Influence of penicillin resistance on outcome in adult patients with invasive pneumococcal pneumonia: is penicillin useful against intermediately resistant strains?

Vicenç Falcó1,*, Benito Almirante1, Queralt Jordano1, Laura Calonge1, Oscar del Valle2, Carles Pigrau1, Ana María Planes2, Joan Gavaldà1 and Albert Pahissa1

1 Infectious Disease Department and 2 Microbiology Department, Hospitals Vall d'Hebron, Universitat Autònoma de Barcelona, P° Vall d'Hebron 119–129, 08035 Barcelona, Spain

Received 30 September 2003; returned 10 November 2003; revised 21 May 2004; accepted 26 May 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives: To compare outcome between patients with pneumonia due to penicillin-susceptible S. pneumoniae and patients with pneumonia due to penicillin intermediately resistant strains and to study the outcome of patients with pneumococcal pneumonia caused by strains with MICs of 0.12–1 mg/L treated empirically during the first 48 h with ß-lactam antibiotics.

Materials and methods: We studied 247 adult patients with invasive pneumococcal pneumonia occurring from 1997 to 2001. The following data were recorded from each patient: socio-demographic characteristics, underlying diseases, clinical presentation, initial severity of pneumonia, initial and subsequent antimicrobial therapy, in-hospital complications, hospital mortality and length of hospital stay. Multivariate analysis was done to identify variables associated with the development of pneumonia caused by a non-susceptible strain.

Results: The overall presence of penicillin non-susceptibility was 26.7%; no strain had an MIC >2 mg/L. Overall mortality was 23.5% in patients with pneumonia caused by intermediately resistant pneumococci and 12.7% in those with pneumonia caused by susceptible strains (P=0.075). Mortality during the first 7 days of admission, considered to be pneumonia-related deaths (13.7% versus 9.9%; P=0.448) was similar in both groups. The multivariate analysis showed that serotype 14 (OR, 140.18; 95% CI, 16.95–1159.20), serotype 19 (OR, 7.53; 95% CI, 1.98–28.7), haematological malignancy or splenectomy (OR, 4.46; 95% CI, 1.5–13.23) and HIV infection (OR, 4.54; 95% CI, 1.54–13.44) were the only independent factors associated with pneumonia caused by penicillin intermediately resistant pneumococci. In patients with strains having MICs of 0.1–1 mg/L, overall mortality was similar in the group of penicillin-treated patients (22.2%) to those treated with broad-spectrum ß-lactams (23.5%).

Conclusions: There is a non-significant trend to higher mortality in patients with pneumococcal pneumonia caused by intermediately resistant strains; however, they do not have a poorer outcome when they are treated with amoxicillin.

Keywords: ß-lactams , penicillin non-susceptible pneumococci , Streptococcus pneumoniae


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
An alarming increase in infections due to penicillin non-susceptible Streptococcus pneumoniae (PNSP) has been documented in nearly all countries.13 In Spain, the overall prevalence of PNSP is 50.1%, with 21.7% of high-level penicillin resistance, according to a recent nationwide multicentre surveillance study.4 Risk factors for acquiring drug-resistant S. pneumoniae infection include prior use of ß-lactam antibiotics, recent hospitalization, residence in an institution, nosocomial pneumonia, episode of pneumonia during the previous year, alcoholism, extremes of age, attendance at a day-care centre, contact with small children, presence of underlying disease, human immunodeficiency virus (HIV) infection and other conditions associated with immunosuppression.5,6

Despite the decreased susceptibility of pneumococci to ß-lactam antibiotics, most studies have not demonstrated an adverse impact of this treatment on mortality in adult patients with PNSP infections712 and data from several studies indicate that most cases can be successfully treated with ß-lactams.7,13 To date, there have been no prospective randomized trials comparing specific antibiotic therapies for PNSP infections; the clinical impact of penicillin non-susceptibility has been evaluated only in observational studies.

Recent recommendations have advocated a revision of the breakpoints that define penicillin activity against S. pneumoniae. Pneumococcal strains having MICs of 1–2 mg/L would be considered intermediately resistant and only strains with MICs ≥4 mg/L would be considered highly resistant.14 To assess the influence of these new penicillin susceptibility categories on the outcome of patients with invasive pneumococcal pneumonia, we studied all cases of this disease occurring from 1997 to 2001. The aims of the study were: (i) to compare outcome between patients with pneumonia due to penicillin-susceptible S. pneumoniae and patients with pneumonia due to penicillin intermediately resistant strains and (ii) to study the outcome of patients with pneumococcal pneumonia caused by strains with MICs of 0.12–1 mg/L treated empirically during the first 48 h with ß-lactam antibiotics.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The study was carried out in the Hospital Universitari Vall d'Hebron in Barcelona, Spain. When Streptococcus pneumoniae is isolated from blood or another normally sterile site at our institution, the patient is evaluated by a member of the Infectious Disease Department. From January 1997 to December 2001, all cases of invasive disease due to S. pneumoniae in patients ≥16 years old were reviewed. During that period, a total of 347 episodes of invasive pneumococcal disease were diagnosed; in 259 of them (74.6%), S. pneumoniae was isolated from blood (245 patients) or pleural fluid (14 patients). The patients' records from 1997 to 1999 were reviewed retrospectively, and from 2000 onwards, the study was conducted prospectively. The following risk factors for pneumococcal infection were recorded in each patient: immunosuppressive condition, smoking, alcoholism, chronic pulmonary disease, diabetes, chronic liver disease and chronic renal failure.

Pneumonia severity was assessed with the Pneumonia Severity Index (PSI).15 For patients reviewed retrospectively, the PSI was evaluated using the data from the medical chart at the moment of admission to the Emergency Department. Patients were classified into two groups: those at low risk of death (risk classes I, II and III) and those at high risk (classes IV and V). In 13 cases, the PSI could not be evaluated.

Antibiotic therapy was initially prescribed by the attending physician according to our hospital protocol. In 1997 and 1998, empirical antibiotic therapy for community-acquired pneumonia included cefuroxime with or without a macrolide. However, because of its lower activity against pneumococci and according to the new guidelines, the protocol was reviewed in 1998 and the second-generation cephalosporin was changed to amoxicillin plus clavulanic acid [1000/125 mg three times daily intravenously (iv)] or a third-generation cephalosporin (ceftriaxone 2 g once daily iv or cefotaxime 1–2 g three times daily iv). Once the susceptibility testing results were known, therapy was re-evaluated by the physician in charge of the patient and by a member of the Infectious Disease Department. Antibiotic therapy usually lasted from 7 to 14 days.

Patients were divided into four groups according to the empirical therapy administered during the first 48 h: (1) group receiving penicillin (those treated with penicillin G, amoxicillin plus clavulanic acid, or piperacillin–tazobactam); (2) group receiving broad-spectrum ß-lactam antibiotics with high activity against pneumococci (those treated with ceftriaxone, cefotaxime, cefepime or imipenem); (3) group receiving other antibiotics (cefuroxime, macrolides, fluoroquinolones or vancomycin); and (4) group receiving no antibiotic therapy. When a macrolide was initially added to another antibiotic, the treatment was considered to be combination therapy with a macrolide.

Definitions

Invasive pneumococcal disease was defined as isolation of S. pneumoniae from a normally sterile site. Invasive pneumococcal pneumonia was diagnosed when a patient had consistent clinical findings plus a new pulmonary infiltrate on chest radiography and isolation of S. pneumoniae in blood and/or pleural fluid cultures. The isolation of S. pneumoniae from sputum was not an inclusion criterion. Patients with one of the following conditions were considered to be immunocompromised: haematological malignancy, splenectomy, solid tumour, solid organ transplant or HIV infection.

Prior hospitalization was defined as admission to the hospital within the previous 3 months. Patients hospitalized in the previous 7 days were excluded because they were considered to have hospital-acquired pneumonia.

Overall mortality was defined as death during hospital admission. Pneumonia-related deaths were defined as those in which pneumonia was the major contributing cause; in those cases in which the cause was not clearly documented, death within 7 days following admission was also considered pneumonia-related. Deaths that did not appear to be pneumonia-related, as determined at the time of medical-record review, and occurred >7 days after admission were coded as non-pneumonia-related deaths (12). Death occurring during the first 24 h after admission was recorded separately, considering that in these cases death was not related to the initial antimicrobial therapy administered.

Microbiological studies

S. pneumoniae strains were identified by Gram stain, optochin susceptibility, bile solubility testing and latex agglutination testing. Susceptibility testing was carried out by a standard broth microdilution method using Mueller–Hinton media supplemented with 3% lysed horse blood. Susceptibility was defined according to the 2002 National Committee for Clinical Laboratory Standards (NCCLS) guidelines.16 Isolates were classified as penicillin-susceptible (PS) (MIC ≤0.06 mg/L), penicillin-intermediate (PI) (MIC 0.12–1 mg/L), or penicillin-resistant (PR) (MIC ≥2 mg/L). Intermediate or resistant isolates were considered to be non-susceptible. Isolates were serotyped at the Spanish Pneumococcal Reference Laboratory (Instituto de Salud Carlos III, Madrid, Spain) with standard antiserum.

Statistical analysis

The following variables were evaluated: age, sex, prior hospitalization, immunosuppressive condition, S. pneumoniae serotype (considering only serotypes obtained in more than 10 cases), intensive care unit (ICU) admission, need for mechanical ventilation, initial severity of pneumonia, shock, empyema, initial antimicrobial therapy, length of hospital stay and mortality. Initial univariate analyses compared only pneumonia caused by PI strains with those caused by PS strains in order to analyse the effect of initial antimicrobial therapy on mortality in the two groups. In the group of patients with PI strains, univariate analysis was carried out to compare the same variables, except for initial antimicrobial therapy, between patients treated initially with any of the penicillins and those treated with broad-spectrum ß-lactam agents. The {chi}2 test or Fisher's exact test was used to compare categorical variables and the Student's t-test to compare continuous variables. Differences were considered significant at P<0.05.

Multivariate analysis using a forward stepwise multiple regression model was carried out to identify the variables independently associated with development of pneumonia by a PI strain. Significant and nearly significant (P<0.1) variables from the univariate analysis were included in the multivariate analysis.

Univariate analysis was also carried out for overall mortality and related mortality and significant variables were introduced in a forward stepwise multiple regression model to identify factors associated with mortality. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Over the study period, 259 patients had invasive pneumococcal pneumonia as defined by positive blood (245) and pleural fluid (14) cultures. All the data were not available in 12 cases and these patients were excluded from the analysis, making a final cohort of 247 patients, 167 (67.6%) males and 80 (32.4%) females, with a mean age of 62.8±18.4 years. A total of 52 (21.1%) patients had been hospitalized within the previous 3 months. Most patients had an underlying condition. Only 14 (5.7%) had no risk factors for pneumococcal infection and in 103 patients (41.7%) more than one risk factor was present. The most common risk factors were immunosuppressive condition, smoking, chronic pulmonary disease, diabetes and chronic liver disease. There were 93 (37.7%) immunocompromised patients: 36 (14.6%) had HIV infection, 29 (11.7%) had haematological malignancy or previous splenectomy, 28 (11.3%) had solid tumours and three (1.2%) were recipients of a solid organ transplant. Six patients had two of these conditions.

The overall presence of PNSP was 26.7%; 51 strains were PI and 15 PR. Figure 1 shows the changes in penicillin and cefotaxime susceptibility over the study period. The susceptibility pattern of all strains to penicillin, cefotaxime, erythromycin, tetracycline, co-trimoxazole and ofloxacin is summarized in Table 1. The most frequently isolated S. pneumoniae serotypes were serotype 3 in 30 (12.1%) cases, serotype 14 in 28 (11.3%), serotype 4 in 22 (8.9%), serotype 1 in 21 (8.5%), serotype 8 in 20 (8.1%) and serotype 19 in 11 (4.5%) cases.



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Figure 1. Susceptibility of S. pneumoniae to penicillin and cefotaxime in adult patients with invasive pneumococcal pneumonia over the study period (1997–2001). The table shows the number of strains with penicillin and cefotaxime susceptibility (S) and non-susceptibility (NS).

 

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Table 1. Susceptibility pattern of strains of S. pneumoniae

 
Among the total of patients, 114 (46.2%) were initially treated with an antibiotic from the penicillin group, 79 (32%) were given a broad-spectrum ß-lactam with high antipneumococcal activity, 53 (21.5%) received other antibiotics and one died before antimicrobials could be administered. In the patients treated with the penicillin group, 104 (91.2%) received co-amoxiclav and in those treated with broad-spectrum ß-lactams, 78 (98.7%) received cefotaxime, ceftriaxone or cefepime. Combination therapy that included a macrolide was initially administered to 55 patients. In seven patients the macrolide was added to an antibiotic from the penicillin group, in 38 to a broad-spectrum ß-lactam and in 10 cases to other antibiotics. In 143 patients in whom therapy was changed, the interval between the start of empirical antibiotic therapy and the subsequent change to another antibiotic was 2.6±1.1 days.

ICU admission was required in 33 (13.4%) patients and 26 (10.5%) of them needed mechanical ventilation. Septic shock was diagnosed in 40 (16.2%) cases and empyema in 37 (15%). Mortality rates are summarized in Table 2.


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Table 2. Mortality of patients with pneumococcal pneumonia

 
Comparison of patients with pneumococcal pneumonia caused by PS and PI strains

A comparison was made of the clinical characteristics of patients with pneumococcal pneumonia caused by PS (181 patients) and PI (51 patients) strains (Table 3). Patients in whom a PI strain was isolated had been hospitalized in the previous 3 months (P=0.018) and had HIV infection (P=0.005) significantly more frequently than patients in whom a PS strain was isolated. There were no differences in initial antimicrobial therapy between the groups. In the penicillin group, the percentages of patients with pneumonia caused by a PS strain (83 cases, 45.9%) and by a PI strain (27 cases, 52.9%) were similar. There were no significant differences in the number of patients treated initially with combined therapy with a macrolide (23.8% of PS strains versus 15.7% of PI strains). Table 4 shows the antimicrobial therapy before and after susceptibility testing was available. Although there was a trend to higher overall mortality in patients with pneumonia caused by PI strains, the difference was not significant. Moreover, there were no significant differences in mortality during the first 7 days of admission and in mortality during the first 24 h after admission.


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Table 3. Comparison of patients with pneumococcal pneumonia caused by penicillin-susceptible and intermediately resistant strains (univariate analysis)

 

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Table 4. Changes of antibiotics once susceptibility results were available in patients with pneumococcal pneumonia caused by penicillin-susceptible and intermediately resistant strains

 
In the multivariate analysis, serotype 14 (OR, 140.18; 95% CI, 16.95–1159.20), serotype 19 (OR, 7.53; 95% CI, 1.98–28.7), haematological malignancy or splenectomy (OR, 4.46; 95% CI, 1.5–13.23) and HIV infection (OR, 4.54; 95% CI, 1.54–13.44) were identified as independent factors associated with infection caused by PI strains. Overall mortality was not associated with pneumonia caused by PI strains.

Patients with pneumococcal pneumonia caused by PI strains

In the patients with pneumonia caused by PI strains, we compared those empirically treated with antibiotics from the penicillin group (27 patients) with those treated with broad-spectrum ß-lactams having high activity against S. pneumoniae (17 patients) (Table 5). The seven patients treated with other antibiotics were excluded from this analysis. None of the patients treated with penicillin received an associated macrolide, whereas seven (41.2%) patients treated with a broad-spectrum ß-lactam also received a macrolide (P=0.001). Patients treated with broad-spectrum ß-lactams tended to have more severe disease than patients treated with penicillin, although the only significant difference in the univariate analysis was the presence of septic shock (P=0.006). Overall and related mortality were similar in the two groups of patients. Once the susceptibility test results were known, 21 of 44 (47.7%) patients were treated with antibiotics from the penicillin group and 13 of 44 (29.6%) with broad-spectrum ß-lactams having high activity against S. pneumoniae (Table 6).


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Table 5. Characteristics of patients with pneumococcal pneumonia caused by strains with intermediate resistance to penicillin according to the initial antibiotic therapy administereda

 

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Table 6. Impact of antimicrobial changes once the susceptibility test results were known on mortality among patients with pneumonia caused by penicillin intermediate strains

 
Patients with pneumococcal pneumonia caused by PR strains

The strains in all 15 patients with pneumonia caused by PR pneumococci had MICs of 2 mg/L. Four patients were empirically treated with antibiotics from the penicillin group, seven with broad-spectrum ß-lactam antibiotics and four with other antibiotics. The four patients treated with penicillin survived, whereas three of the seven patients treated with broad-spectrum ß-lactams died, two of them during the first 7 days. The main difference (though non-significant statistically) was that patients receiving broad-spectrum ß-lactams tended to have a more severe clinical picture (three of the seven patients had septic shock, compared to none of the four patients in the penicillin group).

Analysis of mortality

Univariate (data not shown) and multivariate mortality analyses were carried out. The variables associated with overall mortality included presence of septic shock (OR, 31.2; 95% CI, 8.2–118.6) and solid tumour (OR, 9.4; 95% CI, 2.6–33.6). Pneumonia caused by PS pneumococci was a protective factor for overall mortality (OR, 0.006; 95% CI, 0.07–0.6). In the analysis of pneumonia-related mortality, presence of septic shock (OR, 38.8; 95% CI, 13.1–114.5) was the only associated variable. Once again, therapy with antibiotics from the penicillin group was not associated with increased mortality.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
In 2000, the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group (DRSPTWG) recommended that penicillin susceptibility categories for pneumococcal isolates causing pneumonia should be shifted upwards so that the susceptible category would include all strains with MICs no greater than 1 mg/L, the intermediate category would include strains with MICs up to 2 mg/L and the resistant category would include strains with MICs of no less than 4 mg/L.14 This study analyses the outcome of patients with pneumococcal pneumonia to determine whether patients with pneumonia caused by strains with MICs of 0.12–1 mg/L can be safely treated with penicillin or co-amoxiclav. Our results provide additional evidence to support the growing idea among physicians that patients with pneumococcal pneumonia caused by strains with MICs ≤1 mg/L can be adequately treated with high doses of penicillin and related drugs such as co-amoxiclav.

The impact of penicillin resistance on morbidity and mortality in adult patients with pneumococcal pneumonia is still controversial; several studies report no independent association between penicillin resistance and outcome.7,911,1719 Nevertheless, in some of these works, there is a non-significant trend to higher mortality in patients with pneumonia caused by non-susceptible strains.7,9 In our study, we have defined pneumonia-related deaths according to findings from prior studies on mortality associated with community-acquired pneumonia.12 We have found a non-significant trend to a higher overall mortality among patients with pneumonia caused by PI strains. This higher mortality in this group is, in our opinion, due to non-pneumonia-related mortality because there were no significant differences in pneumonia-related mortality between patients with pneumonia caused by PS and PI strains. When we analysed the causes of death in the 12 patients with non-pneumonia-related mortality, nine of them had a severe immunosuppressive disease to which death was attributed, and it is known that the presence of immunosuppressive conditions is a factor associated with infections by pneumococci with decreased susceptibility to penicillin.5,6 Morbidity was not higher in our patients with PNSP pneumonia and there were no significant differences in the length of hospitalization between patients with pneumonia caused by PS or PI pneumococci. Survival in the first 24 h of antibiotic therapy for pneumococcal bacteraemia is known to be little affected by antibiotics. This is consistent with the smaller differences in mortality in the first 24 h observed in our patients in relation to choice of antibiotics and resistance, compared to overall mortality.

There is little information to suggest that adult patients with pneumococcal pneumonia caused by PI pneumococci can be treated with penicillin or related ß-lactam antibiotics. The rational basis for this approach is that serum concentrations achieved with these drugs are several times higher than the MICs of penicillin.7,9,20 Some authors have attempted to use the time for which serum drug concentrations are greater than MICs (T > MIC) as the dynamic parameter to predict efficacy for time-dependent killing antimicrobial agents, like penicillins and cephalosporins.21 The results of animal models of S. pneumoniae infections with penicillin or cephalosporin treatment showed that when T > MIC was 20% or less than the dosing interval, mortality was 100%. In contrast, mortality rates were 0–10% when serum concentrations were above MICs for longer than 40–50% of the dosing interval.21,22 Serum concentration–time curves after 1 g intravenous amoxicillin plus 200 mg clavulanic acid showed a maximum plasma concentration of nearly 100 mg/L and a T > MIC for a S. pneumoniae strain with an MIC of 2 mg/L exceeding 40% of the dosing interval.23 Patients were analysed according to the empirical therapy administered, with the groups being set up on the basis of similar antipneumococcal activity of the drugs. The group of penicillin-treated patients included those who received amoxicillin, co-amoxiclav and piperacillin/tazobactam; these agents have similar antipneumococcal activity and no increase in their effectiveness has been found with the addition of the beta-lactamase inhibitors.24 In any case, the group is quite homogeneous, since more than 90% received co-amoxiclav. Since cefotaxime and ceftriaxone exhibit the highest activity against penicillin-sensitive and -resistant strains of pneumococci, patients treated with these cephalosporins and cefepime were grouped together.24

In this study, 27 patients with pneumonia caused by a PI strain were treated with co-amoxiclav. Overall mortality was 22.2%, which was similar to that found in 17 patients treated with broad-spectrum ß-lactam antibiotics (23.5%). It is important to note that only one of the patients of the penicillin group was treated simultaneously with a macrolide, so co-amoxiclav was the only antibiotic with antipneumococcal activity that this group of patients received. In this group, we also analysed mortality according to the antimicrobial therapy administered once susceptibility test results were known. Mortality did not vary significantly after the changes in antibiotics; thus we believe that this factor did not have an impact on outcome.

Since this study was not a randomized trial, the results may be affected by some bias, such as differences in the severity of illness between the groups. However, in our opinion, the findings strongly suggest that patients with pneumococcal pneumonia caused by strains with MICs of 0.12–1 mg/L can be effectively treated with penicillin or co-amoxiclav.

In conclusion, although in our study there is a non-significant trend to higher mortality in patients with pneumococcal pneumonia caused by intermediately resistant strains they do not have a poorer outcome when they are treated with amoxicillin or co-amoxiclav. In our opinion, our findings support the initiative of the DRSPTWG 14 aimed at redefining levels of penicillin susceptibility in patients with pneumococcal pneumonia in order to consider strains with MICs ≤1 mg/L as PI. However, at present, the NCCLS has not modified the actual pneumococcal penicillin breakpoints.16 Of course prospective randomized studies would be desirable to confirm our data but, because of the difficulties in recruiting a sufficient number of patients, this kind of study is difficult to perform. So in the meantime a meta-analysis of the data published to date would provide more information on the safety of changing the currently recommended breakpoints to penicillin in patients with pneumococcal pneumonia.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We thank Celine L. Cavallo for English language editing.


    Footnotes
 
* Corresponding author. Tel: +34-93-274-60-90; Fax: +34-93-428-27-62; Email: vfalco{at}vhebron.net


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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