 0·1 0·2 0·5 2·0 5·0 10 1·0 RR Figure 4: Funnel plot for all-cause mortality A plot of the trials’ precision (SE of log [risk ratio (RR)]), as a measure of trial size, against RR on a logarithmic scale.

The graph shows a symmetric, inverted funnel shape.

Dotted line indicates combined eﬀ ect estimate.


or skin or soft-tissue infections.24,33,34,39,40,41,46,54,55,62,63,64,65 Three trials compared cefepime with ceftriaxone or cefotaxime for children with meningitis,49,53,58 and one trial compared cefepime with cefotaxime for gynaecological infections.52 The full daily dose most commonly used for febrile neutropenia was 6 g and for pneumonia was 4 g, although lower doses were assessed.

Overall, 11 723 patients were randomised in these trials.
Adequate allocation concealment and allocation- sequence generation were described in 30 trials (webtable 3).

One trial was triple blind,23 ﬁ ve were double blind,38,50,55,59,60 outcome assessors were blinded in eight trials,18,19,29,36,51,56,62,69 and the remaining were open- label trials.

The score for baseline patient risk factors did not diﬀ er signiﬁ cantly in trials assessing febrile neutropenia (1·12 [0·70–1·79]; 18 trials) or among other trials (1·15 [0·71–1·85]; 26 trials).
All-cause mortality data were available from 41 trials (webtable 3; 7388 patients).15–23,25–32,34,36–39,41,45,47,50–54,56–58,62,63,66–70 Mortality was signiﬁ cantly higher for cefepime than its comparators (1·26 [1·08–1·49]; p=0·005).

No signiﬁ cant heterogeneity was detected for the overall comparison (p=0·94, I2=0%).

All antibiotic comparators were associated with lower all-cause mortality (ﬁ gure 2), with signiﬁ cance piperacillin-tazobactam for (2·14 [1·17–3·89]; p=0·01).
All-cause mortality was higher for cefepime in all types of infections, except for the subgroup with urinary tract infections in which no deaths occurred (ﬁ gure 3).

The diﬀ erence in all-cause mortality was signiﬁ cant for febrile neutropenia (1·42 [1·09–1·84]; p=0·009).

shown [0·86–1·34]).

Blinding and type of analysis (intention- to-treat vs per-protocol analysis) did not aﬀ ect the results.
The proportion of patients with microbiologically documented Gram-negative and Pseudomonas spp infections was 17–97% and 0–40%, respectively.

All- cause mortality for these subgroups of patients was not available.

The association between the percentage of these infections and the studies’ RRs by meta-regression analysis was not signiﬁ cant.
Post-hoc analyses showed no signiﬁ cant associations between trial results and the percentage of adverse events in the cefepime group or the cefepime dose used in the study.

Exclusion of studies that compared cefepime with carbapenems (of broader coverage spectrum) did not eliminate the disadvantage observed for cefepime (1·29 [1·06–1·56]).

Re-analysis of all studies by use of a random-eﬀ ects model gave results that were similar to the ﬁ xed-eﬀ ects model (1·24 [1·05–1·46]).
The funnel plot for all-cause mortality showed studies to evenly distribute within an inverse funnel shape around the combined RR (ﬁ gure 4), which indicated that publication bias was unlikely.

Clinical failure was assessed in all but two trials,29,49 and these analyses included 8911 patients.

Overall, clinical failure was similar for cefepime compared with the comparator drugs (0·98 [0·93–1·03]), and for the diﬀ erent indications (ﬁ gure 5).
No signiﬁ cant diﬀ erence was found among the subgroup of patients with pneumonia or lower [0·82–1·04]; 2427 infections (0·92 respiratory tract patients).

No signiﬁ cant diﬀ erences between cefepime and ceftazidime (0·94 [0·88–1·01]), carbapenems (0·92 [0·79–1·07]), and ceftriaxone or cefotaxime (0·92 [0·76– 1·11]) were detected.

Risk of clinical failure was signiﬁ cantly higher for cefepime versus piperacillin- tazobactam (1·09 [1·01–1·18]; p=0·04).
Studies with adequate allocation concealment yielded an RR for clinical failure of 1·01 (0·95–1·07), whereas studies of unclear concealment methods showed a non- signiﬁ cant advantage for cefepime (0·93 [0·86–1·01]).

Results were similar for adequate allocation generation (1·00 studies (1·01 [0·82–1·23]).

A modiﬁ ed intention-to-treat analysis included 10 786 patients and yielded an RR of 0·98 (0·95– 1·02).
double-blinded [0·95–1·05]) and Microbiological failure was not signiﬁ cantly diﬀ erent for cefepime compared with the comparator drugs (0·92 [0·84–1·02]; 45 trials, 4574 patients).

The RR for the comparison with ceftriaxone or cefotaxime was 0·87 (0·63–1·22; 11 trials, 1023 patients).

Studies of higher methodological quality were associated with greater mortality for cefepime.
Studies reporting adequate allocation concealment yielded a slightly higher RR (1·36 [1·09–1·70]) than studies in which concealment was unclear (1·16 [0·91–1·47]).

Similarly, studies with adequate allocation-sequence generation had higher eﬀ ect estimates than those with 1·07 (1·52 unclear generation [1·20–1·92] vs (0·96 New infections after treatment with cefepime versus comparator drugs occurred with similar frequency in trials, both study groups 4032 patients).
Similarly, there was no signiﬁ cant diﬀ erence overall between cefepime and comparator drugs in the comparison of documented bacterial trials, superinfections 2502 patients).
[0·79–1·17]; 23 [0·74–1·38]; (1·01 15 342 http://infection.thelancet.com Vol 7 May 2007 Review RR (95% CI) 0·95 (0·50–1·78) 0·97 (0·52–1·82) 0·43 (0·20–0·90) 0·97 (0·58–1·62) 1·04 (0·68–1·59) 0·77 (0·50–1·20) 1·08 (0·78–1·49) 1·35 (0·94–1·93) 1·06 (0·88–1·27) 0·78 (0·53–1·16) 0·68 (0·45–1·04) 1·20 (0·93–1·54) 1·04 (0·91–1·18) 0·97 (0·74–1·28) 1·01 (0·81–1·24) 0·92 (0·77–1·11) 1·01 (0·90–1·15) 0·93 (0·82–1·06) 1·09 (0·99–1·19) 1·05 (0·92–1·21) 1·00 (0·96–1·05) 1·60 (0·20–12·99) 0·33 (0·04–3·07) 0·35 (0·06–1·99) 0·67 (0·17–2·68) 0·25 (0·03–2·16) 0·25 (0·03–2·11) 1·58 (0·62–4·06) 0·96 (0·35–2·60) 1·47 (0·60–3·58) 0·89 (0·40–2·02) 0·61 (0·29–1·27) 0·53 (0·23–1·21) 0·97 (0·49–1·94) 0·57 (0·27–1·24) 0·73 (0·37–1·43) 0·78 (0·61–1·00) 0·60 (0·23–1·52) 0·94 (0·71–1·24) 0·94 (0·75–1·17) 0·92 (0·77–1·09) 1·69 (0·34–8·38) 1·39 (0·32–6·04) 1·57 (0·49–5·07) 0·88 (0·37–2·12) 0·90 (0·37–2·17) 1·12 (0·69–1·81) Febrile neutropenia Wang 199967 Kebudi 200145 Jehn 199843 Tamura 200266 Chuang 200226 Mustafa 200151 Bohme 199820 Gomez 200137 Ramphal 199757 Raad 200356 Biron 199819 Cherif 200425 Aoun 199715 Cornely 200230 Chandrasekar 200023 Erman 200132 Glauser 199736 Cordonnier 199728 Bow 200622 Sanz 200261 Subtotal Cefepime (n/N) 9/19 12/32 8/47 16/38 25/58 18/44 30/49 40/90 38/44 32/127 29/168 61/103 54/60 49/100 78/136 68/103 106/133 155/212 209/263 221/432 1258/2258 Test for heterogeneity: χ2=21·68, df=19 (p=0·30), l2=12·4% Test for overall eﬀect: Z=0·15 (p=0·88) Community-acquired pneumonia McCabe 1996b50 Willis 199868 Auﬁero 199716 Edelstein 199131 Huang 200542 Jiang 200344 Zervos 199870 Leophonte 199347 Saito 199259 Saito 199260 Barckow 199317 McCabe 1996a50 Cordero 200127 Bonﬁtto 199921 Grossman 199938 Subtotal Test for heterogeneity: χ2=10·72, df=14 (p=0·71), l2=0% Test for overall eﬀect: Z=1·99 (p=0·05) 3/15 1/40 2/51 4/38 1/50 1/30 10/59 10/75 11/76 9/65 10/37 10/68 14/84 9/74 12/67 107/829 Hospital-acquired pneumonia Lin 200148 5/21 Zanetti 200369 54/132 Beaucaire 199918 73/141 Subtotal 132/294 Test for heterogeneity:
 χ2=0·89, df=2 (p=0·64), l2=0% Test for overall eﬀect: Z=0·96 (p=0·34) Urinary tract/gynaecological infections Preheim 199555 4/26 Schaad 199862 4/99 Gentry 199134 7/59 Newton 199352 14/95 Shariﬁ 199665 12/118 Subtotal 41/397 Test for heterogeneity: χ2=1·17, df=4 (p=0·88), l2=0% Test for overall eﬀect: Z=0·44 (p=0·66) Comparator (n/N) 11/22 12/31 14/35 17/39 24/58 26/49 29/51 34/103 36/44 40/124 41/162 50/101 52/60 54/107 69/121 73/102 107/136 84/107 194/265 211/435 1178/2152 1/8 3/40 3/27 3/19 4/50 4/30 6/56 5/36 7/71 11/71 8/18 8/29 13/76 14/66 15/61 105/658 8/20 60/138 74/134 142/292 2/22 3/103 4/53 6/36 7/62 22/276 Figure 5 (continued on next page) 0·1 0·2 0·5 1 RR (95% CI) 2 5 10 Favours cefepime Favours comparator The frequencies of any adverse event (0·99 [0·94–1·04]; 43 trials, 8806 patients) and adverse events requiring discontinuation (1·20 [0·94–1·52]; 34 trials, 7305 patients) were similar for cefepime versus comparator drugs.
Neurological complications (other than headache) were reported (1·16 trials18,22,25,27,28,38–41,47,52,55,56,59–62,65,68 19 in [0·78–1·13]).
Seizures were reported in one trial and occurred in the imipenem group.56 Discussion The objective of our systematic review was to assess the eﬃ cacy and safety of cefepime, nearly a decade after its http://infection.thelancet.com Vol 7 May 2007 343 Review Meningitis Saez-Llorens 199558 O‘Ryan 199653 Subtotal 12/43 22/103 34/146 Test for heterogeneity: χ2=0·01, df=1 (p=0·92), l2=0% Test for overall eﬀect: Z=0·19 (p=0·85) Other/mixed infections Chang 199824 Gentry 199235 Schrank 199563 Ponce-de-Leon 199954 Schwartz 199664 Kieft 199446 Huang 200241 Hoepelman 199339 Holloway 199640 Gainer 199533 Subtotal 0/19 3/21 2/13 3/22 11/93 8/56 7/24 24/123 35/165 50/196 143/732 Test for heterogeneity: χ2=2·42, df=8 (p=0·97), l2=0% Test for overall eﬀect: Z=0·30 (p=0·77) Total 1715/4656 Test for heterogeneity: χ2=43·42, df=53 (p=0·82), l2=0% Test for overall eﬀect: Z=0·90 (p=0·37) 14/47 23/105 37/152 0/15 0/10 3/15 5/22 4/37 6/58 7/18 29/139 38/164 52/207 144/685 0·94 (0·49–1·80) 0·98 (0·58–1·64) 0·96 (0·64–1·44) Not estimable 3·50 (0·20–61·94) 0·77 (0·15–3·92) 0·60 (0·16–2·21) 1·09 (0·37–3·22) 1·38 (0·51–3·73) 0·75 (0·32–1·76) 0·94 (0·58–1·52) 0·92 (0·61–1·37) 1·02 (0·73–1·42) 0·97 (0·79–1·19) 1628/4215 0·98 (0·93–1·03) 0·1 0·2 0·5 1 RR (95% CI) 2 5 10 Favours cefepime Favours comparator Figure 5 (continued from previous page): Clinical failure by indication Studies are identiﬁ ed by the name of the ﬁ rst author, year of publication, and reference.
Fixed-eﬀ ects meta-analysis used for estimation of combined risk ratio (RR; 95% CI).

Clinical failure is subcategorised by the main infectious diagnosis that deﬁ ned patients for inclusion in the trial.

approval for clinical use.2 We therefore compiled all randomised controlled trials that compared cefepime with a diﬀ erent β-lactam antibiotic.

We allowed only the addition of a non-β-lactam antibiotic to both study groups, thus limiting the diﬀ erence between study arms to the β-lactams compared.
We found all-cause mortality to be signiﬁ cantly higher with cefepime than with other β-lactams.

The RR of 1·26 denotes an increase in all-cause mortality of 26%, with 95% CIs ranging from an increase of 8% to an increase of 49%.

The corresponding number of patients needed to treat with comparator drugs in order to prevent one death with cefepime is 50 (33–100) patients, given a weight adjusted mortality rate in the comparator group of 5·8%.
Further analyses of the mortality outcome and assessment of secondary outcomes did not reveal a speciﬁ c cause for the increased mortality, nor a speciﬁ c patient population at risk.

Among subcategories of patients, signiﬁ cantly increased mortality with cefepime was seen only among neutropenic patients, but the RRs were similar for other types of patients and infections.
We selected all-cause mortality as the primary outcome because it is ultimately the most objective outcome and the main purpose of treating patients with infections.

Other outcomes, such as clinical failure, are inﬂ uenced by providers and outcome assessors, and may be prone to bias, especially in open trials that are assessing a novel broad-spectrum antibiotic.

Even if assessed without bias, treatment failure is not a correlate of antimicrobial eﬃ cacy.
Clinical failure is most often because of treatment discontinuation or modiﬁ cations for various reasons by in the treating physician.

Microbiological eradication may represent antimicrobial eﬃ cacy more closely, but can be the subgroup of patients with assessed only microbiologically documented infections, and does not always correlate with clinical improvement.

Thus, the lack of a sensitive measure of eﬃ cacy in such trials to be monitored and requires all-cause mortality assessed.
In view of in-vitro and microbiological data from previous studies on cefepime, our results are somewhat surprising.

Cefepime provides a broader spectrum of coverage in vitro than most comparator drugs assessed in these trials.4 An advantage has also been claimed with regards to resistance induction, which should result in fewer secondary infections and better outcomes overall.71 Therefore, how can our results be explained?
A spurious ﬁ nding is unlikely given the signiﬁ cance and homogeneity of our results.

Moreover, several points support our ﬁ ndings on mortality.

Studies of lower methodological quality tend to exaggerate spurious treatment eﬀ ects.72,73 In the case of our Review, studies of higher methodological quality were associated with the larger eﬀ ect estimates.

A 52% increase in mortality with cefepime was observed in studies reporting an adequate method for generation of the allocation sequence.
To further assess the possibility led to the that assignment of sicker patients to the cefepime group (including studies in which randomisation methods were not compared patients’ baseline characteristics.

No signiﬁ cant diﬀ erences were found.
We combined studies comparing cefepime with diﬀ erent improper randomisation methods reported) we 344 http://infection.thelancet.com Vol 7 May 2007 Review Search strategy and selection criteria These are described in detail in the Methods section on page 338. hospital-acquired pneumonia.100 Interventions aimed at optimising antibiotic use in hospitals encourage the use of cefepime for these and other indications.101–104 The new data presented in this report may necessitate a change in recommendations and in practice.
Full mortality data must be obtained from all trials done to date.

If mortality is indeed higher with cefepime, analysis of individual patients might clarify its reasons.

Pending that, no new trials with cefepime for moderate to severe infections should be done.

Conﬂ ict of interests We declare we have no conﬂ icts of interests.

Acknowledgments DY and MP contributed equally to the manuscript.
We thank Mina Nishimori for extracting the data from studies in Japanese, and all investigators who provided supplemental data.

We thank the Cochrane Anaesthesia Review Group and the Cochrane Gynaecological Cancer Group for their revision of our protocol and for obtaining and translating several studies.

This Review was supported in part by an EC 5th framework IST grant (TREAT project, grant no.

1999-11459).
1999-11459).

The funding source had no role in study design, collection, analysis, and interpretation of data, writing of the report, or the decision to submit it for publication.

Results for patients with febrile neutropenia are included in a systematic review assessing empirical monotherapy for febrile neutropenia,12 and the results formed the reason for the current Review.
This study was presented in part at the 16th European Congress of Clinical Microbiology and Infectious Diseases; April 1–4, 2006; Nice, France (abstract O156).

The protocol is published in the Cochrane Library, where this Review will be published and updated.105 References 1 Mutnick AH, Rhomberg PR, Sader HS, Jones RN.

Antimicrobial usage and resistance trend relationships from the MYSTIC Programme in North America (1999–2001).

J Antimicrob Chemother 2004; 53: 290–96.

2 US Food and Drug Administration.


Maxipime.

(Cefepime 3 4 5 6 hydrochloride) for injection.

NDA 50-679/S-021.

http://www.fda.

gov/medwatch/SAFETY/2003/03MAR_PI/Maxipime_PI.pdf (accessed March 13, 2007).

Sanders CC.

Cefepime: the next generation?

Clin Infect Dis 1993; 17: 369–79.

Sader HS, Fritsche TR, Jones RN.


Potency and spectrum trends for cefepime tested against 65746 clinical bacterial isolates collected in North American medical centers: results from the SENTRY Antimicrobial Surveillance Program (1998–2003).

Diagn Microbiol Infect Dis 2005; 52: 265–73.

Pfaller MA, Jones RN, Marshall SA, et al.


Inducible amp C beta- lactamase producing Gram-negative bacilli from blood stream infections: frequency, antimicrobial susceptibility, and molecular epidemiology in a national surveillance program (SCOPE).

Diagn Microbiol Infect Dis 1997; 28: 211–19.

Fung-Tomc J, Dougherty TJ, DeOrio FJ, Simich-Jacobson V, Kessler RE.

Activity of cefepime against ceftazidime- and cefotaxime-resistant Gram-negative bacteria and its relationship to beta-lactamase levels.
Antimicrob Agents Chemother 1989; 33: 498–502.

7 Goethaert K, Van Looveren M, Lammens C, et al.

High-dose cefepime as an alternative treatment for infections caused by TEM-24 ESBL-producing Enterobacter aerogenes in severely-ill patients.

Clin Microbiol Infect 2006; 12: 56–62.

8 Goldstein FW.

Cephalosporinase induction and cephalosporin 9 resistance: a longstanding misinterpretation.

Clin Microbiol Infect 2002; 8: 823–25.

Sanders WE Jr, Tenney JH, Kessler RE.


Eﬃ cacy of cefepime in the treatment of infections due to multiply resistant Enterobacter species.

Clin Infect Dis 1996; 23: 454–61.

10 Song W, Moland ES, Hanson ND, Lewis JS, Jorgensen JH, Thomson KS.

Failure of cefepime therapy in treatment of Klebsiella pneumoniae bacteremia.

J Clin Microbiol 2005; 43: 4891–94.

antibiotics for diﬀ erent infectious diagnoses.


However, examination of the forest plots and formal statistical methods indicate that no evidence of heterogeneity of eﬀ ect estimates was present.

Finally, the funnel plot was symmetric, pointing against the existence of small study eﬀ ects, such as publication bias.

renal function.81,82 Non-convulsive We oﬀ er two possible explanations for our results.

The ﬁ rst is an unrecognised adverse event.
Recent reports have described neurotoxic eﬀ ects with cefepime, including encephalopathy and non-convulsive status epilepticus, which have resulted in the addition of this adverse event in the drug application and postmarketing experience of cefepime.74–80 Most reports involve adults with acute or chronic renal failure, but cases of encephalopathy and status epilepticus have been reported in patients with normal status epilepticus can be diﬃ cult to recognise in elderly patients, particularly if there is no history of seizures.83 Delay in diagnosis may result in increased morbidity or mortality.84 Therefore, increased mortality in the cefepime group might be explained by undiagnosed cases of non- convulsive status epilepticus or encephalopathy.
The second possible explanation is inadequate antimicrobial eﬃ cacy in vivo.

Discrepancies between results in vitro and in vivo have been described with cefepime, explained by an inoculum eﬀ ect, poor tissue concentrations, or pharmacodynamic considerations that favour continuous administration of cefepime.85–89 Randomised controlled trials are limited in their ability to assess rare and previously unrecognised outcomes.
Trials of antibiotic treatment are further limited by imprecise eﬃ cacy outcome measures.

Either of the possibilities may exist and should be pursued.

The main limitation of this Review is the lack of complete mortality data.

All-cause mortality was not reported in all studies.

We complemented published data through correspondence with the primary investigators, but did not achieve complete data for all trials.
Nearly all trials that reported ﬁ nancial support were sponsored by Bristol- Myers Squibb, the producer of cefepime.

Confronted with preliminary results from our Review, the company did not supply further data or results for unpublished trials.90–93 We could also not determine the reasons for increased mortality in these trials.
Data extraction was explicitly planned to search for its cause, given results of a previous meta-analysis.12 We thus planned to extract data on mortality for patients with speciﬁ c types of infections and pathogens, but these data were not reported.
the Conclusions In view of the wide choice of alternative antibiotic increased mortality observed with treatments, cefepime, whatever its reasons, should lead us to call for reconsideration of is currently recommended in several guidelines worldwide for the empirical treatment of febrile neutropenia,94–97 severe community-acquired pneumonia,98,99 late-onset its use.
Cefepime and http://infection.thelancet.com Vol 7 May 2007 345 Review 11 Alfandari S, Bonenfant C, Depretere L, Beaucaire G. Use of 27 parenteral antimicrobial agents in north of France hospitals.

Med Mal Infect 2007; 37: 103–07.

12 Paul M, Yahav D, Fraser A, Leibovici L. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta- analysis of randomized controlled trials.

J Antimicrob Chemother 2006; 57: 176–89.

13 Higgins JPT, Green S, eds.


Cochrane handbook for systematic reviews of interventions 4.2.5 [updated May 2005].

http://www.cochrane.org/ resources/handbook/hbook.htm (accessed March 13, 2007).

14 Higgins JP, Thompson SG, Deeks JJ, Altman DG.

Measuring inconsistency in meta-analyses.

BMJ 2003; 327: 557–60.


15 Aoun M, Boogaerts MA, Bosly AJ, Schots H. A multicenter, randomized, prospective, comparative study of cefepime plus vancomycin versus ceftazidime plus vancomycin as empiric therapy in the treatment of febrile episodes in granulocytopenic patients with hematological malignancies.

Joint clinical/statistical review of NDA 50,679/SE1-002.

http://www.fda.gov/cder/foi/nda/97/050679s002.

htm (accessed Mar 30, 2007).

16 Auﬁ ero A, Sturani C, Zanon P, et al.


Cefepime versus ceftazidime in the treatment of lower respiratory tract infections.

J Chemother 1997; 9: 213–18.

17 Barckow D, Schwigon CD.

Cefepime versus cefotaxime in the treatment of lower respiratory tract infections.

J Antimicrob Chemother 1993; 32 (suppl B): 187–93.

18 Beaucaire G, Nicolas MH, Martin C, et al.

Phare study.
Phare study.

Comparative study of combined cefepime-amikacin versus ceftazidime combined with amikacin in the treatment of nosocomial pneumonias in ventilated patients.

Multicenter group study.

Ann Fr Anesth Reanim 1999; 18: 186–95 (in French).

19 Biron P, Fuhrmann C, Cure H, et al.

Cefepime versus imipenem- cilastatin as empirical monotherapy in 400 febrile patients with short duration neutropenia.

CEMIC (Study Group of Infectious Diseases in Cancer).

J Antimicrob Chemother 1998; 42: 511–18.


20 Bohme A, Shah PM, Stille W, Hoelzer D. Piperacillin/tazobactam versus cefepime as initial empirical antimicrobial therapy in febrile neutropenic patients: a prospective randomized pilot study.

Eur J Med Res 1998; 3: 324–30.

21 Bonﬁ tto P, Lamorgese V, De Vietro T, et al.

A randomized trial of cefepime and ceftazidime for the treatment of community-acquired pneumonia.

J Chemother 1999; 11: 273–77.

22 Bow EJ, Rotstein C, Noskin GA, et al.


A randomized, open-label, multicenter comparative study of the eﬃ cacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies.

Clin Infect Dis 2006; 43: 447–59.

23 Chandrasekar PH, Arnow PM.

Cefepime versus ceftazidime as empiric therapy for fever in neutropenic patients with cancer.

Ann Pharmacother 2000; 34: 989–95.

24 Chang SC, Fang CT, Hsueh PR, et al.


Eﬃ cacy and safety of cefepime treatment in Chinese patients with severe bacterial infections: in comparison with ceftazidime treatment.

Int J Antimicrob Agents 1998; 10: 245–48.

25 Cherif H, Bjorkholm M, Engervall P, et al.

A prospective, randomized study comparing cefepime and imipenem-cilastatin in the empirical treatment of febrile neutropenia in patients treated for haematological malignancies.

Scand J Infect Dis 2004; 36: 593–600.


26 Chuang YY, Hung IJ, Yang CP, Jaing TH, Lin TY, Huang YC.

Cefepime versus ceftazidime as empiric monotherapy for fever and neutropenia in children with cancer.

Pediatr Infect Dis J 2002; 21: 203–09.

27 Cordero E, Bouza E, Ruiz I, Pachon J. Cefepime versus cefotaxime for empirical treatment of bacterial pneumonia in HIV-infected patients: an open, randomized trial.

J Antimicrob Chemother 2001; 48: 527–34.

28 Cordonnier C, Herbrecht R, Pico JL, et al.


Cefepime/amikacin versus ceftazidime/amikacin as empirical therapy for febrile episodes in neutropenic patients: a comparative study.

The French Cefepime Study Group.

Clin Infect Dis 1997; 24: 41–51.

29 Cornely OA, Reichert D, Buchheidt D, et al.

Three-armed multicenter randomized study on the empiric treatment of neutropenic fever in a high risk patient population (PEG Study III).
Proceedings of the 41st Interscience Conference on Antimicrobials Agents and Chemotherapy; Dec 16–19, 2001; Chicago, IL, USA.

Abstract L-775.

30 Cornely OA, Bethe U, Seifert H, et al.

A randomized monocentric trial in febrile neutropenic patients: ceftriaxone and gentamicin vs cefepime and gentamicin.

Ann Hematol 2002; 81: 37–43.

31 Edelstein H, Chirurgi V, Oster S, et al.

A randomized trial of cefepime (BMY-28142) and ceftazidime for the treatment of pneumonia.
J Antimicrob Chemother 1991; 28: 569–75.

32 Erman M, Akova M, Akan H, et al.

Comparison of cefepime and ceftazidime in combination with amikacin in the empirical treatment of high-risk patients with febrile neutropenia: a prospective, randomized, multicenter study.

Scand J Infect Dis 2001; 33: 827–31.

33 Gainer B, Ho H, Jauregui L, et al.

Cefepime (FEP) vs ceftazidime (CAZ) for empiric treatment of sepsis with bacteremia.
Proceedings of the 35th Interscience Conference on Antimicrobials Agents and Chemotherapy; Sept 17–20, 1995; San Francisco, CA.

Abstract LM-22.

34 Gentry LO, Rodriguez-Gomez G. Randomized comparison of cefepime and ceftazidime for treatment of skin, surgical wound, and complicated urinary tract infections in hospitalized subjects.

Antimicrob Agents Chemother 1991; 35: 2371–74.


35 Gentry LO, Rodrigez-Gomez G. A randomized study of cefepime versus appropriate comparative antibiotic therapy in the treatment of bone and joint infections.

Proceedings of the 32nd Interscience Conference on Antimicrobials Agents and Chemotherapy; Oct 11–14, 1992; Anaheim, CA, USA.

Abstract 1580.

36 Glauser M, Dekker AW, Van Marwijkkooy M, et al.


A multicenter comparative study of cefepime vs ceftazidime as empiric therapy in the treatment of febrile episodes in neutropenic patients.

Joint clinical/statistical review of NDA 50,679/SE1-002.

http://www.fda.

gov/cder/foi/nda/97/050679s002.htm (accessed Mar 30, 2007).

37 Gomez L, Estrada C, Gomez I, et al.

Cefepime plus amikacin versus piperacillin-tazobactam plus amikacin in the treatment of patients with fever and granulocytopenia.
Proceedings of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; Dec 16–19, 2001; Chicago, IL, USA.

Abstract L-771.

38 Grossman RF, Campbell DA, Landis SJ, et al.

Treatment of community-acquired pneumonia in the elderly: the role of cefepime, a fourth-generation cephalosporin.

J Antimicrob Chemother 1999; 43: 549–54.

39 Hoepelman AI, Kieft H, Aoun M, et al.

International comparative study of cefepime and ceftazidime in the treatment of serious bacterial infections.
J Antimicrob Chemother 1993; 32 (suppl B): 175–86.

40 Holloway WJ, Palmer D. Clinical applications of a new parenteral antibiotic in the treatment of severe bacterial infections.

Am J Med 1996; 100 (suppl 6A): 52S–59S.

41 Huang CK, ChenYS, Lee SS, et al.

Safety and eﬃ cacy of cefepime versus ceftazidime in the treatment of severe infections.

J Microbiol Immunol Infect 2002; 35: 159–67.

42 Huang JJ, Zeng Q, Yu JL.


Therapeutic eﬀ ects of cefepime and 43 44 sulbactam/cefoperazone on moderate and severe respiratory tract infection in children.

Di Yi Jun Yi Da Xue Xue Bao 2005; 25: 1199–200 (in Chinese).

Jehn U, Ruhnke M, Schlimok G, Lew D, Hossfeld K, Huhn D. Randomized comparison of cefepime/amikacin versus ceftazidime/ amikacin as empiric treatment for febrile neutropenia in cancer patients.

The German-Swiss Cefpime Study Group [abstract 332].

Support Care Cancer 1998; 6 (suppl): 312.


Jiang JH, Wang Y.

Comparison of the eﬃ cacy and safety between cefepime and ceftazidime in the treatment of the moderate to severe low-respiratory tract infection.

Chin J Clin Pharmacol Therapeut 2003; 8: 92–94.

45 Kebudi R, Gorgun O, Ayan I, Gurler N, Akici F, Toreci K. Randomized comparison of cefepime versus ceftazidime monotherapy for fever and neutropenia in children with solid tumors.

Med Pediatr Oncol 2001; 36: 434–41.


46 Kieft H, Hoepelman AI, Rozenberg-Arska M, et al.

Cefepime compared with ceftazidime as initial therapy for serious bacterial infections and sepsis syndrome.

Antimicrob Agents Chemother 1994; 38: 415–21.

47 Leophonte P, Bertrand A, Nouvet G, et al.

A comparative study of cefepime and ceftazidime in the treatment of community-acquired lower respiratory tract infections.

J Antimicrob Chemother 1993; 32 (suppl B): 165–73.


346 http://infection.thelancet.com Vol 7 May 2007 Review 48 Lin JC, Yeh KM, Peng MY, Chang FY.

Eﬃ cacy of cefepime versus ceftazidime in the treatment of adult pneumonia.

J Microbiol Immunol Infect 2001; 34: 131–37.

49 Mallet E, Astruc J, Floret D, Kafetzis DA, Nalet V, Gres JJ.

Epidemiologic pattern and clinical management of bacterial meningitis in children.

A European comparative study of cefepime and cefotaxime.
Proceedings of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept 28–Oct 1, 1997; Toronto, ON, Canada.

Abstract K-136.

50 McCabe R, Chirurgi V, Farkas SA, Haddow A, Heinz G, Greene S. A new therapeutic option for the treatment of pneumonia.

Am J Med 1996; 100 (suppl 6A): 60S–67S.

51 Mustafa MM, Carlson L, Tkaczewski I, McCracken GH Jr, Buchanan GR.
Comparative study of cefepime versus ceftazidime in the empiric treatment of pediatric cancer patients with fever and neutropenia.

Pediatr Infect Dis J 2001; 20: 362–69.

52 Newton ER, Yeomans ER, Pastorek JG, Soper DE, Hemsell DL.

Randomized comparative study of cefepime and cefotaxime in the treatment of acute obstetric and gynaecological infections.

J Antimicrob Chemother 1993; 32 (suppl B): 195–204.
53 O’Ryan M, Saez-Llorens X, Santos JI, Mccracken G, Yang J, Tenney J. Cefepime vs ceftriaxone for pediatric meningitis.

Proceedings of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept 15–18, 1996; New Orleans, LA, USA.

Abstract L-023.

54 Ponce-de-Leon A, Lopez-Meneses M, Sifuentes-Osornio J. Cefepime versus ceftazidime for the treatment of serious bacterial infections.

Diagn Microbiol Infect Dis 1999; 35: 263–68.

55 Preheim LC, Childs SJ, Rajfer J, Bittner MJ.


Randomized, double- blind comparison of cefepime and ceftazidime therapy for urinary tract infection.

Curr Ther Res 1995; 56: 729–37.

56 Raad II, Escalante C, Hachem RY, et al.

Treatment of febrile neutropenic patients with cancer who require hospitalization: a prospective randomized study comparing imipenem and cefepime.

Cancer 2003; 98: 1039–47.

57 Ramphal R, Haddow A, McCracken GH.


A comparative study of cefepime vs ceftazidime in the treatment of adult cancer patients with fever and neutropenia.

Joint clinical/statistical review of NDA 50,679/SE1-002.

http://www.fda.gov/cder/foi/nda/97/ 050679s002.htm (accessed Mar 30, 2007).

58 Saez-Llorens X, Castano E, Garcia R, et al.

Prospective randomized comparison of cefepime and cefotaxime for treatment of bacterial meningitis in infants and children.

Antimicrob Agents Chemother 1995; 39: 937–40.


59 Saito A, Shigeno Y, Irabu Y, et al.

A comparative study of cefepime for bacterial pneumonia.

Kansenshogaku Zasshi 1992; 66: 859–85 (in Japanese).

60 Saito A, Shigeno Y, Irabu Y, et al.

A comparative study of cefepime for chronic respiratory tract infections.

Kansenshogaku Zasshi 1992; 66: 886–908 (in Japanese).

61 Sanz MA, Lopez J, Lahuerta JJ, et al.


Cefepime plus amikacin versus piperacillin-tazobactam plus amikacin for initial antibiotic therapy in haematology patients with febrile neutropenia: results of an open, randomized, multicentre trial.

J Antimicrob Chemother 2002; 50: 79–88.

62 Schaad UB, Eskola J, Kafetzis D, et al.

Cefepime vs ceftazidime treatment of pyelonephritis: a European, randomized, controlled study of 300 pediatric cases.
European Society for Paediatric Infectious Diseases (ESPID) Pyelonephritis Study Group.

Pediatr Infect Dis J 1998; 17: 639–44.

63 Schrank JH Jr, Kelly JW, McAllister CK.

Randomized comparison of cefepime and ceftazidime for treatment of hospitalized patients with Gram-negative bacteremia.

Clin Infect Dis 1995; 20: 56–58.

64 Schwartz R, Das-Young LR, Ramirez-Ronda C, Frank E. Current and future management of serious skin and skin-structure infections.

Am J Med 1996; 100 (suppl 6A): 90S–95S.


65 Shariﬁ R, Geckler R, Childs S. Treatment of urinary tract infections: selecting an appropriate broad-spectrum antibiotic for nosocomial infections.

Am J Med 1996; 100 (suppl 6A): 76S–82S.

66 Tamura K, Matsuoka H, Tsukada J, et al.

Cefepime or carbapenem treatment for febrile neutropenia as a single agent is as eﬀ ective as a combination of 4th-generation cephalosporin + aminoglycosides: comparative study.

Am J Hematol 2002; 71: 248–55.


67 Wang FD, Liu CY, Hsu HC, et al.

A comparative study of cefepime versus ceftazidime as empiric therapy of febrile episodes in neutropenic patients.

Chemotherapy 1999; 45: 370–79.

68 Willis R, Gaines J, Nelson M. Cefepime vs cefotaxime in the treatment of pneumonia.

Infect Med 1998; 15: 636–43.

69 Zanetti G, Bally F, Greub G, et al.


Cefepime versus imipenem- cilastatin for treatment of nosocomial pneumonia in intensive care unit patients: a multicenter, evaluator-blind, prospective, randomized study.

Antimicrob Agents Chemother 2003; 47: 3442–47.

70 Zervos M, Nelson M. Cefepime versus ceftriaxone for empiric treatment of hospitalized patients with community-acquired pneumonia.

The Cefepime Study Group.

Antimicrob Agents Chemother 1998; 42: 729–33.

71 Pechere JC, Vladoianu IR.


Development of resistance during ceftazidime and cefepime therapy in a murine peritonitis model.

J Antimicrob Chemother 1992; 29: 563–73.

72 Moher D, Pham B, Jones A, et al.

Does quality of reports of randomised trials aﬀ ect estimates of intervention eﬃ cacy reported in meta-analyses?

Lancet 1998; 352: 609–13.

73 Schulz KF, Chalmers I, Hayes RJ, Altman DG.

Empirical evidence of bias.


Dimensions of methodological quality associated with estimates of treatment eﬀ ects in controlled trials.

JAMA 1995; 273: 408–12.

74 Primavera A, Cocito L, Audenino D. Nonconvulsive status epilepticus during cephalosporin therapy.

Neuropsychobiology 2004; 49: 218–22.

75 Martinez-Rodriguez JE, Barriga FJ, Santamaria J, et al.

Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure.

Am J Med 2001; 111: 115–19.


76 Dixit S, Kurle P, Buyan-Dent L, Sheth RD.

Status epilepticus associated with cefepime.

Neurology 2000; 54: 2153–55.

77 Abanades S, Nolla J, Rodriguez-Campello A, Pedro C, Valls A, Farre M. Reversible coma secondary to cefepime neurotoxicity.

Ann Pharmacother 2004; 38: 606–08.

78 Plensa E, Gallardo E, Ribera JM, Batlle M, Oriol A, Costa J. Nonconvulsive status epilepticus associated with cefepime in a patient undergoing autologous stem cell transplantation.
Bone Marrow Transplant 2004; 33: 119–20.

Jallon P, Fankhauser L, Du Pasquier R, et al.

Severe but reversible encephalopathy associated with cefepime.

Neurophysiol Clin 2000; 30: 383–86.

79 80 US Food and Drug Administration.

FDA drug warning.

NDA 50-679/S-009, S-014 and S-018.

http://www.fda.gov/cder/foi/ appletter/2002/50679slr009,014,018ltr.pdf (accessed March 13, 2006).

81 Capparelli FJ, Diaz MF, Hlavnika A, Wainsztein NA, Leiguarda R, Del Castillo ME.
Cefepime- and ceﬁ xime-induced encephalopathy in a patient with normal renal function.

Neurology 2005; 65: 1840.

82 Maganti R, Jolin D, Rishi D, Biswas A. Nonconvulsive status epilepticus due to cefepime in a patient with normal renal function.

Epilepsy Behav 2006; 8: 312–14.

83 Fernandez-Torre JL, Martinez-Martinez M, Gonzalez-Rato J, et al.

Cephalosporin-induced nonconvulsive status epilepticus: clinical and electroencephalographic features.

Epilepsia 2005; 46: 1550–52.


84 Walker MC, Cockerell OC, Sander JW.

Non-convulsive status epilepticus presenting as a psychiatric condition.

J R Soc Med 1996; 89: 91–92.

85 Kim KS, Bayer AS.

Eﬃ cacy of BMY-28142 in experimental bacteremia and meningitis caused by Escherichia coli and group B streptococci.

Antimicrob Agents Chemother 1985; 28: 51–54.

86 Tomatsu K, Ando S, Masuyoshi S, Hirano M, Miyaki T, Kawaguchi H. Antibacterial activity of BMY-28142, a novel broad- spectrum cephalosporin.
J Antibiot (Tokyo) 1986; 39: 1584–91.

87 Szabo D, Mathe A, Filetoth Z, Anderlik P, Rokusz L, Rozgonyi F. In vitro and in vivo activities of amikacin, cefepime, amikacin plus cefepime, and imipenem against an SHV-5 extended- spectrum beta-lactamase-producing Klebsiella pneumoniae strain.

Antimicrob Agents Chemother 2001; 45: 1287–91.

88 Navas D, Caillon J, Gras-Le Guen C, et al.


Comparison of in vivo intrinsic activity of cefepime and imipenem in a Pseudomonas aeruginosa rabbit endocarditis model: eﬀ ect of combination with tobramycin simulating human serum pharmacokinetics.

J Antimicrob Chemother 2004; 54: 767–71.

http://infection.thelancet.com Vol 7 May 2007 347 Review 89 Lee SY, Kuti JL, Nicolau DP.

Cefepime pharmacodynamics in 97 National Comprehensive Cancer Network.
Clinical practice patients with extended spectrum beta-lactamase (ESBL) and non- ESBL infections.

J Infect 2006; published online Oct 23, 2006; DOI:10.1016/j.jinf.2006.09.004.

guidelines in oncology.

Fever and neutropenia.

http://www.nccn.

org/professionals/physician_gls/PDF/fever.pdf (accessed March 13, 2007).

90 Arrieta AC, Bradley JS.

Empiric use of cefepime in the treatment of serious urinary tract infections in children.

Pediatr Infect Dis J 2001; 20: 350–55.


91 Bradley JS, Arrieta A. Empiric use of cefepime in the treatment of lower respiratory tract infections in children.

Pediatr Infect Dis J 2001; 20: 343–49.

92 US Food and Drug Administration.

A multi-investigator comparative study of cefepime and cefotaxime in the treatment of serious bacterial infections in pediatric subjects.

Application number 50-679/SLR-007.

Rockville, MD: Center for Drug Evaluation and Research, FDA, 1999: 43–46.
93 US Food and Drug Administration.

A multi-investigator 98 Niederman MS, Mandell LA, Anzueto A, et al.

Guidelines for the management of adults with community-acquired pneumonia.

Diagnosis, assessment of severity, antimicrobial therapy, and prevention.

Am J Respir Crit Care Med 2001; 163: 1730–54.

99 Mandell LA, Wunderink RG, Anzueto A, et al.

Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.
Clin Infect Dis 2007; 44 (suppl 2): S27–72.

100 American Thoracic Society, Infectious Diseases Society of America.

Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.

Am J Respir Crit Care Med 2005; 171: 388–416.

comparative study of cefepime and cefuroxime in the treatment of serious bacterial infections in pediatric subjects.

Application number 50-679/SLR-007.


Rockville, MD: Center for Drug Evaluation and Research, FDA, 1999: 42.

101 Bantar C, Vesco E, Heft C, et al.

Replacement of broad-spectrum cephalosporins by piperacillin-tazobactam: impact on sustained high rates of bacterial resistance.

Antimicrob Agents Chemother 2004; 48: 392–95.

94 Hughes WT, Armstrong D, Bodey GP, et al.

2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer.

Clin Infect Dis 2002; 34: 730–51.


102 Du B, Chen D, Liu D, et al.

Restriction of third-generation cephalosporin use decreases infection-related mortality.

Crit Care Med 2003; 31: 1088–93.

95 Link H, Bohme A, Cornely OA, et al.

Antimicrobial therapy of 103 Allegranzi B, Luzzati R, Luzzani A, et al.
Impact of antibiotic unexplained fever in neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society).

Ann Hematol 2003; 82 (suppl 2): S105–17.


96 Masaoka T. Evidence-based recommendations for antimicrobial use in febrile neutropenia in Japan: executive summary.

Clin Infect Dis 2004; 39 (suppl 1): S49–52.

changes in empirical therapy on antimicrobial resistance in intensive care unit-acquired infections.

J Hosp Infect 2002; 52: 136–40.

104 Owens RC Jr, Rice L. Hospital-based strategies for combating resistance.

Clin Infect Dis 2006; 42 (suppl 4): S173–81.


105 Yahav D, Sarid N, Paul M, Borok S, Fraser A, Leibovici L. Cefepime versus other beta-lactam antibiotics for the treatment of infections in non-neutropenic patients.

Cochrane Database Syst Rev 2006; 2: CD006057.

DOI:10.1002/14651858.CD006057.

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